Total synthesis of everninomicin 13,384-1 - Part 2: Synthesis of the FGHA2 fragment

Article abstract of DOI:10.1002/1521-3765(20000901)6:17<3116::AID-CHEM3116>3.0.CO;2-8

The stereoselective synthesis of everninomicin's 13,384-1 (1) FGHA₂ fragment (2) in a suitable form for incorporation into the final target (1) is described. The construction of the FG 1,1′-disaccharide linkage relied on a new method based on tin-acetal chemistry, while for the GH orthoester bridge, a number of approaches were explored. Final success for the latter construction came when a novel 1,2-phenylseleno migration reaction was applied to couple rings G and H, followed by ketene acetal and orthoester formation.

Full text of DOI:10.1002/1521-3765(20000901)6:17<3116::AID-CHEM3116>3.0.CO;2-8

FULL PAPER
Total Synthesis of Everninomicin 13,384-1ÐPart 2:
Synthesis of the FGHA2 Fragment
K. C. Nicolaou,* Helen J. Mitchell, Konstantina C. Fylaktakidou,
Rosa Maria Rodríguez, and Hideo Suzuki[a]
Abstract: The stereoselective synthesis of everninomicinꢀs 13,384-1 (1) FGHA2
fragment (2) in a suitable form for incorporation into the final target (1) is described.
Keywords: carbohydrates ´ everni-
The construction of the FG 1,1'-disaccharide linkage relied on a new method based on
tin-acetal chemistry, while for the GH orthoester bridge, a number of approaches
were explored. Final success for the latter construction came when a novel 1,2-
phenylseleno migration reaction was applied to couple rings G and H, followed by
ketene acetal and orthoester formation.
nomicin ´ orthoester formation ´
phenylseleno glycoside ´ stereocon-
trolled glycosidation
ment F), and orthoester 7 (fragment GH). Further simplifi-
cation of the GH orthoester 7 led to orthoester 8 which was
then disconnected to reveal xylose lactone 9 and threitol
derivative 10 as potential starting materials. Building blocks 5
and 6 were traced back to aromatic system 12 and carbohy-
drate unit 11, respectively.
Introduction
In the preceding paper,[1] we described studies that led to the
construction of a fully substituted and activated A1B(A)C
fragment (see structure 4, Figure 1) designed for the total
synthesis of everninomicin 13,384-1 (1). In this paper we detail
our investigations which culminated in the synthesis of a
suitable FGHA2 fragment (see structure 2, Figure 1) needed
for the intended assembly of 1.
Aside from the orthoester moiety, one of the most serious
challenges presented by the FGHA2 fragment is its 1,1'-
disaccharide linkage. Not only has one to construct this bridge
between polyfunctional and sensitive substrates, but also one
is faced with the problem of controlling its stereochemistry at
the two glycoside bonds. In order to address this issue we
considered the plan outlined in Figure 2, in which a trichloro-
acetimidate derivative of ring G carrying a directing group
(acetate) at position 2 was envisioned as a means to ensure the
a-stereochemistry of the ring G glycoside bond. The utiliza-
tion of the lactol representative of ring F in which the a-
anomer was expected to predominate was thought to be a sure
entry into the a-glycoside (ring F) series, whereas the locking
of the anomeric hydroxyl group into its b-configuration by
forming a five-membered ring tin-acetal was proposed as an
insurance for the generation of the desired b-glycoside bond
(ring F). These ideas proved to be correct as shown in
Scheme 1 in which the results of our initial studies along these
lines are summarized. Thus, when acceptor 13 (R ˆ Bn) was
exposed to donor 14 in the presence of TMSOTf, the 1a,1'a-
disaccharide 15 was formed exclusively in 87% yield as
expected (for abbreviations of protecting groups and reagents,
see legends in schemes). On the other hand, conversion of 13
(R ˆ H) to the tin-acetal 16 followed by in situcoupling with
trichloroacetimidate 14 in the presence of TMSOTf led only
to the desired 1b,1'a-disaccharide 17 in 66% yield. These
initial findings were expanded to a general method[2] for the
Results and Discussion
First-generation approaches to the FGHA2 fragment: Ac-
cording to the defined global retrosynthetic analysis outlined
in Figure 1, the key advanced intermediates for the total
synthesis of 1 were compounds 2 ± 4. Initial inspection of the
FGHA2 fragment 2, revealed several options for further
retrosynthetic simplification. Our first-generation analysis
involved disassembly of this key intermediate through the
indicated disconnections (1,1'-disaccharide and ester bonds)
leading to acyl fluoride 5 (A2 fragment), tin-acetal 6 (frag-
[a] Prof. Dr. K. C. Nicolaou, H. J. Mitchell, Dr. K. C. Fylaktakidou,
Dr. R. M. Rodríguez, Dr. H. Suzuki
Department of Chemistry and The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, California 92093 (USA)
Fax : (‡1) 858-784-2469
E-mail: kcn@scripps.edu
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Chem. Eur. J. 2000, 6, No. 17

3116±3148
Me
Me OMe
OH
O
O
Me
Me
O
Me
OMe O
MeO
O
O
O
O
O
O
O
O
O
O
Cl
O
H
B
O
E
G
O
C
D
F
A2
A1
O
O
O
O
OMe
HO
OH
Me
OH
HO
Me
O
O
HO
OH
OH
Cl
NO2
Me
A
1: everninomicin 13,384-1
Me
OMe
Me
Me
O
OMe O
O
B
O
C
Cl
Me
Me
Glycosylation
Esterification
O
O
F
MeO
O
A1
PMBO
+
HO
O
O
OMe
OBn
G
O
O
D
E
BnO
Me
BnO
NO2
Me
OMe
SePh
O
Me
O
O
O
O
OCCCl3
Cl
Me
H
O
+
F
OAc
OAc NH
A
O
A2
O
O
HO
OMe
BnO
OBn
Me
OBn
OMe
4
2
3
O
O
O
Me
OBz
O
O
nBu
Sn
nBu
BzO
OBz
RO
O
F
O
O
+
+
O
F
TBSO
A2
OBOM
OBOM
TIPSO
O
H
H
G
G
TIPSO
O
O
O
OBn
BnO
OBn
5
7
8
6
Orthoester formation
OH
Me
A2
12
O
SPh
O
OTMS
allylO
O
Oallyl
F
BnO
+
+
Oallyl
HO
H
9
OBn
OTMS
10
HO
OH
O
O
11
Figure 1. First-generation retrosynthetic analysis of FGHA2 fragment 2. Ac ˆ acetyl; Bz ˆ benzoyl; Bn ˆ benzyl; PMB ˆ p-methoxybenzyl; TBS ˆ tbutyl-
dimethylsilyl; TIPS ˆ triisopropylsilyl; TMS ˆ trimethylsilyl; BOM ˆ benzyloxy methoxy.
Figure 2. Devising stereocontrolled entries into 1,1'-disaccharides.
Scheme 1. Synthesis of model 1,1'-disaccharides 15 and 17. a) 1.6 equiv 14,
0.1 equiv TMSOTf, CH2Cl2, 0 ! 258C, 20 min, 87%; b) 1.1 equiv nBu2SnO,
MeOH, reflux, 3 h, 100%; c) 1.6 equiv 14, 0.5 equiv TMSOTf, Et2O, 0 !
258C, 48 h, 66%. Tf ˆ trifluoromethanesulfonyl.
stereocontrolled construction of 1,1'-disaccharides and
1,1':1'',2-trisaccharides as will be discussed in more detail in
Part 4[3] of this series. It was also applied to the final ring FG
system utilized in the total synthesis of 1 (vide infra).
In our initial foray towards the FGHA2 fragment we
adopted tin-acetal 6 containing a TIPS ether at C-4 (see
Figure 1). To prepare this compound, we embarked on the
sequence shown in Scheme 2. Thus, selective monobenzoyla-
tion of mannose derivative 11[4] (BzCl, Et3N, 4-DMAP cat.)
furnished primary benzoate 18 in 91% yield whose silylation
(TIPSOTf, 2,6-lutidine) gave 19 (99%). Basic methanolysis
(NaOH, MeOH, 94% yield) followed by methylation (NaH,
MeI, 92% yield) gave 21 via 20. Acidic hydrolysis of the
acetonide from 21 (TsOH, MeOH) led to diol 22 (87% yield
based on 62% conversion). At this stage, it was anticipated
that the C-3 hydroxyl group (equatorial) would be
Chem. Eur. J. 2000, 6, No. 17
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K. C. Nicolaouet al.
FULL PAPER
Table 1. Synthesis of orthoesters related to the GH fragment.[a]
O
SPh
O
O
SPh
O
RO
HO
RO
R1O
OR1
OTMS
b) TIPSOTf
a) BzCl
R2O
O
TIPSO
OR3
OTMS
X1-8
+
O
H
OBn
O
O
Y1-8
11: R = H
18: R = Bz
19: R = Bz
20: R = H
c) NaOH
TMSOTf
d) MeI, NaH
O
SPh
OBn
O
SPh
OR
MeO
R1O
O
OR1
MeO
f) nBu2SnO;
BnBr
R3O
R2O
TIPSO
TIPSO
H
OBn
OH
O
OR
O
Z1-8
23
21: R = C(Me)2
22: R = H
e) TsOH, MeOH
Entry
Y
X
Yield of Z
[%]
Scheme 2. Attempted synthesis of carbohydrate building block F (6).
a) 1.0 equiv BzCl, 1.2 equiv Et3N, 0.1 equiv 4-DMAP, CH2Cl2, 0 ! 258C,
2 h, 91%; b) 1.2 equiv TIPSOTf, 1.4 equiv 2,6-lutidine, CH2Cl2, 0 ! 258C,
3 h, 99%; c) 0.2 equiv NaOH, MeOH/Et2O 1:1, 258C, 1 h, 94%,
d) 1.2 equiv NaH, 1.6 equiv MeI, DMF, 0 ! 258C, 2 h, 92%; e) 0.03 equiv
TsOH, 1.2 equiv (CH2OH)2, MeOH/Et2O 10:1, 258C, 8 h, 87% based on
62% conversion; f) 1.1 equiv nBu2SnO, toluene, reflux, 3 h; 1.2 equiv BnBr,
0.2 equiv nBu4NI, 25 ! 1108C, 5 h, 81%. Ts ˆ p-toluenesulfonyl;
4-DMAP ˆ 4-dimethylaminopyridine; DMF ˆ dimethylformamide.
R1
R2
R3
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
TPS
Bz
MMB
SEM
Bn
92
[b]
PMB
allyl
allyl
allyl
allyl
allyl
allyl
97
31[d]
[c]
60[d]
[c]
allyl
allyl
97[d]
[a] 1.5 equiv X, 1.0 equiv Y, 0.3 equiv TMSOTf, CH2Cl2, 258C, 12 h;
[b] decomposition; [c] no reaction was observed; [d] ꢀ 1:1 mixture of
diastereoisomers at C-1. SEM ˆ trimethylsilylethoxy methoxy; MMB ˆ m-
methoxybenzyl; TPS ˆ tert-butyldiphenylsilyl.
preferentially benzylated over the C-2 hydroxyl (axial) in a
tin-acetal mediated reaction.[5] In the event, however, benzy-
lation of 22 (nBu2SnO; BnBr, nBu4NI) led to the undesired
C-2 benzyl ether 23 in 81% yield. After several unsuccessful
attempts to reverse this outcome or further manipulate the
product, we decided to re-examine the general strategy for the
construction of the targeted FGHA2 intermediate. In partic-
ular, the construction of the GH orthoester moiety was placed
at higher priority, before returning to ring F.
O
OBn
OAc
O
OBn
OR
b) BnOC(NH)CCl3,
BF3•Et2O
RO
BnO
OAc
OR
Our first attempts to assemble the GH orthoester system
were focused on the reaction of lactones with 1,2-diol
derivatives. The condensation of bis-TMS protected diols
with ketones or esters is a well documented process for the
formation of simple cyclic ketals and orthoesters.[6] In this
context, and while acyclic diols and cis-1,2-cyclohexane type
diols work quite efficiently as partners, trans-1,2-cyclohexane
diols are suspected to present difficulties, and indeed at least
one such case is reported to give only marginal or no yield of
product at all in such condensations.[6] One possible strategy
that avoids the intrinsic strain asssociated with the trans-1,2-
oxygenated polycyclic systems such as the one involved here,
is to employ an open-chain equivalent of ring G which could
later be elaborated to the desired polycyclic framework.
Table 1 summarizes the results of an exploratory study of this
strategy. Although fruitful, this strategy was plagued with
protecting group problems (e.g. entry 2, Table 1) due to the
acidic conditions (TMSOTf) required for the orthoester
formation. However, benzyl and allyl protecting groups (e.g.
entries 1, 3, 8, Table 1) served well and high yields of the
orthoesters were obtained. Initial attempts to selectively
elaborate the fully benzylated orthoester Z1 (entry 1, Table 1)
failed and the use of unsymmetrical diols (entries 4, 6, 8,
Table 1) led to mixtures (ca. 1:1) of diastereoisomers.
Fortunately, it was found that both diastereoisomers Z8
(entry 8, Table 1) could be transformed into a single product
by a series of protecting group exchanges, and therefore this
compound was chosen for further study.
24: R = Ac
25: R = H
26: R = Ac
27: R = H
a) Lipase P
c) K2CO3
d) NaH, allylBr
O
O
O
OR
H
f) Ac2O, DMSO
BnO
Oallyl
BnO
Oallyl
Oallyl
Oallyl
9
28: R = Bn
29: R = H
e) HCl, AcOH
Scheme 3. Synthesis of carbohydrate building block H (9). a) 2.0 equiv
Lipase P (w/w), 2.0 equiv isoamyl alcohol, isooctane, 258C, 96 h, 84%;
b) 0.1 equiv BF3 ´ Et2O, 1.2 equiv BnOC(NH)CCl3, CH2Cl2, 08C, 3 h, 91%;
c) 0.2 equiv K2CO3, MeOH/Et2O 1:1, 258C, 1 h, 97%; d) 2.2 equiv NaH,
3.2 equiv allyl bromide, DMF, 0 ! 258C, 2 h, 92%; e) 1n HCl in AcOH
1:40, 808C, 5 h, 91%; f) Ac2O/DMSO (1:2), 258C, 12 h, 96%. DMSO ˆ
dimethyl sulfoxide.
triacetate 24 to Lipase P[8] in isooctane led to selective
cleavage of the C-4 acetate furnishing 25 in 84% yield.
Compound 25 was then benzylated with BnOC(NH)CCl3 in
the presence of BF3 ´ Et2O leading to 26 (91% yield) which
was subjected to deacetylation (K2CO3, MeOH, 97%) and
bis-allylation of the resulting diol system (NaH, allyl bromide,
92% yield), furnishing 28 via 27. To reach 9, the anomeric
benzyl ether was cleaved (HCl, AcOH, 808C) to afford lactol
29 (91%), and the latter compound was oxidized with DMSO/
Ac2O (96%). The other requisite fragment, bis-TMS ether 10
(see Scheme 4) was prepared from commercially available
2,3-O-isopropylidene-l-threitol by monoallylation (NaH, all-
yl bromide, 93%), benzylation (NaH, BnBr, 97%), acetonide
cleavage (TsOH, MeOH, 96%), and TMS ether formation
(HMDS, TMSCl, 100%).
Lactone Y8 was accessible from xylose benzyl glycoside
24[7] by the sequence shown in Scheme 3. Thus, exposure of
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Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
The attempted construction of the GH orthoester system
(e.g. compound 41, Scheme 4) from building blocks 9 and 10 is
shown in Scheme 4. Thus, mixing of 9 and 10 in the presence
of TMSOTf, followed by cleavage of all three allyl ethers
{[(Ph3P)3RhCl] cat.; OsO4 cat./NMO} furnished triol or-
thoester 31 via 30 as a chromatographically separable mixture
(ca. 1:1) of two diastereoisomers, and in 97% combined yield.
The more polar stereoisomer of 31 was converted to the
differentially protected derivative 35 by the following se-
quence: a) silylation (TBSOTf, 2,6-lutidine, À788C, 92%
yield); b) benzoylation (BzCl, Et3N, 4-DMAP cat., 97%
yield; c) hydrogenolysis (H2, 10% Pd/C, 95% yield); and
d) silylation (TIPSOTf, 2,6-lutidine, 89% yield). The less
polar isomer of 31 was also taken to 35 by implementing the
reverse of the above sequence which proceeded with equal
ease and in similar yields. The remaining secondary alcohol in
35 was protected as a BOM ether (BOMCl, iPr2NEt, 89%)
and the TBS group was selectively removed (PPTS, EtOH,
83%) from the resulting product to afford hydroxy compound
36 via 8. The desired one-carbon homologation was then
carried out by first oxidizing alcohol 36 to the corresponding
aldehyde under Swern conditions[9] [(COCl)2, DMSO, Et3N]
and then adding directly Dondoniꢀs TMS/thiazole reagent[10]
affording 37 (ca. 10:1 mixture of diastereoisomers) in 97%
yield. The major diastereoisomer of 37 was converted to the
TES derivative 38 by exposure to TESOTf and 2,6-lutidine
(89% yield) and before unveiling the aldehyde moiety,
several compounds were prepared and examined for their
crystallinity as potential candidates for X-ray analysis. Thus,
exposure of 38 to K2CO3 in MeOH led to the cleavage of both
benzoate groups as well as the TES ether and the resulting
triol was converted to the tri-p-bromobenzoate 39 (p-BrBzCl,
Et3N, 4-DMAP cat., 86% over two steps), which however,
failed to crystallize.
Fortunately, exposure of 39 to nBu4NF resulted in the
removal of the TIPS group and one of the p-bromobenzoates
(another migrated to the primary alcohol) leading to com-
pound 40 whose crystalline form (m.p. 1848C, CH2Cl2/
hexanes) allowed its X-ray crystallographic analysis[11] (see
ORTEP drawing, Figure 3). This analysis revealed that while
the side chain hydroxyl group configuration was correct, the
orthoester stereochemistry was not (see structure, Figure 3).
Figure 3. ORTEP drawing of orthoester 40 derived from an X-ray
crystallographic analysis.[11]
Inversion of the orthoester stereochemistry could be easily
obtained by simply reversing the TBS and TIPS protection
steps described in the above sequence. In the end, however,
our final drive towards the GH orthoester 41 did not succeed
OTMS
allylO
O
Oallyl
OBn
RO
OR
OBn
RO
OR
OBn
O
BnO
RO
O
TBSO
BnO
a) TMSOTf
c) TBSOTf
Oallyl
+
OTMS
O
BnO
O
O
O
O
10
9
30: R = allyl
31: R = H
32: R = H
b) [(PPh3)3RhCl];
OsO4, NMO
d) BzCl
e) H2, 10% Pd/C
BzO
33: R = Bz
OR
BzO
OBz
OBz
OH
BzO
OBz
OBOM
N
3
2
O
TBSO
O
O
RO
i) Swern [O];
g) BOMCl
OBOM
S
S
5
4
O
RO
O
O
TIPSO
O
O
TIPSO
O
TMS
37: R = H
38: R = TES
34: R = H
35: R = TIPS
8: R = TBS
36: R = H
N
f) TIPSOTf
j) TESOTf
h) PPTS,
EtOH
m) MeOTf; NaBH4;
CuCl2; nBu4NF
k) K2CO3;
BrBzCl
OH
N
OBzBr
OH
OBzBr
HO
OBzBr
OBOM
OBzBr
OBOM
OBz
BzO
O
N
l) nBu4NF
HO
3
2
O
O
1
G
H
OBOM
S
S
O
5
4
BrBzO
O
O
O
O
TIPSO
O
O
41
40
39
Scheme 4. Attempted assembly of GH fragment 41. a) 2.0 equiv 10, 1.0 equiv 9, 0.15 equiv TMSOTf, CH2Cl2, 0 ! 258C, 12 h, 97%, 1:1 mixture of
diastereoisomers; b) i) 4.5 equiv DABCO, 0.07 equiv [(Ph3P)3RhCl], EtOH/H2O 10:1, reflux, 2 h; ii) 4.5 equiv NMO, 0.2 equiv OsO4, Me2CO/H2O 10:1,
258C, 8 h, 97% (two diastereoisomers ca. 1:1 ratio, more polar one shown here); c) 1.1 equiv TBSOTf, 1.5 equiv 2,6-lutidine, CH2Cl2, À788C, 0.5 h, 92%;
d) 2.5 equiv BzCl, 4.0 equiv Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 ! 258C, 2 h, 97%; e) H2, 10% Pd/C 0.1 equiv w/w, EtOAc, 258C, 2 h, 95%; f) 1.1 equiv
TIPSOTf, 1.5 equiv 2,6-lutidine, CH2Cl2, À788C, 0.5 h, 89%; g) 5.0 equiv BOMCl, 10.0 equiv iPr2NEt, CH2Cl2, 508C, 4 h, 89%; h) 0.1 equiv PPTS, EtOH/
THF (3:1), 508C, 6 h, 83%; i) i) 1.8 equiv (COCl)2, 2.0 equiv DMSO, À788C, 2 h; ii) 4.0 equiv Et3N, À78 !À 408C, 2 h; iii) 2.0 equiv TMS-thiazole, À40 !
258C, 12 h; iv) 0.06 equiv PPTS, MeOH, 258C, 2 h, 97%, ca. 10:1 mixture of diastereoisomers; j) 1.1 equiv TESOTf, 1.2 equiv 2,6-lutidine, CH2Cl2, 08C, 0.5 h,
89%; k) 0.5 equiv K2CO3, MeOH, 258C, 1 h; 4.0 equiv BrBzCl, 5.0 equiv Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 ! 258C, 2 h, 86% over two steps; l) 1.3 equiv
nBu4NF, THF, 258C, 1 h, 88%; m) i) 1.2 equiv MeOTf, MeCN, 258C, 0.5 h; ii) 2.4 equiv NaBH4, MeOH, 0 ! 258C, 0.5 h; iii) 1.2 equiv CuCl2, 8.0 equiv CuO,
MeCN/H2O 5:1, 258C, 2 h; iv) 2.5 equiv nBu4NF, THF, 258C, 2 h, decomposition. DABCO ˆ 1,4-diazabicyclo[2. 2.2]octane; NMO ˆ N-methylmorpholine N-
oxide; PPTS ˆ pyridinium p-toluenesulfonate; BrBz ˆ p-bromobenzoyl, TES ˆ triethylsilyl; THF ˆ tetrahydrofuran.
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K. C. Nicolaouet al.
FULL PAPER
in the face of the compoundsꢀ refusal to cyclize into the
tricyclic framework. Thus, while the aldehyde moiety of 38
could be unmasked employing Dondoniꢀs protocol (MeOTf;
NaBH4; CuO/CuCl2),[10] subsequent attempts to remove the
silicon groups with fluoride led to decomposition. Attempts to
functionalize or trap in situ any incipient lactol 41 also failed
and so did attempts to lactonize the corresponding carboxylic
acid which was derived by oxidation of the aldehyde. With
these failed attempts, evidence was accumulating supporting
the notion that the strain caused by the orthoester moiety was
insurmountable, even by this approach. A new plan had to be
devised based on the belief that the FG 1,1'-disaccharide
system would have to be constructed prior to the installation
of the GH orthoester moiety.
F
O
O
SePh
O
F
ROH
O
O
RO
OR
SePh
SePh
IV: R = PG
V: R = H
I: R = H
II: R = SF2NEt2
III
DAST
[O]
O
O
O
O
O
O
O
O
O
Heat
O
HO
HO
VII
SePh
H
O
VIII
VI
Figure 4. Orthoester formation via phenylseleno 1,2-migration followed
.
by glycosylation (I ! II ! III ! IV ) and ring closure after syn-elimination
.
(V! VI ! VII ! VIII ). PG ˆ protecting group.
As a prelude to embarking on our latest plan we wished to
explore and evaluate further methods for orthoester formation.
To this end a number of activated carbohydrate derivatives
were considered and synthesized as potential precursors,
however, all of them failed to produce orthoesters in their
reactions with the diols. Faced with such a daunting problem
exasperated by the special and sensitive structure of our target
molecule, we then decided to use a literature orthoester
synthesis. SinayÈ and co-workers[12] had established a method
for forming 2-deoxy carbohydrate orthoesters starting with
glycals and PhSeCl. Noting that no method had been reported
to be successful in constructing the GH orthoester system of
everninomicin, and being mindful of our previous technology
of 1,2-phenylsulfeno migrations in carbohydrates,[13] we de-
cided to employ a 1,2-phenylseleno migration/selenoxide
elimination/cyclization sequence to form the desired orthoest-
er systems. The general Scheme embodying these concepts is
shown in Figure 4. Thus, armed with the confidence derived
from SinayÈ's work and our own experience with the 1,2-
migration reaction, we initiated a second-generation program
towards the desired FGHA2 fragment.
disconnected between rings G and H as shown, leading to FG
diol 43 and 2-phenylseleno glycosyl fluoride 44 as key building
blocks. A projected, selenium-assisted coupling of 44 and 43
was expected to furnish regio- and stereoselectively trisac-
charide 42 whose functionality is poised for a SinayÈ-type
orthoester formation. Further disassembly of 43 by discon-
nection of its 1,1'-disaccharide bridge led to tin-acetal 45 and
trichloroacetimidate 46 as desired building blocks. The
stereoselective coupling of 45 with 46 was assured by our
methodological studies on this chemistry as summarized
above.
The constructions of the required building blocks 5, 44, 45,
and 46 are shown in Schemes 5 ± 9. Returning to the ring F tin-
acetal and recalling our difficulties with the TIPS group at C-4
(Scheme 2), which apparently thwarted our attempts to
benzylate at C-3 due to its bulk, we now decided to use a
much smaller protecting group at this position. This group had
however, to be replaced later on in the synthesis. The
successful synthesis of tin-acetal 45 is shown in Scheme 5.
Thus, silylation of mannose-derived diol 11 (TBSOTf, 2,6-
lutidine, À788C) furnished compound 47 (97% yield) onto
which the PMB group was installed by the action of NaH and
PMBCl (95% yield) affording, after desilylation (nBu4NF,
95% yield), primary alcohol 48. Methylation of 48 (NaH,
MeI, 95% yield) then led to methyl ether 49 from which the
acetonide group was removed by treatment with TsOH in
MeOH to afford diol 50 (85% yield). Pleasantly, this time the
tin-acetal benzylation protocol (nBu2SnO; BnBr, nBu4NI
Second-generation strategies towards the FGHA2 fragment:
Figure 5 outlines the second-generation retrosynthetic anal-
ysis of the targeted FGHA2 fragment 2 based on the above
findings and our new projections. Thus, disconnection of the
indicated aromatic ester and orthoester bonds, revealed
components 42 (FGH fragment) and 5 (A2 fragment) as
potential precursors. The FGH fragment 42 was further
Esterification
OMe
OBn
G
OMe
BnO
O
O
OTBS
OPMB
O
Me
A2
5
PhSe
OH
O
Me
O
O
O
O
O
O
+
F
O
H
H
G
F
F
A2
O
O
O
O
O
HO
OMe
TIPSO
OMe
BnO
OBn
BnO
OBn
2
42
OBn
OBn
Glycosylation
Orthoester formation
Glycosylation
OMe
OMe
BnO
O
O
O
O
O
NH
OBz
OH
nBu
Sn
nBu
OTBS
OPMB
PhSe
F
G
F
F
Cl3CCO
Oallyl
Oallyl
+
+
O
OH
PMBO
TIPSO
OMe
G
H
O
OBn
OBn
O
44
45
46
43
Figure 5. Revised retrosynthetic analysis of FGHA2 fragment 2.
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Chem. Eur. J. 2000, 6, No. 17
3120

Everninomicin 13,384-1: Part 2
3116±3148
allyl protection (e.g. allyltrichloroacetimidate; allyl bromide;
allyoxycarbonyl chloride) led either to decomposition or
multiple inseparable products.
O
O
SPh
O
O
O
SPh
O
RO
HO
RO
b) NaH, PMBCl
c) nBu4NF, THF
PMBO
Faced with these difficulties, we opted for a second route
which is shown in Scheme 7. Thus, bis-allylation of diisoprop-
yl-l-tartrate (59) (NaH, allyl bromide) gave bis-allyl ether 60
11: R = H
47: R = TBS
48: R = H
d) NaH, MeI
a) TBSOTf
49: R = Me
e) TsOH, MeOH
O
OR
OR
O
SPh
OH
MeO
MeO
g) NBS, H2O, Me2CO
F
OR
Oallyl
O
b) LAH, Et2O
c) NaH, TPSCl
PMBO
PMBO
iPrO
TPSO
OBn
52: R = H
45: R = Sn(nBu)2
OR
OiPr
OH
50: R = H
51: R = Bn
f) nBu2SnO;
BnBr
O
OR
59: R = H
60: R = allyl
Oallyl
61
h) nBu2SnO
a) NaH, allylBr
Scheme 5. Synthesis of tin-acetal building block
F
(45). a) 1.1 equiv
d) Swern [O];
TMS-thiazole
TBSOTf, 1.3 equiv 2,6-lutidine, CH2Cl2, À788C, 0.5 h, 97%; b) 1.1 equiv
NaH, 1.3 equiv PMBCl, 0.2 equiv nBu4NI, DMF/THF 1:1, 0 ! 258C, 4 h,
95%; c) 1.2 equiv nBu4NF, THF, 258C, 1 h, 95%; d) 1.1 equiv NaH,
1.3 equiv MeI, DMF, 0 ! 258C, 1 h, 95%; e) 0.2 equiv TsOH, 2.5 equiv
(CH2OH)2, MeOH, 258C, 5 h, 85%; f) 1.1 equiv nBu2SnO, toluene, reflux,
3 h; 1.5 equiv BnBr, 0.2 equiv nBu4NI, 25 ! 1108C, 5 h, 89%; g) 1.5 equiv
NBS, Me2CO/H2O 10:1, 0 ! 258C, 2 h, 97%; h) 1.1 equiv nBu2SnO,
MeOH, reflux, 3 h, 100%. NBS ˆ N-bromosuccinimide.
O
OR
allylO
TPSO
X
h) MeOTf; NaBH4;
CuO, CuCl2
i) nBu4NF, THF
G
N
allylO
OBz
allylO
S
allylO
65: R = H
46: R = C(NH)CCl3
62: X = OH, H
63: X = O
64: X = OBz, H
e)
j) CCl3CN,
DBU
f)
g) BzCl
Scheme 7. Synthesis of carbohydrate building block G (46). a) 1.93 equiv
NaH, 1.93 equiv allyl bromide, 0.02 equiv nBu4NI, 0.005 equiv [18]crown-6,
THF, 0 ! 258C, 4 h, 97%; b) 1.7 equiv LAH, Et2O, 0 ! 308C, 3 h, 93%;
c) 1.0 equiv NaH, 1.1 equiv TPSCl THF, 0 ! 258C, 4 h, 90%; d) i) 2.0 equiv
(COCl)2, 2.5 equiv DMSO, CH2Cl2, À788C, 2 h; ii) 4.0 equiv Et3N, À78 !
08C, 2 h; iii) 2.0 equiv TMS-thiazole, 0 ! 258C, 12 h; iv) 0.3 equiv PPTS,
MeOH, 258C, 2 h, 91%, 1:1 mixture of diastereoisomers; e) i) 2.0 equiv
(COCl)2, 3.0 equiv DMSO, À788C, 2 h; ii) 4.0 equiv Et3N, À78 ! 08C, 2 h,
96%; f) 1.1 equiv LAH, Et2O, 0 8C, 2 h, 70%; g) 1.1 equiv BzCl, 1.5 equiv
Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 ! 258C, 2 h, 98%; h) i) 1.2 equiv
MeOTf, MeCN, 258C, 15 min; ii) 2.4 equiv NaBH4, MeOH, 08C, 0.5 h;
iii) 1.2 equiv CuCl2, 8.0 equiv CuO, MeCN/H2O 10:1, 258C, 2 h; i) 1.5 equiv
nBu4NF, THF/AcOH 200:1, 258C, 2 h, 81% over four steps; j) 5.0 equiv
CCl3CN, 0.05 equiv DBU, CH2Cl2, 08C, 0.5 h, 85%, ca. 3:1 a:b mixture.
LAH ˆ lithium aluminumhydride; DBU ˆ 1,8-diazabicyclo[5.4.0]undec-7-
ene.
cat.) provided the desired C-3 benzyl ether 51 in high yield
(89%). Finally, the lactol was released from the phenyl-
thioglycoside by the action of NBS/H2O in acetone (97%
yield) and the resulting diol 52 was engaged as the cis-1,2 tin-
acetal 45 by treating with nBu2SnO in refluxing MeOH. The
quantitatively obtained cis-locked tin-acetal 45 was now ready
for coupling with ring G.
The next target was trichloroacetimidate[14] 46 for which
two attempts were necessary before success. Our initial
strategy towards this building block adopted Dondoniꢀs
TMS/thiazole chemistry and is shown in Scheme 6. Thus,
O
O
OR
b) Swern [O];
TMS-thiazole
TPSO
RO
N
(97% yield) whose LAH reduction (93% yield) followed by
monosilylation (NaH, TPSCl, 90%) led to alcohol 61, again
setting the stage for a Dondoni one-carbon homologation.
Swern oxidation [(COCl)2/DMSO] followed by addition of
TMS/thiazole afforded hydroxy compound 62 in 91% yield,
but this time as a 1:1 mixture of diastereoisomers. While
disappointed with the lack of selectivity, we were gratified
with the finding that the wrong diastereoisomer could be
recycled by oxidation [(COCl)2/DMSO, 96% yield] followed
by reduction of the resulting ketone 63. The best ratio of
products was obtained with LAH as the reducing agent (70%
yield, ca. 2:1 ratio in favor of desired isomer 62). Completion
of the sequence included benzoylation of 62 to 64 (BzCl, Et3N,
4-DMAP cat. 98% yield) followed by thiazole cleavage
(MeOTf; NaBH4; CuO/CuCl2) and desilylation (nBu4NF) to
afford lactol 65 in 81% yield overall. Finally, exposure of
lactol 65 to CCl3CN and DBU furnished the desired
trichloroacetimidate 46 in 85% yield as a mixture of anomers
(a:b ca. 3:1).
OH
O
O
S
53: R = H
54: R = TPS
55: R = H
56: R = Bz
a) NaH, TPSCl
c) BzCl, Et3N
d) BCl3•Me2S
OR
OH
OBz
OBz
N
e) allylBr or
allylO(CO)Cl or
allylOC(NH)CCl3
TPSO
TPSO
N
OR
S
OH
57
S
58
Scheme 6. Attempted synthesis of carbohydrate building block G (58).
a) 1.0 equiv NaH, 1.0 equiv TPSCl, THF, 0 ! 258C, 4 h, 90%; b) i) 2.0 e-
quiv (COCl)2, 2.5 equiv DMSO, CH2Cl2, À788C, 2 h; ii) 4.0 equiv Et3N,
À78 ! 08C, 2 h; iii) 2.0 equiv TMS-thiazole, 0 ! 258C, 12 h; iv) 0.1 equiv
PPTS, MeOH, 258C, 2 h, 94%, ca. 10:1 mixture of diastereoisomers;
c) 1.2 equiv BzCl, 1.5 equiv Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 ! 258C,
2 h, 96%; d) 2.0 equiv BCl3 ´ Me2S, CH2Cl2, 08C, 0.5 h, 91% based on 65%
conversion.
monosilylation (NaH, TPSCl) of the commercially available
diol 53 afforded TPS ether 54 (90% yield) setting the stage for
a subsequent Swern oxidation [(COCl)2/DMSO] and in situ
reaction with TMS/thiazole leading, after acidic work-up to
alcohol 55 (94% yield, ca. 10:1 ratio of diastereoisomers, 55
predominating). Benzoylation of 55 (BzCl, Et3N, 4-DMAP
cat., 96% yield) followed by acetonide cleavage led to diol 57.
Unfortunately, all attempts to obtain 58 from this diol through
The required 2-phenylselenoglycosyl fluoride 44 represent-
ing ring H was synthesized from peracetylated xylose (66) as
summarized in Scheme 8. Treatment of 66 with PhSeH[15] in
the presence of BF3 ´ Et2O led to a mixture of b:a (ca. 5:1)
selenoglycosides in 93% yield. The desired b-selenoglycoside
67 was subjected to basic methanolysis (K2CO3, MeOH) and
Chem. Eur. J. 2000, 6, No. 17
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3121

K. C. Nicolaouet al.
FULL PAPER
Orthoester formationÐThe GH model system: Before as-
sembling the FGH fragment, we wanted to explore the
stereochemical outcome of the orthoester formation, and
therefore assembled a simple GH model system, as illustrated
in Scheme 10. Diol 76 was prepared from ring G lactol 65 as
follows: a) methyl glycoside formation (DAST; MeOH,
SnCl2, 62% and a:b ca. 4:1); b) debenzoylation (K2CO3,
MeOH, 95%); c) benzylation (NaH, BnBr, 98%); and
d) allyl deprotection ([(Ph3P)3RhCl]; OsO4/NMO, 95% over
O
R
O
O
SePh
O
b) K2CO3, MeOH
c) CH3(CH3O)C=CH2
AcO
OAc
RO
OAc
66: R = OAc
67: R = SePh
68: R = H
69: R = PMB
d) PMBCl, NaH
a) PhSeH,
BF3•Et2O
e) PPTS, MeOH
O
F
O
SePh
OR1
H
h) DAST
PMBO
SePh
PMBO
OR2
OTBS
70: R1 = R2 = H
44
f) TBSOTf, THF
71: R1 = H, R2 = TBS
72: R1 = TBS, R2 = H
g)
a) DAST; MeOH
b) K2CO3
c) NaH, BnBr
d) [(Ph3P)3RhCl];
OsO4
O
OH
O
OMe
OBn
G
G
Scheme 8. Synthesis of carbohydrate building block H (44). a) ca. 2.0 e-
quiv PhSeH, 0.95 equiv BF3 ´ Et2O, CH2Cl2, 0 ! 258C, 12 h, 93%, a:b ca.
1:5; b) 0.1 equiv K2CO3, MeOH/THF 1:1, 258C, 12 h; c) 1.5 equiv
HO
allylO
MeO
OBz
allylO
OH
65
76
e) nBu2SnO;
OBn
OBn
ˆ
(1:1)
CH3(CH3O)C CH2, 0.1 equiv TFA, DMF, 458C, 3 h, 74% over two steps;
BzCl
MeO
OH
OBz
OH
d) 1.1 equiv NaH, 1.3 equiv PMBCl, 0.2 equiv nBu4NI, DMF, 0 ! 258C, 2 h,
95%; e) 0.2 equiv PPTS, MeOH, 258C, 1 h, 96%; f) 1.1 equiv TBSOTf,
1.5 equiv 2,6-lutidine, THF, À788C, 0.5 h, 91%; g) 1.1 equiv TBSOTf,
1.5 equiv 2,6-lutidine, CH2Cl2, À788C, 0.5 h, 91%; h) 1.5 equiv DAST,
CH2Cl2, 08C, 0.5 h, 100%. DASTˆ (diethylamino)sulfur trifluoride;
TFA ˆ trifluoroacetic acid.
G
G
O
F
O
O
OBz
H
77
78
PMBO
SePh
f) 44, SnCl2,
Et2O
f) 44, SnCl2,
Et2O
OTBS
44
PhSe
OTBS
OPMB
OTBS
OBn
OBn
PhSe
OR
OPMB
MeO
MeO
O
H
H
G
G
O
O
O
OR
O
O
the resulting triol was engaged as the 2,3-acetonide 68 by
reaction with 2-methoxypropene in the presence of TFA
(74% yield for two steps). Protection of the remaining
hydroxyl group in 68 (NaH, PMBCl, nBu4NI cat., 95% yield)
provided PMB ether 69 from which the acetonide was
removed under acidic conditions (PPTS, MeOH, 96% yield)
leading to diol 70. After considerable experimentation it was
discovered that treatment of 70 with TBSOTf-2,6-lutidine in
THF at À788C allowed selective protection at C-3 leading
directly to silyl ether 71 in 91% yield. Remarkably this
selectivity could be reversed by silylation under the same
conditions but in CH2Cl2 solution rather than in THF (91%
yield of 72). Although this serendipitous discovery may be
applicable to other suitable carbohydrate diols, a complete
explanation for its manifestation is not available at present. In
the final step of the sequence, substrate 71 was treated with
DAST which induced a 1,2-migration furnishing 2-phenyl-
selenoglycosyl fluoride 44 in quantitative yield.
79: R = Bz
80: R = H
86: R = Bz
87: R = H
g) NaOH
g) NaOH
h) NaIO4, MeOH
i) Heat
h) NaIO4, MeOH
i) Heat
OBn
OBn
O
OR
OR
MeO
O
MeO
H
OPMB
H
OPMB
G
G
O
O
O
O
O
O
81: R = TBS
82: R = H
83: R = Ms
88: R = TBS
89: R = H
90: R = Ms
j) nBu4NF
j) nBu4NF
k) MsCl
k) MsCl
l) DBU
l) DBU
OBn
O
OBn
O
MeO
MeO
MeO
MeO
H
H
OPMB
OPMB
G
G
O
O
O
O
O
O
O
91
84
m) OsO4
m) OsO4
OH
OBn
OBn
HO
OH
HO
O
O
H
OPMB
H
OPMB
G
G
O
O
O
O
O
85
92
O
O
OMe
OBn
The last requisite fragment for our purposes was acyl
fluoride 5 whose construction is briefly described in Scheme 9.
Thus, benzylation of bis-phenol 73[1] (K2CO3, BnBr, 92%
H
+
G
n) PhSeCl
80 + 87
PMBO
HO
OTBS
OH
93
76
Scheme 10. Assembly of GH model systems 85 and 92. a) i) 2.0 equiv
DAST, CH2Cl2, 08C, 0.5 h; ii) 5.0 equiv MeOH, 1.8 equiv SnCl2, 0 ! 258C,
Et2O, 12 h, 62%, a:b ca. 4:1; b) 1.0 equiv K2CO3, MeOH, 258C, 12 h, 95%;
c) 1.3 equiv NaH, 1.5 equiv BnBr, 0.3 equiv nBu4NI, DMF, 0 ! 258C, 2.5 h,
98%; d) i) 2.5 equiv DABCO, 0.05 equiv [(Ph3P)3RhCl], EtOH/H2O 10:1,
reflux, 2 h; ii) 2.5 equiv NMO, 0.05 equiv OsO4, Me2CO/H2O 10:1, 258C,
8 h, 95% over two steps; e) 1.1 equiv nBu2SnO, toluene, reflux, 3 h;
1.1 equiv BzCl, 0 ! 258C, 1 h, 92%, 1:1 mixture of regioisomers;
f) 1.5 equiv 44, 1.3 equiv SnCl2, 0 ! 258C, Et2O, 3 h, 69 % of 79, 70% of
86; g) 1.2 equiv NaOH, MeOH, 258C, 1 h, 99% of 80, 99% of 87;
h) 10.0 equiv NaIO4, 8.0 equiv NaHCO3, MeOH/CH2Cl2/H2O 3:2:1, 258C,
2 h; i) vinyl acetate/toluene/diisopropylamine 2:2:1, sealed tube, 1408C,
16 h, 70% of 81, 75% of 88; j) 1.2 equiv nBu4NF, THF, 258C, 1 h, 98 % of
82, 97% of 89; k) 1.2 equiv MsCl, 2.0 equiv Et3N, CH2Cl2, 0 ! 258C, 2 h,
97% of 83, 95% of 90; l) 10.0 equiv DBU, toluene, reflux, 24 h, 87% of 84,
87% of 91; m) 1.2 equiv NMO, 0.05 equiv OsO4, Me2CO/H2O 10:1, 258C,
24 h, 71% of 85, 72% of 92; n) i) 1.0 equiv 93, 1.2 equiv PhSeCl, MeCN,
258C, 5 min; ii) 1.5 equiv collidine, 1.2 equiv 76, 258C, 12 h, 54% of 80 and
87 combined. Ms ˆ methanesulfonyl.
Scheme 9. Synthesis of acyl fluoride 5. a) 2.5 equiv BnBr, 4.0 equiv K2CO3,
Me2CO, reflux, 8 h, 92%; b) 2.2 equiv NaClO2, 2.4 equiv NaH2PO4,
DMSO, 0 ! 258C, 12 h, 80%; c) 1.5 equiv (Me2N)2CF PF6À, 2.0 equiv
‡
iPr2NEt, CH2Cl2, 0 ! 258C, 2 h, 80%.
yield) followed by oxidation of the resulting aldehyde 74 to
carboxylic acid 75 (80% yield) followed by exposure to
(Me2N)2CF PF6À[16] in the presence of diisopropylethylamine
‡
yielded chromatographically (silica gel) stable acyl fluoride 5
in 80% yield.
3122
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Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
two steps). Direct coupling of diol 76 with 2-phenylseleno-
glycosyl fluoride 44 led to a moderate yield (65%) of the
disaccharides as a 1:1 mixture of C-3 and C-4 regioisomers. In
comparison, coupling of glycal 93 with 76 afforded only a 54%
yield of a 1:1 mixture of C-3 and C-4 regioisomers (80 and 87)
as well as some b-coupled products. The ring G monoben-
zoates were prepared by exposure of diol 76 to nBu2SnO,
followed by BzCl at 08C furnishing a 1:1 mixture of C-4 and
C-3 benzoates 77 and 78 (92% combined yield). Each
benzoate was then coupled with 2-phenylselenoglycosyl
fluoride 44 in the presence of SnCl2 to afford the glycosides
79 and 86 in 69 and 70% yield, respectively. Basic methanol-
ysis of 79 and 86 (NaOH, MeOH) removed the benzoate
esters, furnishing alcohols 80 and 87 in high yield. Each
alcohol was then subjected to SinayÈ's orthoester protocol[12]
[oxidation: NaIO4 in MeOH/CH2Cl2/H2O 3:2:1; followed by
heating at 1408C for 12 h in vinyl acetate/toluene/diisopropyl-
amine 2:2:1] providing orthoesters 81 and 88 in 70 and 75%
yield, respectively (ca. 8:1 ratio of diastereoisomers in each
case). With the orthoester formation secured, our attention
was turned to the installation of the C-2 hydroxyl group found
on ring H. While, it was presumed that orthoester 88 had the
correct stereochemistry based on the influence of the
anomeric effect[17] (see Figure 6 for reaction intermediates),
both orthoesters were carried through the sequence to test
compatibility to reaction conditions.
OR
O
O
RO
RO
RO
RO
H
OR5
2
G
4
H
O
O
3
1
4
G
2
3
O
O
1
OR5
HO
HO
H
H
OR
5
5
4
4
3
O
O
O
O
O
O
O
1
O
G
G
PMBO
TBSO
PMBO
H
H
1
3
OMe
OMe
2
2
TBSO
undesired stereoisomer
OBn
desired stereoisomer
OBn
Figure 6. Transition states illustrating stereoselective GH orthoester for-
mation. Joining rings G and H with the C-4 oxygen followed by ring closure
was crucial for the formation of the desired orthoester stereoisomer. A C-3
linked disaccharide leads predominantly to the undesired orthoester
stereoisomer.
steps, respectively. Attempts to epoxidize the olefin (mCPBA,
mCPBA/NaHCO3, (CF3)MeC(O)2 led to decomposition or
no reaction. However, exposure of the olefins to OsO4/NMO/
quinuclidine for 24 h facilitated smooth dihydroxylation
providing diols 85 and 92 in 71 and 72% yield, respectively.
Assembly of the FGHA2 fragment: With all building blocks
needed at hand and the model studies for the orthoester
formation completed, the assembly of the entire FGHA2
fragment of everninomicin was initiated as shown in
Scheme 11. Thus, coupling of tin-acetal 45 with trichloroace-
timidate 46 in the presence of TMSOTf followed by acidic
work-up afforded the desired b-mannoside containing 1,1'-
disaccharide 94 in 74% yield. Careful methylation of 94
(NaH, MeI, 87% yield) afforded 95 whose debenzoylation
(NaOH, MeOH, 95% yield) was followed by benzylation
(NaH, BnBr, 90% yield) to afford benzyl ether 97 via 96. The
PMB ether was then exchanged for a TIPS group by
deprotection (DDQ, 91% yield of 98) followed by exposure
to TIPSOTf and 2,6-lutidine furnishing 99 in 97% yield. In
preparation for coupling with the next sugar unit (ring H), the
The TBS groups were removed from 81 and 88 (nBu4NF)
furnishing alcohols 82 and 89, respectively. Several attempts
to implement an a-hydroxylation reaction led to decomposi-
tion, therefore, we decided that elimination to the double
bond followed by epoxidation/opening or dihydroxylation/
inversion would be better alternatives. The alcohols (82 and
89) were mesylated (MsCl/Et3N) to afford 83 and 90, followed
by heating in the presence of DBU to facilitate elimination to
olefins 84 and 91 in 83 and 80% overall yields for the three
OMe
OBz
OMe
OR
O
O
O
nBu
nBu
O
OC(NH)CCl3
MeO
O
O
O
O
Oallyl
Oallyl
Oallyl
Oallyl
+
Sn
F
G
G
F
G
F
a) TMSOTf
c) NaOH
PMBO
O
allylO
OBz
O
PMBO
OR
PMBO
OMe
OBn
Oallyl
OBn
OBn
45
46
94: R = H
95: R = Me
96: R = H
97: R = Bn
b) MeI, NaH
d) NaH, BnBr
e) DDQ
OMe
OMe
OBn
O
O
3
OH
G
F
OMe
O
OBn
OBn
O
O
OCA
4
TIPSO
O
OMe
O
OH
Oallyl
Oallyl
g) [(Ph3P)3RhCl];
OsO4/NMO
h) nBu2SnO;
CACl
OBn
F
G
F
G
100
O
OMe
O
OH
TIPSO
RO
OMe
OMe
OBn
3
OBn
OBn
O
O
43
OCA
OH
98: R = H
99: R = TIPS
G
F
f) TIPSOTf
O
OMe
4
TIPSO
OTBS
OMe
OBn
PhSe
OR
OBn
OPMB
O
O
101
O
F
3
H
G
F
H
i) 44, SnCl2,
Et2O
O
OMe
4
O
O
TIPSO
PMBO
SePh
OBn
OTBS
44
102: R = CA
42: R = H
j) K2CO3
Scheme 11. Assembly of FGH fragment 42. a) i) 2.1 equiv 45, 1.0 equiv 46, 0.5 equiv TMSOTf, CH2Cl2, 0 ! 258C, 12 h; ii) 0.3 equiv PPTS, MeOH, 258C, 1 h,
74% over two steps; b) 1.1 equiv NaH, 3.0 equiv MeI, DMF, 0 ! 258C, 1 h, 87%; c) 0.3 equiv NaOH, MeOH/Et2O 1:1, 258C, 1 h, 95%; d) 1.1 equiv NaH,
1.3 equiv BnBr, 0.2 equiv nBu4NI, DMF, 0 ! 258C, 4 h, 90%; e) 1.5 equiv DDQ, CH2Cl2/H2O 10:1 0 ! 258C, 1 h, 91%; f) 1.2 equiv TIPSOTf, 1.5 equiv 2,6-
lutidine, CH2Cl2, 0 ! 258C, 1 h, 97%; g) i) 2.5 equiv DABCO, 0.1 equiv [(Ph3P)3RhCl], EtOH/H2O 10:1, reflux, 2 h; ii) 2.2 equiv NMO, 0.05 equiv OsO4,
Me2CO/H2O 10:1, 258C, 8 h, 81% over two steps; h) 1.1 equiv nBu2SnO, toluene, reflux, 3 h; 1.05 equiv CACl, 0 ! 258C, 1 h, 97%, 1:1 mixture of
regioisomers; i) 2.0 equiv 44, 1.8 equiv SnCl2, 0 ! 258C, Et2O, 3 h, 92%; j) 0.2 equiv K2CO3, MeOH/Et2O 1:1, 258C, 1 h, 98%. CA ˆ chloroacetyl; DDQ ˆ
2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
Chem. Eur. J. 2000, 6, No. 17
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3123

K. C. Nicolaouet al.
FULL PAPER
allyl groups were removed by
sequential treatment with
[(Ph3P)3RhCl] and OsO4/
NMO furnishing diol 43
(81% yield). At this stage,
and based on the model stud-
ies described above, we postu-
lated that the C-4 glycoside
(i.e., 42, Scheme 11) would
provide the correct orthoester
stereoisomer. An appropriate-
ly C-3 protected derivative of
43 was therefore sought for
further advancement. Despite
many attempts to achieve se-
lective C-3 protection using
tin-acetal chemistry and other
means, the best result was only
a 1:1 mixture of regioisomers
100 and 101, albeit in 97%
combined yield, when the tin-
acetal derived from 43
(nBu2SnO) was reacted with
chloroacetylchloride (CACl).
The two isomers were chro-
OMe
OBn
OTBS
OPMB
OTBS
OMe
OBn
PhSe
OH
O
O
O
3
a) NaIO4, MeOH;
Heat
O
O
3
G
H
OPMB
G
F
H
F
O
O
O
4
O
4
O
RO
O
TIPSO
OMe
OMe
OBn
OBn
106: R = TIPS
107: R = H
42
b) nBu4NF
c) BzCl, Et3N
OMe
OBn
OMe
OBn
OR
O
O
O
O
O
O
H
OPMB
H
OPMB
e) Martin sulfurane
G
F
G
F
O
O
O
O
O
O
RO
BzO
OMe
OMe
OBn
OBn
108: R = TBS
109: R = H
110: R = Bz
111: R = H
f) K2CO3, MeOH
d) nBu4NF
g. TBSCl, NaH
OMe
OBn
O
OMe
OBn
HO
OR
O
O
O
O
O
h) OsO4, NMO
H
OPMB
H
OPMB
G
G
F
F
O
O
OMe
O
O
O
O
TBSO
TBSO
OMe
OBn
OBn
112
113: R = H
114: R = Bz
i) nBu2SnO; BzCl
j) Dess-Martin periodinane
k) Li(tBuO)3AlH, Et2O
OMe
OBn
OMe
OBn
HO
O
OR
OPMB
O
O
O
O
O
O
O
m) CH2Br2, NaOH
H
H
OR
G
F
G
F
O
OMe
O
O
O
O
O
TBSO
TBSO
OMe
OBn
O
Me
OBn
115: R = Bz
116: R = H
117: R = PMB
118: R = H
l) NaOH, MeOH
OBn
F
n) DDQ
O
A2
BnO
OBn
o. NaH; 5
5
matographically
separated
OMe
O
O
O
Me
A2
OMe
OBn
O
O
Me
A2
and the correct hydroxy ester
101 was reacted with 2-phe-
nylselenoglycosyl fluoride 44
in ether and in the presence of
SnCl2 to afford trisaccharide
102 in 92% yield and as a
single anomer. The stereo-di-
recting effect of the selenium
in such coupling reactions was
discussed and rationalized
previously.[18] The chloroace-
tate was then removed from
102 by exposure to K2CO3 in
MeOH furnishing the desired
hydroxy selenide 42 in 98%
yield.
O
O
O
O
O
O
H
O
p) nBu4NF
G
F
H
O
G
F
O
O
O
O
HO
O
O
OMe
BnO
OBn
TBSO
OMe
BnO
OBn
OBn
2
OBn
119
Scheme 13. Completion of the synthesis of the FGHA2 fragment 2. a) i) 10.0 equiv NaIO4, 8.0 equiv NaHCO3,
MeOH/CH2Cl2/H2O 3:2:1, 258C, 2 h; ii) vinyl acetate/toluene/diisopropylamine 2:2:1, sealed tube, 1408C, 12 h,
81% over two steps; b) 1.1 equiv nBu4NF, THF, 08C, 0.5 h, 95%; c) 1.2 equiv BzCl, 1.8 equiv Et3N, 0.2 equiv
4-DMAP, CH2Cl2, 0 ! 258C, 2 h, 97%; d) 1.5 equiv nBu4NF, 0.2 equiv AcOH, THF, 258C, 1 h, 95%; e) 4.0 equiv
Martin sulfurane, 0.05 equiv Et3N, CHCl3, 508C, 2 h, 85%; f) 0.5 equiv K2CO3, MeOH, 258C, 6 h, 90%;
g) 6.0 equiv NaH, 12 equiv TBSCl, 1.0 equiv [18]crown-6, THF, 08C, 2 h, 80%; h) 5.0 equiv NMO, 0.5 equiv
OsO4, 1.0 equiv quinuclidine, Me2CO/H2O 10:1, 258C, 36 h, 70%, 8:1 mixture of diastereoisomers; i) 1.1 equiv
nBu2SnO, MeOH, reflux, 3 h; 1.5 equiv BzCl, 1,4-dioxane, 158C, 0.5 h, 97%, 5:1 mixture of regioisomers;
j) 2.0 equiv Dess ± Martin periodinane, 20 equiv NaHCO3, CH2Cl2, 258C,1 h; k) 1.1 equiv Li(tBuO)3AlH, Et2O,
À108C, 1 h, 80% over two steps; l) 0.5 equiv NaOH, MeOH, 258C, 1 h, 98%; m) 3.0 equiv nBu4NBr,
CH2Br2:50% aqueous NaOH 1:1, 658C, 2 h, 90%; n) 1.5 equiv DDQ, CH2Cl2/H2O 10:1 (pH 7) 0 ! 258C, 1 h,
85%; o) 1.2 equiv NaH, THF, 08C; then 1.5 equiv 5, 0 ! 258C, 2 h, 96%; p) 1.2 equiv nBu4NF, THF, 258C, 1 h,
91%.
The sequence was made more efficient by the development
of a route for funneling the C-4 chloroacetate derivative 100
back into the main path as shown in Scheme 12. Thus,
benzoylation of 100 (BzCl, Et3N, 4-DMAP cat., 96%)
followed by selective removal of the chloroacetate with
Et3N in MeOH furnished the C-3 benzoate 104 (96% yield).
Subsequent coupling of 104 with 2-phenylselenoglycosyl
fluoride 44 in ether and in the presence of SnCl2 led
stereoselectively to 105 in 92% yield. The benzoate group
was then removed from 105 (K2CO3, MeOH) affording the
same alcohol 42 (98% yield) as before.
Our initial attempts to construct the orthoester moiety with
the desired framework are illustrated in Scheme 13. Thus,
exposure of alcohol 42 to the orthoester formation protocol
OMe
OBn
3
OMe
OBn
3
OTBS
OPMB
OMe
OBn
PhSe
OR
c) 44, SnCl2,
Et2O
b) Et3N,
MeOH
O
O
O
O
OR
O
O
OBz
OH
3
G
H
F
G
F
G
F
O
O
O
OCA
4
4
4
O
TIPSO
TIPSO
O
TIPSO
OMe
OMe
OMe
OBn
OBn
OBn
105: R = Bz
42: R = H
100: R = H
103: R = Bz
104
a) BzCl, Et3N
d) K2CO3, MeOH
Scheme 12. Recycling of FG fragment 100 and synthesis of FGH fragment 42. a) 1.2 equiv BzCl, 2.0 equiv Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 ! 258C, 2 h,
96%; b) 2.0 equiv Et3N, MeOH/CH2Cl2 1:1, 408C, 6 h, 96%; c) 2.0 equiv 44, 1.8 equiv SnCl2, 0 ! 258C, Et2O, 3 h, 92%; d) 0.2 equiv K2CO3, MeOH/Et2O 1:1,
258C, 12 h, 98%.
3124
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Everninomicin 13,384-1: Part 2
3116±3148
[NaIO4/NaHCO3 in MeOH/CH2Cl2/H2O 3:2:1; vinyl acetate/
toluene/diisopropylamine 2:2:1, 1408C, 12 h] furnished 2-de-
oxyorthoester 106 in 81% overall yield and as a ca. 8:1
mixture of diastereoisomers (106 predominating). The next
task was to remove the TBS group from ring H, but
unfortunately and unexpectedly, treatment of 106 with
nBu4NF in THF at 08C induced exclusive removal of the
ring F TIPS group. Hoping to avoid the extra steps imposed
by this finding, we opted at this stage to test another route
involving removal of the TBS group from ring H prior to
orthoester formation. We shall return to Scheme 13 shortly.
Thus, returning to 42 and proceeding to Scheme 14, we
found that its treatment with nBu4NF in THF at 08C, indeed
caused cleavage of the TBS group furnishing diol 120
(Scheme 14) in 82% yield (based on 85% conversion).
Furthermore, when diol 120 was subjected to the above
described orthoester formation conditions the orthoester
proceeded well (74% yield) but this time was accompanied
by a Ferrier-type rearrangement leading to what was assumed
(on the basis of our model studies described above) to be the
desired orthoester, that is to say the one with the opposite
stereochemistry to that shown in structure 121. We were
initially excited about this route, in that, it was three steps
shorter and led directly to the allylic orthoester, which was set
for a dihydroxylation reaction. As it turned out, however, this
assumption was wrong, the shown stereochemistry being
proven by X-ray crystallographic analysis of a subsequent
intermediate (vide infra). With the assumption of the correct
stereochemistry, we proceeded to elaborate orthoester 121 to
compound 124 as shown in Scheme 14. Thus, exposure of 121
to dihydroxylation conditions (OsO4 cat./NMO) led to cis-diol
122 in 65% yield and ca. 8:1 ratio of diastereoisomers.
Following unsuccessful attempts to monoprotect this diol for
oxidation/reduction purposes (in order to invert the C-2
stereochemistry of ring H), a different approach was under-
taken. Exposure of 122 to SOCl2 and Et3N, followed by NaIO4
oxidation furnished the cyclic sulfate 123 in 97% overall yield.
Opening of this cyclic sulfate with KOBz in DMF at 1208C
furnished monobenzoate 124, whose 1H-NMR spectrum
revealed a trans relationship at C-2/C-3 but also the wrong
position for the benzoate.
At this stage, an X-ray crystallographic analysis was
deemed important, and fortunately, the p-bromobenzoate
derivative 125 (p-BrBzCl, Et3N, 4-DMAP cat., 100% yield)
crystallized nicely for this purpose (m.p. 1568C, CH2Cl2/
hexanes). The X-ray structure[11] of 125 (see ORTEP drawing
in Figure 7) proved the wrong stereochemistry for the
Figure 7. ORTEP drawing of orthoester 125 derived from an X-ray
crystallographic analysis.[11]
orthoester moiety indicating that the crucial cyclization
(120 ! 121) during orthoester formation had occurred from
the undesired face of the olefin involved.
Hoping to reverse the stereochemical outcome and recall-
ing our model studies, we adopted a plan to construct the
allylic orthoester directly starting from the C-3 coupled
disaccharide as shown in Scheme 15. Thus, monobenzoate
126 was coupled with 2-phenylselenoglycosyl fluoride 44 in
the presence of SnCl2 in ether furnishing C-3 linked trisac-
charide 127 in 60% yield. The benzoate group was then
removed from 127 (NaOH,
OR
OMe
OBn
OMe
OBn
MeOH, 93%) leading to 128
from which the TBS group was
PhSe
OH
OPMB
O
O
O
3
O
O
3
G
b) NaIO4
c) Heat
H
OPMB
F
G
H
F
O
O
cleaved by the action of
nBu4NF to give diol 129 in
81% yield. Treatment of 129
to slightly modified orthoester
formation conditions (NaIO4/
NaHCO3 in MeOH/CH2Cl2/
H2O 12:7:1; followed by heat-
ing at 1408C for 12 h in vinyl
acetate/toluene/diisopropyla-
mine 1:1:2) facilitated the ex-
pected syn-elimination and cyc-
lization and led to allylic or-
thoester 130, unfortunately in
only 45% yield and as a 4:1
inseparable mixture of stereo-
O
4
O
4
O
O
TIPSO
TIPSO
OMe
OMe
OBn
OBn
121
42: R = TBS
120: R = H
a) nBu4NF
d) OsO4, NMO
OMe
OBn
OMe
OBn
RO
O
OBz
RO
OR
O
O
O
O
O
3
G
f) KOBz;
H2SO4
3
G
H
H
OPMB
OPMB
F
F
O
O
O
O
4
4
O
O
TIPSO
TIPSO
OMe
OMe
OBn
OBn
124: R = H
125: R = BrBz
122: R = H
123: R = SO2
g) BrBzCl
e) SOCl2; NaIO4
Scheme 14. Synthesis of FGH intermediates 124 and 125. a) 1.05 equiv nBu4NF, THF, 08C, 15 min, 82% based
on 85% conversion; b) 10.0 equiv NaIO4, 8.0 equiv NaHCO3, MeOH/CH2Cl2/H2O 3:2:1, 258C, 4 h; c) vinyl
acetate/toluene/diisopropylamine 2:2:1, sealed tube, 1408C, 12 h, 74% over two steps; d) 2.5 equiv NMO,
0.5 equiv OsO4, 1.0 equiv quinuclidine, Me2CO/H2O 10:1, 258C, 24 h, 65%; e) 1.5 equiv SOCl2, 3.0 equiv Et3N,
CH2Cl2, 08C, 5 min; 20 equiv NaIO4, 18 equiv NaHCO3, CCl4/MeCN/H2O 1:1:1.5, 0 ! 258C, 1 h, 97% over two
steps; f) 3.0 equiv BzOK, 1.0 equiv [18]crown-6, DMF, 1208C, 1 h; then 0.5n H2SO4 and 0.5n H2O in THF, THF,
08C, 0.5 h, 76%; g) 1.4 equiv BrBzCl, 4.0 equiv Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 ! 258C, 12 h, 100%.
Chem. Eur. J. 2000, 6, No. 17
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3125

K. C. Nicolaouet al.
FULL PAPER
diastereoisomers. The benzoate
was then removed (K2CO3,
MeOH, 98% yield) providing
triol 132 from which the hy-
droxy carbonate 133 was de-
rived upon exposure to triphos-
gene in pyridine (96% yield).
The TBS group was then in-
stalled in 133 with ease
(TBSOTf, 2,6-lutidine, 93%
yield) leading to the corre-
sponding silyl ether (134) from
which the diol 113 was liberated
by cleavage of the carbonate
group (NaOH, MeOH, 95%
yield). The coupling constants
(J) for the H-2 and H-3 protons
OMe
OBn
3
PhSe
O
OMe
OBn
3
OTBS
H OPMB
O
O
O
O
OH
a) 44, SnCl2, Et2O
F
G
G
F
O
O
O
OBz
4
4
OR
TIPSO
TIPSO
OMe
OMe
OBn
OBn
O
F
126
127: R = Bz
128: R = H
H
b) NaOH, MeOH
BMPO
SePh
c) nBu4NF
OTBS
44
OMe
OBn
OMe
OBn PhSe
OH
OPMB
H
d) NaIO4
e) Heat
O
O
O
O
O
3
G
3
O
H
OPMB
F
G
F
O
O
O
O
4
O
4
OH
TIPSO
TIPSO
OMe
OMe
OBn
OBn
129
130
Scheme 15. Synthesis of FGH fragment 130. a) 2.0 equiv 44, 2.0 equiv SnCl2, 0 ! 258C, Et2O, 12 h, 60%;
b) 0.1 equiv NaOH, MeOH, 258C, 1 h, 93%; c) 1.0 equiv nBu4NF, THF, 258C, 1 h, 81%; d) 10.0 equiv NaIO4,
8.0 equiv NaHCO3, MeOH/CH2Cl2/H2O 12:7:1, 258C, 4 h; e) vinyl acetate/toluene/diisopropylamine 1:1:2, sealed
tube, 1408C, 12 h, 45% over two steps.
isomers. Unsatisfied with these results, the more efficient
sequence of Scheme 13 was reactivated.
in 134 and other related derivatives confirmed the config-
uration of the ring H diol system in this series of compounds.
Going back to Scheme 13, diol 113 was regioselectively
converted to the monobenzoate 114 by treatment with
nBu2SnO/BzCl[20] (97% yield, ca. 5:1 ratio with its regioisom-
er, chromatographically separated). The plan was now to
oxidize the remained hydroxy group and then stereoselec-
tively reduce it in order to arrive at the desired trans diol
system on ring H. To this end, several oxidizing agents (e.g.
Dess ± Martin periodinane, Swern, TPAP/NMO, nBu2SnO/
Br2) and reducing agents (e.g. LAH, Li(tBuO)3AlH, Selec-
trides, LiEt3BH, NaBH4, Na(AcO)3BH) were investigated.
The best combination involved oxidation with Dess ± Martin
periodinane[21] followed by reduction with Li(tBuO)3AlH to
afford, via the corresponding ketone, the desired alcohol 115
(80% overall for two steps). The benzoate group was then
removed from 115 (NaOH, MeOH) to furnish diol 116 (98%
yield) and setting the stage for formation of the methylene
acetal moiety. The latter goal was achieved by slow addition of
116 to a mixture of aqueous NaOH, CH2Br2, and nBu4NBr, at
658C[22] leading to the desired compound 117 in 90% yield.
The remaining sequence for the completion of the synthesis of
the FGHA2 fragment (2) involved DDQ-mediated removal of
the PMB group from 117 to afford 118 in 85% yield, followed
by esterification with acyl fluoride 5 in the presence of NaH
As already mentioned above, the orthoester 106 (Scheme 13)
was efficiently (81% yield) obtained from hydroxy selenide
42. Its stereochemistry was established by comparison of the
1H-NMR spectrum of the allylic orthoester 110 generated
from it, and the corresponding spectra of allylic orthoesters
121 (Scheme 14) and 130 (Scheme 15) whose structures were
unambiguously secured through X-ray crystallographic anal-
ysis of crystalline derivative 125 (see Figure 7). Due to
previously obtained results, it was necessary to adopt a
round-about sequence for the procurement of the desired
hydroxy compound 109 (Scheme 13). Thus, alcohol 107
obtained already as described above (nBu4NF, 95% yield)
was benzoylated (BzCl, Et3N, 4-DMAP cat., 97% yield) and
the resulting compound 108 was desilylated (nBu4NF, AcOH,
THF, 95% yield) to afford alcohol 109 which was dehydrated
by exposure to Martin sulfurane[19] furnishing olefin 110 (85%
yield). The stage was now set for a dihydroxylation of ring H,
but before that, it was found necessary to exchange the
benzoate group on ring F with a TBS group in order to ensure
the success of subsequent steps. To this end, benzoate 110 was
exposed to K2CO3 in MeOH furnishing hydroxy compound
111 (90% yield) whose treatment with TBSCl in the presence
of NaH and [18]crown-6 led to silyl ether 112 (80% yield).
Reaction of the highly sensitive
olefinic orthoester 112 with
OMe
OBn
OMe
OBn
HO
O
OH
O
O
O
O
O
OsO4 cat./NMO in the presence
of quinuclidine led to 1,2-diol
113 as the major product (70%
yield, ca. 8:1 mixture of b:a
diastereoisomers). Due to the
extreme sensitivity of orthoest-
ers 110 ± 112, an alternative ap-
proach to compound 113 was
sought and secured as shown in
Scheme 16. Thus, olefin 110 was
treated directly under the dihy-
droxylation conditions (OsO4
cat./NMO) affording diol 131
in 97% yield based on 70%
conversion and ca. 10:1 ratio of
a) OsO4
H
H
OPMB
OPMB
F
G
G
F
O
O
O
O
O
O
RO
BzO
OMe
OMe
OBn
OBn
b) K2CO3
110
131: R = Bz
132: R = H
c) triphosgene
O
OMe
OBn
OMe
OBn
HO
O
OH
O
O
O
O
O
O
O
e) NaOH
H
OPMB
H
OPMB
G
F
G
F
O
OMe
O
OMe
O
O
O
O
TBSO
RO
OBn
OBn
113
133: R = H
d) TBSOTf
134: R = TBS
Scheme 16. Alternative synthesis of FGH fragment 113. a) 5.0 equiv NMO, 0.5 equiv OsO4, 1.0 equiv
quinuclidine, Me2CO/H2O 10:1, 258C, 24 h, 97% based on 70% conversion, 10:1 mixture of diastereoisomers;
b) 0.2 equiv K2CO3, MeOH, 258C, 4 h, 98%; c) 2.0 equiv triphosgene, 20 equiv py, CH2Cl2, À78 ! 258C, 1 h,
96%; d) 1.2 equiv TBSOTf, 1.5 equiv 2,6-lutidine, CH2Cl2, 0 ! 258C, 1 h, 93%; e) 0.5 equiv NaOH, MeOH/Et2O
1:1, 258C, 1 h, 95%. py ˆ pyridine.
3126
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Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
Benzoate 18: BzCl (0.83 mL, 7.27 mmol) was added to a solution of
mannose diol 11[4] (2.27 g, 7.27 mmol), Et3N (1.22 mL, 8.73 mmol), and
4-DMAP (0.09 g, 0.73 mmol) in CH2Cl2 (100 mL) at 08C. The resulting
mixture was warmed to 258C and stirred for 2 h. The reaction mixture was
quenched by the addition of MeOH (10 mL), diluted with CH2Cl2 (100 mL)
and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL).
The organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 60% Et2O in hexanes) to afford benzoate 18 (2.74 g,
91%) as a white foam. 18: Rf ˆ 0.27 (50% Et2O in hexanes); [a]2D2 ˆ ‡87.8
(c ˆ 0.67, CHCl3); IR (thin film): nÄ ˆ 3442, 3062, 2984, 1743, 1454, 1381,
furnishing 119 in 96% yield (again proving the utility of the
acyl fluoride moiety[1]), and finally, desilylation of 119 with
nBu4NF affording target 2 in 91% yield.
Conclusion
In this article, methods were described for the stereoselective
construction of the 1,1'-disaccharide and orthoester linkages
of everninomicin, bridging rings F to G and G to H,
respectively. The first method[2] relied on a cyclic tin-acetal
intermediate to lock the anomeric stereochemistry of ring F,
while the anomeric stereochemistry of ring G was secured
through an acetoxy participating group at C-2. The orthoester
formation method combined a newly developed 1,2-phenyl-
seleno migration in carbohydrate chemistry with elements of
the SinayÈ sequence for orthoester formation and proved
stereoselective depending on the point (C-3 or C-4) of linkage
of the disaccharide unit involved. While both methods
performed admirably in the final strategy for the construction
of the FGHA2 fragment 2 required for the total synthesis of
the targeted everninomicin (1), a closer examination of these
methods is described in Part 4[3] of this series. The following
paper[23] describes the construction of the DE fragment and its
insertion between segments A1B(A)C and FGHA2, as well as
the completion of the total synthesis of everninomicin 13,384-
1 (1).
1274, 1220, 1066, 867, 714 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.95 (d,
J ˆ 8.0 Hz, 2H, ArH), 7.55 (t, J ˆ 7.5 Hz, 1H, ArH), 7.49 ± 7.47 (m, 2H,
ArH), 7.39 (d, J ˆ 7.5 Hz, 2H, ArH), 7.22 ± 7.19 (m, 3H, ArH), 5.85 (s, 1H,
F1), 4.68 (dd, J ˆ 12.0, 5.5 Hz, 1H, F6), 4.47 (dd, J ˆ 12.0, 2.0 Hz, 1H, F6),
4.38 (d, J ˆ 5.5 Hz, 1H, F2), 4.37 ± 4.34 (m, 1H, F4), 4.22 (dd, J ˆ 7.4, 6.0 Hz,
1H, F3), 3.73 ± 3.69 (m, 1H, F5), 3.14 (d, J ˆ 4.5 Hz, 1H, OH), 1.49 (s, 3H,
Me), 1.37 (s, 3H, Me); 13C NMR (125 MHz, CDCl3): d ˆ 165.7, 133.2, 133.0,
131.5, 129.8, 129.5, 129.0, 128.3, 127.5, 109.9, 83.8, 78.0, 76.1, 69.8, 69.5, 63.9,
‡
28.0, 26.3; HRMS (MALDI): calcd for C22H24O6SNa [M‡Na] : 439.1191,
found 439.1205.
TIPS ether 19: TIPSOTf (4.24 mL, 15.78 mmol) was added to a solution of
alcohol 18 (5.48 g, 13.15 mmol) and 2,6-lutidine (2.15 mL, 18.41 mmol) in
CH2Cl2 (200 mL) at 08C and the resulting mixture was warmed to 258C and
stirred for 3 h. The reaction mixture was quenched by the addition of
MeOH (10 mL), diluted with CH2Cl2 (250 mL), and washed with saturated
aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 0 ! 60%
Et2O in hexanes) to afford TIPS ether 19 (7.46 g, 99%) as a white foam. 19:
Rf ˆ 0.62 (50% Et2O in hexanes); [a]2D2 ˆ ‡214.3 (c ˆ 0.21, CHCl3); IR
(thin film): nÄ ˆ 2943, 2867, 1724, 1457, 1381, 1273, 1219, 1162, 1109, 1069,
1027, 881, 751, 711, 686 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.90 (dd, J ˆ
8.0, 1.0 Hz, 2H, ArH), 7.54 ± 7.46 (m, 3H, ArH), 7.36 (t, J ˆ 7.5 Hz, 3H,
ArH), 7.16 ± 7.11 (m, 2H, ArH), 5.80 (s, 1H, F1), 4.65 (dd, J ˆ 12.0, 2.5 Hz,
1H, F6), 4.45 (dd, J ˆ 12.0, 7.0 Hz, 1H, F6), 4.39 (dd, J ˆ 4.0, 2.0 Hz, 1H,
F2), 4.37 (dd, J ˆ 6.0, 2.0 Hz, 1H, F3), 4.18 (t, J ˆ 6.5 Hz, 1H, F4), 3.97 (dd,
J ˆ 9.5, 7.0 Hz, 1H, F5), 1.54 (s, 3H, Me), 1.38 (s, 3H, Me), 1.22 ± 1.06 (m,
21H, iPr3Si); 13C NMR (150 MHz, CDCl3): d ˆ 166.2, 133.4, 132.8, 131.0,
129.9, 129.7, 128.9, 128.2, 127.2, 109.4, 83.8, 78.8, 76.2, 71.5, 70.5, 64.3, 27.9,
Experimental Section
General: For general techniques and procedures, see Part 1[1] in this series.
Disaccharide 15: For a general procedure for the preparation of disacchar-
ides 15 and 17, refer to paper 4[3] in this series. 15: Rf ˆ 0.38 (60% ether in
hexanes); [a]2D2 ˆ ‡31.6 (c ˆ 0.9, CHCl3); IR (thin film): nÄ ˆ 3030, 2920,
1732, 1453, 1366, 1234, 1099, 1025, 826, 741, 698 cmÀ1; 1H NMR (600 MHz,
CDCl3): d ˆ 7.38 ± 7.20 (m, 30H, ArH), 5.26 (dd, J ˆ 3.2, 1.9 Hz, 1H, H2'),
5.19 (d, J ˆ 1.7 Hz, 1H, H1), 5.14 (d, J ˆ 1.5 Hz, 1H, H1'), 4.91 ± 4.49 (m,
12H, CH2Ar), 4.09 (dd, J ˆ 9.9, 9.8 Hz, 1H, H4'), 3.88 (dd, J ˆ 9.9, 9.8 Hz,
1H, H4), 3.86 ± 3.83 (m, 2H, H6, H6'), 3.80 (dd, J ˆ 9.3, 3.2 Hz, 1H, H3'),
3.78 (ddd, J ˆ 10.0, 4.1, 1.6 Hz, 1H, H5'), 3.73 ± 3.71 (m, 2H, H6, H6'), 3.62
(dd, J ˆ 2.3, 1.6 Hz, 1H, H2), 3.59 (dd, J ˆ 10.7, 1.6 Hz, 1H, H3), 3.55 (ddd,
J ˆ 10.0, 4.4, 1.5 Hz, 1H, H5), 2.13 (s, 3H, OAc); 13C NMR (150 MHz,
CDCl3): d ˆ 170.2, 138.3, 138.2, 138.2, 138.1, 138.0, 137.9, 137.7, 128.4, 128.4,
128.3, 128.3, 128.1, 128.0, 128.0, 128.0, 127.8, 127.8, 127.8, 127.7, 127.7, 127.5,
93.2, 93.1, 79.4, 77.7, 75.3, 75.2, 74.4, 74.0, 74.0, 73.5, 73.3, 72.5, 72.3, 72.1,
71.8, 68.6, 68.5, 68.2, 21.0; 13C NMR (150 MHz, CDCl3; proton coupled):
d ˆ 93.2 (JC,H ˆ 174.1 Hz), 93.1 (JC,H ˆ 175.1 Hz); HRMS (FAB): calcd for
‡
26.3, 18.2, 18.1, 12.6; HRMS (MALDI): calcd for C31H44O6SSiNa [M‡Na] :
595.2525, found 595.2519.
Alcohol 20: NaOH (50 mg, 1.19 mmol) was added to a solution of 19
(3.42 g, 5.97 mmol) in MeOH/Et2O (1:1, 30 mL) at 258C and the resulting
mixture was stirred for 1 h. The reaction mixture was quenched by the
addition of saturated aqueous NH4Cl (5 mL), diluted with Et2O (200 mL)
and washed with brine (20 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 80% Et2O in
hexanes) to afford alcohol 20 (2.63 g, 94%) as a white foam. 20: Rf ˆ 0.54
(50% Et2O in hexanes); [a]2D2 ˆ ‡156.4 (c ˆ 1.07, CHCl3); IR (thin film):
nÄ ˆ 3498, 2942, 2866, 1460, 1381, 1243, 1217, 1163, 1104, 1065, 1019, 874, 753,
685 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.50 (d, J ˆ 7.2 Hz, 2H, ArH),
7.34 ± 7.26 (m, 3H, ArH), 5.76 (s, 1H, F1), 4.34 (dd, J ˆ 5.8, 0.6 Hz, 1H, F2),
4.15 (t, J ˆ 6.3 Hz, 1H, F4), 4.04 (ddd, J ˆ 9.0, 5.8, 2.8 Hz, 1H, F5), 3.86 (dd,
J ˆ 9.5, 6.6 Hz, 1H, F3), 3.80 (dd, J ˆ 11.6, 2.8 Hz, 1H, F6), 3.70 (dd, J ˆ
11.6, 5.8 Hz, 1H, F6), 1.50 (s, 3H, Me), 1.36 (s, 3H, Me), 1.21 ± 1.10 (m, 21H,
iPr3Si); 13C NMR (125 MHz, CDCl3): d ˆ 132.3, 129.1, 127.8, 109.3, 84.0,
78.9, 76.1, 72.1, 71.2, 62.3, 27.8, 26.3, 18.2, 12.6; HRMS (MALDI): calcd for
‡
C63H66O12Cs [M‡Cs] : 1147.3609, found 1147.3678.
Disaccharide 17: Rf ˆ 0.15 (60% ether in hexanes); [a]2D2 ˆ ‡29.4 (c ˆ 0.49,
CHCl3); IR (thin film): nÄ ˆ 3467, 3030, 2918, 2864, 1742, 1496, 1453, 1368,
1237, 1103, 1051, 911, 738, 698 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.38 ±
7.17 (m, 30H, ArH), 5.40 (dd, J ˆ 3.1, 1.8 Hz, 1H, H2'), 5.17 (d, J ˆ 1.6 Hz,
1H, H1'), 4.89 ± 4.32 (m, 12H, CH2Ar), 4.68 (s, 1H, H1), 4.14 (brd, J ˆ
10.3 Hz, 1H, H5'), 4.12 (d, J ˆ 3.0 Hz, 1H, H2), 4.07 (dd, J ˆ 9.7, 3.2 Hz, 1H,
H3'), 3.98 (dd, J ˆ 9.9, 9.8 Hz, 1H, H4'), 3.87 (dd, J ˆ 9.8, 9.4 Hz, 1H, H4),
3.70 (dd, J ˆ 10.9, 3.0 Hz, 1H, H6'), 3.65 (d, J ˆ 2.6 Hz, 2H, H6), 3.60 (dd,
J ˆ 11.0, 2.5 Hz, 1H, H6'), 3.56 (dd, J ˆ 9.3, 2.9 Hz, 1H, H3), 3.42 (dt, J ˆ
9.8, 2.7 Hz, 1H, H5), 2.15 (s, 3H, OAc); 13C NMR (150 MHz, CDCl3): d ˆ
170.5, 138.6, 138.2, 138.1, 137.9, 137.6, 128.5, 128.4, 128.3, 128.3, 128.2, 128.0,
128.0, 127.9, 127.9, 127.7, 127.6, 127.5, 127.4, 99.2, 98.0, 81.3, 77.8, 75.5, 75.1,
74.9, 74.0, 73.7, 73.3, 73.2, 72.2, 72.1, 71.5, 68.9, 68.6, 68.2, 21.1; 13C NMR
‡
C24H40O5SSiNa [M‡Na] : 491.2263, found 491.2244.
Methyl ether 21: NaH (0.237 g, 5.91 mmol) was added to a solution of
alcohol 20 (2.31 g, 4.93 mmol) in DMF (25 mL) at 08C and the resulting
mixture was stirred for 15 min. MeI (0.50 mL, 7.89 mmol) was added and
the resulting mixture was warmed to 258C and stirred for 2 h. The reaction
mixture was quenched by the addition of saturated aqueous NH4Cl (5 mL),
diluted with Et2O (200 mL) and washed with brine (20 mL). The organic
layer was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 70% Et2O in hexanes) to afford methyl ether 21 (2.20 g, 92%) as a
white solid. 21: Rf ˆ 0.61 (50% Et2O in hexanes); [a]2D2 ˆ ‡197.5 (c ˆ 0.40,
CHCl3); IR (thin film): nÄ ˆ 2942, 2866, 1459, 1380, 1243, 1219, 1163, 1107,
(150 MHz, CDCl3; proton coupled): d ˆ 99.2 (JC,H ˆ 156.9 Hz), 98.0 (JC,H
ˆ
‡
171.3 Hz); HRMS (FAB): calcd for C56H60O12Cs [M‡Cs] : 1057.3139,
found 1057.3111.
Chem. Eur. J. 2000, 6, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3127 $ 17.50+.50/0
3127

K. C. Nicolaouet al.
FULL PAPER
1071, 879, 752, 685 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.53 (d, J ˆ
(250 mL) and washed with saturated aqueous NaHCO3 (50 mL) and brine
(50 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 100% Et2O in hexanes) to afford the
desired benzyl ether 26 (6.28 g, 91%) as a white foam. 26: Rf ˆ 0.31 (70%
Et2O in hexanes); [a]2D2 ˆ ‡76.8 (c ˆ 0.59, CHCl3); IR (thin film): nÄ ˆ 3032,
2939, 2882, 1751, 1455, 1369, 1242, 1056, 735, 700 cmÀ1; 1H NMR (500 MHz,
CDCl3): d ˆ 7.38 ± 7.18 (m, 10H, ArH), 5.53 (t, J ˆ 9.5 Hz, 1H, H3), 5.00 (d,
J ˆ 3.5 Hz, 1H, H1), 4.76 (dd, J ˆ 10.0, 3.5 Hz, 1H, H2), 4.74, 4.48 (AB, J ˆ
12.5 Hz, 2H, CH2Ar), 4.61, 4.56 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 3.72 (d, J ˆ
7.5 Hz, 1H, H5), 3.71 (d, J ˆ 9.5 Hz, 1H, H5), 3.62 (ddd, J ˆ 9.0, 9.0, 7.0 Hz,
1H, H4), 2.02 (s, 6H, OAc); 13C NMR (125 MHz, CDCl3): d ˆ 170.3, 169.9,
137.8, 136.9, 128.4, 127.9, 127.7, 127.6, 94.8, 75.7, 72.9, 71.3, 71.1, 69.2, 59.7,
7.5 Hz, 2H, ArH), 7.32 ± 7.24 (m, 3H, ArH), 5.74 (s, 1H, F1), 4.33 (dd,
J ˆ 6.0, 1.0 Hz, 1H, F2), 4.13 (t, J ˆ 6.5 Hz, 1H, F4), 4.07 (ddd, J ˆ 9.5, 5.0,
2.5 Hz, 1H, F5), 3.96 (dd, J ˆ 9.5, 6.5 Hz, 1H, F3), 3.65 (dd, J ˆ 10.0, 4.5 Hz,
1H, F6), 3.53 (dd, J ˆ 10.0, 2.0 Hz, 1H, F6), 3.29 (s, 3H, OMe), 1.49 (s, 3H,
Me), 1.34 (s, 3H, Me), 1.22 ± 1.08 (m, 21H, iPr3Si); 13C NMR (125 MHz,
CDCl3): d ˆ 133.8, 131.6, 128.9, 127.4, 109.3, 84.3, 79.1, 76.3, 71.7, 71.2, 70.7,
58.9, 27.8, 26.3, 18.2, 12.6; HRMS (MALDI): calcd for C25H42O5SSiNa
‡
[M‡Na] : 505.2420, found 505.2487.
Diol 22: TsOH (17.0 mg, 0.091 mmol) was added to a solution of methyl
ether 21 (1.46 g, 3.02 mmol) and ethylene glycol (1.20 mL, 3.63 mmol) in
MeOH/Et2O (10:1, 22 mL) at 258C and the resulting mixture was stirred
for 8 h. The reaction mixture was quenched by the addition of Et3N
(10 mL) and the solvents were removed under reduced pressure. The
residue was diluted with CH2Cl2 (200 mL) and washed with saturated
aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 0 ! 100%
EtOAc in hexanes) to afford diol 22 (0.72 g, 54%) as a white foam, and
recovered starting material (0.56 g, 38%). 22: Rf ˆ 0.20 (70% Et2O in
hexanes); [a]2D2 ˆ ‡194.5 (c ˆ 1.0, CHCl3); IR (thin film): nÄ ˆ 3372, 2941,
2865, 1461, 1101, 1024, 883, 778, 688 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ
7.47 ± 7.21 (m, 5H, ArH), 5.50 (s, 1H, F1), 4.16 (dd, J ˆ 3.3, 1.9 Hz, 1H, F2),
4.02 (ddd, J ˆ 9.6, 3.7, 2.2 Hz, 1H, F5), 3.96 (dd, J ˆ 11.4, 4.1 Hz, 1H, F6),
3.91 (dd, J ˆ 11.4, 1.9 Hz, 1H, F6), 3.89 (dt, J ˆ 9.2, 3.3 Hz, 1H, F3), 3.59 (s,
3H, OMe), 3.55 (t, J ˆ 9.6 Hz, 1H, F4), 2.86 (brs, 2H, OH), 1.22 ± 1.08 (m,
21H, iPr3Si); 13C NMR (125 MHz, CDCl3): d ˆ 134.4, 131.0, 128.9, 127.1,
87.5, 77.4, 73.4, 72.4, 72.1, 62.6, 60.6, 17.9, 17.9, 11.9; HRMS (MALDI): calcd
‡
20.9, 20.6; HRMS (MALDI): calcd for C23H26O7Na [M‡Na] : 437.1576,
found 437.1588.
Diol 27: K2CO3 (0.410 g, 2.96 mmol) was added to a solution of benzyl ether
26 (6.14 g, 14.81 mmol) in MeOH/Et2O (1:1, 80 mL) at 258C and the
resulting mixture was stirred for 1 h. The reaction mixture was quenched by
the addition of saturated aqueous NH4Cl (5 mL), diluted with Et2O
(200 mL) and washed with brine (20 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 0 ! 100%
Et2O in hexanes) to afford diol 27 (4.75 g, 97%) as a white foam. 27: Rf ˆ
0.21 (100% Et2O); [a]2D2 ˆ ‡96.9 (c ˆ 0.29, CHCl3); IR (thin film): nÄ ˆ
3435, 3031, 2932, 1496, 1454, 1370, 1211, 1134, 1062, 943, 734, 699 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.36 ± 7.28 (m, 10H, ArH), 4.90 (d, J ˆ
4.0 Hz, 1H, H1), 4.75, 4.48 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.72, 4.64 (AB,
J ˆ 11.5 Hz, 2H, CH2Ar), 3.83 (t, J ˆ 9.0 Hz, 1H, H3), 3.68 (dd, J ˆ 10.5,
5.0 Hz, 1H, H5), 3.57 (t, J ˆ 10.5 Hz, 1H, H5), 3.51 (dd, J ˆ 9.5, 4.0 Hz, 1H,
H2), 3.51 ± 3.45 (m, 1H, H4); 13C NMR (125 MHz, CDCl3): d ˆ 138.0, 136.9,
128.5, 128.0, 97.3, 77.4, 74.2, 73.1, 72.4, 69.5, 60.0, 15.2; HRMS (MALDI):
‡
for C22H38O5SSiNa [M‡Na] : 465.2101, found 465.2115.
Benzyl ether 23: nBu2SnO (0.322 g, 1.29 mmol) was added to a solution of
diol 22 (0.52 g, 1.18 mmol) in toluene (10 mL) and the resulting mixture was
refluxed with removal of H2O using a Dean Stark apparatus for 3 h. The
reaction mixture was cooled to 258C and BnBr (0.17 mL, 1.41 mmol) and
nBu4NI (0.087 g, 0.235 mmol) were added. The reaction mixture was
refluxed again for 5 h, and then quenched by the addition of H2O (1 mL).
The solvents were removed under reduced pressure and the residue was
purified by flash column chromatography (silica gel, 0 ! 80% Et2O in
hexanes) to afford benzyl ether 23 (0.51 g, 81%) as a white foam. 23: Rf ˆ
0.58 (70% Et2O in hexanes); [a]2D2 ˆ ‡67.9 (c ˆ 0.95, CHCl3); IR (thin
‡
calcd for C19H22O5Na [M‡Na] : 353.1359, found 353.1346.
Bis-allyl ether 28: NaH (1.21 g, 30.17 mmol) was added to a solution of diol
27 (4.53 g, 13.71 mmol) in DMF (75 mL) at 08C and the resulting mixture
was stirred for 15 min. Allyl bromide (3.85 mL, 44.43 mmol) was added and
the resulting mixture was warmed to 258C and stirred for 2 h. The reaction
mixture was quenched by the addition of saturated aqueous NH4Cl
(15 mL), diluted with Et2O (200 mL) and washed with brine (20 mL). The
organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 50% Et2O in hexanes) to afford bis-allyl ether 28
film): nÄ ˆ 3551, 2941, 2865, 1458, 1391, 1104, 1020, 884, 740, 680 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.51 ± 7.27 (m, 10H, ArH), 5.61 (d, J ˆ
1.9 Hz, 1H, F1), 4.76, 4.47 (AB, J ˆ 11.8 Hz, 2H, CH2Ar), 4.11 (ddd, J ˆ 8.8,
5.1, 2.2 Hz, 1H, F5), 4.00 (t, J ˆ 8.8 Hz, 1H, F4), 3.94 (dd, J ˆ 3.7, 1.9 Hz,
1H, F2), 3.73 (dd, J ˆ 7.4, 3.7 Hz, 1H, F3), 3.72 (dd, J ˆ 10.6, 5.1 Hz, 1H,
F6), 3.63 (dd, J ˆ 10.3, 1.9 Hz, 1H, F6), 3.35 (s, 3H, OMe), 2.30 (brs, 1H,
OH), 1.22 ± 1.08 (m, 21H, iPr3Si); 13C NMR (125 MHz, CDCl3): d ˆ 137.3,
134.2, 131.8, 129.0, 128.6, 128.1, 127.9, 127.4, 84.9, 79.2, 73.5, 72.3, 72.1, 71.4,
(5.59 g, 92%) as a white solid. 28: Rf ˆ 0.30 (30% Et2O in hexanes); [a]D22
ˆ
‡103.9 (c ˆ 0.54, CHCl3); IR (thin film): nÄ ˆ 3064, 3030, 2917, 1648, 1605,
1495, 1455, 1351, 1074, 932, 734, 699 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ
ˆ
7.43 ± 7.31 (m, 10H, ArH), 6.07 ± 5.99 (m, 1H, CH CH2), 5.93 ± 5.85 (m, 1H,
ˆ
CH CH2), 5.35 (d, J ˆ 17.5 Hz, 1H, CH2-E), 5.27 (d, J ˆ 17.5 Hz, 1H, CH2-
E), 5.18 (d, J ˆ 10.0 Hz, 1H, CH2-Z), 5.16 (d, J ˆ 10.0 Hz, 1H, CH2-Z), 4.87
(d, J ˆ 3.5 Hz, 1H, H1), 4.81, 4.58 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.77, 4.66
(AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.45 ± 4.35 (m, 2H, OCH2), 4.17 ± 4.05 (m,
2H, OCH2), 3.81 (t, J ˆ 9.0 Hz, 1H, H3), 3.66 ± 3.51 (m, 3H, H4, H5, H5),
3.37 (dd, J ˆ 9.5, 3.5 Hz, 1H, H2); 13C NMR (125 MHz, CDCl3): d ˆ 135.4,
134.8, 128.3, 128.3, 128.0, 127.7, 117.1, 116.3, 95.4, 81.0, 79.4, 77.8, 74.3, 73.5,
‡
70.7, 59.0, 18.3, 13.0; HRMS (MALDI): calcd for C29H44O5SSiNa [M‡Na] :
555.2571, found 555.2583.
Alcohol 25: Lipase P (13.0 g, Amano) was added to a solution of triacetate
24[7] (6.50 g, 17.74 mmol) and isoamyl alcohol (3.86 mL, 35.48 mmol) in
isooctane (600 mL) at 258C and the resulting mixture was shaken for 96 h.
The reaction mixture was filtered and the enzyme pad was washed with
hexanes (250 mL) and CH2Cl2 (250 mL). The solvents were removed under
reduced pressure and the residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 100% Et2O in hexanes) to afford alcohol 25 (4.83 g,
84%) as a white foam. 25: Rf ˆ 0.16 (70% Et2O in hexanes); [a]2D2 ˆ ‡120.1
(c ˆ 3.09, CHCl3); IR (thin film): nÄ ˆ 3460, 3032, 2939, 2885, 1750, 1736,
1369, 1241, 1046, 940, 701 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.37 ± 7.30
(m, 5H, ArH), 5.25 (t, J ˆ 10.0 Hz, 1H, H3), 5.01 (d, J ˆ 3.5 Hz, 1H, H1),
4.81 (dd, J ˆ 10.0, 3.5 Hz, 1H, H2), 4.76, 4.50 (AB, J ˆ 12.0 Hz, 2H,
CH2Ar), 3.82 ± 3.65 (m, 3H, H4, H5, H5), 2.66 (d, J ˆ 5.0 Hz, 1H, OH), 2.10
(s, 3H, OAc), 2.03 (s, 3H, OAc); 13C NMR (125 MHz, CDCl3): d ˆ 171.5,
170.5, 136.5, 128.4, 128.0, 127.8, 94.7, 74.0, 70.5, 69.6, 69.3, 61.8, 20.9, 20.7;
‡
72.1, 68.6, 60.6; HRMS (MALDI): calcd for C25H30O5Na [M‡Na] :
433.1985, found 433.1965.
Lactol 29: HCl (2.0 mL, 1n aq solution) was added to a solution of bis-allyl
ether 28 (3.85 g, 9.38 mmol) in AcOH (80 mL) at 258C and the resulting
mixture was heated to 808C and stirred for 5 h. The reaction mixture was
quenched by the addition of saturated aqueous NaHCO3 (100 mL), diluted
with CH2Cl2 (500 mL) and washed with saturated aqueous NaHCO3
(50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 100% Et2O in
hexanes) to afford lactol 29 (2.73 g, 91%) as a white foam. 29: Rf ˆ 0.19
(50% Et2O in hexanes); [a]2D2 ˆ ‡14.8 (c ˆ 1.47, CHCl3); IR (thin film): nÄ ˆ
‡
3394, 3080, 2871, 1649, 1456, 1351, 1074, 994, 927, 738, 700 cmÀ1; H NMR
HRMS (MALDI): calcd for C16H20O7Na [M‡Na] : 347.1107, found
1
347.1112.
(500 MHz, CDCl3, ca. 1:1 mixture of anomers): d ˆ 7.35 ± 7.26 (m, 10H,
ˆ
Benzyl ether 26: BF3 ´ Et2O (0.21 mL, 1.67 mmol) was added to a solution
of alcohol 25 (5.40 g, 16.65 mmol) and benzyltrichloroacetimidate
(3.71 mL, 19.97 mmol) in CH2Cl2 (200 mL) at 08C and the resulting
mixture was stirred for 3 h. The reaction mixture was quenched by the
addition of saturated aqueous NaHCO3 (10 mL), diluted with CH2Cl2
ArH), 6.01 ± 5.88 (m, 4H, CH CH2), 5.50 (d, J ˆ 17.5 Hz, 4H, CH2-E),
5.21 ± 5.16 (m, 4H, CH2-Z), 4.74, 4.64 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.73,
4.62 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.58 (dd, J ˆ 7.0, 5.5 Hz, 1H, H1),
4.36 ± 4.15 (m, 9H, OCH2, H-1), 3.91 (dd, J ˆ 11.5, 5.0 Hz, 1H, H5), 3.77 (t,
J ˆ 10.5 Hz, 1H, H-3), 3.69 (t, J ˆ 9.0 Hz, 1H, H3), 3.65 (dd, J ˆ 11.0,
3128
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3128 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
5.5 Hz, 1H, H5), 3.56 ± 3.46 (m, 2H, H4), 3.42 (t, J ˆ 9.0 Hz, 1H, H-2), 3.36
(dd, J ˆ 9.0, 3.5 Hz, 1H, H2), 3.33 (d, J ˆ 6.0 Hz, 1H, OH), 3.23 (dd, J ˆ
11.5, 9.5 Hz, 1H, H5), 3.14 (dd, J ˆ 8.5, 7.0 Hz, 1H, H5), 2.99 (d, J ˆ 3.0 Hz,
1H, OH); 13C NMR (125 MHz, CDCl3): d ˆ 137.5, 137.2, 135.2, 135.1, 135.0,
134.5, 128.4, 127.8, 127.7, 117.7, 117.1, 116.8, 116.7, 97.5, 91.5, 83.0, 81.9, 80.2,
79.2, 77.3, 74.2, 73.6, 73.3, 72.5, 63.8, 60.3; HRMS (MALDI): calcd for
pressure and the residue was diluted with Et2O (500 mL) and washed with
brine (50 mL). The organic layer was dried (Na2SO4), and the solvents were
removed under reduced pressure.
GH orthoester 30: Lactone 9 (2.52 g, 7.93 mmol) and the crude bis-TMS
ether 10 were azeotroped with benzene (3 Â 10 mL) and then dried under
high vacuum for 1 h. The residue was dissolved in CH2Cl2 (50 mL) and
cooled to 08C. TMSOTf (2.38 mL, 0.5m solution in CH2Cl2, 1.19 mmol) was
added and the resulting mixture was warmed to 258C and stirred for 12 h.
The reaction mixture was quenched by the addition of saturated aqueous
NaHCO3 (20 mL), diluted with CH2Cl2, (500 mL) and washed with brine
(50 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 80% Et2O in hexanes) to afford GH
orthoester 30 (3.97 g, 97%, 1:1 mixture of inseparable diastereoisomers) as
a white foam. 30: Rf ˆ 0.58 (50% Et2O in hexanes); IR (thin film): nÄ ˆ 3065,
‡
C18H24O5Na [M‡Na] : 343.1521, found 343.1513.
Lactone 9: Ac2O (4.0 mL) was added to a solution of lactol 29 (2.70 g,
8.43 mmol) in DMSO (8.0 mL) at 258C and the resulting mixture was
stirred for 12 h. The reaction mixture was quenched by the addition of ice
(100 mL), diluted with Et2O (500 mL), and washed with brine (50 mL). The
organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 60% Et2O in hexanes) to afford lactone 9 (2.58 g,
96%) as a white foam. 9: Rf ˆ 0.21 (50% Et2O in hexanes); [a]2D2 ˆ ‡98.6
(c ˆ 0.14, CHCl3); IR (thin film): nÄ ˆ 3063, 3031, 2917, 1751, 1495, 1455,
3030, 2864, 1455, 1365, 1234, 1077, 1000, 923, 727, 699 cmÀ1 1H NMR
;
1258, 1142, 1075, 873, 739, 698 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ
(600 MHz, CDCl3): d ˆ 7.36 ± 7.27 (m, 20H, ArH), 6.00 ± 5.79 (m, 6H,
ˆ
CH CH2), 5.30 ± 5.03 (m, 12H, CH2), 4.76, 4.61 (AB, J ˆ 11.6 Hz, 2H,
ˆ
7.36 ± 7.28 (m, 5H, ArH), 5.97 ± 5.84 (m, 2H, CH CH2), 5.34 (ddt, J ˆ 17.0,
1.5, 1.5 Hz, 1H, CH2-E), 5.28 (ddt, J ˆ 17.0, 1.5, 1.5 Hz, 1H, CH2-E), 5.21
(ddt, J ˆ 11.0, 1.5, 1.5 Hz, 1H, CH2-Z), 5.20 (ddt, J ˆ 11.0, 1.5, 1.5 Hz, 1H,
CH2-Z), 4.60, 4.56 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.46 ± 4.42 (m, 1H,
OCH2), 4.39 (dd, J ˆ 12.0, 3.0 Hz, 1H, H5), 4.28 (dd, J ˆ 12.0, 2.0 Hz, 1H,
H5), 4.18 ± 4.05 (m, 3H, OCH2), 4.04 (d, J ˆ 6.5 Hz, 1H, H2), 3.76 (dt, J ˆ
7.0, 2.0 Hz, 1H, H3), 3.73 (dt, J ˆ 3.5, 2.0 Hz, 1H, H4); 13C NMR (125 MHz,
CDCl3): d ˆ 169.9, 136.9, 133.8, 133.6, 128.4, 128.0, 127.7, 118.1, 117.6, 81.1,
81.0, 77.9, 74.9, 72.3, 71.4, 70.4, 65.5; HRMS (MALDI): calcd for
CH2Ar), 4.75, 4.60 (AB, J ˆ 11.6 Hz, 2H, CH2Ar), 4.56 (brs, 4H, CH2Ar),
4.44 ± 4.18 (m, 12H, OCH2), 4.03 ± 3.97 (m, 4H), 3.77 ± 3.51 (m, 16H), 3.46
(t, J ˆ 10.6 Hz, 1H), 3.41 (dd, J ˆ 9.4, 1.7 Hz, 1H); 13C NMR (150 MHz,
CDCl3): d ˆ 138.3, 137.8, 135.3, 135.0, 135.0, 134.4, 128.4, 127.7, 127.7, 127.6,
127.1, 120.5, 117.3, 117.1, 117.0, 116.6, 82.8, 78.9, 78.9, 78.7, 78.6, 78.4, 78.3,
77.5, 74.5, 74.3, 73.6, 73.5, 73.4, 72.3, 71.2, 70.0, 62.2; HRMS (MALDI):
‡
calcd for C32H40O8Na [M‡Na] : 575.2621, found 575.2631.
GH triol 31 (bottom diastereoisomer): [(Ph3P)3RhCl] (0.20 g, 0.21 mmol)
was added to a solution of GH orthoester 30 (1.48 g, 2.86 mmol) and
DABCO (1.45 g, 12.89 mmol) in EtOH/H2O (10:1, 25 mL, degassed 1 h) at
258C. The resulting mixture was refluxed for 2 h and then cooled. The
reaction mixture was diluted with CH2Cl2 (200 mL) and washed with
saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The solvents were
removed under reduced pressure and then the residue was dissolved in
acetone/H2O (10:1, 25 mL). NMO (1.51 g, 12.89 mmol) and OsO4 (0.30 mL,
2.5% solution in tBuOH) were added and the reaction mixture was stirred
for 8 h at 258C. The reaction mixture was diluted with CH2Cl2 (300 mL)
and washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL).
The organic layer was dried (Na2SO4), the solvents were removed under
reduced pressure, and the residue was purified by flash column chroma-
tography (silica gel, 0 ! 10% MeOH in CH2Cl2) to afford GH triol 31
(0.58 g of each diastereoisomer, 97% overall yield) as a white foam. More
polar diastereoisomer: 31: Rf ˆ 0.11 (100% EtOAc); [a]2D2 ˆ ‡25.2 (c ˆ
0.21, CHCl3); IR (thin film): nÄ ˆ 3415, 3032, 2892, 1454, 1368, 1233, 1073,
‡
C18H22O5Na [M‡Na] : 341.1365, found 341.1363.
Bis-TMS ether 10: NaH (0.90 g, 22.67 mmol) was added to a solution of the
2,3-O-isopropylidene-l-threitol (3.50 g, 21.58 mmol) in DMF (50 mL) at
08C and the resulting mixture was stirred for 15 min. BnBr (2.34 mL,
23.74 mmol) was added and the resulting mixture was warmed to 258C and
stirred for 2 h. The reaction mixture was quenched by the addition of
saturated aqueous NH4Cl (20 mL), diluted with Et2O (500 mL), and
washed with brine (50 mL). The organic layer was dried (Na2SO4) and the
solvents were removed under reduced pressure. The residue was purified
by flash column chromatography (silica gel, 0 ! 80% Et2O in hexanes) to
afford the alcohol (5.00 g, 92%) as a colorless oil. alcohol: Rf ˆ 0.27 (70%
Et2O in hexanes); [a]2D2 ˆ ‡7.50 (c ˆ 1.22, CHCl3); IR (thin film): nÄ ˆ 3479,
3032, 2987, 2873, 1454, 1376, 1214, 1167, 1075, 990, 847, 738, 700 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.35 ± 7.25 (m, 5H, ArH), 4.56 (brs, 2H,
CH2Ar), 4.03 (dt, J ˆ 6.9, 4.4 Hz, 1H, CHO), 3.92 (dt, J ˆ 7.2, 3.7 Hz, 1H,
CHO), 3.73 (dd, J ˆ 9.8, 3.5 Hz, 1H, CH2), 3.65 (dd, J ˆ 4.2, 3.7 Hz, 1H,
CH2), 3.64 (t, J ˆ 3.7 Hz, 1H, CH2), 3.54 (dd, J ˆ 8.4, 4.6 Hz, 1H, CH2), 2.62
(brs, 1H, OH), 1.40 (s, 6H, Me); 13C NMR (150 MHz, CDCl3): d ˆ 137.5,
128.3, 127.7, 127.6, 109.2, 79.4, 76.1, 73.5, 62.2, 26.8; HRMS (MALDI): calcd
910, 736, 700 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.34 ± 7.24 (m, 10H,
ArH), 4.75, 4.59 (AB, J ˆ 11.8 Hz, 2H, CH2Ar), 4.57 ± 4.48 (m, 5H, CH2Ar,
G4, G5, G5), 4.21 (ddd, J ˆ 4.6, 4.6, 2.3 Hz, 1H, G3), 3.88 (dd, J ˆ 12.8,
2.0 Hz, 1H, G2), 3.87 (t, J ˆ 9.4 Hz, 1H, H3), 3.68 (d, J ˆ 9.7 Hz, 1H, H2),
3.67 ± 3.62 (m, 1H, H5), 3.54 (dd, J ˆ 12.6, 2.5 Hz, 1H, G2), 3.53 ± 3.46 (m,
2H, H4, OH), 3.44 (t, J ˆ 10.6 Hz, 1H, H5), 2.08 (s, 2H, OH); 13C NMR
(150 MHz, CDCl3): d ˆ 138.3, 137.6, 128.4, 128.3, 127.6, 127.5, 120.2, 81.2,
80.0, 77.2, 76.9, 74.7, 73.2, 73.1, 71.9, 71.3, 62.3, 61.9; HRMS (FAB): calcd for
‡
for C14H20O4Na [M‡Na] : 275.1259, found 275.1256. NaH (0.90 g,
22.67 mmol) was added to
a solution of the above alcohol (5.00 g,
20.00 mmol) in DMF (50 mL) at 08C and the resulting mixture was stirred
for 15 min. Allyl bromide (2.05 mL, 23.74 mmol) was added and the
resulting mixture was warmed to 258C and stirred for 2 h. The reaction
mixture was quenched by the addition of saturated aqueous NH4Cl
(15 mL), diluted with Et2O (500 mL), and washed with brine (50 mL). The
organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was dissolved in MeOH (30 mL) and 1n
aqueous HCl (3 mL) was added. The reaction mixture was stirred for 1 h,
Et3N (5 mL) was added, and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 100% Et2O) to afford the diol (4.90 g, 98%) as a white solid. diol:
Rf ˆ 0.16 (70% Et2O in hexanes); [a]2D2 ˆ À3.9 (c ˆ 0.97, CHCl3); IR (thin
‡
C23H28O8Na [M‡Na] : 455.1682, found 455.1687.
GH TBS ether 32: TBSOTf (0.93 mL, 4.05 mmol) was added to a solution
of GH triol (bottom diastereoisomer) 31 (1.54 g, 3.68 mmol) and 2,6-
lutidine (0.64 mL, 5.52 mmol) in CH2Cl2 (20 mL) at À788C and the
resulting mixture was stirred for 0.5 h. The reaction mixture was quenched
by the addition of MeOH (1.0 mL), diluted with CH2Cl2 (250 mL) and
washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The
organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 60% EtOAc in hexanes) to afford GH TBS ether 32
(1.85 g, 92%) as a white foam. 32: Rf ˆ 0.28 (40% EtOAc in hexanes);
[a]2D2 ˆ ‡25.4 (c ˆ 0.95, CHCl3); IR (thin film): nÄ ˆ 3445, 3032, 2930, 2858,
film): nÄ ˆ 3420, 3052, 2938, 2873, 1454, 1317, 1275, 1115, 1072, 933 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.36 ± 7.28 (m, 5H, ArH), 5.92 ± 5.85 (m,
ˆ
1H, CH CH2), 5.26 (ddd, J ˆ 17.0, 1.5, 1.5 Hz, 1H, CH2-E), 5.19 (ddd, J ˆ
10.5, 1.5, 1.5 Hz, 1H, CH2-Z), 4.57, 4.54 (AB, J ˆ 12.0 Hz, 2H, CH2Ar),
4.04 ± 3.98 (m, 2H, OCH2), 3.88 ± 3.84 (m, 2H, CHOH, CHOH), 3.65 ± 3.48
(m, 4H, CH2O, CH2O), 2.90 (d, J ˆ 7.0 Hz, 1H, OH), 2.89 (d, J ˆ 7.0 Hz,
1H, OH); 13C NMR (125 MHz, CDCl3): d ˆ 137.7, 134.2, 128.5, 127.8, 117.4,
73.5, 72.4, 71.9, 71.9, 70.5, 70.5; HRMS (MALDI): calcd for C14H20O4Na
1457, 1364, 1255, 1072, 1003, 839, 780, 699 cmÀ1 1H NMR (600 MHz,
;
CDCl3): d ˆ 7.36 ± 7.25 (m, 10H, ArH), 4.75, 4.62 (AB, J ˆ 11.8 Hz, 2H,
CH2Ar), 4.55 (brs, 2H, CH2Ar), 4.20 (ddd, J ˆ 6.0, 6.0, 6.0 Hz, 1H, G4),
4.20 (dt, J ˆ 6.2, 3.7 Hz, 1H, G3), 3.92 (dd, J ˆ 11.0, 4.3 Hz, 1H, G2), 3.85
(dd, J ˆ 11.0, 3.5 Hz, 1H, G2), 3.83 (brt, J ˆ 8.9 Hz, 1H, H3), 3.71 (dt, J ˆ
2.3, 2.3 Hz, 1H, H5), 3.67 (dd, J ˆ 9.9, 6.4 Hz, 1H, G5), 3.61 (brd, J ˆ
9.2 Hz, 1H, H2), 3.58 (dd, J ˆ 9.9, 5.7 Hz, 1H, G5), 3.53 ± 3.48 (m, 2H, H4,
H5), 3.00 (brs, 1H, OH), 2.89 (s, 1H, OH), 0.89 (s, 9H, tBuSi), 0.08 (s, 6H,
MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 138.1, 137.7, 128.4, 128.4, 127.8,
‡
[M‡Na] : 275.1259, found 275.1257. TMSCl (0.020 mL, 0.200 mmol) was
added to a solution of the above diol (5.00 g, 19.82 mmol) and HMDS
(41.80 mL, 198.2 mmol) in MeCN (100 mL) at 08C and the resulting
mixture was stirred for 15 min. The solvents were removed under reduced
Chem. Eur. J. 2000, 6, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3129 $ 17.50+.50/0
3129

K. C. Nicolaouet al.
FULL PAPER
127.7, 127.6, 120.2, 79.4, 78.5, 76.8, 75.1 73.4, 73.0, 72.2, 71.5, 63.2, 62.4, 60.3,
GH BOM ether 8: BOMCl (0.79 mL, 5.68 mmol) was added to a solution of
GH alcohol 35 (0.83 g, 1.14 mmol) and diisopropylethylamine (2.0 mL,
11.35 mmol) in CH2Cl2 (1 mL) and the resulting mixture was heated at
508C and stirred for 4 h. The reaction mixture was quenched by the
addition of saturated aqueous NaHCO3 (20 mL), diluted with CH2Cl2
(250 mL), and washed with saturated aqueous NaHCO3 (20 mL) and brine
(20 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 50% Et2O in hexanes) to afford GH BOM
ether 8 (0.86 g, 89%) as a white foam. 8: Rf ˆ 0.32 (30% Et2O in hexanes);
[a]2D2 ˆ ‡84.7 (c ˆ 0.45, CHCl3); IR (thin film): nÄ ˆ 3033, 2947, 2865, 1736,
1456, 1266, 1112, 1047, 838, 710 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 8.00
(d, J ˆ 7.3 Hz, 2H, ArH), 7.95 (d, J ˆ 7.3 Hz, 2H, ArH), 7.55 ± 7.17 (m, 11H,
ArH), 5.84 (t, J ˆ 9.9 Hz, 1H, H3), 5.59 (d, J ˆ 10.0 Hz, 1H, H2), 4.77, 4.74
(AB, J ˆ 7.1 Hz, 2H, OCH2O), 4.52, 4.42 (AB, J ˆ 11.9 Hz, 2H, CH2Ar),
4.29 (ddd, J ˆ 6.2, 6.2, 6.2 Hz, 1H, G4), 4.19 (ddd, J ˆ 5.5, 5.5, 5.5 Hz, 1H,
G3), 4.12 (ddd, J ˆ 10.4, 10.4, 5.8 Hz, 1H, H4), 4.06 (dd, J ˆ 11.1, 5.8 Hz,
1H, H5), 3.95 (dd, J ˆ 10.5, 5.4 Hz, 1H, G2), 3.91 (dd, J ˆ 10.5, 5.4 Hz, 1H,
G2), 3.88 (t, J ˆ 10.9 Hz, 1H, H5), 3.55 (dd, J ˆ 10.2, 5.2 Hz, 1H, G5), 3.36
(dd, J ˆ 10.2, 6.8 Hz, 1H, G5), 1.16 ± 1.07 (m, 21H, iPr3Si), 0.72 (s, 9H,
tBuSi), À0.18, À0.23 (2 Â s, 2 Â 3H, MeSi); 13C NMR (150 MHz, CDCl3):
d ˆ 165.6, 165.1, 137.2, 133.1, 133.0, 129.8, 129.7, 129.4, 129.2, 128.3, 128.3,
127.8, 127.6, 127.5, 118.9, 94.5, 81.7, 78.9, 74.5, 73.3, 69.8, 69.5, 64.2, 63.4, 62.8,
25.6, 17.9, 11.8, À5.8, À6.0; HRMS (MALDI): calcd for C46H66O11Si2Na
‡
25.8, 18.3, 14.1, À5.5; HRMS (FAB): calcd for C29H42O8SiNa [M‡Na] :
569.2547, found 569.2556.
GH dibenzoate 33: BzCl (1.0 mL, 8.23 mmol) was added to a solution of
GH diol 32 (1.80 g, 3.29 mmol), Et3N (1.84 mL, 13.17 mmol) and 4-DMAP
(0.08 g, 0.66 mmol) in CH2Cl2 (20 mL) at 08C. The resulting mixture was
warmed to 258C and stirred for 2 h. The reaction mixture was quenched by
the addition of MeOH (1.0 mL), diluted with CH2Cl2 (100 mL) and washed
with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic
layer was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 70% Et2O in hexanes) to afford GH dibenzoate 33 (2.41 g, 97%)
as a white foam. 33: Rf ˆ 0.41 (50% Et2O in hexanes); [a]2D2 ˆ ‡63.0 (c ˆ
0.44, CHCl3); IR (thin film): nÄ ˆ 3032, 2931, 2858, 1733, 1604, 1454, 1366,
1272, 1106, 1026, 912, 840, 780, 735, 708 cmÀ1; 1H NMR (600 MHz, CDCl3):
d ˆ 8.01 (d, J ˆ 8.0 Hz, 2H, ArH), 7.96 (d, J ˆ 7.5 Hz, 2H, ArH), 7.50 ± 7.17
(m, 16H, ArH), 5.90 (dd, J ˆ 10.3, 8.6 Hz, 1H, H3), 5.55 (d, J ˆ 10.3 Hz,
1H, H2), 4.64 (brs, 2H, CH2Ar), 4.60, 4.56 (AB, J ˆ 12.2 Hz, 2H, CH2Ar),
4.34 (ddd, J ˆ 6.4, 6.4, 4.7 Hz, 1H, G3), 4.21 ± 4.17 (m, 1H, G4), 3.94 ± 3.85
(m, 2H, H4, H5), 3.82 (t, J ˆ 2.3 Hz, 1H, H5), 3.73 (dd, J ˆ 10.2, 6.8 Hz, 1H,
G2), 3.66 (dd, J ˆ 10.2, 5.2 Hz, 1H, G2), 3.57 (dd, J ˆ 10.4, 5.2 Hz, 1H, G5),
3.34 (dd, J ˆ 10.4, 7.1 Hz, 1H, G5), 0.74 (s, 9H, tBuSi), À0.16 (s, 3H, MeSi),
À0.21 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 165.5, 165.1, 137.8,
137.6, 133.0, 132.9, 129.7, 129.6, 128.3, 128.2, 127.6, 127.6, 119.1, 80.2, 78.9,
75.2, 73.5, 73.3, 72.7, 71.3, 69.6, 64.4, 63.2, 62.3, 31.5, 27.0, 25.5, 15.2, À5.8,
‡
[M‡Na] : 873.4041, found 873.4032.
‡
À6.0; HRMS (MALDI): calcd for C43H50O10SiNa [M‡Na] : 777.3071,
GH alcohol 36: PPTS (30 mg, 0.088 mmol) was added to a solution of GH
TBS ether 8 (0.75 g, 0.88 mmol) in EtOH/THF (3:1, 2 mL) and the resulting
mixture was heated to 508C and stirred for 6 h. The reaction mixture was
quenched by the addition of saturated aqueous NaHCO3 (20 mL), diluted
with CH2Cl2 (250 mL) and washed with saturated aqueous NaHCO3
(20 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 70% Et2O in
hexanes) to afford GH alcohol 36 (0.69 g, 83%) as a white foam. 36: Rf ˆ
0.26 (50% Et2O in hexanes); [a]2D2 ˆ ‡90.9 (c ˆ 0.11, CHCl3); IR (thin
film): nÄ ˆ 3517, 3034, 2944, 2867, 1732, 1604, 1454, 1267, 1112, 1045, 914, 884,
found 777.3084.
GH diol 34: 10% Pd/C (200 mg) was added to a solution of GH di-benzoate
33 (2.20 g, 2.91 mmol) in EtOAc (10 mL) and the resulting mixture was
stirred under 1 atm of H2 (balloon) at 258C for 2 h. The reaction mixture
was diluted with EtOAc (150 mL) and filtered through a short pad of Celite
and the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 100% Et2O in
hexanes) to afford GH diol 34 (1.59 g, 95%) as a white foam. 34: Rf ˆ 0.18
(40% EtOAc in hexanes); [a]2D2 ˆ ‡21.3 (c ˆ 0.23, CHCl3); IR (thin film):
1
nÄ ˆ 3425, 2931, 2858, 1734, 1454, 1260, 1117, 1029, 839, 711 cmÀ1; H NMR
735, 710 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.99 (d, J ˆ 8.0 Hz, 2H,
(600 MHz, CDCl3): d ˆ 8.00 (d, J ˆ 8.1 Hz, 2H, ArH), 7.93 (d, J ˆ 8.1 Hz,
2H, ArH), 7.52 ± 7.44 (m, 2H, ArH), 7.38 (t, J ˆ 8.0 Hz, 2H, ArH), 7.33 (t,
J ˆ 8.0 Hz, 2H, ArH), 5.61 (d, J ˆ 10.1 Hz, 1H, H2), 5.54 (dd, J ˆ 10.0,
8.9 Hz, 1H, H3), 4.28 ± 4.22 (m, 2H, G3, G4), 4.12 ± 4.08 (m, 1H, H5), 4.05
(dd, J ˆ 11.1, 5.8 Hz, 1H, H4), 3.84 (t, J ˆ 10.7 Hz, 1H, H5), 3.83 (dd, J ˆ
12.0, 3.5 Hz, 1H, G2), 3.77 (dd, J ˆ 12.0, 5.1 Hz, 1H, G2), 3.64 (dd, J ˆ 10.1,
4.8 Hz, 1H, G5), 3.25 (dd, J ˆ 10.1, 7.8 Hz, 1H, G5), 3.02 (brs, 1H, OH),
0.73 (s, 9H, tBuSi), À0.15, À0.19 (2 Â s, 2 Â 3H, MeSi); 13C NMR
(150 MHz, CDCl3): d ˆ 167.3, 165.2, 133.5, 133.4, 129.9, 129.7, 129.0, 128.8,
128.5, 128.4, 119.0, 83.1, 78.0, 76.2, 69.2, 69.1, 64.5, 63.7, 63.2, 25.6, 18.0, 14.1,
ArH), 7.96 (d, J ˆ 8.1 Hz, 2H, ArH), 7.51 ± 7.25 (m, 9H, ArH), 7.17 (d, J ˆ
8.2 Hz, 2H, ArH), 5.84 (t, J ˆ 9.9 Hz, 1H, H3), 5.58 (d, J ˆ 10.1 Hz, 1H,
H2), 4.78, 4.75 (AB, J ˆ 7.2 Hz, 2H, OCH2O), 4.52, 4.44 (AB, J ˆ 11.9 Hz,
2H, CH2Ar), 4.40 (dt, J ˆ 7.7, 4.0 Hz, 1H, G4), 4.21 (dd, J ˆ 7.3, 4.5 Hz, 1H,
G3), 4.14 (ddd, J ˆ 10.5, 10.5, 5.8 Hz, 1H, H4), 4.02 (dd, J ˆ 11.2, 5.4 Hz,
1H, H5), 4.02 (dd, J ˆ 9.9, 5.3 Hz, 1H, G2), 3.86 (dd, J ˆ 10.0, 7.5 Hz, 1H,
G2), 3.81 (t, J ˆ 11.0 Hz, 1H, H5), 3.68 (dd, J ˆ 12.3, 3.6 Hz, 1H, G5), 3.46
(dd, J ˆ 12.3, 4.4 Hz, 1H, G5), 1.91 (brs, 1H, OH), 1.17 ± 1.08 (m, 21H,
iPr3Si); 13C NMR (150 MHz, CDCl3): d ˆ 165.6, 165.5, 137.1, 133.4, 133.1,
129.7, 129.7, 129.3, 128.8, 128.4, 128.3, 127.7, 127.5, 119.6, 94.5, 80.5, 79.4,
74.3, 73.1, 70.1, 69.5, 63.8, 62.7, 61.9, 17.9, 11.8; HRMS (MALDI): calcd for
‡
À5.8, À5.9; HRMS (MALDI): calcd for C29H38O10SiNa [M‡Na] :
597.2126, found 597.2117.
‡
C40H52O11SiNa [M‡Na] : 759.3176, found 759.3165.
GH TIPS ether 35: TIPSOTf (0.53 mL, 1.95 mmol) was added to a solution
of GH diol 34 (1.02 g, 1.77 mmol) and 2,6-lutidine (0.31 mL, 2.66 mmol) in
CH2Cl2 (20 mL) at À788C and the resulting mixture was stirred for 0.5 h.
The reaction mixture was quenched by the addition of MeOH (1.0 mL),
diluted with CH2Cl2 (250 mL) and washed with saturated aqueous
NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4)
and the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 60% Et2O in
hexanes) to afford GH TIPS ether 35 (1.15 g, 89%) as a white foam. 35:
Rf ˆ 0.41 (50% Et2O in hexanes); [a]2D2 ˆ ‡105.5 (c ˆ 0.11, CHCl3); IR
(thin film): nÄ ˆ 3491, 3068, 2866, 2847, 1734, 1603, 1456, 1316, 1256, 1114,
GH thiazole 37: DMSO (94 mL, 1.06 mmol) was added dropwise to a
solution of oxalyl chloride (92 mL, 0.95 mmol) in CH2Cl2 (5 mL) at À788C
and the resulting mixture was stirred for 10 min. GH alcohol 36 (0.39 g,
0.53 mmol) was dissolved in CH2Cl2 (5 mL) and added to the reaction
mixture via cannula over 15 min. The reaction mixture was stirred at
À788C for 2 h, and then Et3N (0.30 mL, 2.17 mmol) was added and the
reaction mixture was allowed to warm to À408C over 2 h. TMS-thiazole
(0.17 g, 1.06 mmol) was added and the reaction mixture was allowed to
warm to 258C over 12 h. The reaction mixture was diluted with CH2Cl2
(200 mL) and washed with H2O (20 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was dissolved in MeOH (10 mL) and PPTS (0.02 g, 0.03 mmol) was
added. The resulting mixture was stirred for 2 h at 258C and then Et3N
(2 mL) was added. The solvents were removed under reduced pressure and
the residue was purified by flash column chromatography (silica gel, 0 !
60% Et2O in hexanes) to afford GH thiazole 37 (0.43 g, 97%) as a white
foam. 37: Rf ˆ 0.25 (50% Et2O in hexanes); [a]2D2 ˆ ‡47.7 (c ˆ 0.13, CHCl3);
1070, 1028, 839, 710 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 8.01 (d, J ˆ
8.1 Hz, 2H, ArH), 7.94 (d, J ˆ 8.1 Hz, 2H, ArH), 7.52 ± 7.33 (m, 6H, ArH),
5.61 (d, J ˆ 10.1 Hz, 1H, H2), 5.49 (t, J ˆ 10.1 Hz, 1H, H3), 4.28 (dd, J ˆ 6.3,
6.3 Hz, 1H, G4), 4.17 (dd, J ˆ 5.6, 5.6 Hz, 1H, G3), 4.08 (ddd, J ˆ 10.0, 10.0,
6.0 Hz, 1H, H4), 3.98 (dd, J ˆ 11.5, 5.9 Hz, 1H, H5), 3.94 (dd, J ˆ 10.4,
5.5 Hz, 1H, G2), 3.90 (dd, J ˆ 10.4, 5.5 Hz, 1H, G2), 3.82 (t, J ˆ 11.1 Hz,
1H, H5), 3.55 (dd, J ˆ 10.4, 5.3 Hz, 1H, G5), 3.38 (dd, J ˆ 10.4, 6.6 Hz, 1H,
G5), 3.26 (s, 1H, OH), 1.14 ± 1.07 (m, 21H, iPr3Si), 0.71 (s, 9H, tBuSi),
À0.18, À0.22 (2  s, 2  3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ
167.6, 165.2, 133.5, 133.3, 129.9, 129.8, 129.2, 128.8, 128.4, 128.4, 118.9,
81.8, 79.0, 69.5, 66.2, 64.3, 63.5, 25.7, 18.1, 11.9, À5.8, À5.9; HRMS
IR (thin film): nÄ ˆ 3748, 2940, 2864, 1735, 1265, 1117, 1029, 710 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 8.00 ± 7.15 (m, 17H, ArH), 5.84 (t, J ˆ
9.9 Hz, 1H, H3), 5.60 (d, J ˆ 10.3 Hz, 1H, H2), 4.93 (brs, 1H), 4.75, 4.73
(AB, J ˆ 7.2 Hz, 2H, OCH2O), 4.63 (brs, 1H), 4.52 (brs, 1H), 4.46, 4.41
(AB, J ˆ 11.9 Hz, 2H, CH2Ar), 4.10 (ddd, J ˆ 10.5, 10.5, 5.8 Hz, 1H, H4),
‡
(MALDI): calcd for C38H58O10Si2Na [M‡Na] : 753.3461, found 753.3462.
3130
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3130 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
4.05 (dd, J ˆ 11.3, 5.7 Hz, 1H, H5), 3.89 (t, J ˆ 10.9 Hz, 1H, H5), 3.88 ± 3.82
(m, 2H), 3.77 (s, 1H), 1.17 ± 1.08 (m, 21H, iPr3Si); 13C NMR (150 MHz,
CDCl3): d ˆ 165.5, 165.5, 137.2, 133.6, 133.1, 129.8, 129.7, 129.3, 128.6, 128.4,
128.3, 128.1, 127.7, 127.6, 119.1, 94.7, 74.5, 73.3, 70.0, 69.6, 63.9, 63.0, 29.7,
diol 40 (0.075 g, 88%) as a white solid. 40: Rf ˆ 0.11 (70% Et2O in
hexanes); m.p. 1848C, CH2Cl2/hexanes; [a]2D2 ˆ ‡23.8 (c ˆ 0.17, CHCl3); IR
(thin film): nÄ ˆ 3387, 2952, 1727, 1590, 1454, 1397, 1270, 1040, 911, 848,
1
752 cmÀ1; H NMR (500 MHz, CDCl3): d ˆ 7.88 (d, J ˆ 8.5 Hz, 2H, ArH),
‡
17.9, 11.9; HRMS (MALDI): calcd for C43H53NO11SSiNa [M‡Na] :
7.86 (d, J ˆ 8.5 Hz, 2H, ArH), 7.66 (d, J ˆ 3.5 Hz, 1H, CH-TH), 7.57 (d, J ˆ
8.5 Hz, 2H, ArH), 7.52 (d, J ˆ 8.5 Hz, 2H, ArH), 7.31 ± 7.14 (m, 6H, ArH,
CH-TH), 5.38 (brs, 1H, G2), 5.37 (t, J ˆ 9.6 Hz, 1H, H3), 4.96 (brs, 1H,
G3), 4.81 (brs, 1H, OH), 4.78 (dt, J ˆ 4.8, 4.8 Hz, 1H, G4), 4.74, 4.72 (AB,
J ˆ 8.8 Hz, 2H, OCH2O), 4.47, 4.42 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 4.41 (dd,
J ˆ 11.8, 7.7 Hz, 1H, G5), 4.27 (dd, J ˆ 11.8, 5.9 Hz, 1H, G5), 3.98 (ddd, J ˆ
10.3, 10.3, 5.9 Hz, 1H, H4), 3.92 (d, J ˆ 10.1 Hz, 1H, H2), 3.89 (dd, J ˆ 11.7,
5.9 Hz, 2H, H5), 3.63 (t, J ˆ 11.8 Hz, 1H, H5); 13C NMR (150 MHz,
CDCl3): d ˆ 166.8, 165.3, 137.0, 131.9, 131.7, 131.3, 128.8, 128.5, 128.4, 128.0,
127.8, 127.5, 121.1, 119.6, 94.7, 81.9, 76.7, 76.4, 73.4, 72.0, 72.0, 69.8, 65.1, 63.0;
842.3006, found 842.2993.
GH TES ether 38: TESOTf (62 mL, 0.27 mmol) was added to a solution of
GH alcohol 37 (0.201 g, 0.25 mmol) and 2,6-lutidine (30 mL, 0.27 mmol) in
CH2Cl2 (0.5 mL) at 08C and the resulting mixture was stirred for 0.5 h. The
reaction mixture was quenched by the addition of MeOH (0.1 mL), diluted
with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3
(10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 60% Et2O in
hexanes) to afford GH TES ether 38 (0.213 g, 89%) as a white foam. 38:
Rf ˆ 0.53 (50% Et2O in hexanes); [a]2D2 ˆ À17.5 (c ˆ 0.08, CHCl3); IR (thin
‡
HRMS (MALDI): calcd for C34H32Br2NO11S [M‡H] : 820.0064, found
820.0029.
film): nÄ ˆ 2940, 2873, 1736, 1454, 1266, 1094, 1070, 709 cmÀ1
;
1H NMR
TBS ether 47: TBSOTf (24.80 mL, 108.0 mmol) was added to a solution of
mannose diol 11[4] (30.66 g, 98.15 mmol) and 2,6-lutidine (14.86 mL,
127.60 mmol) in CH2Cl2 (500 mL) at À788C and the resulting mixture
was stirred for 0.5 h. The reaction mixture was quenched by the addition of
MeOH (10 mL), diluted with CH2Cl2 (750 mL) and washed with saturated
aqueous NaHCO3 (100 mL) and brine (100 mL). The organic layer was
dried (Na2SO4) and the solvents were removed under reduced pressure.
The residue was purified by flash column chromatography (silica gel, 0 !
40% Et2O in hexanes) to afford TBS ether 47 (40.50 g, 97%) as a white
foam. 47: Rf ˆ 0.45 (50% Et2O in hexanes); [a]2D2 ˆ ‡146.8 (c ˆ 0.63,
CHCl3); IR (thin film): nÄ ˆ 3456, 2931, 2854, 1474, 1381, 1248, 1220, 1160,
(600 MHz, CDCl3): d ˆ 7.94 (d, J ˆ 7.9 Hz, 2H, ArH), 7.90 (d, J ˆ 7.9 Hz,
2H, ArH), 7.50 ± 7.14 (m, 12H, ArH), 6.90 (d, J ˆ 3.0 Hz, 1H, CH-TH), 5.75
(t, J ˆ 9.4 Hz, 1H, H3), 5.56 (d, J ˆ 10.0 Hz, 1H, H2), 4.91 (d, J ˆ 5.4 Hz,
1H, G2), 4.73, 4.71 (AB, J ˆ 7.1 Hz, 2H, OCH2O), 4.58 (t, J ˆ 5.8 Hz, 1H,
G3), 4.49, 4.39 (AB, J ˆ 11.9 Hz, 2H, CH2Ar), 4.45 ± 4.42 (m, 1H, G4), 4.04
(ddd, J ˆ 9.6, 9.6, 5.7 Hz, 1H, H4), 4.01 (dd, J ˆ 11.3, 5.7 Hz, 1H, H5),
3.89 ± 3.82 (m, 3H, G5, G5, H5), 1.17 ± 1.08 (m, 21H, iPr3Si), 0.74 (t, J ˆ
8.0 Hz, 9H, SiCH2CH3), 0.35 (q, J ˆ 8.0 Hz, 6H, SiCH2); 13C NMR
(150 MHz, CDCl3): d ˆ 165.6, 164.9, 141.7, 137.3, 133.0, 132.9, 130.0, 129.7,
129.6, 129.5, 128.3, 128.2, 127.7, 127.6, 119.4, 118.7, 94.6, 80.9, 74.5, 73.7, 71.8,
69.5, 69.5, 63.9, 62.7, 18.0, 11.9, 6.5, 4.4; HRMS (MALDI): calcd for
1065, 870, 835, 779, 744 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.48 ± 7.46
‡
C49H68NO11SSi2 [M‡H] : 934.4046, found 934.4011.
(m, 2H, ArH), 7.30 ± 7.25 (m, 3H, ArH), 5.75 (s, 1H, F1), 4.33 (dd, J ˆ 5.7,
1.1 Hz, 1H, F2), 4.18 (dd, J ˆ 7.4, 5.9 Hz, 1H, F3), 3.99 (ddd, J ˆ 10.0, 4.9,
4.9 Hz, 1H, F5), 3.86 ± 3.83 (m, 2H, F4, F6), 3.74 (dd, J ˆ 10.6, 5.7 Hz, 1H,
F6), 3.00 (brs, 1H, OH), 1.54 (s, 3H, Me), 1.38 (s, 3H, Me), 0.89 (s, 9H,
tBuSi), 0.05 (s, 6H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 132.4, 131.7,
129.0, 127.5, 109.8, 83.7, 78.0, 75.9, 72.0, 69.7, 64.3, 28.0, 26.3, 25.8, 19.6, À5.5;
GH tribenzoate 39: K2CO3 (9.0 mg, 0.062 mmol) was added to a solution of
GH TES ether 38 (0.115 g, 0.123 mmol) in MeOH (1 mL) at 258C and the
resulting mixture was stirred for 1 h. The reaction mixture was quenched by
the addition of saturated aqueous NH4Cl (1 mL), diluted with Et2O
(100 mL) and washed with brine (10 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 0 ! 100%
Et2O in hexanes) to afford the triol (0.068 g) as a white foam. BrBzCl
(0.097 g, 0.44 mmol) was added to a solution of the above triol (0.068 g,
0.111 mmol), Et3N (0.077 mL, 0.55 mmol) and 4-DMAP (0.003 g,
0.022 mmol) in CH2Cl2 (1 mL) at 08C. The resulting mixture was warmed
to 258C and stirred for 2 h. The reaction mixture was quenched by the
addition of MeOH (0.5 mL), diluted with CH2Cl2 (100 mL) and washed
with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic
layer was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 70% Et2O in hexanes) to afford GH tribenzoate 39 (0.122 g, 86%
over two steps) as a white foam. 39: Rf ˆ 0.64 (50% Et2O in hexanes);
[a]2D2 ˆ ‡21.4 (c ˆ 0.31, CHCl3); IR (thin film): nÄ ˆ 2944, 2866, 1736, 1590,
‡
HRMS (MALDI): calcd for C21H34O5SSiNa [M‡Na] : 449.1794, found
449.1808.
Alcohol 48: NaH (4.18 g, 104.42 mmol) was added to a solution of alcohol
47 (40.50 g, 94.92 mmol) in DMF/THF (1:1, 400 mL) at 08C and the
resulting mixture was stirred for 15 min. PMBCl (16.73 mL, 123.41 mmol)
and nBu4NI (7.01 g, 19.00 mmol) were added and the resulting mixture was
warmed to 258C and stirred for 4 h. The reaction mixture was quenched by
the addition of saturated aqueous NH4Cl (50 mL), diluted with Et2O
(1.0 L) and washed with brine (2 Â 100 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 0 ! 70%
Et2O in hexanes) to afford the PMB ether (49.31 g, 95%) as a white foam.
PMB ether: Rf ˆ 0.75 (50% Et2O in hexanes); [a]2D2 ˆ ‡158.8 (c ˆ 0.83,
CHCl3); IR (thin film): nÄ ˆ 2987, 2931, 2884, 1613, 1515, 1460, 1380, 1248,
1486, 1397, 1267, 1098, 1012, 909, 846, 751, 733, 683 cmÀ1 1H NMR
;
1219, 1163, 1104, 1073, 872, 835, 779 cmÀ1 1H NMR (500 MHz, CDCl3):
;
(600 MHz, CDCl3): d ˆ 7.74 (d, J ˆ 6.8 Hz, 2H, ArH), 7.68 (d, J ˆ 6.8 Hz,
2H, ArH), 7.57 (d, J ˆ 6.8 Hz, 2H, ArH), 7.48 (d, J ˆ 2.9 Hz, 1H, CH-TH),
7.45 (d, J ˆ 6.8 Hz, 2H, ArH), 7.40 (d, J ˆ 6.8 Hz, 2H, ArH), 7.35 (d, J ˆ
6.8 Hz, 2H, ArH), 7.29 ± 7.13 (m, 5H, ArH), 6.93 (d, J ˆ 2.9 Hz, 1H, CH-
TH), 6.47 (d, J ˆ 3.4 Hz, 1H, G2), 5.72 (t, J ˆ 10.1 Hz, 1H, H3), 5.51 (d, J ˆ
10.1 Hz, 1H, H2), 4.94 (dd, J ˆ 6.8, 3.4 Hz, 1H, G3), 4.73, 4.70 (AB, J ˆ
7.2 Hz, 2H, OCH2O), 4.62 (dt, J ˆ 5.2, 5.2 Hz, 1H, G4), 4.47, 4.40 (AB, J ˆ
11.9 Hz, 2H, CH2Ar), 4.07 ± 4.02 (m, 2H, H4, H5), 3.92 (d, J ˆ 5.1 Hz, 2H,
G5, G5), 3.87 ± 3.81 (m, 1H, H5), 1.16 ± 0.86 (m, 21H, iPr3Si); 13C NMR
(150 MHz, CDCl3): d ˆ 164.8, 164.2, 163.8, 142.6, 137.0, 131.7, 131.7, 131.5,
131.2, 131.2, 131.1, 128.9, 128.5, 128.4, 127.9, 127.7, 127.6, 127.5, 127.4, 119.9,
118.5, 94.7, 79.6, 78.7, 74.4, 73.6, 71.4, 69.6, 69.4, 63.9, 62.7, 17.9, 11.9; HRMS
d ˆ 7.51 ± 7.48 (m, 2H, ArH), 7.31 ± 7.23 (m, 5H, ArH), 6.88 (d, J ˆ 8.5 Hz,
2H, PMB), 5.76 (s, 1H, F1), 4.83, 4.58 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.35
(t, J ˆ 5.5 Hz, 1H, F3), 4.34 (s, 1H, F2), 4.02 (ddd, J ˆ 10.0, 4.0, 2.0 Hz, 1H,
F5), 3.84 (dd, J ˆ 11.5, 4.0 Hz, 1H, F6), 3.80 (s, 3H, OMe), 3.73 (dd, J ˆ 11.5,
2.0 Hz, 1H, F6), 3.70 (dd, J ˆ 10.0, 7.0 Hz, 1H, F4), 1.51 (s, 3H, Me), 1.39 (s,
3H, Me), 0.88 (s, 9H, tBuSi), 0.02, 0.01 (2 Â s, 2 Â 3H, MeSi); 13C NMR
(125 MHz, CDCl3): d ˆ 159.2, 133.7, 131.5, 130.5, 129.6, 128.8, 127.3, 113.7,
109.4, 83.9, 78.6, 76.4, 75.2, 72.8, 71.2, 62.3, 55.2, 27.9, 26.5, 25.9, 18.3, À5.2,
‡
À5.3; HRMS (MALDI): calcd for C29H42O6SSiNa [M‡Na] : 569.2369,
found 569.2391. nBu4NF (98.80 mL, 98.76 mmol) was added to a solution of
the above PMB ether (45.00 g, 82.30 mmol) in THF (400 mL) and the
resulting mixture was stirred at 258C for 1 h. The solvents were removed
under reduced pressure and the residue was purified by flash column
chromatography (silica gel, 0 ! 60% Et2O in hexanes) to afford alcohol 48
(33.82 g, 95%) as a white solid. 48: Rf ˆ 0.26 (50% Et2O in hexanes);
[a]2D2 ˆ ‡182.4 (c ˆ 0.55, CHCl3); IR (thin film): nÄ ˆ 3416, 2982, 2934, 1613,
1515, 1379, 1304, 1246, 1219, 1162, 1086, 1080, 870, 816, 753 cmÀ1; 1H NMR
(500 MHz, CDCl3): d ˆ 7.48 ± 7.46 (m, 2H, ArH), 7.34 ± 7.27 (m, 5H, ArH),
6.88 (d, J ˆ 8.5 Hz, 2H, PMB), 5.80 (s, 1H, F1), 4.84, 4.57 (AB, J ˆ 11.5 Hz,
2H, CH2Ar), 4.37 (dd, J ˆ 7.4, 5.9 Hz, 1H, F3), 4.36 (s, 1H, F2), 4.10 (ddd,
J ˆ 10.0, 4.5, 3.0 Hz, 1H, F5), 3.81 (s, 3H, OMe), 3.74 (ddd, J ˆ 12.0, 6.5,
4.0 Hz, 1H, F6), 3.59 (ddd, J ˆ 12.0, 7.5, 5.0 Hz, 1H, F6), 3.59 (dd, J ˆ 10.0,
‡
(MALDI): calcd for C50H54Br3NO12SSiNa [M‡Na] : 1182.0558, found
1182.0603.
GH diol 40: nBu4NF (0.135 mL, 0.135 mmol) was added to a solution of
GH tribenzoate 39 (0.12 g, 0.104 mmol) in THF (1 mL) and the resulting
mixture was stirred at 258C for 1 h. The reaction mixture was quenched by
the addition of saturated aqueous NH4Cl (0.5 mL), diluted with CH2Cl2
(100 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine
(10 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 100% Et2O in hexanes) to afford the GH
Chem. Eur. J. 2000, 6, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3131 $ 17.50+.50/0
3131

K. C. Nicolaouet al.
FULL PAPER
6.5 Hz, 1H, F4), 1.64 (t, J ˆ 6.5 Hz, 1H, OH), 1.52 (s, 3H, Me), 1.40 (s, 3H,
Me); 13C NMR (125 MHz, CDCl3): d ˆ 159.0, 132.3, 129.7, 129.1, 127.9,
113.8, 109.5, 83.8, 78.5, 76.3, 75.9, 72.7, 70.0, 62.3, 55.3, 28.0, 26.4; HRMS
(MALDI): calcd for C23H28O6SNa [M‡Na] : 455.1499, found 455.1503.
mixture was quenched by the addition of saturated aqueous NaHCO3
(100 mL), diluted with CH2Cl2 (1.5 L) and washed with brine (10 mL). The
organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 100% EtOAc in hexanes) to afford ring F lactol 52
(26.33 g, 97%) as a white foam. 52: Rf ˆ 0.10 (100% Et2O); [a]2D2 ˆ ‡9.0
(c ˆ 0.50, CHCl3); IR (thin film): nÄ ˆ 3391, 2931, 1712, 1613, 1515, 1455,
‡
Methyl ether 49: NaH (3.42 g, 85.53 mmol) was added to a solution of
alcohol 48 (33.63 g, 77.75 mmol) in DMF (200 mL) at 08C and the resulting
mixture was stirred for 15 min. MeI (6.29 mL, 101.08 mmol) was added and
the resulting mixture was warmed to 258C and stirred for 1 h. The reaction
mixture was quenched by the addition of saturated aqueous NH4Cl
(50 mL), diluted with Et2O (1.0 L), and washed with brine (2 Â 100 mL).
The organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 70% Et2O in hexanes) to afford methyl ether 49
(33.00 g, 95%) as a white solid. 49: Rf ˆ 0.43 (50% Et2O in hexanes);
[a]2D2 ˆ ‡170.5 (c ˆ 2.23, CHCl3); IR (thin film): nÄ ˆ 2983, 2933, 1612, 1585,
1517, 1466, 1379, 1304, 1244, 1072, 910, 871, 823, 753, 717, 693 cmÀ1; 1H NMR
(500 MHz, CDCl3): d ˆ 7.52 ± 7.50 (m, 2H, ArH), 7.32 ± 7.24 (m, 5H, ArH),
6.89 (d, J ˆ 8.5 Hz, 2H, PMB), 5.82 (s, 1H, F1), 4.84, 4.58 (AB, J ˆ 11.0 Hz,
2H, CH2Ar), 4.37 (s, 1H, F2), 4.35 (t, J ˆ 7.0 Hz, 1H, F4), 4.17 (ddd, J ˆ
10.0, 4.0, 2.0 Hz, 1H, F5), 3.79 (s, 3H, OMe), 3.73 ± 3.68 (m, 1H, F3), 3.62
(dd, J ˆ 10.5, 4.0 Hz, 1H, F6), 3.52 (dd, J ˆ 10.5, 2.0 Hz, 1H, F6), 3.31 (s,
3H, OMe), 1.53 (s, 3H, Me), 1.39 (s, 3H, Me); 13C NMR (125 MHz,
CDCl3): d ˆ 159.1, 133.3, 131.6, 131.5, 130.2, 129.4, 129.2, 128.7, 127.3, 113.6,
109.3, 84.0, 78.5, 76.3, 75.2, 74.1, 72.7, 71.0, 69.5, 59.0, 57.6, 55.0, 27.8, 26.3;
1367, 1250, 1178, 1093, 821 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.37 ±
7.22 (m, 7H, ArH), 6.86 (d, J ˆ 8.5 Hz, 2H, PMB), 5.25 (brs, 1H, F1), 4.80,
4.50 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.71, 4.68 (AB, J ˆ 11.5 Hz, 2H,
CH2Ar), 4.06 (brs, 1H, F2), 4.03 ± 4.00 (m, 1H, F5), 3.94 (dd, J ˆ 9.0, 3.0 Hz,
1H, F3), 3.80 (s, 3H, OMe), 3.68 (t, J ˆ 9.5 Hz, 1H, F4), 3.61 ± 3.53 (m, 2H,
F6, F6), 3.34 (s, 3H, OMe), 2.85 (d, J ˆ 2.5 Hz, 1H, OH), 2.30 (brs, 1H,
OH); 13C NMR (150 MHz, CDCl3): d ˆ 159.2, 137.9, 130.4, 129.6, 128.4,
127.8, 113.7, 93.8, 79.6, 74.7, 74.2, 71.9, 70.2, 68.5, 58.9, 55.2, 29.5; HRMS
‡
(MALDI): calcd for C22H28O7Na [M‡Na] : 427.1733, found 427.1724.
Ring F tin-acetal 45: nBu2SnO (6.59 g, 26.50 mmol) was added to a solution
of ring F diol 52 (9.74 g, 25.47 mmol) in MeOH (150 mL) and the resulting
mixture was refluxed for 3 h. The solvents were removed under reduced
pressure and the residue was azeotroped with benzene (25 mL) and used
crude in the next reaction.
Alcohol 54: NaH (3.82 g, 95.4 mmol) was dissolved in THF (100 mL) in a
500 mL, three-neck flask, (with two 250 mL dropping funnels attached) and
cooled to 08C. 2,3-O-Isopropylidene-l-threitol 53 (15.48 g, 95.4 mmol) was
placed in one of the addition funnels and diluted with THF (100 mL). The
diol solution was added dropwise to the NaH solution over 45 min and then
the resulting mixture was warmed to 258C and stirred for 1 h. TPSCl
(24.82 mL, 95.4 mmol) was placed in the second dropping funnel and
diluted with THF (100 mL). The reaction mixture was cooled to 08C and
then the TPSCl solution was added dropwise to the reaction mixture over
45 min with vigorous stirring. The resulting mixture was warmed to 258C
and stirred for 4 h. The reaction mixture was quenched by the addition of
saturated aqueous NH4Cl (100 mL), diluted with Et2O (1.0 L) and washed
with brine (2 Â 100 mL). The organic layer was dried (Na2SO4), and the
solvents were removed under reduced pressure. The residue was purified
by flash column chromatography (silica gel, 0 ! 80% Et2O in hexanes) to
afford alcohol 54 (34.41 g, 90%) as a colorless oil. 54: Rf ˆ 0.34 (50% Et2O
in hexanes); [a]2D2 ˆ À8.5 (c ˆ 0.20, CHCl3); IR (thin film): nÄ ˆ 3445, 2930,
‡
HRMS (MALDI): calcd for C24H30O6SNa [M‡Na] : 469.1655, found
469.1672.
Diol 50: TsOH (2.78 g, 14.63 mmol) was added to a solution of methyl ether
49 (32.68 g, 73.18 mmol) and ethylene glycol (9.70 mL, 183.00 mmol) in
MeOH (500 mL) at 258C and the resulting mixture was stirred for 5 h. The
reaction mixture was quenched by the addition of Et3N (100 mL) and the
solvents were removed under reduced pressure. The residue was diluted
with CH2Cl2 (1.0 L) and washed with saturated aqueous NaHCO3 (100 mL)
and brine (100 mL). The organic layer was dried (Na2SO4) and the solvents
were removed under reduced pressure. The residue was purified by flash
column chromatography (silica gel, 0 ! 100% EtOAc in hexanes) to afford
diol 50 (25.29 g, 85%) as a white foam. 50: Rf ˆ 0.21 (100% Et2O); [a]D22
ˆ
‡197.2 (c ˆ 0.72, CHCl3); IR (thin film): nÄ ˆ 3339, 2905, 1617, 1517, 1459,
1
1250, 1098, 823, 749 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 7.46 ± 7.44 (m,
2840, 1639, 1462, 1429, 1385, 1231, 1116, 1072 cmÀ1 1H NMR (500 MHz,
;
2H, ArH), 7.31 ± 7.23 (m, 5H, ArH), 6.90 (d, J ˆ 8.6 Hz, 2H, PMB), 5.56 (d,
J ˆ 1.3 Hz, 1H, F1), 4.71, 4.64 (AB, J ˆ 11.1 Hz, 2H, CH2Ar), 4.19 (ddd, J ˆ
9.6, 3.5, 2.0 Hz, 1H, F5), 4.15 (dd, J ˆ 3.3, 1.6 Hz, 1H, F2), 3.91 (ddd, J ˆ 9.2,
6.0, 3.3 Hz, 1H, F3), 3.83 (t, J ˆ 9.6 Hz, 1H, F4), 3.80 (s, 3H, OMe), 3.71
(dd, J ˆ 10.7, 3.5 Hz, 1H, F6), 3.57 (dd, J ˆ 10.7, 2.0 Hz, 1H, F6), 3.37 (s, 3H,
OMe), 2.86 (brs, 2H, OH); 13C NMR (150 MHz, CDCl3): d ˆ 159.3, 137.7,
131.3, 130.4, 129.6, 129.0, 128.0, 127.8, 127.3, 113.8, 87.3, 80.1, 74.9, 73.9, 72.0,
CDCl3): d ˆ 7.69 ± 7.66 (m, 4H, ArH), 7.46 ± 7.38 (m, 6H, ArH), 4.08 (dt, J ˆ
8.0, 4.0 Hz, 1H), 3.97 (ddd, J ˆ 8.0, 6.0, 4.0 Hz, 1H), 3.84 ± 3.80 (m, 2H),
3.75 (dd, J ˆ 10.5, 6.0 Hz, 1H), 3.66 (ddd, J ˆ 12.5, 8.0, 4.5 Hz, 1H), 2.17
(dd, J ˆ 8.0, 5.0 Hz, 1H, OH), 1.42 (s, 3H, Me), 1.40 (s, 3H, Me), 1.07 (s, 9H,
tBuSi); 13C NMR (125 MHz, CDCl3): d ˆ 135.6, 132.8, 129.9, 127.8, 109.2,
79.5, 64.1, 62.5, 27.1, 26.8, 19.2; HRMS (MALDI): calcd for C23H32O4SiNa
‡
‡
71.0, 69.9, 59.1, 55.3; HRMS (MALDI): calcd for C21H26O6SNa [M‡Na] :
[M‡Na] : 423.1967, found 423.1982.
429.1348, found 429.1338.
Thiazole 55: DMSO (3.77 mL, 53.07 mmol) was added dropwise to a
solution of oxalyl chloride (3.70 mL, 42.45 mmol) in CH2Cl2 (100 mL) at
À788C and the resulting mixture was stirred for 10 min. Alcohol 54 (8.50 g,
21.23 mmol) was dissolved in CH2Cl2 (100 mL) and added to the reaction
mixture via cannula over 15 min. The reaction mixture was stirred at
À788C for 2 h, and then Et3N (11.83 mL, 84.91 mmol) was added and the
reaction mixture was allowed to warm to 08C over 2 h. TMS-thiazole
(6.70 g, 42.45 mmol) was added and the reaction mixture was allowed to
warm to 258C over 12 h. The reaction mixture was diluted with CH2Cl2
(1.0 L) and washed with H2O (150 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was dissolved in MeOH (200 mL) and PPTS (0.100 g, 0.32 mmol)
was added. The resulting mixture was stirred for 2 h at 25 8C and then Et3N
(5 mL) was added. The solvents were removed under reduced pressure and
the residue was purified by flash column chromatography (silica gel, 0 !
40% Et2O in hexanes) to afford thiazole 55 (9.65 g, 94%) as a white foam.
55: Rf ˆ 0.22 (50% Et2O in hexanes); [a]2D2 ˆ À23.7 (c ˆ 0.83, CHCl3); IR
(thin film): nÄ ˆ 3379, 3071, 2917, 2862, 1501, 1473, 1424, 1380, 1248, 1204,
Benzyl ether 51: nBu2SnO (22.00 g, 88.33 mmol) was added to a solution of
diol 50 (32.64 g, 80.30 mmol) in toluene (500 mL) and the resulting mixture
was refluxed with removal of H2O using a Dean Stark apparatus for 3 h.
The reaction mixture was cooled to 258C and BnBr (14.33 mL,
120.45 mmol) and nBu4NI (5.93 g, 16.06 mmol) were added. The reaction
mixture was refluxed again for 5 h, and then the reaction mixture was
quenched by the addition of H2O (5 mL). The solvents were removed
under reduced pressure and the residue was purified by flash column
chromatography (silica gel, 0 ! 80% Et2O in hexanes) to afford benzyl
ether 51 (35.50 g, 89%) as a white foam. 51: Rf ˆ 0.18 (70% Et2O in
hexanes); [a]2D2 ˆ ‡176.6 (c ˆ 0.94, CHCl3); IR (thin film): nÄ ˆ 3418, 3060,
2889, 2836, 1612, 1584, 1515, 1458, 1303, 1249, 1096, 1034, 851, 795, 769, 741,
698 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.47 ± 7.25 (m, 12H, ArH), 6.89
(d, J ˆ 8.5 Hz, 2H, PMB), 5.61 (s, 1H, F1), 4.81, 4.57 (AB, J ˆ 10.5 Hz, 2H,
CH2Ar), 4.74 (s, 2H, CH2Ar), 4.25 ± 4.24 (m, 1H, F2), 4.20 (ddd, J ˆ 9.7, 3.6,
1.6 Hz, 1H, F5), 3.87 (t, J ˆ 9.4 Hz, 1H, F4), 3.87 (dd, J ˆ 9.2, 3.1 Hz, 1H,
F3), 3.81 (s, 3H, OMe), 3.68 (dd, J ˆ 10.8, 4.1 Hz, 1H, F6), 3.55 (dd, J ˆ
10.8, 1.7 Hz, 1H, F6), 3.35 (s, 3H, OMe), 2.75 (brs, 1H, OH); 13C NMR
(150 MHz, CDCl3): d ˆ 159.3, 133.9, 131.2, 130.3, 129.6, 129.0, 127.3, 113.9,
87.8, 75.2, 74.4, 72.2, 71.6, 71.0, 59.1, 55.2; HRMS (MALDI): calcd for
1110, 1083, 989, 703 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.73 (d, J ˆ
3.5 Hz, 1H, CH-TH), 7.68 ± 7.62 (m, 4H, ArH), 7.44 ± 7.36 (m, 6H, ArH),
7.29 (d, J ˆ 3.5 Hz, 1H, CH-TH), 5.20 (dd, J ˆ 5.5, 3.0 Hz, 1H, G2), 4.44
(dd, J ˆ 7.5, 5.5 Hz, 1H, G3), 4.22 (ddd, J ˆ 7.5, 7.5, 4.0 Hz, 1H, G4), 3.67
(brd, J ˆ 3.0 Hz, 1H, OH), 3.63 (dd, J ˆ 11.0, 4.0 Hz, 1H, G5), 3.36 (dd, J ˆ
11.0, 4.0 Hz, 1H, G5), 1.44 (brs, 6H, Me), 1.04 (s, 9H, tBuSi); 13C NMR
(125 MHz, CDCl3): d ˆ 169.9, 142.3, 135.7, 132.9, 129.7, 127.7, 119.4, 109.8,
‡
C28H32O6SNa [M‡Na] : 519.1817, found 519.1832.
Ring F lactol 52: NBS (17.92 g, 100.67 mmol) was added to a solution of
alcohol 51 (33.33 g, 67.11 mmol) in acetone/H2O (10:1, 440 mL) at 08C and
the resulting mixture was warmed to 258C and stirred for 2 h. The reaction
3132
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3132 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
79.6, 78.0, 71.8, 63.8, 27.1, 26.7, 19.2; HRMS (MALDI): calcd for
C26H33NO4SSiNa [M‡Na] : 506.1797, found 506.1810.
ether solution was then added dropwise to the LAH solution over 45 min.
The resulting mixture was refluxed for 3 h and then cooled to 08C. The
reaction was quenched by the careful addition of H2O (25 mL) and a 4n
aqueous NaOH solution (25 mL). The reaction mixture was diluted with
Et2O (1.0 L) and stirred for 12 h. The reaction mixture was filtered and the
solvents were removed under reduced pressure to afford the crude diol
(64.85 g, 93%) as a colorless oil. diol: Rf ˆ 0.18 (100% Et2O); [a]2D2 ˆ À2.5
‡
Benzoate 56: BzCl (2.78 mL, 23.94 mmol) was added to a solution of
alcohol 55 (9.65 g, 19.95 mmol), Et3N (4.20 mL, 30.00 mmol) and 4-DMAP
(0.48 g, 3.99 mmol) in CH2Cl2 (100 mL) at 08C. The resulting mixture was
warmed to 258C and stirred for 2 h. The reaction mixture was quenched by
the addition of MeOH (10 mL), diluted with CH2Cl2 (350 mL) and washed
with saturated aqueous NaHCO3 (50 mL) and brine (20 mL). The organic
layer was dried (Na2SO4), and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 60% Et2O in hexanes) to afford benzoate 56 (11.23 g, 96%) as a
white foam. 56: Rf ˆ 0.41 (50% Et2O in hexanes); [a]2D2 ˆ À49.5 (c ˆ 0.76,
CHCl3); IR (thin film): nÄ ˆ 3070, 2931, 2857, 1730, 1427, 1261, 1110,
(c ˆ 0.28, CHCl3); IR (thin film): nÄ ˆ 3410, 2924, 1458, 1426, 1052, 996,
1
927 cmÀ1; H NMR (500 MHz, CDCl3): d ˆ 5.92 ± 5.84 (m, 2H, CH CH2),
ˆ
5.24 (ddd, J ˆ 17.5, 3.5, 1.5 Hz, 2H, CH2-E), 5.15 (ddd, J ˆ 10.5, 2.5, 1.0 Hz,
2H, CH2-Z), 4.10 (dddd, J ˆ 12.5, 5.5, 1.0, 1.0 Hz, 4H, CH2OH), 3.75 ± 3.70
(m, 2H, OCH2), 3.65 ± 3.61 (m, 2H, OCH2), 3.56 ± 3.53 (m, 2H, CH), 3.03 (t,
J ˆ 6.0 Hz, 2H, OH); 13C NMR (125 MHz, CDCl3): d ˆ 134.6, 117.3, 78.9,
‡
1
71.5, 60.6; HRMS (MALDI): calcd for C10H18O4Na [M‡Na] : 225.1103,
706 cmÀ1; H NMR (500 MHz, CDCl3): d ˆ 8.10 (d, J ˆ 8.0 Hz, 2H, ArH),
found 225.1111. NaH (14.55 g, 0.364 mol) was suspended in THF (1.0 L) in
a 5 L, three-neck flask, (with two 500 mL dropping funnels attached) and
cooled to 08C. The above crude diol (73.58 g, 0.364 mol) was placed in one
of the addition funnels and diluted with THF (300 mL). The diol solution
was added dropwise to the NaH solution over 45 min and then the resulting
mixture was warmed to 258C and stirred for 1 h. TPSCl (104.06 mL,
0.400 mol) was placed in the second dropping funnel and diluted with THF
(200 mL). The reaction mixture was cooled to 08C and then the TPSCl
solution was added dropwise to the reaction mixture over 45 min with
vigorous stirring. The resulting mixture was warmed to 258C and stirred for
4 h. The reaction mixture was quenched by the addition of saturated
aqueous NH4Cl (150 mL), diluted with Et2O (2.0 L) and washed with brine
(2 Â 100 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 80% Et2O in hexanes) to afford alcohol 61
(144.28 g, 90%) as a colorless oil. 61: Rf ˆ 0.50 (50% Et2O in hexanes);
[a]2D2 ˆ ‡1.60 (c ˆ 2.31, CHCl3); IR (thin film): nÄ ˆ 3453, 3072, 2932, 2857,
7.78 (d, J ˆ 3.0 Hz, 1H, CH-TH), 7.70 ± 7.34 (m, 13H, ArH), 7.31 (d, J ˆ
3.0 Hz, 1H, CH-TH), 6.60 (d, J ˆ 4.5 Hz, 1H, G2), 4.81 (dd, J ˆ 8.0, 4.5 Hz,
1H, G3), 4.39 (ddd, J ˆ 7.5, 7.5, 3.5 Hz, 1H, G4), 3.78 (dd, J ˆ 11.5, 3.5 Hz,
1H, G5), 3.58 (dd, J ˆ 11.5, 3.5 Hz, 1H, G5), 1.45 (s, 3H, Me), 1.25 (s, 3H,
Me), 1.05 (s, 9H, tBuSi); 13C NMR (125 MHz, CDCl3): d ˆ 165.7, 165.0,
142.7, 135.7, 133.5, 133.1, 130.0, 129.7, 128.5, 127.6, 119.7, 110.4, 78.4, 78.4,
72.9, 63.5, 27.4, 26.8, 19.2; HRMS (MALDI): calcd for C33H37NO5SSiNa
‡
[M‡Na] : 610.2059, found 610.2053.
Ring G diol 57: BCl3 ´ Me2S (3.80 mL, 7.62 mmol) was added to a solution of
acetonide 56 (2.24 g, 3.81 mmol) in CH2Cl2 (20 mL) at 08C and the
resulting mixture was stirred for 0.5 h. The reaction mixture was quenched
by the careful addition of saturated aqueous NaHCO3 (10 mL), diluted
with CH2Cl2 (250 mL) and washed with saturated aqueous NaHCO3
(10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 100% Et2O in
hexanes) to afford ring G diol 57 (1.24 g, 59%) as a white foam and
recovered starting material (0.78 g, 35%). 57: Rf ˆ 0.18 (70% Et2O in
hexanes); [a]2D2 ˆ À7.8 (c ˆ 0.46, CHCl3); IR (thin film): nÄ ˆ 3439, 3070,
1470, 1110, 996, 925, 824, 741, 705, 613, 506 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d ˆ 7.74 ± 7.71 (m, 4H, ArH), 7.45 ± 7.40 (m, 6H, ArH), 5.97 ± 5.85
ˆ
(m, 2H, CH CH2), 5.28 (ddd, J ˆ 17.0, 3.0, 1.5 Hz, 1H, CH2-E), 5.23 (ddd,
2931, 2857, 1727, 1427, 1267, 1110, 824, 706 cmÀ1 1H NMR (500 MHz,
;
J ˆ 17.0, 3.0, 1.5 Hz, 1H, CH2-E), 5.18 (ddd, J ˆ 10.0, 3.0, 1.5 Hz, 1H, CH2-
Z), 5.16 (ddd, J ˆ 10.0, 3.0, 1.5 Hz, 1H, CH2-Z), 4.17 (s, 1H, CH), 4.16 (s,
1H, CH), 4.14 ± 4.10 (m, 1H, OCH2), 3.88 ± 3.78 (m, 3H, OCH2, CH2),
3.73 ± 3.67 (m, 3H, OCH2, CH2OH), 3.61 ± 3.58 (m, 1H, CH2OH), 2.58 ±
2.55 (m, 1H, OH), 1.09 (s, 9H, tBuSi); 13C NMR (125 MHz, CDCl3): d ˆ
135.6, 135.5, 134.9, 134.8, 133.1, 129.7 127.7, 117.0, 80.0, 78.8, 72.0, 71.9, 62.6,
CDCl3): d ˆ 8.13 (d, J ˆ 8.1 Hz, 2H, ArH), 7.82 (d, J ˆ 2.7 Hz, 1H, CH-TH),
7.70 ± 7.26 (m, 14H, ArH), 6.46 (d, J ˆ 6.5 Hz, 1H, G2), 4.47 (dd, J ˆ 6.1,
1.4 Hz, 1H, G3), 3.99 (ddd, J ˆ 6.1, 6.1, 1.4 Hz, 1H, G4), 3.81 (d, J ˆ 6.1 Hz,
2H, G5, G5), 3.51 (s, 2H, OH), 1.07 (s, 9H, tBuSi); 13C NMR (125 MHz,
CDCl3): d ˆ 168.4, 165.2, 141.8, 139.8, 135.5, 133.7 133.0, 130.1, 129.8, 129.0,
128.7, 128.6, 127.8, 120.2, 72.8, 71.9, 69.9, 64.9, 26.8, 19.2; HRMS (MALDI):
‡
61.8, 26.7, 19.1; HRMS (MALDI): calcd for C26H36O4SiNa [M‡Na] :
‡
calcd for C30H33NO5SSiNa [M‡Na] : 570.1746, found 570.1762.
463.2275, found 463.2286.
Bis-allyl ether 60: NaH (58.74 g, 1.469 mol) was dissolved in THF (2 L) in a
5 L, three-neck flask, (with two 500 mL dropping funnels attached) and
cooled to 08C. Diisopropyl-l-tartrate (59) (160.0 mL, 0.761 mol) was
placed in one of addition funnels and diluted with THF (300 mL). The
tartrate solution was added dropwise to the NaH solution over 45 min and
then the resulting mixture was warmed to 258C and stirred for 1 h. nBu4NI
(5.62 g, 15.22 mmol) and [18]crown-6 (1.01 g, 3.86 mmol) were added and
the resulting mixture was cooled to 0 8C. Allyl bromide (127.08 mL,
1.469 mol) was placed in the second dropping funnel and added dropwise to
the reaction mixture over 45 min with vigorous stirring. The resulting
mixture was warmed to 258C and stirred for 4 h. The reaction mixture was
quenched by the addition of saturated aqueous NH4Cl (150 mL), diluted
with Et2O (2.0 L) and washed with brine (2 Â 100 mL). The organic layer
was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 30% Et2O in hexanes) to afford bis-allyl ether 60 (211.0 g, 97%) as
a colorless oil. 60: Rf ˆ 0.56 (50% Et2O in hexanes); [a]2D2 ˆ ‡55.8 (c ˆ 0.66,
CHCl3); IR (thin film): nÄ ˆ 2982, 2937, 1753, 1726, 1458, 1375, 1273, 1205,
1162, 1104, 996, 993 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 5.88 ± 5.80 (m,
Thiazole 62: DMSO (29.03 mL, 0.328 mol) was added dropwise to a
solution of oxalyl chloride (18.31 mL, 0.262 mol) in CH2Cl2 (800 mL) at
À788C and the resulting mixture was stirred for 10 min. Alcohol 61
(71.11 g, 0.131 mol) was dissolved in CH2Cl2 (800 mL) and added to the
reaction mixture via cannula over 15 min. The reaction mixture was stirred
at À788C for 2 h, and then Et3N (73.11 mL, 0.524 mol) was added and the
reaction mixture was allowed to warm to 08C over 2 h. TMS-thiazole
(41.25 g, 0.262 mol) was added and the reaction mixture was allowed to
warm to 258C over 12 h. The reaction mixture was diluted with CH2Cl2
(1.0 L) and washed with H2O (150 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was dissolved in MeOH (500 mL) and PPTS (1.05, 0.032 mol) was
added. The resulting mixture was stirred for 2 h at 258C and then Et3N
(50.00 mL) was added. The solvents were removed under reduced pressure
and the residue was purified by flash column chromatography (silica gel,
0 ! 40% Et2O in hexanes) to afford the desired ring G alcohol 62 (38.50 g,
46%) and the undesired ring G alcohol (38.00 g, 45%) as white foams.
Desired 60: Rf ˆ 0.28 (50% Et2O in hexanes); [a]2D2 ˆ ‡10.4 (c ˆ 0.23,
CHCl3); IR (thin film): nÄ ˆ 3417, 3072, 2931, 2857, 1469, 1427, 1111, 928, 923,
ˆ
2H, CH CH2), 5.21 (ddd, J ˆ 17.0, 3.0, 1.5 Hz, 2H, CH2-E), 5.14 (dm, J ˆ
10.5 Hz, 2H, CH2-Z), 5.11 (sept, J ˆ 6.0 Hz, 2H, CH(Me)2), 4.33 (s, 2H,
CH), 4.30 ± 4.23 (m, 2H, OCH2), 3.94 ± 3.89 (m, 2H, OCH2), 1.27 (d, J ˆ
6.0 Hz, 6H, CH(Me)2), 1.26 (d, J ˆ 6.0 Hz, 6H, CH(Me)2); 13C NMR
(125 MHz, CDCl3): d ˆ 168.8, 133.8, 118.0, 78.6, 72.6, 68.9, 21.8; HRMS
704 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.81 (d, J ˆ 3.5 Hz, 1H, TH-
CH), 7.64 (brd, J ˆ 8.0 Hz, 2H, ArH), 7.58 (brd, J ˆ 6.5 Hz, 2H, ArH),
ˆ
7.45 ± 7.32 (m, 7H, ArH, TH-CH), 5.91 ± 5.74 (m, 2H, CH CH2), 5.34 (dd,
J ˆ 6.5, 5.0 Hz, 1H, G2), 5.28 (dd, J ˆ 17.0, 1.0 Hz, 1H, CH2-E), 5.15 (dd,
J ˆ 10.5, 1.0 Hz, 1H, CH2-Z), 5.09 (dd, J ˆ 17.0, 1.0 Hz, 1H, CH2-E), 5.07
(dd, J ˆ 10.0, 1.0 Hz, 1H, CH2-Z), 4.72 (d, J ˆ 6.5 Hz, 1H, OH), 4.16 (dd,
J ˆ 12.5, 5.5 Hz, 1H, OCH2), 4.12 (dd, J ˆ 5.0, 2.5 Hz, 1H, G3), 4.07 (dd,
J ˆ 12.5, 5.5 Hz, 1H, OCH2), 3.95 (dd, J ˆ 12.5, 5.5 Hz, 1H, OCH2), 3.95
(dd, J ˆ 10.5, 7.0 Hz, 1H, G5), 3.70 (dd, J ˆ 10.5, 5.5 Hz, 1H, G5), 3.70 (dd,
J ˆ 12.5, 6.0 Hz, 1H, OCH2), 3.52 ± 3.50 (m, 1H, G4), 1.03 (s, 9H, tBuSi);
‡
(MALDI): calcd for C16H26O6Na [M‡Na] : 337.1622, found 337.1615.
Alcohol 61: LAH (22.25 g, 0.586 mol) was suspended in Et2O (2 L) in a 5 L,
three-neck flask, (with one 500 mL dropping funnel, and one large
condenser attached). The resulting mixture was refluxed for 30 min and
then removed from the heat. Bis-allyl ether 60 (108.37 g, 0.345 mol) was
added to the addition funnel and diluted with Et2O (300 mL). The allyl
Chem. Eur. J. 2000, 6, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3133 $ 17.50+.50/0
3133

K. C. Nicolaouet al.
FULL PAPER
13C NMR (125 MHz, CDCl3): d ˆ 173.5, 142.8, 135.6, 135.5, 134.3, 134.0,
3.84 (m, 3H, G5, G5, OCH2), 3.72 (dd, J ˆ 12.4, 6.4 Hz, 1H, OCH2), 3.70 ±
3.67 (m, 1H, G4), 1.10 (s, 9H, tBuSi); 13C NMR (150 MHz, CDCl3): d ˆ
166.7, 166.3, 142.3, 135.6, 135.5, 134.6, 134.4, 129.8, 129.7, 128.4, 127.7, 120.2,
117.6, 117.3, 79.2, 78.6, 74.2, 72.2, 71.4, 62.0, 26.8, 19.2; HRMS (MALDI):
133.0, 129.8, 127.7, 119.0, 118.0, 117.9, 79.7, 78.6, 72.3, 72.0, 61.8, 26.8, 19.1;
‡
HRMS (MALDI): calcd for C29H37NO4SSiNa [M‡Na] : 546.2110, found
546.2118. Undesired ring G alcohol: Rf ˆ 0.37 (50% Et2O in hexanes);
[a]2D2 ˆ ‡4.30 (c ˆ 2.21, CHCl3); IR (thin film): nÄ ˆ 3383, 3072, 2932, 2858,
1470, 1427, 1111, 996, 927, 824, 741, 705 cmÀ1; 1H NMR (500 MHz, CDCl3):
d ˆ 7.79 (d, J ˆ 3.0 Hz, 1H, CH-TH), 7.68 (d, J ˆ 7.5 Hz, 2H, ArH), 7.63 (d,
J ˆ 8.0 Hz, 2H, ArH), 7.45 ± 7.34 (m, 6H, ArH), 7.31 (d, J ˆ 3.0 Hz, 1H, CH-
‡
calcd for C36H41NO5SSiNa [M‡Na] : 650.2367, found 650.2339.
Ring G lactol 65: MeOTf (5.96 mL, 48.62 mmol) was added to a solution of
benzoate 64 (25.44 g, 40.52 mmol) and 4 Š MS in MeCN (200 mL) at 258C
and the resulting mixture was stirred for 15 min. The solvents were
removed under reduced pressure, and the residue was dissolved in MeOH
(200 mL) and cooled to 08C. NaBH4 (3.68 g, 97.24 mmol) was added
portionwise and the resulting mixture was stirred for 0.5 h. The reaction
mixture was quenched by the addition of acetone (10 mL), filtered through
a pad of Celite, and the solvents were removed under reduced pressure. The
residue was dissolved in MeCN/sH2O (10:1, 220 mL) and CuO (25.78 g,
0.324 mol) was added. CuCl2 (7.27 g, 48.62 mmol) was added portionwise
followed by vigorous stirring for 2 h at 258C. The reaction mixture was
diluted with Et2O (500 mL), filtered through a pad of Celite, and the
solvents were removed under reduced pressure. The residue was dissolved
in THF (200 mL) and nBu4NF (60.78 mL, 60.78 mmol) and AcOH (1.0 mL)
were added. The resulting mixture was stirred at 258C for 2 h. The reaction
mixture was diluted with CH2Cl2 (750 mL) and washed with saturated
aqueous NaHCO3 (100 mL) and brine (100 mL). The organic layer was
dried (Na2SO4) and the solvents were removed under reduced pressure.
The residue was purified by flash column chromatography (silica gel, 0 !
100% Et2O in hexanes) to afford ring G lactol 65 (10.97 g, 81% over four
steps) as a white foam. 65: Rf ˆ 0.42 (70% Et2O in hexanes); [a]2D2 ˆ ‡36.7
(c ˆ 0.70, CHCl3); IR (thin film): nÄ ˆ 3411, 3074, 2934, 1723, 1453, 1356,
ˆ
TH), 5.92 ± 5.77 (m, 2H, CH CH2), 5.37 (d, J ˆ 5.0 Hz, 1H, G2), 5.26 (dd,
J ˆ 17.5, 1.5 Hz, 1H, CH2-E), 5.15 (brd, J ˆ 10.0 Hz, 1H, CH2-Z), 5.13 (dd,
J ˆ 17.5, 1.5 Hz, 1H, CH2-E), 5.08 (brd, J ˆ 10.0 Hz, 1H, CH2-Z), 4.91 (brs,
1H, OH), 4.19 ± 4.15 (m, 3H, G3, OCH2), 4.09 (dd, J ˆ 12.5, 6.0 Hz, 1H,
OCH2), 3.99 (dd, J ˆ 12.0, 6.0 Hz, 1H, OCH2), 3.90 (dd, J ˆ 10.0, 6.5 Hz,
1H, G5), 3.82 (dd, J ˆ 10.5, 5.5 Hz, 1H, G5), 3.76 (dd, J ˆ 12.0, 6.0 Hz, 1H,
OCH2), 3.61 ± 3.58 (m, 1H, G4), 1.08 (s, 9H, tBuSi); 13C NMR (125 MHz,
CDCl3): d ˆ 173.5, 142.5, 135.4, 134.2, 133.9, 132.9, 129.9, 127.6, 118.9, 117.5,
79.4, 78.8, 71.8, 71.8, 61.7, 26.6, 18.9; HRMS (MALDI): calcd for
‡
C29H38NO4SSi [M‡H] : 524.2291, found 524.2305.
Ketone 63: DMSO (13.92 mL, 0.196 mol) was added dropwise to a solution
of oxalyl chloride (11.43 mL, 0.130 mol) in CH2Cl2 (200 mL) at À788C and
the resulting mixture was stirred for 10 min. Undesired ring G alcohol 62
(34.25 g, 0.065 mol) was dissolved in CH2Cl2 (200 mL) and added to the
reaction mixture via cannula over 15 min. The reaction mixture was stirred
at À788C for 2 h, and then Et3N (36.46 mL, 0.261 mol) was added and the
reaction mixture was allowed to warm to 08C over 2 h. The reaction
mixture was diluted with CH2Cl2 (1.0 L) and washed with H2O (150 mL).
The organic layer was dried (Na2SO4), the solvents were removed under
reduced pressure, and the residue was purified by flash column chroma-
tography (silica gel, 0 ! 40% Et2O in hexanes) to afford ketone 63 (32.75 g,
96%) as a white foam. 63: Rf ˆ 0.49 (50% Et2O in hexanes); [a]2D2 ˆ ‡8.94
(c ˆ 1.51, CHCl3); IR (thin film): nÄ ˆ 3073, 2932, 2857, 1697, 1474, 1427,
1389, 1111, 996, 931, 823, 705, 613, 505 cmÀ1; 1H NMR (600 MHz, CDCl3):
d ˆ 8.04 (d, J ˆ 3.0 Hz, 1H, CH-TH), 7.78 ± 7.70 (m, 5H, ArH, CH-TH),
1273, 1117, 929, 712 cmÀ1
8.5 Hz, 2H, ArH), 7.60 ± 7.56 (m, 1H, ArH), 7.48 ± 7.44 (m, 2H, ArH), 5.96 ±
;
1H NMR (500 MHz, CDCl3): d ˆ 8.07 (d, J ˆ
ˆ
5.84 (m, 2H, CH CH2), 5.40 (d, J ˆ 3.5 Hz, 1H, G2), 5.31 (dd, J ˆ 17.5,
1.5 Hz, 1H, CH2-E), 5.27 (dm, J ˆ 17.0 Hz, 1H, CH2-E), 5.21 ± 5.18 (m, 2H,
G1, CH2-Z), 5.14 (dm, J ˆ 9.0 Hz, 1H, CH2-Z), 4.22 ± 4.10 (m, 4H, OCH2),
3.95 (dd, J ˆ 7.5, 3.0 Hz, 1H, G5), 3.92 ± 3.84 (m, 2H, G3, G4), 3.76 (dd, J ˆ
7.5, 5.0 Hz, 1H, G5), 2.87 (d, J ˆ 5.5 Hz, 1H, OH); 13C NMR (125 MHz,
CDCl3): d ˆ 166.0, 134.7, 134.5, 133.3, 133.1, 129.7, 128.4, 128.3, 118.5, 117.6,
117.0, 92.7, 82.1, 76.0, 74.1, 72.7, 71.8, 71.2, 70.6, 69.5, 66.0, 61.6; HRMS
ˆ
7.41 ± 7.38 (m, 6H, ArH), 5.98 ± 5.91 (m, 1H, CH CH2), 5.54 ± 5.46 (m, 1H,
ˆ
CH CH2), 5.43 (d, J ˆ 3.2 Hz, 1H, G3), 5.25 (dd, J ˆ 17.2, 1.4 Hz, 1H, CH2-
E), 5.15 (dd, J ˆ 10.4, 1.1 Hz, 1H, CH2-Z), 4.87 (dd, J ˆ 17.2, 1.4 Hz, 1H,
CH2-E), 4.82 (dd, J ˆ 10.4, 1.0 Hz, 1H, CH2-Z), 4.32 ± 4.26 (m, 2H, G4,
OCH2), 4.04 ± 4.00 (m, 2H, G5, OCH2), 3.88 (dd, J ˆ 12.8, 5.5 Hz, 1H,
OCH2), 3.80 (dd, J ˆ 10.2, 5.5 Hz, 1H, G5), 3.67 (dd, J ˆ 12.8, 5.5 Hz, 1H,
OCH2), 1.09 (s, 9H, tBuSi); 13C NMR (150 MHz, CDCl3): d ˆ 190.8, 165.4,
144.5, 135.6, 135.4, 134.3, 133.2, 129.6, 127.6, 126.2, 117.8, 117.2, 80.8, 79.2,
72.3, 71.9, 65.7, 62.0, 26.7, 19.0, 15.2; HRMS (MALDI): calcd for
‡
(MALDI): calcd for C18H22O6Na [M‡Na] : 357.1309, found 357.1295.
Ring G trichloroacetimidate 46: DBU (0.22 mL, 0.020 mmol) was added to
a solution of ring G lactol 65 (12.05 g, 36.04 mmol) and Cl3CCN (18.07 mL,
180.20 mmol) in CH2Cl2 (200 mL) at 08C and the resulting mixture was
stirred 0.5 h. The solvents were removed under reduced pressure and the
residue was purified by flash column chromatography (silica gel, 0 ! 100%
EtOAc in hexanes) to afford ring G trichloroacetimdiate 46 (14.67 g, 85%)
as a white foam. 46: Rf ˆ 0.80 (70% Et2O in hexanes); 1H NMR (600 MHz,
CDCl3): d ˆ 8.70 (s, 1H, NH), 8.08 (d, J ˆ 8.3 Hz, 2H, ArH), 7.59 (t, J ˆ
8.5 Hz, 1H, ArH), 7.47 (t, J ˆ 7.8 Hz, 2H, ArH), 6.28 (d, J ˆ 2.5 Hz, 1H,
‡
C29H35NO4SSiNa [M‡Na] : 544.1948, found 544.1948.
Reduction of Ketone 63: LAH (3.4 g, 108.0 mmol) was added to a solution
of ketone 61 (12.00 g, 98.15 mmol) in Et2O (200 mL) at 08C and the
resulting mixture was stirred for 2 h. The reaction mixture was quenched by
the addition of saturated aqueous NH4Cl (20 mL), diluted with CH2Cl2
(750 mL) and washed with saturated aqueous NaHCO3 (100 mL) and brine
(100 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 40% Et2O in hexanes) to afford the ring G
alcohols 62 (8.4 g, 70%, 2:1 mixture of desired:undesired) as white foams.
ˆ
G1), 5.96 ± 5.85 (m, 2H, CH CH2), 5.65 (t, J ˆ 2.7 Hz, 1H, G2), 5.31 (dd,
J ˆ 17.2, 1.5 Hz, 1H, CH2-E), 5.27 (dd, J ˆ 17.1, 1.5 Hz, 1H, CH2-E), 5.20
(dd, J ˆ 10.3, 1.0 Hz, 1H, CH2-Z), 5.14 (dd, J ˆ 10.3, 1.0 Hz, 1H, CH2-Z),
4.28 (dd, J ˆ 12.7, 5.2 Hz, 1H, OCH2), 4.22 ± 4.11 (m, 3H, OCH2), 4.04 (dd,
J ˆ 11.4, 5.1 Hz, 1H, G5), 3.96 (dd, J ˆ 8.9, 3.2 Hz, 1H, G3), 3.93 (ddd, J ˆ
9.1, 9.1, 4.1 Hz, 1H, G4), 3.78 (dd, J ˆ 11.4, 9.8 Hz, 1H, G5); 13C NMR
(150 MHz, CDCl3): d ˆ 165.5, 160.3, 134.7, 134.3, 133.4, 129.9, 129.5, 128.4,
117.5, 117.3, 95.3, 76.4, 76.1, 73.4, 72.7, 71.2, 68.4, 63.6.
Benzoate 64: BzCl (5.00 mL, 43.05 mmol) was added to a solution of
desired alcohol 62 (20.50 g, 39.14 mmol), Et3N (8.18 mL, 58.70 mmol), and
4-DMAP (0.96 g, 7.80 mmol) in CH2Cl2 (200 mL) at 08C. The resulting
mixture was warmed to 258C and stirred for 2 h. The reaction mixture was
quenched by the addition of MeOH (10 mL), diluted with CH2Cl2 (750 mL)
and washed with saturated aqueous NaHCO3 (100 mL) and brine
(100 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 60% Et2O in hexanes) to afford benzoate
64 (24.08 g, 98%) as a white foam. 64: Rf ˆ 0.49 (50% Et2O in hexanes);
[a]2D2 ˆ À6.83 (c ˆ 2.08, CHCl3); IR (thin film): nÄ ˆ 3071, 2931, 2857, 1726,
1453, 1427, 1266, 1110, 997, 928, 746, 707, 613, 506 cmÀ1; 1H NMR (600 MHz,
CDCl3): d ˆ 8.09 (d, J ˆ 8.3 Hz, 2H, ArH), 7.81 (d, J ˆ 3.2 Hz, 1H, TH-CH),
7.71 ± 7.69 (m, 4H, ArH), 7.60 (t, J ˆ 7.5 Hz, 1H, ArH), 7.48 ± 7.36 (m, 8H,
ArH), 7.35 (d, J ˆ 3.2 Hz, 1H, TH-CH), 6.50 (d, J ˆ 7.0 Hz, 1H, G2), 5.74 ±
Seleno-glycoside 67: BF3 ´ Et2O (32.2 mL, 0.253 mol) was added to a
solution of peracetylated xylose 66 (84.76 g, 0.266 mol) and PhSeH
(120 mL, 5.0m solution in CH2Cl2, 0.532 mmol) in CH2Cl2 (1.0 L) at 08C.
The reaction mixture was warmed to 258C and stirred for 12 h. The
reaction mixture was quenched by the addition of Et3N (50 mL), diluted
with CH2Cl2 (800 mL) and washed with saturated aqueous NaHCO3
(100 mL) and brine (100 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 100% Et2O in
hexanes) to afford seleno-glycoside 67 (103.13 g, 93%, a:b ca. 1:5) as a
white foam. 67: Rf ˆ 0.33 (70% Et2O in hexanes); [a]2D2 ˆ À83.2 (c ˆ 6.51,
CHCl3); IR (thin film): nÄ ˆ 3056, 2976, 2868, 1752, 1578, 1477, 1438, 1370,
1245, 1222, 1061, 742 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.55 (brd, J ˆ
7.5 Hz, 2H, ArH), 7.29 ± 7.24 (m, 3H, ArH), 5.16 (d, J ˆ 6.5 Hz, 1H, H1),
5.10 (t, J ˆ 6.5 Hz, 1H, H2), 5.01 (t, J ˆ 6.5 Hz, 1H, H3), 4.84 (ddd, J ˆ 7.0,
7.0, 4.0 Hz, 1H, H4), 4.33 (dd, J ˆ 12.5, 4.5 Hz, 1H, H5), 3.51 (dd, J ˆ 12.5,
7.0 Hz, 1H, H5), 2.06 (s, 6H, OAc), 2.03 (s, 3H, OAc); 13C NMR (125 MHz,
ˆ
5.65 (m, 2H, CH CH2), 5.09 (dd, J ˆ 17.0, 1.5 Hz, 1H, CH2-E), 5.03 (dd, J ˆ
10.1, 1.0 Hz, 1H, CH2-Z), 4.94 (dd, J ˆ 17.2, 1.5 Hz, 1H, CH2-E), 4.87 (dd,
J ˆ 10.0, 1.0 Hz, 1H, CH2-Z), 4.44 (dd, J ˆ 7.0, 3.2 Hz, 1H, G3), 4.01 (dd,
J ˆ 12.3, 6.2 Hz, 1H, OCH2), 3.93 (dd, J ˆ 12.4, 5.7 Hz, 1H, OCH2), 3.90 ±
3134
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3134 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
CDCl3): d ˆ 169.6, 169.3, 169.2, 134.2, 129.0, 128.3, 128.1, 82.1, 70.2, 70.0,
hexanes) to afford H-3 TBS ether 71 (18.40 g, 91%) as a white foam. 71:
Rf ˆ 0.76 (30% Et2O in hexanes); [a]2D2 ˆ À185.3 (c ˆ 1.92, CHCl3); IR
(thin film): nÄ ˆ 3490, 3048, 2951, 1843, 1607, 1581, 1516, 1467, 1440, 1252,
1095, 1042, 842, 783, 740 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.62 ± 7.60
(m, 2H, ArH), 7.29 ± 7.24 (m, 5H, ArH), 6.90 (d, J ˆ 8.5 Hz, 2H, PMB), 5.65
(brs, 1H, H1), 4.67, 4.52 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.14 (brd, J ˆ
11.0 Hz, 1H, H5), 3.96 (brs, 1H, H3), 3.89 (brd, J ˆ 11.0 Hz, 1H, H5), 3.81
(s, 3H, OMe), 3.81 ± 3.79 (m, 1H, H2), 3.35 (s, 1H, H4), 0.95 (s, 9H, tBuSi),
0.13, 0.06 (2  s, 2  3H, MeSi); 13C NMR (125 MHz, CDCl3): d ˆ 159.5,
133.8, 132.7, 129.5, 128.8, 127.5, 126.9, 113.9, 86.8, 75.4, 72.9, 71.0, 67.2, 59.4,
55.2, 25.8, 18.1, À5.0, À5.3; HRMS (FAB): calcd for C25H36O5SeSiCs
‡
67.8, 64.7, 20.7, 20.6; HRMS (FAB): calcd for C17H20O7SeCs [M‡Cs] :
548.9429, found 548.9412.
Alcohol 68: K2CO3 (2.94 g, 0.021 mol) was added to a solution of seleno-
glycoside 67 (88.70 g, 0.213 mol) in MeOH/THF (1:1, 1.0 L) and the
mixture was stirred for 12 h at 258C. The reaction mixture was quenched by
the addition of Amberlyst (5.0 g), diluted with CH2Cl2 (800 mL) and
filtered. The solvents were removed under reduced pressure and the
residue was azeotroped with toluene (2 Â 100 mL). The residue was
dissolved in DMF (400 mL) and heated to 458C. 2-Methoxypropene
(30.61 mL, 0.320 mol) and TFA (0.10 mL, 0.021 mol) were added and the
reaction mixture was stirred for 3 h. The reaction was quenched with Et3N
(50 mL), the solvents were removed under reduced pressure, and the
residue was purified by flash column chromatography (silica gel, 0 ! 100%
Et2O in hexanes) to afford alcohol 68 (51.92 g, 74% over two steps) as a
white foam. 68: Rf ˆ 0.24 (70% Et2O in hexanes); [a]2D2 ˆ À47.0 (c ˆ 1.63,
CHCl3); IR (thin film): nÄ ˆ 3430, 2984, 2889, 1477, 1438, 1382, 1372, 1228,
‡
[M‡Cs] : 657.0553, found 657.0575.
H-2 TBS ether 72: TBSOTf (0.97 mL, 4.23 mmol) was added to a solution
of diol 70 (1.58 g, 38.48 mmol) and 2,6-lutidine (0.67 mL, 5.77 mmol) in
CH2Cl2 (20.0 mL) at À788C. The resulting mixture was stirred for 0.5 h.
The reaction mixture was quenched by the addition of MeOH (1.0 mL),
diluted with CH2Cl2 (100 mL) and washed with saturated aqueous
NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4)
and the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 50% Et2O in
hexanes) to afford H-2 TBS ether 72 (1.84 g, 91%) as a white foam. 72:
Rf ˆ 0.76 (30% Et2O in hexanes); [a]2D2 ˆ À132.3 (c ˆ 0.85, CHCl3); IR
(thin film): nÄ ˆ 3480, 3057, 2955, 2856, 1612, 1582, 1514, 1473, 1251, 1076,
1
1148, 1048, 836, 741 cmÀ1; H NMR (500 MHz, CDCl3): d ˆ 7.68 ± 7.66 (m,
2H, ArH), 7.35 ± 7.25 (m, 3H, ArH), 4.99 (d, J ˆ 9.5 Hz, 1H, H1), 4.11 (dd,
J ˆ 11.5, 5.5 Hz, 1H, H5), 3.96 ± 3.91 (m, 1H, H4), 3.49 (t, J ˆ 9.0 Hz, 1H,
H3), 3.22 (t, J ˆ 9.5 Hz, 1H, H2), 3.20 (dd, J ˆ 11.5, 5.0 Hz, 1H, H5), 2.51 (d,
J ˆ 4.0 Hz, 1H, OH), 1.48 (s, 3H, Me), 1.40 (s, 3H, Me); 13C NMR
(125 MHz, CDCl3): d ˆ 135.4, 128.9, 128.4, 110.9, 82.8, 80.5, 75.8, 70.6, 69.0,
‡
26.5; HRMS (FAB): calcd for C14H19O4Se [M‡H] : 331.0449, found
839, 779, 739 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.62 ± 7.60 (m, 2H,
331.0461.
ArH), 7.29 ± 7.26 (m, 3H, ArH), 7.24 (d, J ˆ 8.5 Hz, 2H, PMB), 6.88 (d, J ˆ
8.5 Hz, 2H, PMB), 4.79 (d, J ˆ 9.5 Hz, 1H, H1), 4.57, 4.53 (AB, J ˆ 11.5 Hz,
2H, CH2Ar), 4.02 (dd, J ˆ 11.5, 5.0 Hz, 1H, H5), 3.79 (s, 3H, OMe), 3.58
(dd, J ˆ 9.5, 8.0 Hz, 1H, H2), 3.51 (dt, J ˆ 9.0, 3.0 Hz, 1H, H3), 3.45 (ddd,
J ˆ 9.0, 9.0, 5.0 Hz, 1H, H4), 3.15 (dd, J ˆ 11.5, 10.0 Hz, 1H, H5), 2.72 (d,
J ˆ 3.0 Hz, 1H, OH), 0.97 (s, 9H, tBuSi), 0.20, 0.17 (2  s, 2  3H, MeSi);
13C NMR (125 MHz, CDCl3): d ˆ 159.5, 133.7, 129.9, 129.7, 129.4, 128.8,
127.4, 113.9, 86.3, 77.3, 74.6, 72.5, 72.5, 68.1, 55.1, 26.1, À3.8, À4.4; HRMS
PMB ether 69: NaH (2.16 g, 53.89 mmol) was added to a solution of alcohol
68 (16.13 g, 49.00 mmol) in DMF (150 mL) at 08C and the resulting mixture
was stirred for 5 min. PMBCl (8.64 mL, 63.69 mmol) and nBu4NI (3.62 g,
9.79 mmol) were added and the resulting mixture was warmed to 258C and
stirred for 2 h. The reaction mixture was quenched by the addition of
saturated aqueous NH4Cl (50 mL), diluted with Et2O (800 mL) and washed
with brine (2 Â 50 mL). The organic layer was dried (Na2SO4) and the
solvents were removed under reduced pressure. The residue was purified
by flash column chromatography (silica gel, 0 ! 100% Et2O in hexanes) to
afford PMB ether 69 (20.92 g, 95%) as a white foam. 69: Rf ˆ 0.42 (50%
Et2O in hexanes); [a]2D2 ˆ À4.0 (c ˆ 4.53, CHCl3); IR (thin film): nÄ ˆ 3058,
2985, 2888, 1614, 1580, 1518, 1455, 1382, 1303, 1249, 1150, 1038, 969, 837,
787, 742, 692, 510 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.67 (d, J ˆ 8.2 Hz,
2H, ArH), 7.37 ± 7.25 (m, 5H, ArH), 6.87 (d, J ˆ 8.6 Hz, 2H, PMB), 5.01 (d,
J ˆ 9.6 Hz, 1H, H1), 4.73, 4.50 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.07 (dd, J ˆ
11.8, 5.1 Hz, 1H, H5), 3.79 (s, 3H, OMe), 3.72 (ddd, J ˆ 8.9, 8.9, 5.2 Hz, 1H,
H4), 3.61 (t, J ˆ 9.0 Hz, 1H, H5), 3.24 ± 3.21 (m, 2H, H2, H3), 1.50 (s, 3H,
Me), 1.43 (s, 3H, Me); 13C NMR (150 MHz, CDCl3): d ˆ 159.3, 135.2, 130.0,
129.5, 128.9, 128.3, 126.8, 113.7, 110.8, 82.3, 80.5, 76.0, 75.1, 71.6, 69.1, 55.2,
‡
(FAB): calcd for C25H36O5SeSiCs [M‡Cs] : 657.0553, found 657.0575.
Bis-benzyl ether 74: K2CO3 (6.36 g, 46.0 mmol) was added to a solution of
aldehyde 73[1] (1.75 g, 11.5 mmol) and BnBr (3.42 mL, 28.8 mmol) in
acetone (60 mL) at 258C and the resulting mixture was refluxed for 8 h.
The reaction mixture was filtered and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 60% Et2O in hexanes) to afford bis-benzyl ether 74
(3.52 g, 92%) as a white foam. 74: Rf ˆ 0.40 (60% Et2O in hexanes); IR
(thin film): nÄ ˆ 3033, 2925, 2871, 2783, 1679, 1603, 1498, 1450, 1378, 1319,
1155, 1092, 1044, 910, 834, 738, 698 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ
10.60 (s, 1H, CHO), 7.43 ± 7.40 (m, 10H, ArH), 6.50 (s, 1H, ArH (A2)), 6.44
(s, 1H, ArH (A2)), 5.10 (s, 2H, CH2Ar), 5.09 (s, 2H, CH2Ar), 2.62 (s, 3H,
Me); 13C NMR (150 MHz, CDCl3): d ˆ 190.3, 164.1, 163.3, 144.6, 136.0,
135.9, 128.6, 128.6, 128.2, 128.1, 127.5, 127.2, 117.7, 109.7, 97.7, 70.4, 70.0, 22.3;
‡
26.7, 26.6; HRMS (FAB): calcd for C22H26O5SeCs [M‡Cs] : 583.0001,
found 583.0014.
‡
HRMS (MALDI): calcd for C22H20O3Na [M‡Na] : 355.1310, found
Diol 70: PPTS (2.09 g, 8.31 mmol) was added to a solution of acetonide 69
(18.74 g, 41.56 mmol) dissolved in MeOH (500 mL). The reaction mixture
was stirred at 258C for 1 h and then the reaction was quenched by the
addition of Et3N (50 mL). The solvents were removed under reduced
pressure and the residue was purified by flash column chromatography
(silica gel, 0 ! 100% Et2O in hexanes) to afford diol 70 (16.36 g, 96%) as a
white foam. 70: Rf ˆ 0.43 (100% Et2O); [a]2D2 ˆ À84.7 (c ˆ 1.03, CHCl3); IR
355.1331.
Aromatic acid 75: NaH2PO4 ´ H2O (1.20 g, 8.66 mmol, dissolved in 1 mL
H2O) was added to a solution of aldehyde 74 (1.20 g, 3.61 mmol) in DMSO
(20 mL) at 08C. NaClO2 (0.75 g, 8.30 mmol, dissolved in 1.0 mL H2O) was
then added and the resulting mixture was warmed slowly to 258C and
stirred for 12 h. The reaction mixture was diluted with saturated aqueous
NaHCO3 (50 mL) and washed with EtOAc (20 mL). The aqueous layer was
then acidified to pH 1 with aqueous HCl and washed with EtOAc
(200 mL). The organic layer was dried (Na2SO4), and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 100% EtOAc in hexanes) to afford
aromatic acid 75 (1.01 g, 80%) as a white solid. 75: Rf ˆ 0.30 (70% Et2O
in hexanes); IR (thin film): nÄ ˆ 3436 ± 2872, 1690, 1590, 1449, 1384, 1320,
(thin film): nÄ ˆ 3426, 3056, 2909, 1612, 1513, 1249, 1053, 821, 740 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.63 ± 7.61 (m, 2H, ArH), 7.32 ± 7.24 (m,
5H, ArH), 6.87 (d, J ˆ 8.5 Hz, 2H, PMB), 4.91 (d, J ˆ 8.0 Hz, 1H, H1), 4.58
(brs, 2H, CH2Ar), 4.13 (dd, J ˆ 11.5, 4.0 Hz, 1H, H5), 3.80 (s, 3H, OMe),
3.70 (dd, J ˆ 8.0, 8.0, 2.5 Hz, 1H, H3), 3.51 ± 3.45 (m, 1H, H4), 3.44 (dd, J ˆ
7.5, 4.0 Hz, 1H, H2), 3.34 (dd, J ˆ 12.0, 9.0 Hz, 1H, H5), 3.06 (d, J ˆ 4.0 Hz,
1H, OH), 2.82 (d, J ˆ 3.0 Hz, 1H, OH); 13C NMR (125 MHz, CDCl3): d ˆ
159.5, 134.6, 129.7, 129.5, 129.1, 128.1, 114.1, 85.7, 76.3, 74.6, 72.5, 72.5, 66.6,
1
1167, 1102, 832, 750, 697 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 7.42 ± 7.26
‡
55.3; HRMS (FAB): calcd for C19H22O5SeNa [M‡Na] : 433.0530, found
(m, 10H, ArH), 6.53 (d, J ˆ 1.9 Hz, 1H, ArH (A2)), 6.52 (d, J ˆ 1.9 Hz, 1H,
ArH (A2)), 5.14 (s, 2H, CH2Ar), 5.06 (s, 2H, CH2Ar), 2.55 (s, 3H, Me);
13C NMR (150 MHz, CDCl3): d ˆ 168.4, 161.2, 158.5, 143.8, 136.1, 135.3,
128.8, 128.7, 128.5, 128.3, 127.5, 113.1, 110.3, 98.7, 71.6, 70.1, 22.5; HRMS
433.0515.
H-3 TBS ether 71: TBSOTf (9.72 mL, 42.32 mmol) was added to a solution
of diol 70 (15.75 g, 38.48 mmol) and 2,6-lutidine (6.72 mL, 57.72 mmol) in
THF (200 mL) at À788C. The resulting mixture was stirred for 0.5 h. The
reaction mixture was quenched by the addition of MeOH (10 mL), diluted
with CH2Cl2 (800 mL), and washed with saturated aqueous NaHCO3
(100 mL) and brine (100 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 50% Et2O in
‡
(MALDI): calcd for C22H20O4Na [M‡Na] : 371.1259, found 371.1275.
‡
À
Aromatic A2 acyl fluoride 5: (Me2N)2CF PF6 (0.318 g, 1.21 mmol) was
added to
a solution of aromatic acid 75 (0.280 g, 0.804 mmol) and
diisopropylethyamine (0.280 mL, 1.61 mmol) in CH2Cl2 (4 mL) at 08C
and the resulting mixture was warmed to 258C and stirred for 2 h. The
solvents were removed under reduced pressure and the residue was
Chem. Eur. J. 2000, 6, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3135 $ 17.50+.50/0
3135

K. C. Nicolaouet al.
FULL PAPER
purified by flash column chromatography (silica gel, 0 ! 50% Et2O in
hexanes) to afford aromatic A2 acyl fluoride 5 (0.225 g, 80%) as a white
solid. 5: Rf ˆ 0.79 (80% Et2O in hexanes); IR (thin film): nÄ ˆ 2925, 1790,
1590, 1443, 1320, 1220, 1155, 1085, 997, 736, 696 cmÀ1; 1H NMR (600 MHz,
CDCl3): d ˆ 7.43 ± 7.26 (m, 10H, ArH), 6.48 (s, 1H, ArH (A2)), 6.47 (s, 1H,
ArH (A2)), 5.11 (s, 2H, CH2Ar), 5.06 (s, 2H, CH2Ar), 2.46 (s, 3H, Me);
13C NMR (150 MHz, CDCl3): d ˆ 162.7, 143.7, 136.0, 135.9, 128.7, 128.6,
128.5, 128.5, 128.4, 128.2, 128.1, 128.0, 127.5, 127.2, 126.9, 109.2, 98.5, 70.6,
white foam. Ring G benzyl ether: Rf ˆ 0.50 (30% Et2O in hexanes); [a]D22
À28.42 (c ˆ 0.38, CHCl3); IR (thin film): nÄ ˆ 2910, 1495, 1455, 1358, 1312,
1198, 1135, 1065, 995, 965, 924, 779 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ
ˆ
ˆ
7.39 ± 7.26 (m, 5H, ArH), 5.95 ± 5.86 (m, 2H, CH CH2), 5.31 (ddm, J ˆ 15.2,
2.0 Hz, 1H, CH2-E), 5.27 (ddm, J ˆ 15.2, 2.0 Hz, 1H, CH2-E), 5.20 ± 5.14
(m, 2H, CH2-Z), 4.77, 4.72 (AB, J ˆ 12.2 Hz, 2H, CH2Ar), 4.61 (d, J ˆ
3.0 Hz, 1H, G1), 4.20 ± 4.08 (m, 4H, OCH2), 3.83 ± 3.75 (m, 2H, G5, G5),
3.70 (t, J ˆ 3.0 Hz, 1H, G2), 3.65 (dd, J ˆ 8.2, 3.2 Hz, 1H, G3), 3.46 (ddd,
J ˆ 9.5, 9.5, 2.0 Hz, 1H, G4), 3.34 (s, 3H, OMe); 13C NMR (150 MHz,
CDCl3): d ˆ 135.1, 135.1, 128.3, 127.9, 127.6, 116.5, 116.4, 100.0, 78.5, 75.4,
74.5, 73.2, 71.8, 71.6, 61.3, 55.0; HRMS (FAB): calcd for C19H26O5Na
‡
70.2, 21.6; HRMS (MALDI): calcd for C22H19FO3Na [M‡Na] : 373.1216,
found 373.1226.
‡
[M‡Na] : 357.1678, found 357.1672. [(Ph3P)3RhCl] (138 mg, 0.15 mmol)
Diol 76: DAST (1.7 mL, 12.87 mmol) was added to a solution of lactol 65
(2.15 g, 6.44 mmol) in CH2Cl2 (43 mL) at 08C and the resulting mixture was
stirred for 0.5 h. The reaction mixture was quenched by the addition of
saturated aqueous NaHCO3 (100 mL), diluted with CH2Cl2 (500 mL) and
washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The
organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The crude glycosyl fluoride was azeotroped with benzene
(3 Â 10 mL) and then dried under high vacuum for 1 h. Et2O (43 mL) and
4 Š MS were added and the mixture was cooled to 08C and stirred for
5 min. MeOH (1.3 mL, 32.18 mmol) and SnCl2 (2.20 g, 11.59 mmol) were
added in one portion and the resulting mixture was warmed to 258C and
stirred for 12 h. The reaction mixture was quenched by the addition of Et3N
(20 mL), diluted with CH2Cl2 (500 mL) and washed with saturated aqueous
NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried
(Na2SO4), the solvents were removed under reduced pressure, and the
residue was purified by flash column chromatography (silica gel, 0 ! 60%
Et2O in hexanes) to afford the ring G methyl glycoside (1.39 g, 62%, a:b ca.
4:1, separable) as white foams. Methyl glycoside: Rf ˆ 0.44 (30% Et2O in
hexanes); [a]2D2 ˆ ‡31.84 (c ˆ 7.65, CHCl3); IR (thin film): nÄ ˆ 3076, 2979,
2886, 1724, 1648, 1603, 1452, 1362, 1320, 1270, 1116, 1026, 928, 896,
was added to a solution of the above ring G benzyl ether (994 mg,
2.98 mmol) and DABCO (835 mg, 7.44 mmol) in EtOH/H2O (10:1, 22 mL,
degassed 1 h) at 258C. The resulting mixture was refluxed for 2 h. The
reaction mixture was diluted with CH2Cl2 (200 mL) and washed with
saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The solvents were
removed under reduced pressure and then the residue was dissolved in
acetone/H2O (10:1, 20 mL). NMO (874 mg, 7.44 mmol) and OsO4 (0.5 mL,
2.5% solution in tBuOH) were added and the reaction mixture was stirred
for 8 h at 258C. The reaction mixture was diluted with CH2Cl2 (200 mL)
and washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL).
The organic layer was dried (Na2SO4), the solvents were removed under
reduced pressure, and the residue was purified by flash column chroma-
tography (silica gel, 0 ! 100% EtOAc in hexanes) to afford diol 76
(719 mg, 95% over two steps) as a white foam. 76: Rf ˆ 0.13 (80% Et2O in
hexanes); [a]2D2 ˆ À9.19 (c ˆ 10.45, CHCl3); IR (thin film): nÄ ˆ 3417, 2932,
1612, 1495, 1456, 1379, 1310, 1249, 1196, 1135, 1065, 996, 968, 911, 886 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.43 ± 7.26 (m, 5H, ArH), 4.67, 4.60 (AB,
J ˆ 11.5 Hz, 2H, CH2Ar), 4.62 (d, J ˆ 2.0 Hz, 1H, G1), 3.86 (ddd, J ˆ 8.5,
8.5, 5.0 Hz, 1H, G4), 3.76 (dd, J ˆ 8.5, 3.5 Hz, 1H, G3), 3.70 (dd, J ˆ 11.5,
5.0 Hz, 1H, G5), 3.65 (t, J ˆ 3.0 Hz, 1H, G2), 3.41 (dd, J ˆ 11.0, 9.5 Hz, 1H,
G5), 3.32 (s, 3H, OMe); 13C NMR (125 MHz, CDCl3): d ˆ 137.7, 132.0,
128.5, 128.4, 128.3, 127.8, 99.0, 77.7, 73.1, 71.5, 67.8, 62.3, 55.0; HRMS (FAB):
857 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 8.06 (dd, J ˆ 8.0, 1.0 Hz, 2H,
ArH), 7.54 (t, J ˆ 7.3 Hz, 1H, ArH), 7.43 (t, J ˆ 8.0 Hz, 2H, ArH), 5.94 ±
ˆ
5.80 (m, 2H, CH CH2), 5.45 (t, J ˆ 2.2 Hz, 1H, G2), 5.28 (ddm, J ˆ 18.2,
‡
calcd for C13H18O5Na [M‡Na] : 277.1052, found 277.048.
2.0 Hz, 1H, CH2-E), 5.24 (ddm, J ˆ 18.2, 2.0 Hz, 1H, CH2-E), 5.15 (ddm,
J ˆ 10.2, 1.7 Hz, 1H, CH2-Z), 5.09 (ddm, J ˆ 10.2, 1.7 Hz, 1H, CH2-Z), 4.73
(d, J ˆ 2.5 Hz, 1H, G1), 4.25 (ddt, J ˆ 14.0, 5.5, 1.7 Hz, 1H, OCH2), 4.18 ±
4.05 (m, 2H, OCH2), 4.08 (ddt, J ˆ 14.0, 5.5, 1.7 Hz, 1H, OCH2), 3.85 ± 3.78
(m, 3H, G3, G5, G5), 3.58 ± 3.53 (m, 1H, G4), 3.37 (s, 3H, OMe); 13C NMR
(125 MHz, CDCl3): d ˆ 165.6, 134.9, 134.6, 133.0, 129.7, 128.3, 116.7, 116.6,
98.9, 76.7, 73.9, 72.3, 70.7, 69.7, 60.9, 54.9; HRMS (FAB): calcd for
Benzoates 77 and 78: nBu2SnO (1.20 g, 4.80 mmol) was added to a solution
of ring G diol 76 (1.11 g, 4.37 mmol) in toluene (50 mL) and the resulting
mixture was refluxed with removal of H2O using a Dean Stark apparatus
for 3 h. The reaction mixture was cooled to 08C and BzCl (0.55 mL,
4.80 mmol) was added. The reaction mixture was warmed to 258C and
stirred for 1 h. The reaction mixture was diluted with EtOAc (200 mL) and
washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The
organic layer was dried (Na2SO4), the solvents were removed under
reduced pressure, and the residue was purified by flash column chroma-
tography (silica gel, 0 ! 100% Et2O in hexanes) to afford ring G benzoates
77 and 78 (1.44 g, 92%, 1:1 mixture of G3 and G4 regioisomers) as white
foams. 77: Rf ˆ 0.44 (70% Et2O in hexanes); [a]2D2 ˆ ‡36.59 (c ˆ 0.85,
CHCl3); IR (thin film): nÄ ˆ 3460, 2919, 1721, 1604, 1513, 1454, 1386, 1319,
1270, 1116, 1030, 962, 887, 712 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 8.04
(dd, J ˆ 8.5, 1.0 Hz, 2H, ArH), 7.56 (t, J ˆ 7.3 Hz, 1H, ArH), 7.43 (t, J ˆ
8.0 Hz, 2H, ArH), 7.39 ± 7.26 (m, 5H, ArH), 5.27 (ddd, J ˆ 8.0, 8.0, 4.5 Hz,
1H, G4), 4.80, 4.65 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.73 (d, J ˆ 3.0 Hz, 1H,
G1), 4.08 (dt, J ˆ 8.0, 3.5 Hz, 1H, G3), 3.94 (dd, J ˆ 11.5, 4.5 Hz, 1H, G5),
3.74 (t, J ˆ 3.5 Hz, 1H, G2), 3.71 (dd, J ˆ 11.5, 8.2 Hz, 1H, G5), 3.44 (s, 3H,
OMe), 2.51 (d, J ˆ 8.0 Hz, 1H, OH); 13C NMR (125 MHz, CDCl3): d ˆ
166.5, 138.5, 133.2, 129.8, 128.6, 128.3, 128.0, 127.9, 99.3, 77.6, 73.4, 70.9, 69.1,
‡
C19H24O6Na [M‡Na] : 371.1471, found 371.1482. Ring G alcohol: K2CO3
(440 mg, 3.19 mmol) was added to a solution of the above ring G a-methyl
glycoside (1.11 g, 3.19 mmol) in MeOH (30 mL) at 258C and the resulting
mixture was stirred for 12 h. The reaction mixture was quenched by the
addition of saturated aqueous NH4Cl (50 mL), diluted with Et2O (500 mL)
and washed with brine (2 Â 50 mL). The organic layer was dried (Na2SO4)
and the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 100% Et2O in
hexanes) to afford the ring G alcohol (0.74 g, 95%) as a white foam.
Ring G alcohol: Rf ˆ 0.19 (50% Et2O in hexanes); [a]2D2 ˆ À55.63 (c ˆ 0.76,
CHCl3); IR (thin film): nÄ ˆ 3457, 2932, 1647, 1459, 1423, 1357, 1134, 1061,
1022, 926, 857, 769 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 5.82 ± 5.70 (m,
ˆ
2H, CH CH2), 5.16 (ddm, J ˆ 17.5, 1.5 Hz 1H, CH2-E), 5.13 (ddm, J ˆ 17.5,
1.5 Hz, 1H, CH2-E), 5.03 (ddm J ˆ 10.2, 1.5 Hz, 1H, CH2-Z), 5.00 (ddm, J ˆ
10.2, 1.5 Hz, 1H, CH2-Z), 4.83 (d, J ˆ 2.5 Hz, 1H, G1), 4.05 ± 4.02 (m, 2H,
OCH2), 4.01 (ddt, J ˆ 14.0, 5.5, 1.5 Hz, 1H, OCH2), 3.95 (ddt, J ˆ 14.0, 5.5,
1.5 Hz, 1H, OCH2), 3.77 (dd, J ˆ 5.7, 3.2 Hz, 1H, G2), 3.60 ± 3.54 (m, 2H,
G5, G5), 3.46 (dd, J ˆ 8.3, 3.2 Hz, 1H, G3), 3.34 ± 3.28 (m, 1H, G4), 3.21 (s,
3H, OMe), 2.98 (d, J ˆ 3.0 Hz, 1H, OH); 13C NMR (125 MHz, CDCl3): d ˆ
134.6, 134.4, 116.6, 116.3, 100.3, 77.8, 73.4, 71.4, 71.4, 68.4, 60.3, 54.6; HRMS
‡
60.4, 55.7; HRMS (FAB): calcd for C20H22O6Na [M‡Na] : 381.1314, found
381.1324. 78: Rf ˆ 0.26 (70% Et2O in hexanes); [a]2D2 ˆ À6.34 (c ˆ 1.42,
CHCl3); IR (thin film): nÄ ˆ 3470, 2929, 1720, 1453, 1274, 1121, 1063, 837,
1
713 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 8.03 (d, J ˆ 8.3 Hz, 2H, ArH),
7.57 (t, J ˆ 7.4 Hz, 1H, ArH), 7.43 (t, J ˆ 8.0 Hz, 2H, ArH), 7.35 ± 7.19 (m,
5H, ArH), 5.30 (dd, J ˆ 9.2, 3.3 Hz, 1H, G3), 4.70 (d, J ˆ 3.0 Hz, 1H, G1),
4.65 (s, 2H, CH2Ar), 4.28 (ddd, J ˆ 9.4, 9.4, 5.2 Hz, 1H, G4), 3.91 (t, J ˆ
2.9 Hz, 1H, G2), 3.86 (dd, J ˆ 11.2, 5.2 Hz, 1H, G5), 3.59 (t, J ˆ 10.9 Hz,
1H, G5), 3.39 (s, 3H, OMe), 2.30 (d, J ˆ 5.5 Hz, 1H, OH); 13C NMR
(150 MHz, CDCl3): d ˆ 166.6, 137.6, 133.2, 129.8, 129.6, 128.4, 128.3, 127.7,
99.4, 75.7, 74.7, 73.2, 65.9, 62.9, 55.1; HRMS (FAB): calcd for C20H22O6Na
‡
(FAB): calcd for C12H20O5Na [M‡Na] : 267.1208, found 267.1207. Ring G
benzyl ether: NaH (0.16 g, 3.95 mmol) was added to a solution of the above
ring G alcohol (0.74 g, 3.03 mmol) in DMF (15 mL) at 08C and the
resulting mixture was stirred for 5 min. BnBr (0.54 mL, 4.55 mmol) and
nBu4NI (336 mg, 0.91 mmol) were added and the resulting mixture was
warmed to 258C and stirred for 2.5 h. The reaction mixture was quenched
by the addition of saturated aqueous NH4Cl (50 mL), diluted with Et2O
(200 mL) and washed with brine (2 Â 50 mL). The organic layer was dried
(Na2SO4), and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 0 ! 40%
Et2O in hexanes) to afford the ring G benzyl ether (994 mg, 98%) as a
‡
[M‡Na] : 381.1314, found 381.1322.
Disaccharides 79 and 86: DAST (0.39 mL, 2.70 mmol) was added to a
solution of ring H alcohol 71 (0.95 g, 1.80 mmol) in CH2Cl2 (8.0 mL) at 08C
and the resulting mixture was stirred for 0.5 h. The reaction mixture was
3136
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0947-6539/00/0617-3136 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
‡
quenched by the addition of saturated aqueous NaHCO3 (10 mL), diluted
with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3
(10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The crude ring H
glycosyl fluoride 44 (0.95 g, 1.80 mmol) and ring G alcohol 77 (0.43 g,
1.20 mmol) were azeotroped with benzene (3 Â 10 mL) and then dried
under high vacuum for 1 h. Et2O (6.0 mL) and 4 Š MS were added, the
mixture was cooled to 08C and stirred for 5 min. SnCl2 (0.30 g, 1.60 mmol)
was added in one portion and the resulting mixture was warmed to 258C
and stirred for 3 h. The reaction mixture was quenched by the addition of
Et3N (5 mL), diluted with CH2Cl2 (200 mL), and washed with saturated
aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 50% Et2O
in hexanes) to afford GH disaccharide 79 (0.71 g, 69%) as a white foam. 79:
Rf ˆ 0.54 (50% Et2O in hexanes); [a]2D2 ˆ ‡17.38 (c ˆ 0.65, CHCl3); IR
(thin film): nÄ ˆ 2931, 1719, 1607, 1507, 1455, 1367, 1255, 1108, 1067, 1032, 832,
for C38H52O9SeSiNa [M‡Na] : 783.2443, found 783.2411. GH disaccharide
86 was treated in a similar fashion to afford GH alcohol 87 (99%) as a white
foam. 87: Rf ˆ 0.17 (50% Et2O in hexanes); [a]2D2 ˆ ‡17.27 (c ˆ 0.22,
CHCl3); IR (thin film): nÄ ˆ 3435, 2930, 2856, 1612, 1581, 1513, 1461, 1358,
1302, 1250, 1132, 1067, 1033, 834, 777, 738 cmÀ1 1H NMR (600 MHz,
;
CDCl3): d ˆ 7.50 (d, J ˆ 8.3 Hz, 2H, ArH), 7.35 ± 7.12 (m, 10H, ArH), 6.83
(d, J ˆ 8.7 Hz, 2H, PMB), 4.83, 4.63 (AB, J ˆ 12.3 Hz, 2H, CH2Ar), 4.75 (d,
J ˆ 9.2 Hz, 1H, H1), 4.58, 4.44 (AB, J ˆ 12.3 Hz, 2H, CH2Ar), 4.49 (s, 1H,
G1), 4.25 (brs, 1H, H3), 3.94 (d, J ˆ 12.2 Hz, 1H, H5), 3.89 (d, J ˆ 12.2 Hz,
1H, H5), 3.87 (ddd, J ˆ 9.2, 9.2, 5.3 Hz, 1H, G4), 3.76 (s, 3H, OMe), 3.74
(dd, J ˆ 9.2, 3.5 Hz, 1H, G3), 3.70 (brs, 1H, G2), 3.59 (dd, J ˆ 11.4, 5.3 Hz,
1H, G5), 3.53 (dd, J ˆ 8.8, 3.0 Hz, 1H, H2), 3.20 (s, 3H, OMe), 3.18 (brs,
1H, H4), 3.12 (t, J ˆ 11.0 Hz, 1H, G5), 1.72 (brs, 1H, OH), 0.85 (s, 9H,
tBuSi), 0.09, À0.11 (2  s, 2  3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ
159.4, 138.5, 132.1, 131.2, 129.7, 129.4, 128.7, 128.3, 127.7, 127.5, 126.4, 113.9,
102.8, 99.6, 79.0, 77.4, 74.7, 73.7, 72.9, 70.9, 70.4, 63.4, 59.8, 55.2, 54.9, 48.9,
25.8, 25.8, 18.0, À4.4, À4.7; HRMS (FAB): calcd for C38H52O9SeSiCs
‡
779, 708 cmÀ1
;
1H NMR (600 MHz, C6D6, 340 K): d ˆ 8.09 (d, J ˆ 8.4 Hz,
[M‡Cs] : 893.1600, found 893.1632.
2H, ArH), 7.64 (d, J ˆ 7.9 Hz, 2H, ArH), 7.32 (d, J ˆ 7.3 Hz, 2H, ArH),
7.24 ± 7.12 (m, 2H, ArH), 7.10 ± 7.04 (m, 6H, ArH), 6.95 ± 6.88 (m, 3H,
ArH), 6.74 (d, J ˆ 8.6 Hz, 2H, PMB), 5.77 ± 5.68 (m, 1H, G4), 5.37 (d, J ˆ
5.0 Hz, 1H, H1), 4.60 (d, J ˆ 4.3 Hz, 1H, G1), 4.55, 4.49 (AB, J ˆ 11.9 Hz,
2H, CH2Ar), 4.48 (dd, J ˆ 7.4, 3.2 Hz, 1H, G3), 4.46 (dd, J ˆ 6.2, 3.8 Hz,
1H, H2), 4.32 (s, 2H, CH2Ar), 3.99 (dd, J ˆ 5.0, 3.9 Hz, 1H, H2), 3.91 (dd,
J ˆ 11.6, 4.2 Hz, 1H, G5), 3.85 ± 3.75 (m, 3H, G2, H5, H5), 3.70 (dd, J ˆ
11.6, 7.0 Hz, 1H, G5), 3.53 ± 3.50 (m, 1H, H4), 3.36 (s, 3H, OMe), 3.14 (s,
3H, OMe), 0.97 (s, 9H, tBuSi), 0.15, 0.01 (2 Â s, 2 Â 3H, MeSi); 13C NMR
(150 MHz, C6D6, 340 K): d ˆ 165.5, 160.0, 139.3, 133.9, 132.7, 131.3, 131.0,
130.2, 129.5, 129.2, 128.5, 128.4, 128.3, 127.6, 127.1, 114.3, 100.9, 78.3, 76.5,
76.3, 74.8, 73.7, 73.1, 71.9, 70.4, 62.7, 61.7, 55.1, 54.9, 51.5, 26.2, 18.4, À4.3,
Orthoesters 81 and 88: NaIO4 (0.60 g, 2.70 mmol) and NaHCO3 (0.19 g,
2.20 mmol) were added to a solution of GH alcohol 80 (0.210 g, 0.28 mmol)
in MeOH/CH2Cl2/H2O (3:2:1, 2.1 mL) and the resulting mixture was stirred
at 258C for 4 h. The reaction mixture was diluted with CH2Cl2 (250 mL)
and washed with saturated aqueous NH4Cl (20 mL) and brine (20 mL). The
organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The crude selenoxide was dissolved in toluene (2 mL)
and transferred by cannula to a sealed tube. The flask was washed with
toluene (2 Â 2 mL) and the organics were transferred to the sealed tube.
Diisopropylamine (3 mL) and vinyl acetate (6 mL) were added, and the
tube was sealed and heated to 1408C for 12 h. After cooling, the reaction
mixture was concentrated and the residue was purified by flash column
chromatography (silica gel, 0 ! 80% Et2O in hexanes) to afford the GH
orthoester 81 (0.120 g, 70% over two steps) as a white foam. 81: Rf ˆ 0.27
(30% Et2O in hexanes); [a]2D2 ˆ À12.8 (c ˆ 14.7, CHCl3); IR (thin film): nÄ ˆ
2931, 1612, 1586, 1514, 1385, 1359, 1319, 1250, 1210, 1175, 1113, 1040, 983,
955, 920, 866, 837, 778 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.25 ± 7.15 (m,
7H, ArH), 6.76 (d, J ˆ 8.6 Hz, 2H, PMB), 4.71, 4.51 (AB, J ˆ 11.7 Hz, 2H,
CH2Ar), 4.58 (s, 1H, G1), 4.53, 4.43 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 4.00 ±
3.92 (m, 4H, G2, G3, G5, G4), 3.87 (ddd, J ˆ 9.4, 7.5, 4.9 Hz, 1H, H3), 3.72 ±
3.68 (m, 4H, H5, OMe), 3.62 (t, J ˆ 9.9 Hz, 1H, G5), 3.45 (dd, J ˆ 11.6,
8.8 Hz, 1H, H5), 3.25 ± 3.20 (m, 4H, H4, OMe), 2.03 (dd, J ˆ 13.1, 4.9 Hz,
1H, H2), 1.83 (dd, J ˆ 13.1, 9.5 Hz, 1H, H2), 0.80 (s, 9H, tBuSi), À0.02 (s,
6H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 159.1, 137.8, 130.5, 129.4,
129.2, 128.3, 127.6, 119.3, 113.6, 100.3, 77.8, 77.3, 75.5, 72.9, 72.4, 70.7, 70.2,
63.3, 62.8, 55.2, 55.1, 40.2, 25.7, 17.9, 11.0, À4.7, À4.8; HRMS (FAB): calcd
‡
À4.5; HRMS (FAB): calcd for C45H56O10SeSiCs [M‡Cs] : 997.1863, found
997.1880. Alcohol 78 was coupled in a similar fashion to afford GH
disaccharide 86 (70%) as a white foam. 86: Rf ˆ 0.61 (70% Et2O in
hexanes); [a]2D2 ˆ ‡13.98 (c ˆ 1.13, CHCl3); IR (thin film): nÄ ˆ 2931, 2860,
1719, 1608, 1584, 1507, 1455, 1355, 1249, 1114, 1067, 1038, 831, 773, 708 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 8.08 (d, J ˆ 7.0 Hz, 2H, ArH), 7.55 ± 7.50
(m, 3H, ArH), 7.40 (d, J ˆ 7.7 Hz, 2H, ArH), 7.24 ± 7.14 (m, 8H, ArH), 7.09
(d, J ˆ 8.8 Hz, 2H, PMB), 6.79 (d, J ˆ 8.8 Hz, 2H, PMB), 5.38 (dd, J ˆ 8.9,
3.3 Hz, 1H, G3), 4.80 (d, J ˆ 7.0 Hz, 1H, H1), 4.60 (d, J ˆ 2.6 Hz, 1H, G1),
4.58, 4.55 (AB, J ˆ 11.8 Hz, 2H, CH2Ar), 4.40, 4.31 (AB, J ˆ 11.9 Hz, 2H,
CH2Ar), 4.24 (ddd, J ˆ 9.1, 9.1, 5.1 Hz, 1H, G4), 4.14 (t, J ˆ 4.0 Hz, 1H,
H3), 3.86 (t, J ˆ 3.1 Hz, 1H, G2), 3.77 (s, 3H, OMe), 3.62 (dd, J ˆ 11.4,
5.3 Hz, 1H, G5), 3.55 ± 3.48 (m, 3H, H2, H5, H5), 3.41 (dd, J ˆ 11.0, 9.6 Hz,
1H, G5), 3.31 (s, 3H, OMe), 3.18 ± 3.12 (brs, 1H, H4), 0.86 (s, 9H, tBuSi),
0.06, À0.13 (2  s, 2  3H, MeSi); 13C NMR (150 MHz, CDCl3,): d ˆ 165.5,
159.2, 137.8, 132.8, 132.6, 130.3, 130.2, 129.9, 129.2, 128.8, 128.3, 128.2, 127.7,
127.6, 126.6, 113.7, 99.4, 75.6, 75.0, 73.2, 72.6, 72.4, 70.9, 62.2, 60.4, 55.3, 55.1,
50.0, 25.8, 18.0, À4.5, À4.8; HRMS (MALDI): calcd for C45H56O10SeSiNa
‡
for C32H46O9SiCs [M‡Cs] : 735.1965, found 735.1940. GH alcohol 87 was
treated in similar manner to afford GH orthoester 88 (75%) as a white
foam. 88: Rf ˆ 0.59 (60% Et2O in hexanes); [a]2D2 ˆ À7.78 (c ˆ 0.27, CHCl3);
IR (thin film): nÄ ˆ 2931, 1725, 1608, 1514, 1461, 1378, 1249, 1108, 1032, 950,
‡
[M‡Na] : 887.2705, found 887.2730.
908, 826, 779 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.35 ± 7.21 (m, 7H,
ArH), 6.84 (d, J ˆ 8.6 Hz, 2H, PMB), 4.88, 4.58 (AB, J ˆ 11.7 Hz, 2H,
CH2Ar), 4.69 (brs, 1H, G1), 4.65, 4.49 (AB, J ˆ 11.4 Hz, 2H, CH2Ar), 4.36
(ddd, J ˆ 10.4, 10.4, 4.6 Hz, 1H, G4), 4.05 (t, J ˆ 1.9 Hz, 1H, G2), 4.04 (dd,
J ˆ 10.0, 4.6 Hz, 1H, G5), 3.97 (ddd, J ˆ 10.5, 8.2, 5.2 Hz, 1H, H3), 3.80 (dd,
J ˆ 9.9, 2.5 Hz, 1H, G3), 3.78 (s, 3H, OMe), 3.77 (dd, J ˆ 9.4, 5.1 Hz, 1H,
H5), 3.69 (t, J ˆ 10.2 Hz, 1H, G5), 3.52 (t, J ˆ 10.7 Hz, 1H, H5), 3.35 (ddd,
J ˆ 9.8, 8.3, 5.1 Hz, 1H, H4), 3.32 (s, 3H, OMe), 2.06 (dd, J ˆ 12.9, 5.2 Hz,
1H, H2), 1.88 (dd, J ˆ 12.9, 10.7 Hz, 1H, H2), 0.89 (s, 9H, tBuSi), 0.09, 0.08
(2  s, 2  3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 159.2, 138.0, 130.4,
129.4, 128.3, 127.7, 127.6, 119.6, 113.7, 100.7, 79.9, 77.9, 75.6, 73.1, 73.0, 70.8,
69.4, 63.0, 62.8, 55.3, 55.2, 40.9, 29.7, 25.8, 18.0, À4.5, À4.7; HRMS (FAB):
Alcohols 80 and 87: NaOH (0.014 g, 0.35 mmol) was added to a solution of
GH disaccharide 79 (0.25 g, 0.29 mmol) in MeOH (1.5 mL) at 258C and the
resulting mixture was stirred for 1 h. The reaction mixture was quenched by
the addition of saturated aqueous NH4Cl (5 mL), diluted with Et2O
(200 mL) and washed with brine (2 Â 10 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 0 ! 100%
Et2O in hexanes) to afford GH alcohol 80 (0.220 g, 99%) as a white foam.
80: Rf ˆ 0.55 (100% Et2O); [a]2D2 ˆ ‡20.77 (c ˆ 0.98, CHCl3); IR (thin
film): nÄ ˆ 3436, 2931, 1608, 1578, 1507, 1461, 1354, 1296, 1249, 1132, 1067,
1032, 832, 773, 738, 697 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.56 (dd, J ˆ
7.8, 1.9 Hz, 2H, ArH), 7.35 ± 7.06 (m, 10H, ArH), 6.83 (d, J ˆ 6.7 Hz, 2H,
PMB), 4.79 (d, J ˆ 8.9 Hz, 1H, H1), 4.58, 4.44 (AB, J ˆ 12.1 Hz, 2H,
CH2Ar), 4.49 (s, 1H, G1), 4.36, 4.28 (AB, J ˆ 12.1 Hz, 2H, CH2Ar), 4.26
(brs, 1H, H3), 4.10 (m, 1H, G4), 3.97 (d, J ˆ 12.3 Hz, 1H, H5), 3.92 (d, J ˆ
12.3 Hz, 1H, H5), 3.82 (dd, J ˆ 11.0, 5.7 Hz, 1H, G5), 3.77 (s, 3H, OMe),
3.74 ± 3.70 (m, 2H, G2, G3), 3.64 (dd, J ˆ 8.9, 2.7 Hz, 1H, H2), 3.38 (t, J ˆ
10.7 Hz, 1H, G5), 3.28 (s, 3H, OMe), 3.22 (brs, 1H, H4), 1.25 (brs, 1H,
OH), 0.88 (s, 9H, tBuSi), 0.13, À0.09 (2 Â s, 2 Â 3H, MeSi); 13C NMR
(150 MHz, CDCl3): d ˆ 159.4, 138.6, 131.6, 131.3, 129.7, 129.4, 128.9, 128.1,
127.4, 127.2, 126.4, 113.9, 102.3, 99.7, 83.3, 76.8, 74.7, 73.2, 73.1, 71.0, 65.6,
63.6, 62.4, 55.3, 54.7, 49.2, 25.9, 18.1, À4.5, À4.6; HRMS (MALDI): calcd
‡
calcd for C32H46O9SiCs [M‡Cs] : 735.1965, found 735.1940.
Alcohols 82 and 89: nBu4NF (0.22 mL, 1.0m solution in THF, 0.22 mmol)
was added quickly to a solution of GH orthoester 81 (0.11 g, 0.18 mmol) in
THF (1.0 mL) at 258C and the resulting mixture was stirred for 1 h. The
reaction mixture was quenched by the addition of saturated aqueous
NH4Cl (2 mL), diluted with CH2Cl2 (100 mL) and washed with brine (2 Â
5 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The solvents were removed under
reduced pressure and the residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 100% Et2O in hexanes) to afford GH alcohol 82
(0.087 g, 98%) as a white foam. 82: Rf ˆ 0.32 (80% Et2O in hexanes);
Chem. Eur. J. 2000, 6, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3137 $ 17.50+.50/0
3137

K. C. Nicolaouet al.
FULL PAPER
[a]2D2 ˆ À38.2 (c ˆ 0.48, CHCl3); IR (thin film): nÄ ˆ 3372, 2938, 1720, 1611,
and the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 60% Et2O in
hexanes) to afford GH olefin 84 (0.070 g, 87%) as a white foam. 84: Rf ˆ
0.48 (70% Et2O in hexanes); [a]2D2 ˆ ‡14.8 (c ˆ 0.70, CHCl3); IR (thin
film): nÄ ˆ 2922, 1744, 1612, 1513, 1452, 1366, 1248, 1165, 1116, 1070, 1036,
1509, 1454, 1364, 1303, 1243, 1207, 1170, 1116, 1080, 1032, 983, 911, 808, 742,
1
693 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 7.25 ± 7.15 (m, 7H, ArH), 6.79
(d, J ˆ 8.6 Hz, 2H, PMB), 4.67, 4.54 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.62 (d,
J ˆ 1.1 Hz, 1H, G1), 4.50, 4.43 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.03 ± 3.98
(m, 3H, G2, G3, G5), 3.96 ± 3.93 (m, 1H, G4), 3.91 (brs, 1H, H3), 3.86 (dd,
J ˆ 11.9, 3.8 Hz, 1H, H5), 3.71 (s, 3H, OMe), 3.65 (t, J ˆ 9.6 Hz, 1H, G5),
3.59 (dd, J ˆ 11.8, 7.2 Hz, 1H, H5), 3.29 (dt, J ˆ 7.0, 3.9 Hz, 1H, H4), 3.25 (s,
3H, OMe), 2.64 (d, J ˆ 3.2 Hz, 1H, OH), 2.25 (dd, J ˆ 13.3, 4.6 Hz, 1H,
H2), 1.86 (dd, J ˆ 13.3, 8.4 Hz, 1H, H2); 13C NMR (150 MHz, CDCl3): d ˆ
159.4, 137.7, 130.0, 129.4, 128.4, 127.8, 127.7, 119.4, 113.9, 100.2, 77.7, 76.5,
75.5, 72.9, 71.7, 70.9, 68.7, 63.2, 62.4, 55.2, 55.2, 37.5; HRMS (FAB): calcd for
1
984, 953 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 7.34 ± 7.24 (m, 5H, ArH),
7.31 ± 7.24 (m, 2H, ArH), 6.86 (d, J ˆ 8.7 Hz, 2H, PMB), 6.17 (dd, J ˆ 10.1,
4.7 Hz, 1H, H3), 5.82 (d, J ˆ 10.1 Hz, 1H, H2), 4.81, 4.61 (AB, J ˆ 12.0 Hz,
2H, CH2Ar), 4.71 (d, J ˆ 1.1 Hz, 1H, G1), 4.55, 4.54 (AB, J ˆ 11.5 Hz, 2H,
CH2Ar), 4.16 ± 4.02 (m, 6H, G2, G4, G3, G5, H5, H5), 3.89 ± 3.85 (m, 1H,
H4), 3.82 ± 3.78 (m, 4H, G5, OMe), 3.33 (s, 3H, OMe); 13C NMR
(150 MHz, CDCl3): d ˆ 159.3, 137.9, 130.3, 129.3, 128.5, 128.4, 127.7, 127.6,
125.8, 115.7, 113.8, 100.3, 77.1, 75.9, 72.9, 71.2, 70.0, 66.9, 65.9, 63.3, 55.3,
‡
C26H33O9 [M‡H] : 489.2124, found 489.2290. GH orthoestser 88 was
‡
treated in a similar manner to afford alcohol 89 (97%) as a white foam. 89:
Rf ˆ 0.19 (80% Et2O in hexanes); [a]2D2 ˆ À35.54 (c ˆ 0.65, CHCl3); IR
(thin film): nÄ ˆ 3507, 2931, 1608, 1508, 1455, 1355, 1308, 1243, 1208, 1108,
55.2, 30.3; HRMS (FAB): calcd for C26H30O8Cs [M‡Cs] : 603.0995, found
603.0975. Mesylate 90 was treated in a similar manner to afford olefin 91
(87%) as a white foam. 91: Rf ˆ 0.47 (70% Et2O in hexanes); [a]2D2 ˆ À3.03
(c ˆ 2.05, CHCl3); IR (thin film): nÄ ˆ 2924, 1612, 1513, 1456, 1410, 1323,
1
1079, 1032, 949, 908, 814, 767, 697 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ
7.29 ± 7.14 (m, 7H, ArH), 6.78 (d, J ˆ 8.6 Hz, 2H, PMB), 4.80, 4.52 (AB, J ˆ
11.9 Hz, 2H, CH2Ar), 4.60 (d, J ˆ 1.0 Hz, 1H, G1), 4.50, 4.43 (AB, J ˆ
11.5 Hz, 2H, CH2Ar), 4.30 (ddd, J ˆ 10.4, 10.4, 4.6 Hz, 1H, G4), 3.98 (dd,
J ˆ 11.0, 4.7 Hz, 1H, G5), 3.96 (brs, 1H, G2), 3.92 (ddd, J ˆ 9.2, 7.4, 4.7 Hz,
1H, H3), 3.88 (dd, J ˆ 11.6, 4.2 Hz, 1H, H5), 3.75 (dd, J ˆ 10.0, 2.4 Hz, 1H,
G3), 3.70 (s, 3H, OMe), 3.63 (t, J ˆ 10.2 Hz, 1H, G5), 3.57 (dd, J ˆ 11.7,
8.0 Hz, 1H, H5), 3.30 (dt, J ˆ 7.6, 4.1 Hz, 1H, H4), 3.24 (s, 3H, OMe), 3.00
(brs, 1H, OH), 2.20 (dd, J ˆ 13.0, 4.7 Hz, 1H, H2), 1.82 (dd, J ˆ 13.1, 9.2 Hz,
1H, H2); 13C NMR (150 MHz, CDCl3): d ˆ 159.3, 137.9, 130.0, 129.4, 128.2,
127.7, 127.6, 119.6, 113.9, 100.5, 79.9, 75.4, 72.9, 72.0, 69.3, 68.9, 62.6, 55.2,
1303, 1249, 1164, 1116, 1066, 1036, 983, 952 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d ˆ 7.41 ± 7.25 (m, 7H, ArH), 6.87 (d, J ˆ 8.5 Hz, 2H, PMB), 6.17
(dd, J ˆ 10.0, 4.0 Hz, 1H, H3), 4.78 (d, J ˆ 10.0 Hz, 1H, H2), 4.97, 4.65 (AB,
J ˆ 12.0 Hz, 2H, CH2Ar), 4.71 (s, 1H, G1), 4.56 (s, 2H, CH2Ar), 4.39 (ddd,
J ˆ 10.5, 10.5, 4.5 Hz, 1H, G4), 4.16 ± 4.06 (m, 4H, G2, G5, H5, H5), 3.90
(m, 1H, H4), 3.87 (dd, J ˆ 10.0, 2.5 Hz, 1H, G3), 3.80 (s, 3H, OMe), 3.74 (t,
J ˆ 10.0 Hz, 1H, G5), 3.34 (s, 3H, OMe); 13C NMR (125 MHz, CDCl3): d ˆ
159.5, 137.9, 130.6, 129.3, 128.3, 128.1, 127.9, 127.6, 113.8, 100.7, 80.2, 75.4,
72.3, 70.3, 68.7, 67.1, 65.7, 62.9, 55.2, 55.2, 30.3; HRMS (FAB): calcd for
‡
C26H30O8Cs [M‡Cs] : 603.0995, found 603.1009.
‡
55.1, 46.1, 38.1, 30.2, 11.4; HRMS (FAB): calcd for C26H32O9Na [M‡Na] :
511.1944, found 511.1957.
Diols 85 and 92: OsO4 (0.05 mL, 2.5% solution in tBuOH) was added to a
solution of GH olefin 84 (0.065 g, 0.14 mmol) and NMO (0.019 mg,
0.16 mmol) in acetone/H2O (10:1, 1 mL), and the reaction mixture was
stirred for 24 h at 258C. The reaction mixture was diluted with CH2Cl2
(100 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine
(10 mL). The organic layer was dried (Na2SO4), the solvents were removed
under reduced pressure, and the residue was purified by flash column
chromatography (silica gel, 0 ! 100% EtOAc in hexanes) to afford GH cis-
Mesylates 83 and 90: MsCl (0.016 mL, 0.21 mmol) was added to a solution
of GH alcohol 82 (0.085 g, 0.17 mmol) and Et3N (0.050 mL, 0.35 mmol) in
CH2Cl2 (1.0 mL) at 08C. The resulting mixture was warmed to 258C and
stirred for 2 h. The reaction mixture was quenched by the addition of
MeOH (1.0 mL), diluted with CH2Cl2 (350 mL) and washed with saturated
aqueous NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 0 ! 80%
Et2O in hexanes) to afford GH mesylate 83 (0.095 g, 97%) as a white foam.
83: Rf ˆ 0.13 (60% Et2O in hexanes); [a]2D2 ˆ À21.3 (c ˆ 0.35, CHCl3); IR
(thin film): nÄ ˆ 2919, 1608, 1513, 1455, 1355, 1320, 1249, 1208, 1173, 1114,
diol 85 (0.050 g, 71%) as a white foam. 85: Rf ˆ 0.20 (100% Et2O); [a]D22
ˆ
À11.43 (c ˆ 0.7, CHCl3); IR (thin film): nÄ ˆ 3435, 2924, 1628, 1611, 1567,
1496, 1248, 1172, 1115, 1071, 1034, 991, 814 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d ˆ 7.36 ± 7.21 (m, 7H, ArH), 6.87 (d, J ˆ 8.6 Hz, 2H, PMB), 4.74
(d, J ˆ 1.5 Hz, 1H, G1), 4.71 (s, 2H, CH2Ar), 4.59, 4.52 (AB, J ˆ 11.5 Hz,
2H, CH2Ar), 4.20 (ddd, J ˆ 10.5, 10.5, 4.5 Hz, 1H, G4), 4.13 (brs, 1H, H2),
4.10 ± 4.02 (m, 4H, G2, G5, H3, H5), 4.96 (dd, J ˆ 12.5, 2.5 Hz, 1H, G3),
3.80 (s, 3H, OMe), 3.76 (dd, J ˆ 7.0, 5.1 Hz, 1H, H5), 3.75 (t, J ˆ 10.2 Hz,
1H, G5), 3.64 ± 3.61 (m, 1H, H4), 3.35 (s, 3H, OMe), 2.54 (d, J ˆ 7.0 Hz, 1H,
OH), 2.32 (d, J ˆ 7.0 Hz, 1H, OH); 13C NMR (125 MHz, CDCl3): d ˆ 129.3,
128.5, 127.9, 127.6, 113.9, 100.0, 77.7, 76.1, 75.0, 73.1, 72.1, 71.4, 71.4, 69.2,
1
1079, 1032, 961, 926, 855 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 7.33 ± 7.25
(m, 5H, ArH), 7.22 (d, J ˆ 8.6 Hz, 2H, PMB), 6.85 (d, J ˆ 8.6 Hz, 2H,
PMB), 4.80 (ddd, J ˆ 10.0, 7.8, 5.4 Hz, 1H, H3), 4.74, 4.60 (AB, J ˆ 12.0 Hz,
2H, CH2Ar), 4.67 (d, J ˆ 1.1 Hz, 1H, G1), 4.54 (s, 2H, CH2Ar), 4.09 (ddd,
J ˆ 10.1, 10.1, 4.5 Hz, 1H, G4), 4.06 (t, J ˆ 1.3 Hz, 1H, G2), 4.04 (dd, J ˆ 9.9,
2.4 Hz, 1H, G3), 4.01 (dd, J ˆ 9.5, 4.4 Hz, 1H, G5), 3.92 ± 3.86 (m, 1H, H5),
3.78 (s, 3H, OMe), 3.69 (t, J ˆ 10.0 Hz, 1H, G5), 3.63 ± 3.58 (m, 2H, H4,
H5), 3.31 (s, 3H, OMe), 2.93 (s, 3H, Me), 2.45 (dd, J ˆ 13.1, 5.2 Hz, 1H,
H2), 2.17 (dd, J ˆ 13.1, 10.2 Hz, 1H, H2); 13C NMR (150 MHz, CDCl3): d ˆ
159.5, 137.7, 129.5, 129.4, 128.4, 127.8, 127.7, 118.5, 113.9, 100.2, 79.0, 78.2,
75.4, 74.3, 72.9, 72.5, 71.1, 63.1, 62.4, 55.3, 55.2, 38.2, 30.3, 29.7; HRMS
‡
63.3, 62.1, 55.3, 30.3; HRMS (FAB): calcd for C26H32O10Cs [M‡Cs] :
637.1050, found 637.1073. Olefin 91 was treated in a similar manner to
afford diol 92 (72%) as a white foam. 92: Rf ˆ 0.11 (100% Et2O); [a]D22
ˆ
À37.58 (c ˆ 0.62, CHCl3); IR (thin film): nÄ ˆ 3389, 2931, 1608, 1508, 1461,
1396, 1361, 1246, 1168, 1111, 1064, 1033, 973, 808 cmÀ1; 1H NMR (600 MHz,
CDCl3): d ˆ 7.35 ± 7.20 (m, 7H, ArH), 6.85 (d, J ˆ 8.5 Hz, 2H, PMB), 4.88,
4.59 (AB, J ˆ 11.9 Hz, 2H, CH2Ar), 4.66 (s, 1H, G1), 4.57, 4.54 (AB, J ˆ
11.6 Hz, 2H, CH2Ar), 4.37 (ddd, J ˆ 10.4, 10.4, 4.6 Hz, 1H, G4), 4.08 (dd,
J ˆ 9.6, 4.6 Hz, 1H, G5), 4.06 ± 4.03 (m, 3H, G2, H2, H3), 3.97 (dd, J ˆ 12.3,
3.2 Hz, 1H, H5), 3.91 (dd, J ˆ 10.1, 2.3 Hz, 1H, G3), 3.77 (s, 3H, OMe), 3.74
(t, J ˆ 9.6 Hz, 1H, G5), 3.72 (t, J ˆ 6.0 Hz, 1H, H5), 3.66 ± 3.63 (m, 1H, H4),
3.30 (s, 3H, OMe), 2.75 (brs, 1H, OH); 13C NMR (125 MHz, CDCl3): d ˆ
159.2, 137.8, 129.3, 128.2, 127.7, 127.6, 119.4, 113.8, 100.4, 80.8, 75.3, 74.8,
72.9, 71.6, 71.4, 69.5, 69.4, 62.5, 62.2, 55.2, 55.1; HRMS (MALDI): calcd for
‡
(MALDI): calcd for C27H34O11SNa [M‡Na] : 589.1719, found 589.1722.
Alcohol 89 was treated in a similar fashion to afford mesylate 90 (95%) as a
white foam. 90: Rf ˆ 0.19 (80% Et2O in hexanes); [a]2D2 ˆ À6.5 (c ˆ 0.74,
CHCl3); IR (thin film): nÄ ˆ 2931, 1608, 1508, 1455, 1408, 1355, 1325, 1249,
1208, 1173, 1108, 1038, 961, 914, 849, 755 cmÀ1 1H NMR (600 MHz,
;
CDCl3): d ˆ 7.24 ± 7.14 (m, 5H, ArH), 7.12 (d, J ˆ 8.6 Hz, 2H, PMB), 6.76
(d, J ˆ 8.6 Hz, 2H, PMB), 4.74, 4.49 (AB, J ˆ 11.8 Hz, 2H, CH2Ar), 4.73
(ddd, J ˆ 11.0, 8.5, 5.4 Hz, 1H, H3), 4.59 (d, J ˆ 0.9 Hz, 1H, G1), 4.46, 4.44
(AB, J ˆ 11.3 Hz, 2H, CH2Ar), 4.25 (ddd, J ˆ 10.4, 10.4, 4.6 Hz, 1H, G4),
3.96 (brs, 1H, G2), 3.94 (dd, J ˆ 9.5, 4.6 Hz, 1H, G5), 3.81 (dd, J ˆ 10.7,
4.6 Hz, 1H, H5), 3.75 (dd, J ˆ 10.0, 2.4 Hz, 1H, G3), 3.69 (s, 3H, OMe), 3.60
(t, J ˆ 10.0 Hz, 1H, G5), 3.53 (dt, J ˆ 9.9, 4.9 Hz, 1H, H4), 3.50 (t, J ˆ
10.4 Hz, 1H, H5), 3.22 (s, 3H, OMe), 2.87 (s, 3H, Me), 2.32 (dd, J ˆ 12.8,
5.4 Hz, 1H, H2), 2.04 (dd, J ˆ 12.8, 11.0 Hz, 1H, H2); 13C NMR (150 MHz,
CDCl3): d ˆ 159.6, 137.8, 129.6, 129.3, 128.4, 127.7, 127.6, 118.8, 113.9, 100.4,
80.1, 79.4, 75.6, 74.6, 73.1, 72.7, 69.8, 62.5, 55.3, 55.2, 38.7, 38.2; HRMS
‡
C26H32O10Na [M‡Na] : 527.1893, found 527.1897.
Ring H glycal 93: Rf ˆ 0.68 (50% Et2O in hexanes); [a]2D2 ˆ À16.6 (c ˆ 0.29,
CHCl3); IR (thin film): nÄ ˆ 2930, 2857, 1648, 1615, 1515, 1469, 1301, 1246,
1175, 1092, 917, 836, 778 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.27 (d, J ˆ
8.7 Hz, 2H, PMB), 6.88 (d, J ˆ 8.7 Hz, 2H, PMB), 6.44 (d, J ˆ 6.2 Hz, 1H,
H1), 4.77 (ddd, J ˆ 5.9, 4.5, 1.1 Hz, 1H, H2), 4.60, 4.57 (AB, J ˆ 11.8 Hz,
2H, CH2Ar), 4.02 ± 4.01 (m, 1H, H3), 4.00 (dd, J ˆ 11.7, 4.5 Hz, 1H, H5),
3.91 (dd, J ˆ 11.7, 2.1 Hz, 1H, H5), 3.80 (s, 3H, OMe), 3.47 ± 3.45 (m, 1H,
H4), 0.89 (s, 9H, tBuSi), 0.10 (s, 6H, MeSi); 13C NMR (125 MHz, CDCl3):
d ˆ 159.3, 145.3, 130.2, 129.3, 113.8, 102.2, 75.0, 71.0, 63.5, 55.2, 25.8, 18.0,
‡
(MALDI): calcd for C27H34O11SNa [M‡Na] : 589.1719, found 589.1722.
Olefins 84 and 91: DBU (0.21 mL, 1.67 mmol) was added to a solution of
GH mesylate 83 (0.095 g, 0.17 mmol) in toluene (3 mL) at 258C. The
resulting mixture was refluxed for 24 h. The reaction mixture was cooled
3138
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3138 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
‡
À4.4, À4.7; HRMS (MALDI): calcd for C19H30O4SiNa [M‡Na] : 373.1811,
ArH), 7.23 (d, J ˆ 8.5 Hz, 2H, PMB), 6.86 (d, J ˆ 8.5 Hz, 2H, PMB), 5.95 ±
ˆ
found 373.1829.
5.86 (m, 2H, CH CH2), 5.28 (dm, J ˆ 17.5 Hz, 2H, CH2-E), 5.20 ± 5.17 (m,
3H, G1, CH2-Z), 4.83, 4.52 (AB, J ˆ 10.5 Hz, 2H, CH2Ar), 4.74, 4.71 (AB,
J ˆ 11.5 Hz, 2H, CH2Ar), 4.65 (s, 1H, F1), 4.21 ± 4.09 (m, 4H, OCH2), 4.08
(dd, J ˆ 5.0, 2.5 Hz, 1H, G2), 3.82 ± 3.73 (m, 6H, G4, G5, F4, OMe), 3.64 ±
3.55 (m, 7H, F2, F6, F6, G3, OMe), 3.51 (dd, J ˆ 9.5, 3.0 Hz, 1H, F3), 3.46
(dd, J ˆ 9.5, 9.5 Hz, 1H, G5), 3.36 ± 3.31 (m, 1H, F5), 3.35 (s, 3H, OMe),
2.52 (d, J ˆ 2.0 Hz, 1H, OH); 13C NMR (125 MHz, CDCl3): d ˆ 159.0,
138.2, 134.7, 134.6, 131.3, 129.7, 128.5, 127.8, 127.7, 117.3, 113.8, 96.5, 96.1,
81.9, 78.1, 77.7, 75.5, 74.9, 74.3, 73.6, 72.3, 72.1, 71.4, 71.2, 68.4, 61.9, 61.6,
FG alcohol 94: Ring G trichloroacetimidate 46 (9.80 g, 12.73 mmol) and
ring F tin-acetal 45 (17.25 g, 26.50 mmol) were azeotroped with benzene
(3 Â 30 mL) and then dried under high vacuum for 1 h. CH2Cl2 (100 mL)
was added, the resulting mixture was cooled to 08C and TMSOTf (1.23 mL,
6.14 mmol) was added dropwise. The reaction mixture was warmed to 258C
and stirred 12 h. The reaction mixture was quenched by the addition of
Et3N (20 mL), diluted with CH2Cl2 (800 mL) and washed with saturated
aqueous NaHCO3 (100 mL) and brine (100 mL). The organic layer was
dried (Na2SO4) and the solvents were removed under reduced pressure.
The residue was dissolved in MeOH (100 mL) and PPTS (1.0 g, 3.82 mmol)
was added. The reaction mixture was stirred at 258C for 1 h and then the
reaction mixture was quenched by the addition of Et3N (20 mL). The
solvents were removed under reduced pressure and the residue was
purified by flash column chromatography (silica gel, 0 ! 100% Et2O in
hexanes) to afford FG alcohol 94 (10.82 g, 74% over two steps) as a white
foam. 94: Rf ˆ 0.26 (70% Et2O in hexanes); [a]2D2 ˆ À14.2 (c ˆ 3.11,
CHCl3); IR (thin film): nÄ ˆ 3458, 3066, 3009, 2886, 1726, 1611, 1514, 1452,
‡
59.2, 55.3; HRMS (FAB): calcd for C34H46O11Cs [M‡Cs] : 763.2094, found
763.2073.
FG benzyl ether 97: NaH (0.89 g, 22.15 mmol) was added to a solution of
FG alcohol 96 (12.70 g, 20.14 mmol) in DMF (100 mL) at 08C and the
resulting mixture was stirred for 5 min. BnBr (2.57 mL, 26.18 mmol) and
nBu4NI (1.48 g, 4.03 mmol) were added and the resulting mixture was
warmed to 258C and stirred for 4 h. The reaction mixture was quenched by
the addition of saturated aqueous NH4Cl (50 mL), diluted with Et2O
(800 mL) and washed with brine (2 Â 50 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 0 ! 100%
Et2O in hexanes) to afford FG benzyl ether 97 (13.06 g, 90%) as a white
foam. 97: Rf ˆ 0.18 (70% Et2O in hexanes); [a]2D2 ˆ À31.6 (c ˆ 1.73,
CHCl3); IR (thin film): nÄ ˆ 3064, 3031, 2882, 1612, 1514, 1456, 1368, 1304,
1365, 1269, 1104, 1033, 1000, 931, 754, 713 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d ˆ 8.06 (d, J ˆ 8.0 Hz, 2H, ArH), 7.57 (t, J ˆ 7.5 Hz, 1H, ArH),
7.46 ± 7.32 (m, 7H, ArH), 7.25 (d, J ˆ 8.5 Hz, 2H, PMB), 6.87 (d, J ˆ 8.5 Hz,
ˆ
2H, PMB), 5.90 ± 5.82 (m, 2H, CH CH2), 5.64 (t, J ˆ 2.5 Hz, 1H, G2), 5.30
(d, J ˆ 2.5 Hz, 1H, G1), 5.29 (dd, J ˆ 17.5, 1.8 Hz, 1H, CH2-E), 5.25 (dd, J ˆ
17.5, 1.8 Hz, 1H, CH2-E), 5.19 (dd, J ˆ 10.5, 1.1 Hz, 1H, CH2-Z), 5.11 (dd,
J ˆ 10.5, 1.1 Hz, 1H, CH2-Z), 4.84, 4.56 (AB, J ˆ 10.5 Hz, 2H, CH2Ar), 4.79,
4.70 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.71 (s, 1H, F1), 4.25, 4.18, 4.12, 4.03
(4  dd, J ˆ 12.9, 5.9 Hz, 4H, OCH2), 4.08 (d, J ˆ 2.9 Hz, 1H, F2), 3.92 (t,
J ˆ 9.5 Hz, 1H, F4), 3.90 ± 3.82 (m, 3H, G3, G4, G5), 3.80 (s, 3H, OMe),
3.64 ± 3.54 (m, 4H, F3, F6, F6, G5), 3.38 ± 3.54 (m, 1H, F5), 3.36 (s, 3H,
OMe), 2.41 (d, J ˆ 2.5 Hz, 1H, OH); 13C NMR (125 MHz, CDCl3): d ˆ
165.2, 159.3, 137.7, 134.8, 134.5, 133.1, 130.4, 129.9, 129.8, 129.7, 128.5, 128.3,
127.9, 127.8, 117.0, 116.8, 113.8, 95.0, 94.7, 81.2, 76.6, 75.3, 74.8, 73.6, 73.4,
72.6, 71.4, 71.1, 70.7, 68.9, 68.2, 61.8, 59.3, 55.2; HRMS (FAB): calcd for
1249, 1102, 1055, 1005, 927, 737 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ
7.40 ± 7.30 (m, 10H, ArH), 7.24 (d, J ˆ 8.5 Hz, 2H, PMB), 6.87 (d, J ˆ 8.5 Hz,
ˆ
2H, PMB), 5.96 ± 5.85 (m, 2H, CH CH2), 5.29 (dd, J ˆ 17.5, 2.0 Hz, 1H,
CH2-E), 5.27 (dd, J ˆ 17.5, 2.0 Hz, 1H, CH2-E), 5.20 (d, J ˆ 2.0 Hz, 1H, G1),
5.18 (dd, J ˆ 10.5, 1.0 Hz, 1H, CH2-Z), 5.14 (dd, J ˆ 10.5, 1.0 Hz, 1H, CH2-
Z), 4.84, 4.52 (AB, J ˆ 10.5 Hz, 2H, CH2Ar), 4.78, 4.68 (AB, J ˆ 12.5 Hz,
2H, CH2Ar), 4.74, 4.71 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.62 (s, 1H, F1), 4.27
(dd, J ˆ 12.5, 5.5 Hz, 1H, OCH2), 4.14 (dd, J ˆ 12.5, 5.5 Hz, 1H, OCH2),
4.11 ± 4.05 (m, 2H, OCH2), 3.91 (t, J ˆ 2.0 Hz, 1H, G2), 3.90 (ddd, J ˆ 10.0,
10.0, 5.5 Hz, 1H, G4), 3.83 ± 3.78 (m, 5H, G5, F4, OMe), 3.65 (dd, J ˆ 9.5,
3.0 Hz, 1H, G3), 3.63 (s, 3H, OMe), 3.60 (d, J ˆ 1.5 Hz, 1H, F2), 3.57 ± 3.54
(m, 2H, F6, F6), 3.51 (dd, J ˆ 9.5, 3.0 Hz, 1H, F3), 3.40 (t, J ˆ 9.5 Hz, 1H,
G5), 3.34 (s, 3H, OMe), 3.33 ± 3.30 (m, 1H, F5); 13C NMR (125 MHz,
CDCl3): d ˆ 159.3, 138.3, 138.0, 134.9, 130.5, 129.7, 128.5, 128.2, 127.8, 127.7,
127.5, 117.0, 116.7, 113.8, 95.8, 95.3, 81.8, 78.3, 78.1, 75.5, 75.1, 74.9, 74.2, 74.1,
73.2, 72.6, 72.0, 71.3, 71.1, 62.0, 59.2, 55.2; HRMS (FAB): calcd for
‡
C40H48O12Cs [M‡Cs] : 853.2200, found 853.2231.
FG methyl ether 95: NaH (0.497 g, 12.43 mmol) was added to a solution of
FG alcohol 94 (8.13 g, 11.29 mmol) and MeI (2.10 mL, 33.88 mmol) in
DMF (60 mL) at 08C. The resulting mixture was warmed to 258C and
stirred for 1 h. The reaction mixture was quenched by the addition of
saturated aqueous NH4Cl (50 mL), diluted with Et2O (500 mL), and
washed with brine (2 Â 50 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 80% Et2O in
hexanes) to afford FG methyl ether 95 (7.21 g, 87%) as a white foam. 95:
Rf ˆ 0.35 (70% Et2O in hexanes); [a]2D2 ˆ À14.1 (c ˆ 2.02, CHCl3); IR (thin
film): nÄ ˆ 3067, 2978, 2885, 1728, 1610, 1514, 1451, 1352, 1286, 1104, 932, 856,
824, 767, 714 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 8.06 (d, J ˆ 8.4 Hz, 2H,
ArH), 7.58 ± 7.31 (m, 8H, ArH), 7.23 (d, J ˆ 8.6 Hz, 2H, PMB), 6.86 (d, J ˆ
‡
C41H52O11Cs [M‡Cs] : 853.2564, found 853.2587.
FG alcohol 98: DDQ (3.87 g, 17.06 mmol) was added to a solution of FG
PMB ether 97 (8.20 g, 11.38 mmol) in CH2Cl2/H2O (10:1, 110 mL) at 08C
and the resulting mixture was warmed to 258C and stirred for 1 h. The
reaction mixture was diluted with CH2Cl2 (500 mL) and washed with
saturated aqueous NaHCO3 (80 mL) and brine (80 mL). The organic layer
was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 100% Et2O) to afford FG alcohol 98 (6.22 g, 91%) as a white foam.
98: Rf ˆ 0.29 (100% Et2O); [a]2D2 ˆ À74.8 (c ˆ 0.93, CHCl3); IR (thin film):
ˆ
8.6 Hz, 2H, PMB), 5.94 ± 5.82 (m, 2H, CH CH2), 5.65 (t, J ˆ 2.5 Hz, 1H,
G2), 5.29 (dm, J ˆ 15.8 Hz, 1H, CH2-E), 5.26 (d, J ˆ 2.5 Hz, 1H, G1), 5.23
(dm, J ˆ 15.8 Hz, 1H, CH2-E), 5.19 (dm, J ˆ 10.0 Hz, 1H, CH2-Z), 5.11
(dm, J ˆ 10.0 Hz, 1H, CH2-Z), 4.84, 4.53 (AB, J ˆ 10.5 Hz, 2H, CH2Ar),
4.76, 4.72 (AB, J ˆ 11.9 Hz, 2H, CH2Ar), 4.66 (s, 1H, F1), 4.30 ± 4.03 (m,
4H, OCH2), 3.89 ± 3.79 (m, 7H, G3, G4, G5, F4, OMe), 3.66 (s, 3H, OMe),
3.63 ± 3.52 (m, 5H, F2, F3, F6, F6, G5), 3.35 (s, 3H, OMe), 3.35 ± 3.31 (m,
1H, F5); 13C NMR (150 MHz, CDCl3): d ˆ 165.1, 159.3, 138.0, 134.8, 134.6,
133.0, 130.5, 129.9, 129.9, 129.7, 128.5, 128.3, 127.8, 127.7, 117.1, 113.8, 95.8,
95.0, 81.8, 78.0, 76.5, 75.8, 74.9, 74.3, 73.7, 72.8, 72.0, 71.4, 70.6, 69.0, 61.9,
nÄ ˆ 3456, 3064, 2882, 1453, 1374, 1199, 1106, 999, 928, 737, 701 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.38 ± 7.27 (m, 10H, ArH), 5.96 ± 5.85 (m,
ˆ
2H, CH CH2), 5.29 (dm, J ˆ 17.5 Hz, 1H, CH2-E), 5.25 (dm, J ˆ 17.5 Hz,
1H, CH2-E), 5.20 (d, J ˆ 2.5 Hz, 1H, G1), 5.18 (dm, J ˆ 10.5 Hz, 1H, CH2-
Z), 5.14 (dm, J ˆ 10.5 Hz, 1H, CH2-Z), 4.76, 4.68 (AB, J ˆ 12.0 Hz, 2H,
CH2Ar), 4.75, 4.63 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.68 (s, 1H, F1), 4.26
(ddm, J ˆ 12.5, 5.5 Hz, 1H, OCH2), 4.13 (ddm, J ˆ 12.5, 5.5 Hz, 1H, OCH2),
4.10 ± 4.07 (m, 2H, OCH2), 3.91 ± 3.88 (m, 1H, G4), 3.90 (t, J ˆ 2.5 Hz, 1H,
G2), 3.86 (dt, J ˆ 8.5, 2.0 Hz, 1H, F4), 3.82 (dd, J ˆ 11.0, 5.5 Hz, 1H, G5),
3.70 (dd, J ˆ 10.5, 4.0 Hz, 1H, F6), 3.65 (dd, J ˆ 9.0, 3.0 Hz, 1H, G3), 3.61
(dd, J ˆ 10.5, 5.5 Hz, 1H, F6), 3.58 (s, 3H, OMe), 3.57 (d, J ˆ 3.0 Hz, 1H,
F2), 3.40 (t, J ˆ 10.5 Hz, 1H, G5), 3.37 (s, 3H, OMe), 3.36 ± 3.32 (m, 2H, F3,
F5); 13C NMR (125 MHz, CDCl3): d ˆ 138.2, 137.7, 134.9, 128.6, 128.2,
128.0, 127.8, 127.7, 127.6, 117.1, 116.7, 95.8, 95.4, 81.3, 78.3, 77.3, 75.0, 74.9,
74.1, 73.2, 72.7, 71.8, 71.1, 68.1, 62.1, 61.9, 59.4; HRMS (FAB): calcd for
‡
59.3, 55.3; HRMS (FAB): calcd for C41H50O12Cs [M‡Cs] : 867.2357, found
867.2329.
FG alcohol 96: NaOH (0.23 g, 5.76 mmol) was added to a solution of FG
benzoate 95 (14.10 g, 19.19 mmol) in MeOH/Et2O (1:1, 140 mL) at 258C
and the resulting mixture was stirred for 1 h. The reaction mixture was
quenched by the addition of saturated aqueous NH4Cl (50 mL), diluted
with Et2O (500 mL) and washed with brine (2 Â 50 mL). The organic layer
was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 100% Et2O in hexanes) to afford FG alcohol 96 (11.50 g, 95%) as a
white foam. 96: Rf ˆ 0.20 (100% Et2O); [a]2D2 ˆ À49.8 (c ˆ 1.24, CHCl3); IR
(thin film): nÄ ˆ 3469, 3067, 2883, 1612, 1514, 1457, 1372, 1249, 1100, 1035,
‡
C33H44O10Cs [M‡Cs] : 733.1989, found 733.2010.
FG TIPS ether 99: TIPSOTf (5.34 mL, 19.98 mmol) was added to a
solution of FG alcohol 98 (10.00 g, 16.64 mmol) and 2,6-lutidine (2.91 mL,
24.97 mmol) in CH2Cl2 (85 mL) at 08C. The resulting mixture was warmed
to 258C and stirred for 1 h. The reaction mixture was quenched by the
addition of MeOH (10 mL), diluted with CH2Cl2 (800 mL) and washed with
1002, 930, 735 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.40 ± 7.29 (m, 5H,
Chem. Eur. J. 2000, 6, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3139 $ 17.50+.50/0
3139

K. C. Nicolaouet al.
FULL PAPER
saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The organic
layer was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 80% Et2O in hexanes) to afford FG TIPS ether 99 (12.22 g, 97%)
as a white foam. 99: Rf ˆ 0.67 (70% Et2O in hexanes); [a]2D2 ˆ À43.9 (c ˆ
5.50, CHCl3); IR (thin film): nÄ ˆ 3031, 2941, 2866, 1457, 1364, 1311, 1256,
1200, 1105, 997, 885, 830, 738, 700, 679 cmÀ1; 1H NMR (500 MHz, CDCl3):
5.9 Hz, 1H, F6), 3.54 (s, 3H, OMe), 3.53 (dd, J ˆ 11.6, 5.7 Hz, 1H, G5),
3.42 ± 3.38 (m, 2H, F3, F5), 3.34 (s, 3H, OMe), 2.21 (brs, 1H, OH), 1.10 ±
0.95 (m, 21H, iPr3Si); 13C NMR (150 MHz, CDCl3): d ˆ 165.7, 138.0, 137.5,
128.4, 128.2, 128.0, 127.9, 127.5, 95.4, 94.4, 82.0, 77.3, 76.3, 75.9, 75.5, 73.3,
72.0, 70.9, 68.1, 65.3, 63.2, 61.3, 58.9, 40.6, 30.1, 18.3, 18.1, 13.0; HRMS
‡
(FAB): calcd for C38H57ClO11SiCs [M‡Cs] : 885.2413, found 885.2443. G-4
chloroacetate 100: Rf ˆ 0.30 (70% Et2O in hexanes); [a]2D2 ˆ À30.2 (c ˆ
0.33, CHCl3); IR (thin film): nÄ ˆ 3493, 2942, 2865, 1738, 1454, 1384, 1261,
ˆ
d ˆ 7.38 ± 7.24 (m, 10H, ArH), 5.90 ± 5.84 (m, 2H, CH CH2), 5.29 (dm, J ˆ
17.5 Hz, 1H, CH2-E), 5.25 (dm, J ˆ 17.5 Hz, 1H, CH2-E), 5.24 (d, J ˆ 2.5 Hz,
1H, G1), 5.17 (dm, J ˆ 10.0 Hz, 1H, CH2-Z), 5.12 (dm, J ˆ 10.0 Hz, 1H,
CH2-Z), 4.77, 4.70 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.76 (s, 1H, F1), 4.70, 4.41
(AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.28 ± 4.25 (m, 1H, OCH2), 4.16 ± 4.12 (m,
1H, OCH2), 4.08 ± 4.03 (m, 2H, OCH2), 4.01 (t, J ˆ 8.5 Hz, 1H, F4), 3.91
(ddd, J ˆ 10.5, 10.5, 5.0 Hz, 1H, G4), 3.90 (t, J ˆ 2.5 Hz, 1H, G2), 3.82 (dd,
J ˆ 11.0, 5.5 Hz, 1H, G5), 3.72 (dd, J ˆ 10.5, 2.0 Hz, 1H, F6), 3.66 (d, J ˆ
3.0 Hz, 1H, F2), 3.64 (dd, J ˆ 9.0, 3.0 Hz, 1H, G3), 3.58 (dd, J ˆ 10.5, 6.0 Hz,
1H, F6), 3.51 (s, 3H, OMe), 3.45 (t, J ˆ 10.5 Hz, 1H, G5), 3.38 ± 3.35 (m,
2H, F3, F5), 3.33 (s, 3H, OMe), 1.05 ± 0.97 (m, 21H, iPr3Si); 13C NMR
(125 MHz, CDCl3): d ˆ 138.2, 138.0, 134.9, 128.2, 128.0, 127.7, 127.4, 116.9,
116.5, 95.5, 95.2, 82.4, 78.3, 76.7, 76.3, 75.0, 74.1, 73.0, 72.6, 71.8, 71.0, 70.6,
68.0, 61.9, 61.4, 58.9, 18.2, 18.0, 13.0; HRMS (FAB): calcd for C42H64O10SiCs
1200, 1113, 1057, 1029, 1007, 884, 748 cmÀ1 1H NMR (500 MHz, CDCl3):
;
d ˆ 7.37 ± 7.27 (m, 10H, ArH), 5.35 (d, J ˆ 2.0 Hz, 1H, G1), 5.15 (ddd, J ˆ
10.0, 10.0, 4.0 Hz, 1H, G4), 4.81 (s, 1H, F1), 4.80, 4.57 (AB, J ˆ 12.0 Hz, 2H,
CH2Ar), 4.73, 4.44 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.11, 4.07 (AB, J ˆ
15.0 Hz, 2H, CH2Cl), 4.05 (t, J ˆ 8.5 Hz, 1H, F4), 3.91 (dd, J ˆ 9.5,
3.5 Hz, 1H, G3), 3.89 ± 3.86 (m, 1H, G2), 3.85 (dd, J ˆ 11.0, 5.5 Hz, 1H,
G5), 3.73 ± 3.70 (m, 2H, F2, F6), 3.65 (dd, J ˆ 10.5, 6.0 Hz, 1H, F6), 3.57 (t,
J ˆ 10.0 Hz, 1H, G5), 3.54 (s, 3H, OMe), 3.44 ± 3.39 (m, 2H, F3, F5), 3.34 (s,
3H, OMe), 2.35 (d, J ˆ 10.0 Hz, 1H, OH), 1.06 ± 0.90 (m, 21H, iPr3Si);
13C NMR (125 MHz, CDCl3): d ˆ 166.9, 138.0, 137.3, 128.6, 128.1, 128.1,
127.9, 127.5, 127.4, 95.7, 94.0, 82.1, 77.7, 77.4, 76.3, 73.1, 72.0, 71.9, 70.8, 68.6,
68.1, 61.2, 59.9, 58.9, 40.7, 18.2, 18.0, 13.0; HRMS (FAB): calcd for
‡
C38H57ClO11SiCs [M‡Cs] : 885.2413, found 885.2444.
‡
[M‡Cs] : 889.3323, found 889.3355.
FGH trisaccharide 102: DAST (0.85 mL, 6.45 mmol) was added to a
solution of ring H alcohol 71 (2.26 g, 4.30 mmol) in CH2Cl2 (20 mL) at 08C
and the resulting mixture was stirred for 0.5 h. The reaction mixture was
quenched by the addition of saturated aqueous NaHCO3 (10 mL), diluted
with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3
(10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The crude ring H
glycosyl fluoride 44 (2.30 g, 4.30 mmol) and FG alcohol 101 (1.62 g,
2.15 mmol) were azeotroped with benzene (3 Â 10 mL) and then dried
under high vacuum for 1 h. Et2O (12.0 mL) and 4 Š MS were added, and
the mixture was cooled to 08C and stirred for 5 min. SnCl2 (0.734 g,
3.87 mmol) was added in one portion and the resulting mixture was
warmed to 258C and stirred for 3 h. The reaction mixture was quenched by
the addition of Et3N (10 mL), diluted with CH2Cl2 (500 mL) and washed
with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). The organic
layer was dried (Na2SO4), and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 50% Et2O in hexanes) to afford FGH trisaccharide 102 (2.49 g, 92%)
as a white foam. 102: Rf ˆ 0.32 (50% Et2O in hexanes); [a]2D2 ˆ ‡2.26 (c ˆ
1.37, CHCl3); IR (thin film): nÄ ˆ 2995, 2865, 1770, 1732, 1614, 1580, 1514,
FG diol 43: [(Ph3P)3RhCl] (1.57 g, 1.70 mmol) was added to a solution of
FG bis-allyl ether 99 (12.80 g, 16.91 mmol) and DABCO (4.74 g,
42.27 mmol) in EtOH/H2O (10:1, 150 mL, degassed 1 h) at 258C. The
resulting mixture was refluxed for 2 h. The reaction mixture was diluted
with CH2Cl2 (800 mL) and washed with saturated aqueous NaHCO3
(100 mL) and brine (100 mL). The solvents were removed under reduced
pressure and then the residue was dissolved in acetone/H2O (10:1, 150 mL).
NMO (4.38 g, 37.19 mmol) and OsO4 (1.0 mL, 2.5% solution in tBuOH)
were added and the reaction mixture was stirred for 8 h at 258C. The
reaction mixture was diluted with CH2Cl2 (800 mL) and washed with
saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The organic
layer was dried (Na2SO4), the solvents were removed under reduced
pressure, and the residue was purified by flash column chromatography
(silica gel, 0 ! 100% EtOAc in hexanes) to afford FG diol 43 (9.27 g, 81%
over two steps) as a white foam. 43: Rf ˆ 0.24 (100% Et2O); [a]2D2 ˆ À42.9
(c ˆ 0.80, CHCl3); IR (thin film): nÄ ˆ 3441, 2943, 2866, 1465, 1373, 1313,
1253, 1201, 1119, 1052, 995, 885, 773, 690, 678 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d ˆ 7.37 ± 7.28 (m, 10H, ArH), 5.37 (d, J ˆ 1.5 Hz, 1H, G1), 4.80 (s,
1H, F1), 4.76, 4.52 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.71, 4.42 (AB, J ˆ
11.5 Hz, 2H, CH2Ar), 4.02 (t, J ˆ 9.0 Hz, 1H, F4), 3.92 ± 3.87 (m, 1H,
G4), 3.86 (dd, J ˆ 3.5, 2.0 Hz, 1H, G2), 3.79 (dd, J ˆ 11.0, 5.5 Hz, 1H, G5),
3.73 ± 3.68 (m, 3H, F2, F6, G3), 3.64 (dd, J ˆ 10.5, 6.0 Hz, 1H, F6), 3.51 (s,
3H, OMe), 3.47 (t, J ˆ 10.5 Hz, 1H, G5), 3.42 ± 3.37 (m, 1H, F5), 3.38 (dd,
J ˆ 8.5, 3.0 Hz, 1H, F3), 3.34 (s, 3H, OMe), 2.64 (d, J ˆ 2.5 Hz, 1H, OH),
2.41 (d, J ˆ 9.5 Hz, 1H, OH), 1.06 ± 0.97 (m, 21H, iPr3Si); 13C NMR
(125 MHz, CDCl3): d ˆ 138.0, 137.3, 128.6, 128.2, 128.0, 127.9, 127.5, 127.5,
95.5, 94.1, 82.3, 77.7, 77.3, 76.3, 73.0, 72.0, 71.5, 70.8, 68.1, 62.6, 61.4, 58.9,
1470, 1384, 1254, 1114, 834, 753, 697 cmÀ1 1H NMR (600 MHz, CDCl3):
;
d ˆ 7.52 (d, J ˆ 7.1 Hz, 2H, ArH), 7.36 ± 7.27 (m, 10H, ArH), 7.23 (d, J ˆ
8.5 Hz, 2H, ArH), 7.16 (t, J ˆ 7.5 Hz, 2H, ArH), 7.06 (t, J ˆ 7.3 Hz, 1H,
ArH), 6.86 (d, J ˆ 8.6 Hz, 2H, PMB), 5.24 (d, J ˆ 2.3 Hz, 1H, G1), 5.23 (dd,
J ˆ 9.9, 3.3 Hz, 1H, G3), 4.74 (d, J ˆ 7.9 Hz, 1H, H1), 4.67 (s, 1H, F1), 4.66,
4.61 (AB, J ˆ 12.1 Hz, 2H, CH2Ar), 4.64, 4.35 (AB, J ˆ 11.1 Hz, 2H,
CH2Ar), 4.57, 4.47 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.23 (brs, 1H, H3), 4.20
(ddd, J ˆ 10.0, 10.0, 5.6 Hz, 1H, G4), 4.08, 3.96 (AB, J ˆ 15.2 Hz, 2H,
CH2Cl), 3.97 (t, J ˆ 8.6 Hz, 1H, F4), 3.92 (t, J ˆ 2.4 Hz, 1H, G2), 3.84 ± 3.78
(m, 6H, OMe, F2, G5, H5), 3.69 (dd, J ˆ 10.5, 1.9 Hz, 1H, F6), 3.59 (dd, J ˆ
10.5, 6.1 Hz, 1H, F6), 3.51 ± 3.49 (m, 2H, H2, H5), 3.47 (s, 3H, OMe), 3.33 ±
3.28 (m, 6H, F3, F5, G5, OMe), 3.23 (brs, 1H, H4), 1.08 ± 0.95 (m, 21H,
iPr3Si), 0.90 (s, 9H, tBuSi), 0.12, À0.06 (2 Â s, 2 Â 3H, MeSi); 13C NMR
(150 MHz, CDCl3): d ˆ 166.5, 159.3, 138.0, 137.8, 131.6, 130.0, 129.3, 128.7,
128.4, 128.1, 128.0, 127.8, 127.5, 126.1, 113.9, 101.4, 95.3, 94.3, 82.1, 77.4, 76.2,
75.9, 75.0, 73.4, 72.8, 71.9, 71.0, 70.4, 68.0, 62.8, 61.8, 60.9, 59.0, 55.3, 41.0,
25.8, 18.2, 18.0, 13.0, À4.4, À4.8; HRMS (FAB): calcd for C63H91ClO15Se-
‡
30.3, 18.2, 18.1, 13.0; HRMS (FAB): calcd for C36H56O10SiCs [M‡Cs] :
809.2697, found 809.2730.
FG chloroacetates 100 and 101: nBu2SnO (3.87 g, 15.56 mmol) was added
to a solution of FG diol 43 (9.52 g, 14.06 mmol) in toluene (200 mL) and the
resulting mixture was refluxed with removal of H2O using a Dean Stark
apparatus for 3 h. The reaction mixture was cooled to 08C and chloroacetyl
chloride (CACl) (1.18 mL, 14.77 mmol) was added. The reaction mixture
was warmed to 258C and stirred for 1 h. The reaction mixture was diluted
with EtOAc (500 mL) and washed with saturated aqueous NaHCO3
(80 mL) and brine (80 mL). The organic layer was dried (Na2SO4), the
solvents were removed under reduced pressure, and the residue was
purified by flash column chromatography (silica gel, 0 ! 100% Et2O in
hexanes) to afford FG chloroacetates 100 and 101 (10.34 g, 97%, 1:1
mixture of G3 and G4 regioisomers) as a white foam. G-3 chloroacetate
101: Rf ˆ 0.21 (70% Et2O in hexanes); [a]2D2 ˆ À30.7 (c ˆ 0.30, CHCl3); IR
‡
Si2Cs [M‡Cs] : 1391.3805, found 1391.3720.
FGH alcohol 42: K2CO3 (0.10 g, 0.72 mmol) was added to a solution of
FGH trisaccharide 102 (or 105) (4.52 g, 3.60 mmol) in MeOH/Et2O (1:1,
18 mL) at 258C and the resulting mixture was stirred for 1 h. The reaction
mixture was quenched by the addition of saturated aqueous NH4Cl
(50 mL), diluted with Et2O (500 mL), and washed with brine (2 Â 50 mL).
The organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 100% Et2O in hexanes) to afford FGH alcohol 42
(4.16 g, 98%) as a white foam. 42: Rf ˆ 0.18 (50% EtOAc in hexanes);
[a]2D2 ˆ À22.7 (c ˆ 2.7, CHCl3); IR (thin film): nÄ ˆ 3451, 3051, 2930, 2863,
1612, 1582, 1513, 1463, 1383, 1357, 1304, 1251, 1110, 1031, 942, 885,
(thin film): nÄ ˆ 3434, 2945, 2863, 1760, 1500, 1423, 1114 cmÀ1
;
1H NMR
(600 MHz, CDCl3): d ˆ 7.37 ± 7.27 (m, 10H, ArH), 5.32 (d, J ˆ 2.0 Hz, 1H,
G1), 5.05 (dd, J ˆ 9.8, 3.2 Hz, 1H, G3), 4.81 (s, 1H, F1), 4.72, 4.54 (AB, J ˆ
12.0 Hz, 2H, CH2Ar), 4.70, 4.44 (AB, J ˆ 11.2 Hz, 2H, CH2Ar), 4.27 ± 4.23
(m, 1H, G4), 4.03 (t, J ˆ 8.4 Hz, 1H, F4), 3.99 (dd, J ˆ 3.1, 2.4 Hz, 1H, G2),
3.98, 3.87 (AB, J ˆ 14.9 Hz, 2H, CH2Cl), 3.86 (dd, J ˆ 11.7, 6.0 Hz, 1H, G5),
3.71 (dd, J ˆ 10.4, 5.9 Hz, 1H, F6), 3.70 (s, 1H, F2), 3.64 (dd, J ˆ 10.4,
883 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.55 (d, J ˆ 7.1 Hz, 2H, ArH),
3140
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Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
7.39 ± 7.25 (m, 14H, ArH), 7.15 (t, J ˆ 7.8 Hz, 2H, ArH), 7.06 (t, J ˆ 7.3 Hz,
1H, ArH), 6.82 (d, J ˆ 8.6 Hz, 2H, PMB), 5.16 (d, J ˆ 1.7 Hz, 1H, G1), 4.87,
4.69 (AB, J ˆ 12.2 Hz, 2H, CH2Ar), 4.80 (d, J ˆ 9.1 Hz, 1H, H1), 4.69, 4.40
(AB, J ˆ 11.1 Hz, 2H, CH2Ar), 4.66 (s, 1H, F1), 4.61, 4.47 (AB, J ˆ 12.1 Hz,
2H, CH2Ar), 4.30 (brs, 1H, H3), 4.01 ± 3.92 (m, 5H, F4, H5, H5, G4, G2),
3.83 ± 3.79 (m, 1H, G3), 3.80 (s, 3H, OMe), 3.71 ± 3.68 (m, 2H, G5, F6), 3.61
(dd, J ˆ 9.1, 2.7 Hz, 1H, H2), 3.56 (dd, J ˆ 10.5, 6.1 Hz, 1H, F6), 3.51 (d, J ˆ
2.6 Hz, 1H, F2), 3.47 (s, 3H, OMe), 3.33 ± 3.31 (m, 2H, F3, F5), 3.32 (s, 3H,
OMe), 3.22 (brs, 1H, H4), 3.15 (t, J ˆ 10.9 Hz, 1H, G5), 1.02 ± 0.96 (m,
21H, iPr3Si), 0.90 (s, 9H, tBuSi), 0.14, À0.07 (2 Â s, 2 Â 3H, MeSi);
13C NMR (150 MHz, CDCl3): d ˆ 159.4, 138.4, 138.0, 131.6, 129.6, 129.4,
128.5, 128.4, 128.2, 128.1, 127.6, 127.5, 127.4, 127.4, 127.2, 126.0, 113.9, 102.8,
95.6, 95.2, 82.2, 78.9, 77.4, 76.8, 76.3, 74.4, 73.6, 72.9, 71.9, 70.8, 70.5, 70.1,
68.0, 63.4, 61.5, 60.3, 59.0, 55.2, 48.4, 25.7, 18.2, 18.0, 18.0, 18.0, 13.2, 13.0,
(10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and
the solvents were removed under reduced pressure. The crude ring H
glycosyl fluoride 44 (1.80 g, 3.22 mmol) and FG alcohol 104 (1.26 g,
1.61 mmol) were azeotroped with benzene (3 Â 10 mL) and then dried
under high vacuum for 1 h. Et2O (8 mL) and 4 Š MS were added, and the
mixture was cooled to 08C and stirred for 5 min. SnCl2 (0.55 g, 2.90 mmol)
was added in one portion and the resulting mixture was warmed to 258C
and stirred for 3 h. The reaction mixture was quenched by the addition of
Et3N (10 mL), diluted with CH2Cl2 (500 mL) and washed with saturated
aqueous NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried
(Na2SO4), and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 0 ! 50%
Et2O in hexanes) to afford FGH trisaccharide (Bz) 105 (1.91 g, 92%) as a
white foam. 105: Rf ˆ 0.28 (30% Et2O in hexanes); [a]2D2 ˆ À55.8 (c ˆ 3.12,
CHCl3); IR (thin film): nÄ ˆ 3065, 2931, 2862, 1726, 1611, 1582, 1513, 1458,
‡
À4.4, À4.8; HRMS (FAB): calcd for C61H90O14SeSi2Cs [M‡Cs] :
1315.4089, found 1315.4022.
1356, 1250, 1109, 1040, 908, 835, 736 cmÀ1 1H NMR (600 MHz, CDCl3):
;
d ˆ 8.08 (d, J ˆ 8.3 Hz, 2H, ArH), 7.54 (d, J ˆ 7.2 Hz, 4H, ArH), 7.42 ± 7.08
(m, 16H, ArH), 6.80 (d, J ˆ 8.6 Hz, 2H, PMB), 5.41 (dd, J ˆ 9.6, 3.3 Hz, 1H,
G3), 5.29 (d, J ˆ 2.0 Hz, 1H, G1), 4.82 (d, J ˆ 7.8 Hz, 1H, H1), 4.72 (s, 1H,
F1), 4.69, 4.60 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.64, 4.60 (AB, J ˆ 12.0 Hz,
2H, CH2Ar), 4.40, 4.26 (AB, J ˆ 11.9 Hz, 2H, CH2Ar), 4.37 (ddd, J ˆ 10.0,
10.0, 5.6 Hz, 1H, G4), 4.17 (t, J ˆ 3.5 Hz, 1H, H3), 4.05 (t, J ˆ 2.4 Hz, 1H,
G2), 3.99 (t, J ˆ 8.8 Hz, 1H, F4), 3.78 (s, 3H, OMe), 3.72 (d, J ˆ 1.7 Hz, 1H,
F2), 3.71 ± 3.78 (m, 1H, F6), 3.61 (dd, J ˆ 10.8, 6.1 Hz, 1H, F6), 3.55 (s, 3H,
OMe), 3.52 (dd, J ˆ 7.8, 3.1 Hz, 1H, H2), 3.36 ± 3.46 (m, 3H, F3, F5, G5),
3.32 (s, 3H, OMe), 3.23 (s, 1H, H4), 1.09 ± 0.96 (m, 21H, iPr3Si), 0.89 (s, 9H,
tBuSi), 0.09, À0.12 (2  s, 2  3H, MeSi); 13C NMR (125 MHz, CDCl3): d ˆ
165.3, 159.3, 138.1, 137.8, 132.6, 131.9, 129.9, 129.2, 128.7, 128.2, 128.1, 128.0,
127.7, 127.6, 127.5, 126.2, 113.7, 101.4, 95.3, 94.4, 82.2, 77.5, 76.2, 74.9, 73.4,
72.9, 72.1, 72.0, 70.5, 68.2, 62.2, 61.0, 59.0, 55.2, 49.0, 25.8, 18.2, 18.1, 13.0,
FG benzoate 103: BzCl (1.20 mL, 8.19 mmol) was added to a solution of
FG alcohol 100 (5.14 g, 6.82 mmol), Et3N (1.50 mL, 13.23 mmol) and
4-DMAP (0.20 g, 1.36 mmol) in CH2Cl2 (35 mL) at 08C. The resulting
mixture was warmed to 258C and stirred for 2 h. The reaction mixture was
quenched by the addition of MeOH (1.0 mL), diluted with CH2Cl2
(350 mL) and washed with saturated aqueous NaHCO3 (50 mL) and brine
(50 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 60% Et2O in hexanes) to afford FG
benzoate 103 (5.62 g, 96%) as a white foam. 103: Rf ˆ 0.41 (50% Et2O in
hexanes); [a]2D2 ˆ À111.0 (c ˆ 0.47, CHCl3); IR (thin film): nÄ ˆ 2942, 2865,
1728, 1452, 1269, 1112, 883, 751 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.99
(brd, J ˆ 7.9 Hz, 2H, ArH), 7.58 (t, J ˆ 7.4 Hz, 1H, ArH), 7.44 (t, J ˆ 8.0 Hz,
2H, ArH), 7.40 (brd, J ˆ 7.2 Hz, 2H, ArH), 7.35 (t, J ˆ 7.1 Hz, 2H, ArH),
7.30 ± 7.26 (m, 3H, ArH), 7.21 ± 7.17 (m, 3H, ArH), 5.66 (ddd, J ˆ 10.1, 10.1,
5.5 Hz, 1H, G4), 5.51 (dd, J ˆ 10.0, 3.3 Hz, 1H, G3), 5.39 (d, J ˆ 2.1 Hz, 1H,
G1), 4.86 (s, 1H, F1), 4.76, 4.47 (AB, J ˆ 11.3 Hz, 2H, CH2Ar), 4.68, 4.63
(AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.14 (t, J ˆ 2.8 Hz, 1H, G2), 4.07 (t, J ˆ
8.3 Hz, 1H, F4), 4.00 (dd, J ˆ 10.9, 5.6 Hz, 1H, G5), 3.96, 3.93 (AB, J ˆ
10.1 Hz, 2H, CH2Cl), 3.75 ± 3.68 (m, 3H, F2, F6, G5), 3.66 (dd, J ˆ 10.5,
5.9 Hz, 1H, F6), 3.62 (s, 3H, OMe), 3.46 ± 3.42 (m, 2H, F3, F5), 3.34 (s, 3H,
OMe), 1.27 ± 0.99 (m, 21H, iPr3Si); 13C NMR (150 MHz, CDCl3): d ˆ 166.5,
165.3, 138.0, 137.4, 133.3, 129.8, 129.3, 128.4, 128.3, 128.1, 127.7, 127.5, 95.5,
94.5, 81.9, 77.4, 76.2, 75.7, 73.4, 71.9, 70.9, 70.8, 68.7, 68.0, 61.4, 60.5, 58.9,
‡
À4.5, À4.8; HRMS (FAB): calcd for C68H94O15SeSi2Cs [M‡Cs] :
1419.4351, found 1419.4434.
FGH orthoester 106: NaIO4 (1.103 g, 5.16 mmol) and NaHCO3 (0.350 g,
4.13 mmol) were added to
a solution of FGH alcohol 42 (0.610 g,
0.516 mmol) in MeOH/CH2Cl2/H2O (3:2:1, 12 mL) and the resulting
mixture was stirred at 258C for 2 h. The reaction mixture was diluted with
CH2Cl2 (500 mL) and washed with saturated aqueous NH4Cl (50 mL) and
brine (50 mL). The organic layer was dried (Na2SO4), and the solvents were
removed under reduced pressure. The crude selenoxide was dissolved in
toluene (12 mL) and transferred by cannula to six sealed tubes (2 mL each,
20 mL size). The flask was washed with toluene (2 Â 12 mL) and the
organics were transferred to the tubes (4 mL to each tube). Diisopropyl-
amine (3 mL) and vinyl acetate (6 mL) were added to each tube, and the
tubes were sealed and heated to 1408C for 12 h. After cooling, the reaction
mixture was concentrated and the residue was purified by flash column
chromatography (silica gel, 0 ! 80% Et2O in hexanes, 1% Et3N) to afford
FGH orthoester 106 (430 mg, 81% over two steps) as a white foam. 106:
Rf ˆ 0.47 (40% EtOAc in hexanes); IR (thin film): nÄ ˆ 3037, 2943, 2861,
‡
40.5, 18.2, 18.1, 12.9; HRMS (FAB): calcd for C45H61ClO12SiCs [M‡Cs] :
989.2675, found 989.2710.
FG alcohol 104: Et3N (1.50 mL, 13.23 mmol) was added to a solution of FG
benzoate 103 (5.14 g, 6.82 mmol) in CH2Cl2/MeOH (1:1, 40 mL) at 258C.
The resulting mixture was warmed to 408C and stirred for 6 h. The reaction
mixture was diluted with CH2Cl2 (350 mL) and washed with brine (50 mL).
The organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 80% Et2O in hexanes) to afford FG alcohol 104
(5.62 g, 96%) as a white foam. 104: Rf ˆ 0.35 (70% Et2O in hexanes);
[a]2D2 ˆ À50.2 (c ˆ 1.06, CHCl3); IR (thin film): nÄ ˆ 3443, 2943, 2865, 1725,
1
1614, 1514, 1463, 1250, 1110, 918, 836, 780, 733 cmÀ1; H NMR (600 MHz,
CDCl3): d ˆ 7.36 ± 7.21 (m, 12H, ArH), 6.86 (d, J ˆ 8.5 Hz, 2H, PMB), 5.30
(s, 1H, G1), 4.87, 4.61 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 4.78 (s, 1H, F1), 4.72,
4.43 (AB, J ˆ 11.2 Hz, 2H, CH2Ar), 4.66, 4.51 (AB, J ˆ 11.4 Hz, 2H,
CH2Ar), 4.45 (ddd, J ˆ 9.4, 9.4, 4.5 Hz, 1H, G4), 4.24 (s, 1H, G2), 4.11 (dd,
J ˆ 9.6, 4.6 Hz, 1H, G5), 4.04 (t, J ˆ 8.5 Hz, 1H, F4), 4.03 ± 3.97 (m, 1H,
H3), 3.83 (dd, J ˆ 10.1, 2.1 Hz, 1H, G3), 3.80 ± 3.76 (m, 1H, H5), 3.78 (s, 3H,
OMe), 3.77 (t, J ˆ 10.1 Hz, 1H, G5), 3.69 (dd, J ˆ 10.6, 2.4 Hz, 1H, F6), 3.67
(d, J ˆ 2.4 Hz, 1H, F2), 3.59 (dd, J ˆ 10.6, 5.9 Hz, 1H, F6), 3.54 (t, J ˆ
10.3 Hz, 1H, H5), 3.52 (s, 3H, OMe), 3.40 ± 3.36 (m, 3H, F3, F5, H4), 3.32
(s, 3H, OMe), 2.07 (dd, J ˆ 13.0, 5.1 Hz, 1H, H2), 1.90 (dd, J ˆ 13.0,
10.6 Hz, 1H, H2), 1.06 ± 0.97 (m, 21H, iPr3Si), 0.90 (s, 9H, tBuSi), 0.10, 0.08
(2  s, 2  3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 159.2, 138.0, 137.9,
130.4, 129.3, 128.3, 128.1, 127.7, 127.5, 127.3, 119.6, 113.7, 96.4, 95.9, 82.2,
79.6, 77.8, 77.3, 76.3, 75.8, 73.2, 72.9, 72.4, 70.9, 70.7, 69.2, 67.9, 63.5, 63.0,
61.2, 58.9, 55.2, 40.2, 30.2, 29.6, 25.7, 18.2, 18.0, 12.0, À4.5, À4.8; HRMS
1453, 1381, 1315, 1275, 1200, 1116, 996, 908, 884, 829, 781, 734, 716 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 8.01 (d, J ˆ 8.2 Hz, 2H, ArH), 7.59 (t, J ˆ
7.5 Hz, 1H, ArH), 7.44 (t, J ˆ 7.6 Hz, 2H, ArH), 7.38 (d, J ˆ 7.1 Hz, 2H,
ArH), 7.35 ± 7.32 (m, 3H, ArH), 7.29 ± 7.22 (m, 5H, ArH), 5.37 (d, J ˆ
2.0 Hz, 1H, G1), 5.30 (dd, J ˆ 9.7, 3.3 Hz, 1H, G3), 4.85 (s, 1H, F1), 4.73,
4.45 (AB, J ˆ 11.3 Hz, 2H, CH2Ar), 4.71, 4.65 (AB, J ˆ 11.9 Hz, 2H,
CH2Ar), 4.38 (ddd, J ˆ 10.0, 10.0, 5.5 Hz, 1H, G4), 4.08 (t, J ˆ 2.3 Hz, 1H,
G2), 4.06 (t, J ˆ 8.5 Hz, 1H, F4), 3.93 (dd, J ˆ 11.1, 5.5 Hz, 1H, G5), 3.74 ±
3.72 (m, 2H, F2, F6), 3.64 (dd, J ˆ 10.2, 6.1 Hz, 1H, F6), 3.62 (t, J ˆ 10.2 Hz,
1H, G5), 3.59 (s, 3H, OMe), 3.44 ± 3.40 (m, 2H, F3, F5), 3.34 (s, 3H, OMe),
2.45 (brs, 1H, OH), 1.08 ± 0.97 (m, 21H, iPr3Si); 13C NMR (150 MHz,
CDCl3): d ˆ 167.2, 137.7, 137.6, 133.3, 129.8, 129.7, 128.4, 128.3, 128.2, 127.7,
127.5, 95.5, 94.6, 82.6, 77.4, 76.3, 76.1, 74.8, 73.4, 72.0, 70.8, 68.1, 65.9, 63.4,
‡
‡
(FAB): calcd for C55H84O14Si2Cs [M‡Cs] : 1157.4454, found 1157.4402.
61.5, 59.0, 18.2, 18.1, 13.0; HRMS (FAB): calcd for C43H60O11SiCs [M‡Cs] :
913.2959, found 913.2989.
FGH alcohol 107: nBu4NF (1.18 mL, 1.0m solution in THF, 1.18 mmol) was
added to a solution of FGH orthoester 106 (1.10 g, 1.07 mmol) in THF
(6 mL) at 08C and the resulting mixture was stirred for 0.5 h. The reaction
mixture was quenched by the addition of saturated aqueous NH4Cl (5 mL),
diluted with CH2Cl2 (250 mL) and washed with brine (50 mL). The organic
layer was dried (Na2SO4) and the solvents were removed under reduced
FGH trisaccharide 105 (Bz): DAST (0.64 mL, 4.83 mmol) was added to a
solution of ring H alcohol 71 (1.69 g, 3.22 mmol) in CH2Cl2 (16 mL) at 08C
and the resulting mixture was stirred for 0.5 h. The reaction mixture was
quenched by the addition of saturated aqueous NaHCO3 (10 mL), diluted
with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3
Chem. Eur. J. 2000, 6, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3141 $ 17.50+.50/0
3141

K. C. Nicolaouet al.
FULL PAPER
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 70% Et2O in hexanes) to afford FGH alcohol 107 (0.886 g, 95%)
as a white foam. 107: Rf ˆ 0.58 (100% Et2O); [a]2D2 ˆ À24.0 (c ˆ 0.47,
CHCl3); IR (thin film): nÄ ˆ 3478, 2930, 2873, 1608, 1508, 1461, 1379, 1314,
1250, 1109, 1050, 916, 826, 785, 738 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ
7.36 ± 7.22 (m, 12H, ArH), 6.84 (d, J ˆ 8.6 Hz, 2H, PMB), 5.25 (d, J ˆ
0.9 Hz, 1H, G1), 4.85, 4.57 (AB, J ˆ 11.6 Hz, 2H, CH2Ar), 4.74, 4.62 (AB,
J ˆ 12.0 Hz, 2H, CH2Ar), 4.65 (s, 1H, F1), 4.64, 4.50 (AB, J ˆ 11.4 Hz, 2H,
CH2Ar), 4.41 (ddd, J ˆ 10.6, 10.6, 4.6 Hz, 1H, G4), 4.23 (s, 1H, G2), 4.10
(dd, J ˆ 9.6, 4.6 Hz, 1H, G5), 3.97 (ddd, J ˆ 10.6, 8.2, 5.3 Hz, 1H, H3), 3.86
(t, J ˆ 9.5 Hz, 1H, F4), 3.80 ± 3.72 (m, 2H, G3, H5), 3.77 (s, 3H, OMe), 3.70
(t, J ˆ 10.5 Hz, 1H, G5), 3.67 (dd, J ˆ 10.7, 3.8 Hz, 1H, F6), 3.60 (dd, J ˆ
10.6, 5.5 Hz, 1H, F6), 3.59 (s, 3H, OMe), 3.58 ± 3.48 (brs, 1H, F2), 3.52 (t,
J ˆ 11.2 Hz, 1H, H5), 3.38 ± 3.20 (m, 3H, H4, F3, F5), 3.26 (s, 3H, OMe),
2.67 (s, 1H, OH), 2.06 (dd, J ˆ 13.0, 5.2 Hz, 1H, H2), 1.89 (dd, J ˆ 13.0,
10.6 Hz, 1H, H2), 0.89 (s, 9H, tBuSi), À0.01, À0.02 (2 Â s, 2 Â 3H, MeSi);
13C NMR (125 MHz, CDCl3): d ˆ 159.2, 137.8, 137.7, 130.3, 129.3, 128.5,
128.2, 128.0, 127.7, 127.6, 127.6, 125.4, 119.7, 113.7, 96.6, 96.3, 81.4, 79.6, 77.8,
77.4, 75.7, 74.9, 73.2, 72.9, 72.5, 71.9, 70.7, 69.2, 67.9, 63.7, 63.0, 61.7, 59.4, 55.2,
40.8, 30.2, 25.7, 17.9, À4.5, À4.8; HRMS (FAB): calcd for C46H64O14SiCs
4.2 Hz, 1H, H4), 3.25 (s, 3H, OMe), 2.64 (d, J ˆ 4.2 Hz, 1H, OH), 2.30 (dd,
J ˆ 13.1, 4.8 Hz, 1H, H2), 1.94 (dd, J ˆ 13.1, 9.4 Hz, 1H, H2); 13C NMR
(150 MHz, CDCl3): d ˆ 165.4, 159.5, 137.8, 137.4, 133.2, 129.9, 129.7, 129.7,
128.6, 127.8, 127.6, 119.8, 114.0, 96.2, 95.6, 79.7, 78.6, 77.5, 75.5, 74.4, 73.2,
72.0 71.9, 71.6 69.2, 69.0, 68.9, 65.8, 63.6, 62.7, 61.9, 59.3, 55.3, 37.9; HRMS
‡
(FAB): calcd for C47H54O15Cs [M‡Cs] : 991.2517, found 991.2551.
FGH olefin 110: Martin sulfurane dehydrating agent (0.77 g, 1.14 mmol)
was added to a solution of FGH alcohol 109 (0.245 g, 0.285 mmol) and Et3N
(2.0 mL, 0.014 mmol) in CHCl3 (1.5 mL) at 258C and the resulting mixture
was heated to 508C and stirred for 2 h. The solvents were removed under
reduced pressure and the residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 100% Et2O in hexanes) to afford FGH olefin 110
(0.204 g, 85%) as a white foam. 110: Rf ˆ 0.27 (80% Et2O in hexanes);
[a]2D2 ˆ À40.3 (c ˆ 1.02, CHCl3); IR (thin film): nÄ ˆ 2924, 1727, 1265, 1113,
1044, 710 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 8.06 (d, J ˆ 8.0 Hz, 2H,
ArH), 7.66 (t, J ˆ 7.3 Hz, 1H, ArH), 7.53 (t, J ˆ 7.6 Hz, 2H, ArH), 7.46 ± 7.25
(m, 12H, ArH), 6.95 (d, J ˆ 8.6 Hz, 2H, PMB), 6.27 (dd, J ˆ 10.0, 3.6 Hz,
1H, H3), 5.87 (dd, J ˆ 10.0, 1.1 Hz, 1H, H2), 5.54 (t, J ˆ 9.0 Hz, 1H, F4),
5.41 (s, 1H, G1), 5.03, 4.72 (AB, J ˆ 11.8 Hz, 2H, CH2Ar), 4.84 (s, 1H, F1),
4.74, 4.61 (AB, J ˆ 12.5 Hz, 2H, CH2Ar), 4.64 (s, 2H, CH2Ar), 4.54 (ddd,
J ˆ 10.4, 10.4, 4.6 Hz, 1H, G4), 4.36 (brs, 1H, G2), 4.32 ± 4.14 (m, 2H, G5,
H5), 4.00 (ddd, J ˆ 6.9, 6.9, 2.9 Hz, 1H, H4), 3.96 (dd, J ˆ 9.9, 2.2 Hz, 1H,
G3), 3.87 (s, 3H, OMe), 3.84 (t, J ˆ 10.3 Hz, 1H, G5), 3.74 ± 3.67 (m, 4H,
F2, F3, F5, H5), 3.71 (s, 3H, OMe), 3.61 ± 3.58 (m, 2H, F6), 3.33 (s, 3H,
OMe); 13C NMR (125 MHz, CDCl3): d ˆ 165.3, 159.3, 137.8, 137.4, 133.1,
131.2, 130.1, 129.7, 129.4, 128.4, 128.3, 127.9, 127.7, 127.6, 127.5, 116.0, 113.8,
96.4, 95.6, 79.9, 78.6, 77.5, 75.4, 74.4, 73.2, 71.9, 71.6, 70.3, 68.9, 68.5, 67.0,
‡
[M‡Cs] : 1001.3120, found 1001.3167.
FGH benzoate 108: BzCl (75.0 mL, 0.648 mmol) was added to a solution of
FGH alcohol 107 (0.469 g, 0.540 mmol), Et3N (135 mL, 0.971 mmol) and
4-DMAP (13 mg, 0.108 mmol) in CH2Cl2 (3.0 mL) at 08C. The resulting
mixture was warmed to 258C and stirred for 2 h. The reaction mixture was
quenched by the addition of MeOH (0.5 mL), diluted with CH2Cl2
(100 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine
(10 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 100% Et2O in hexanes) to afford FGH
benzoate 108 (0.510 g, 97%) as a white foam. 108: Rf ˆ 0.44 (60% Et2O in
hexanes); [a]2D2 ˆ À45.5 (c ˆ 0.32, CHCl3); IR (thin film): nÄ ˆ 2931, 2896,
‡
65.8, 61.8, 59.3, 55.2, 15.2; HRMS (FAB): calcd for C47H52O14Cs [M‡Cs] :
973.2411, found 973.2445.
FGH alcohol 111: K2CO3 (9.0 mg, 0.065 mmol) was added to a solution of
FGH benzoate 110 (0.110 g, 0.131 mmol) in MeOH (1.0 mL) at 258C and
the resulting mixture was stirred for 6 h. The solvents were removed under
reduced pressure and the residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 100% Et2O in hexanes) to afford FGH alcohol 111
(87 mg, 90%) as a white foam. 111: Rf ˆ 0.43 (100% Et2O); [a]2D2 ˆ À42.3
(c ˆ 0.13, CHCl3); IR (thin film): nÄ ˆ 3448, 2924, 1610, 1513, 1452, 1249,
1167, 1102, 1050 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.38 ± 7.27 (m, 12H,
ArH), 6.86 (d, J ˆ 8.6 Hz, 2H, PMB), 6.18 (dd, J ˆ 10.0, 3.7 Hz, 1H, H3),
5.78 (dd, J ˆ 10.0, 1.0 Hz, 1H, H2), 5.29 (d, J ˆ 1.1 Hz, 1H, G1), 5.01 (s, 1H,
F1), 4.94, 4.62 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 4.77, 4.66 (AB, J ˆ 11.9 Hz,
2H, CH2Ar), 4.68 (s, 2H, CH2Ar), 4.45 (ddd, J ˆ 10.5, 10.5, 4.6 Hz, 1H,
G4), 4.26 (brs, 1H, G2), 4.16 ± 4.06 (m, 3H, G5, H5, H5), 3.92 (ddd, J ˆ 3.9,
3.9, 3.9 Hz, 1H, H4), 3.88 (t, J ˆ 9.4 Hz, 1H, F4), 3.84 (dd, J ˆ 10.0, 2.4 Hz,
1H, G3), 3.80 (s, 3H, OMe), 3.73 (t, J ˆ 10.2 Hz, 1H, G5), 3.69 (dd, J ˆ 10.0,
4.0 Hz, 1H, F6), 3.62 (dd, J ˆ 10.0, 5.5 Hz, 1H, F6), 3.58 (s, 3H, OMe), 3.56
(d, J ˆ 2.9 Hz, 1H, F2), 3.37 (s, 3H, OMe), 3.36 ± 3.33 (m, 2H, F3, F5), 2.68
(s, 1H, OH); 13C NMR (150 MHz, CDCl3): d ˆ 137.9, 131.3, 130.2, 129.4,
128.6, 128.4, 128.0, 127.8, 127.7, 113.9, 96.4, 95.9, 81.5, 79.4, 75.6, 74.9, 73.2,
72.7, 70.4, 68.6, 68.2, 68.0, 67.1, 65.8, 64.4, 61.8, 59.5, 55.3, 46.5; HRMS
1
1725, 1614, 1508, 1455, 1255, 1102, 1037, 914, 832, 779, 732 cmÀ1; H NMR
(500 MHz, CDCl3): d ˆ 8.07 (d, J ˆ 7.1 Hz, 2H, ArH), 7.68 (t, J ˆ 7.4 Hz,
1H, ArH), 7.53 (t, J ˆ 7.6 Hz, 2H, ArH), 7.46 ± 7.20 (m, 12H, ArH), 6.93 (d,
J ˆ 8.6 Hz, 2H, PMB), 5.55 (t, J ˆ 9.3 Hz, 1H, F4), 5.39 (d, J ˆ 1.2 Hz, 1H,
G1), 4.97, 4.68 (AB, J ˆ 11.6 Hz, 2H, CH2Ar), 4.84 (s, 1H, F1), 4.75, 4.62
(AB, J ˆ 12.7 Hz, 2H, CH2Ar), 4.75, 4.59 (AB, J ˆ 11.0 Hz, 2H, CH2Ar),
4.53 (ddd, J ˆ 10.4, 10.4, 6.0 Hz, 1H, G4), 4.36 (brs, 1H, G2), 4.21 (dd, J ˆ
9.5, 4.6 Hz, 1H, G5), 4.09 (ddd, J ˆ 10.5, 8.2, 5.1 Hz, 1H, H3), 3.92 (dd, J ˆ
10.0, 2.3 Hz, 1H, G3), 3.90 ± 3.85 (m, 1H, H5), 3.87 (s, 3H, OMe), 3.83 (t,
J ˆ 10.3 Hz, 1H, G5), 3.74 (s, 3H, OMe), 3.73 ± 3.56 (m, 6H, F2, F3, F5, F6,
F6, H5), 3.46 (ddd, J ˆ 9.8, 8.4, 4.7 Hz, 1H, H4), 3.33 (s, 3H, OMe), 2.15
(dd, J ˆ 13.0, 5.2 Hz, 1H, H2), 2.00 (dd, J ˆ 13.0, 10.7 Hz, 1H, H2), 0.99 (s,
9H, tBuSi), 0.19, 0.18 (2 Â s, 2 Â 3H, MeSi); 13C NMR (125 MHz, CDCl3):
d ˆ 165.3, 159.2, 156.3, 137.8, 137.4, 133.1, 130.4, 129.7, 129.7, 129.4, 128.4,
128.3, 128.3, 127.8, 127.6, 127.6, 125.4, 119.7, 113.7, 96.7, 96.0, 80.0, 78.7, 78.0,
77.5, 75.7, 74.4, 73.3, 72.9, 71.9, 71.6, 70.7, 69.2, 68.9, 63.7, 63.0, 61.8, 59.3, 55.2,
40.8, 30.2, 25.7, 18.0, À4.5, À4.8; HRMS (FAB): calcd for C53H68O15SiCs
‡
‡
[M‡Cs] : 1105.3382, found 1105.3333.
(FAB): calcd for C40H48O13Cs [M‡Cs] : 869.2149, found 869.2118.
FGH alcohol 109: nBu4NF (1.08 mL, 1.0m solution in THF, 1.08 mmol) was
added to a solution of FGH benzoate 108 (0.700 g, 0.719 mmol) and AcOH
(8.0 mL, 0.144 mmol) in THF (4 mL) at 258C and the resulting mixture was
stirred for 1 h. The reaction mixture was quenched by the addition of
saturated aqueous NaHCO3 (5 mL), diluted with CH2Cl2 (250 mL) and
washed with brine (50 mL). The organic layer was dried (Na2SO4) and the
solvents were removed under reduced pressure. The residue was purified
by flash column chromatography (silica gel, 0 ! 100% Et2O in hexanes) to
afford FGH alcohol 109 (0.587 g, 95%) as a white foam. 109: Rf ˆ 0.46
(100% Et2O); [a]2D2 ˆ À46.3 (c ˆ 0.30, CHCl3); IR (thin film): nÄ ˆ 2908,
1725, 1602, 1514, 1361, 1265, 1096, 1043, 808, 712 cmÀ1; 1H NMR (600 MHz,
CDCl3): d ˆ 7.99 (d, J ˆ 7.2 Hz, 2H, ArH), 7.59 (t, J ˆ 7.4 Hz, 1H, ArH), 7.45
(t, J ˆ 7.7 Hz, 2H, ArH), 7.36 ± 7.16 (m, 12H, ArH), 6.88 (d, J ˆ 8.6 Hz, 2H,
PMB), 5.46 (t, J ˆ 9.5 Hz, 1H, F4), 5.33 (s, 1H, G1), 4.88, 4.60 (AB, J ˆ
11.6 Hz, 2H, CH2Ar), 4.76 (s, 1H, F1), 4.67, 4.54 (AB, J ˆ 12.4 Hz, 2H,
CH2Ar), 4.62, 4.53 (AB, J ˆ 11.2 Hz, 2H, CH2Ar), 4.46 (ddd, J ˆ 10.5, 10.5,
4.6 Hz, 1H, G4), 4.27 (brs, 1H, G2), 4.14 (dd, J ˆ 9.5, 4.6 Hz, 1H, G5), 4.02
(ddd, J ˆ 12.3, 8.8, 4.3 Hz, 1H, H3), 3.98 (dd, J ˆ 11.8, 4.2 Hz, 1H, H5), 3.84
(dd, J ˆ 10.0, 2.4 Hz, 1H, G3), 3.80 (s, 3H, OMe), 3.76 (t, J ˆ 10.4 Hz, 1H,
G5), 3.66 ± 3.62 (m, 3H, F2, F3, F5), 3.64 (s, 3H, OMe), 3.61 (ddd, J ˆ 9.4,
6.0, 3.7 Hz, 1H, H5), 3.54 ± 3.51 (m, 2H, F6, F6), 3.41 (ddd, J ˆ 7.8, 7.8,
FGH TBS ether 112: NaH (28 mg, 0.709 mmol) was added to a solution of
FGH alcohol 111 (87 mg, 0.118 mmol) and [18]crown-6 (50 mg,
0.118 mmol) in THF (0.6 mL) at 08C and the resulting mixture was stirred
for 15 min. TBSCl (38 mg, 0.236 mmol) was added at 10 min intervals (6 Â )
and the resulting mixture was stirred for 1 h. The reaction mixture was
quenched by slow addition of saturated aqueous NaHCO3 (1 mL), diluted
with CH2Cl2 (200 mL) and washed with brine (10 mL). The organic layer
was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 70% Et2O in hexanes) to afford FGH TBS ether 112 (81 mg, 80%)
as a white foam. 112: Rf ˆ 0.59 (80% Et2O in hexanes); [a]2D2 ˆ À24.6 (c ˆ
0.23, CHCl3); IR (thin film): nÄ ˆ 2926, 1611, 1513, 1462, 1250, 1110, 1032,
837, 779 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.37 ± 7.25 (m, 12H, ArH),
6.86 (d, J ˆ 8.6 Hz, 2H, PMB), 6.16 (dd, J ˆ 9.8, 3.2 Hz, 1H, H3), 5.76 (dd,
J ˆ 10.1, 1.0 Hz, 1H, H2), 5.32 (s, 1H, G1), 4.92, 4.63 (AB, J ˆ 11.6 Hz, 2H,
CH2Ar), 4.78 (s, 1H, F1), 4.65, 4.61 (AB, J ˆ 11.4 Hz, 2H, CH2Ar), 4.54 (s,
2H, CH2Ar), 4.42 (ddd, J ˆ 10.5, 10.5, 4.5 Hz, 1H, G4), 4.24 (brs, 1H, G2),
4.12 ± 4.03 (m, 3H, G5, H5, H5), 3.91 (brt, J ˆ 3.8 Hz, 1H, H4), 3.86 (t, J ˆ
8.9 Hz, 1H, F4), 3.82 (dd, J ˆ 10.0, 2.4 Hz, 1H, G3), 3.79 (s, 3H, OMe), 3.69
(t, J ˆ 10.5 Hz, 1H, G5), 3.60 (brd, J ˆ 10.3 Hz, 1H, F6), 3.54 ± 3.47 (m, 2H,
F2, F6), 3.51 (s, 3H, OMe), 3.31 (s, 3H, OMe), 3.30 ± 3.25 (m, 2H, F3, F5),
3142
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3142 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
0.88 (s, 9H, tBuSi), 0.04, 0.03 (2 Â s, 2 Â 3H, MeSi); 13C NMR (150 MHz,
CDCl3): d ˆ 137.9, 137.5, 131.2, 129.4, 128.3, 128.3, 127.9, 127.8, 127.7, 127.6,
113.8, 96.2, 95.9, 82.1, 80.0, 75.3, 73.2, 71.6, 71.3, 70.3, 68.6, 67.5, 67.0, 63.6,
59.1, 55.3, 38.7, 29.7, 25.9, 18.1, À3.7, À5.2; HRMS (FAB): calcd for
130.2, 129.8, 129.6, 129.6, 129.5, 129.4, 128.5, 128.4, 128.3, 127.8, 127.6, 127.6,
126.9, 119.2, 113.8, 95.8, 95.7, 82.2, 80.9, 75.6, 73.3, 72.7, 71.8, 71.8, 71.3, 71.2,
69.4, 68.5, 67.5, 65.8, 63.4, 63.0, 61.8, 59.1, 55.2, 25.9, 18.1, 15.2, À3.7, À5.1;
‡
HRMS (MALDI): calcd for C53H68O16SiNa [M‡Na] : 1011.4174, found
‡
C46H62O13SiCs [M‡Cs] : 983.3014, found 983.3036.
1011.4205.
FGH cis-diol 113 from 112: OsO4 (0.10 mL, 2.5% solution in tBuOH) was
added to a solution of FGH olefin 112 (201 mg, 0.106 mmol), NMO
(59.0 mg, 0.526 mmol), and quinuclidine (27.0 mg, 0.106 mmol) in acetone/
H2O (10:1, 1 mL) and the reaction mixture was stirred for 36 h at 258C. The
reaction mixture was diluted with CH2Cl2 (100 mL) and washed with
saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer
was dried (Na2SO4), the solvents were removed under reduced pressure,
and the residue was purified by flash column chromatography (silica gel,
0 ! 100% EtOAc in hexanes) to afford FGH diol 113 (144 mg, 70%, ca.
8:1 mixture of diastereoisomers) as a white foam, identical to that
described below.
FGH inverted alcohol 115: Dess ± Martin periodinane (73 mg, 0.172 mmol)
was added to a solution of FGH alcohol 114 (85 mg, 0.086 mmol) and
NaHCO3 (144 mg, 1.719 mmol) in CH2Cl2 (0.5 mL) at 258C and the
resulting mixture was stirred for 1 h. The reaction mixture was diluted with
CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3 (10 mL)
and brine (10 mL). The organic layer was dried (Na2SO4) and the solvents
were removed under reduced pressure to afford the crude FGH ketone
(85 mg) as a white foam. Crude ketone: Rf ˆ 0.35 (60% EtOAc in
hexanes); IR (thin film): nÄ ˆ 2926, 2872, 1766, 1719, 1608, 1514, 1467,
1367, 1249, 1102, 1038, 838 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 8.06 (d,
J ˆ 7.4 Hz, 2H, ArH), 7.61 (t, J ˆ 7.4 Hz, 1H, ArH), 7.48 (t, J ˆ 7.9 Hz, 2H,
ArH), 7.41 ± 7.25 (m, 10H, ArH), 7.17 (d, J ˆ 8.5 Hz, 2H, PMB), 6.80 (d, J ˆ
8.5 Hz, 2H, PMB), 5.97 (d, J ˆ 9.6 Hz, 1H, H3), 5.36 (s, 1H, G1), 4.84, 4.64
(AB, J ˆ 11.6 Hz, 2H, CH2Ar), 4.68 (s, 1H, F1), 4.62 ± 4.57 (m, 4H, CH2Ar),
4.49 (ddd, J ˆ 10.5, 10.5, 4.6 Hz, 1H, G4), 4.29 (brs, 2H, G2), 4.14 (dd, J ˆ
9.8, 4.8 Hz, 1H, G5), 4.11 (dd, J ˆ 9.7, 6.0 Hz, 1H, H5), 4.07 ± 4.03 (m, 1H,
H4), 3.88 (dd, J ˆ 10.3, 2.4 Hz, 1H, G3), 3.86 (t, J ˆ 9.1 Hz, 1H, F4), 3.81 ±
3.75 (m, 2H, G5, H5), 3.77 (s, 3H, OMe), 3.61 (dd, J ˆ 10.5, 1.8 Hz, 1H, F6),
3.55 (dd, J ˆ 10.5, 5.5 Hz, 1H, F6), 3.51 (s, 3H, OMe), 3.46 (d, J ˆ 3.1 Hz,
1H, F2), 3.32 (s, 3H, OMe), 3.31 ± 3.26 (m, 2H, F3, F5), 0.86 (s, 9H, tBuSi),
0.04 (s, 6H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 188.8, 165.1, 159.6,
137.8, 137.6, 133.0, 130.0, 129.6, 129.1, 129.0, 128.5, 128.4, 128.3, 127.8, 127.7,
127.5, 113.9, 95.6, 95.3, 82.1, 80.4, 78.6, 76.5, 75.9, 73.4, 73.2, 71.5, 71.3, 70.6,
67.5, 63.1, 62.7, 62.0, 59.0, 55.2, 53.4, 30.3, 29.7, 25.9, 18.1, À3.7, À5.1; HRMS
FGH cis-diol 113 from 134: NaOH (4.0 mg, 0.089 mmol) was added to a
solution of FGH TBS ether 134 (163 mg, 0.179 mmol) in MeOH/Et2O (1:1,
1.0 mL) at 258C and the resulting mixture was stirred for 1 h. The reaction
mixture was quenched by the addition of saturated aqueous NH4Cl (5 mL),
diluted with Et2O (100 mL) and washed with brine (10 mL). The organic
layer was dried (Na2SO4), and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 100% Et2O in hexanes) to afford FGH cis-diol 113 (150 mg, 95%)
as a white foam. 113: Rf ˆ 0.32 (70% EtOAc in hexanes); [a]2D2 ˆ À24.0
(c ˆ 0.12, CHCl3); IR (thin film): nÄ ˆ 3453, 2929, 1612, 1514, 1464, 1382,
1
1250, 1108, 838, 781, 737 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 7.39 ± 7.24
(m, 12H, ArH), 6.88 (d, J ˆ 8.4 Hz, 2H, PMB), 5.30 (s, 1H, G1), 4.88, 4.61
(AB, J ˆ 11.8 Hz, 2H, CH2Ar), 4.66 (s, 1H, F1), 4.64, 4.58 (AB, J ˆ 11.8 Hz,
2H, CH2Ar), 4.58, 4.54 (AB, J ˆ 10.1 Hz, 2H, CH2Ar), 4.44 (ddd, J ˆ 10.5,
10.5, 4.6 Hz, 1H, G4), 4.26 (brs, 1H, G2), 4.13 (dd, J ˆ 9.5, 4.6 Hz, 1H, G5),
4.06 ± 4.03 (m, 2H, H2, H3), 3.97 (dd, J ˆ 12.0, 3.2 Hz, 1H, H5), 3.89 (dd,
J ˆ 10.2, 2.2 Hz, 1H, G3), 3.73 (dd, J ˆ 12.5, 5.8 Hz, 1H, H5), 3.86 (t, J ˆ
9.0 Hz, 1H, F4), 3.80 (s, 3H, OMe), 3.74 (t, J ˆ 10.5 Hz, 1H, G5), 3.68 ± 3.66
(m, 1H, H4), 3.61 (dd, J ˆ 10.6, 1.8 Hz, 1H, F6), 3.51 (s, 3H, OMe), 3.53
(dd, J ˆ 10.5, 5.6 Hz, 1H, F6), 3.51 (brs, 1H, F2), 3.33 (s, 3H, OMe), 3.33 ±
3.25 (m, 2H, F3, F5), 2.71 (d, J ˆ 6.5 Hz, 1H, OH), 2.56 (d, J ˆ 5.4 Hz, 1H,
OH), 0.86 (s, 9H, tBuSi), 0.04, 0.03 (2 Â s, 2 Â 3H, MeSi); 13C NMR
(150 MHz, CDCl3): d ˆ 159.4, 157.7, 137.8, 129.8, 129.4, 128.3, 128.3, 127.7,
127.7, 119.5, 113.9, 95.9, 82.9, 80.7, 77.1, 77.1, 75.6, 74.7, 73.2, 71.8, 71.5, 71.3,
69.6, 69.3, 63.3, 62.3, 61.7, 59.0, 55.2, 30.2, 25.9, 18.1, À3.8, À5.2; HRMS
‡
(FAB): calcd for C53H66O16SiCs [M‡Cs] : 1119.3174, found 1119.3133. The
above crude ketone was azeotroped with benzene (2 Â 2 mL) and then
pumped under high vacuum for 1 h. The residue was dissolved in Et2O
(1.0 mL) and cooled to À108C. Li(tBuO)3AlH (95 mL, 1.0m solution in
THF, 0.095 mmol) was added and the reaction mixture was stirred for 1 h.
The reaction mixture was quenched by the addition of saturated aqueous
NH4Cl (1 mL), diluted with CH2Cl2 (100 mL) and washed with saturated
aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried
(Na2SO4), the solvents were removed under reduced pressure, and the
residue was purified by flash column chromatography (silica gel, 0 ! 100%
Et2O in hexanes) to afford FGH inverted alcohol 115 (68 mg, 80% over
two steps) as a white foam. 115: Rf ˆ 0.34 (50% EtOAc in hexanes); [a]D22
ˆ
‡
À19.2 (c ˆ 0.12, CHCl3); IR (thin film): nÄ ˆ 3448, 2943, 2861, 1725, 1614,
(MALDI): calcd for C46H64O15SiCs [M‡Cs] : 1017.3069, found 1017.3030.
1514, 1455, 1372, 1308, 1255, 1108, 1079, 1032, 843, 779 cmÀ1 1H NMR
;
FGH benzoate 114: nBu2SnO (47 mg, 0.189 mmol) was added to a solution
of FGH diol 113 (152 mg, 0.172 mmol) in MeOH (3.0 mL) and the resulting
mixture was refluxed for 3 h. The reaction mixture was cooled and the
solvents were removed under reduced pressure. The residue was azeo-
troped with 1,4-dioxane (2 Â 2 mL) and then pumped under high vacuum
for 1 h. The residue was dissolved in 1,4-dioxane (1.0 mL) and cooled to
158C. BzCl (31 mL, 0.257 mmol) was added and the reaction mixture was
stirred for 0.5 h. The reaction mixture was diluted with CH2Cl2 (100 mL)
and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL).
The organic layer was dried (Na2SO4), the solvents were removed under
reduced pressure, and the residue was purified by flash column chroma-
tography (silica gel, 0 ! 100% Et2O in hexanes) to afford FGH benzoate
114 (135 mg of H3 and 30 mg of H2, 97%, 5:1 mixture of H3:H2
regioisomers) as a white foam. 114: Rf ˆ 0.24 (40% EtOAc in hexanes);
[a]2D2 ˆ À17.2 (c ˆ 0.17, CHCl3); IR (thin film): nÄ ˆ 3438, 2929, 2896, 1719,
(600 MHz, CDCl3): d ˆ 8.04 (d, J ˆ 7.1 Hz, 2H, ArH), 7.61 (t, J ˆ 7.4 Hz,
1H, ArH), 7.47 (t, J ˆ 7.9 Hz, 2H, ArH), 7.37 ± 7.29 (m, 10H, ArH), 7.12 (d,
J ˆ 8.6 Hz, 2H, PMB), 6.75 (d, J ˆ 8.6 Hz, 2H, PMB), 5.43 (t, J ˆ 9.2 Hz,
1H, H3), 5.34 (s, 1H, G1), 4.87, 4.66 (AB, J ˆ 11.6 Hz, 2H, CH2Ar), 4.67 (s,
1H, F1), 4.63, 4.56 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.53, 4.50 (AB, J ˆ
11.0 Hz, 2H, CH2Ar), 4.48 (ddd, J ˆ 10.5, 10.5, 6.1 Hz, 1H, G4), 4.30
(brs, 1H, G2), 4.11 (dd, J ˆ 9.6, 4.5 Hz, 1H, G5), 4.00 (dd, J ˆ 10.2, 2.3 Hz,
1H, G3), 3.90 (dd, J ˆ 11.4, 5.4 Hz, 1H, H5), 3.87 (t, J ˆ 9.0 Hz, 1H, F4),
3.82 ± 3.76 (m, 3H, G5, H2, H4), 3.76 (s, 3H, OMe), 3.69 (t, J ˆ 11.0 Hz, 1H,
H5), 3.62 (dd, J ˆ 10.4, 1.8 Hz, 1H, F6), 3.55 (dd, J ˆ 10.8, 5.3 Hz, 1H, F6),
3.52 (s, 3H, OMe), 3.49 (brs, 1H, F2), 3.33 (s, 3H, OMe), 3.29 ± 3.27 (m,
2H, F3, F5), 2.49 (d, J ˆ 8.3 Hz, 1H, OH), 0.86 (s, 9H, tBuSi), 0.04, 0.03
(2  s, 2  3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 167.1, 159.4, 137.9,
137.8, 133.4, 129.9, 129.5, 129.5, 128.4, 128.3, 127.8, 127.7, 127.7, 127.6, 119.3,
113.8, 95.7, 82.0, 81.7, 77.1, 76.7, 75.8, 73.6, 73.4, 72.7, 71.9, 71.4, 71.4, 69.7, 67.5,
63.3, 62.5, 61.8, 59.0, 55.2, 29.7, 25.9, 18.1, À3.7, À5.1; HRMS (FAB): calcd
1608, 1514, 1455, 1373, 1261, 1096, 1043, 838, 785, 720 cmÀ1 1H NMR
;
(600 MHz, CDCl3): d ˆ 8.08 (d, J ˆ 7.2 Hz, 2H, ArH), 7.61 (t, J ˆ 7.4 Hz,
1H, ArH), 7.47 (t, J ˆ 7.9 Hz, 2H, ArH), 7.41 ± 7.25 (m, 12H, ArH), 6.83 (d,
J ˆ 8.7 Hz, 2H, PMB), 5.55 (dd, J ˆ 5.8, 3.8 Hz, 1H, H3), 5.31 (d, J ˆ 0.7 Hz,
1H, G1), 4.93, 4.63 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 4.68 (s, 1H, F1), 4.63,
4.56 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 4.62 (s, 2H, CH2Ar), 4.51 (ddd, J ˆ
10.6, 10.6, 4.6 Hz, 1H, G4), 4.29 (brs, 2H, G2, H2), 4.17 (dd, J ˆ 9.5, 4.6 Hz,
1H, G5), 4.05 (dd, J ˆ 12.1, 3.1 Hz, 1H, H5), 3.92 (dd, J ˆ 10.2, 2.3 Hz, 1H,
G3), 3.86 (t, J ˆ 9.1 Hz, 1H, F4), 3.86 ± 3.84 (m, 1H, H4), 3.81 (dd, J ˆ 12.1,
5.4 Hz, 1H, H5), 3.78 (s, 3H, OMe), 3.75 (t, J ˆ 10.3 Hz, 1H, G5), 3.62 (dd,
J ˆ 10.6, 1.8 Hz, 1H, F6), 3.54 (dd, J ˆ 10.6, 5.4 Hz, 1H, F6), 3.52 (s, 3H,
OMe), 3.50 (d, J ˆ 2.6 Hz, 1H, F2), 3.33 (s, 3H, OMe), 3.30 ± 3.27 (m, 2H,
F3, F5), 2.36 (s, 1H, OH), 0.86 (s, 9H, tBuSi), 0.04, 0.02 (2 Â s, 2 Â 3H,
MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 165.6, 159.4, 137.9, 137.8, 133.4,
‡
for C53H68O16SiNa [M‡Na] : 1011.4174, found 1011.4202.
FGH trans-diol 116: NaOH (2.0 mg, 0.061 mmol) was added to a solution
of FGH benzoate 115 (120 mg, 0.121 mmol) in MeOH (1.0 mL) at 258C
and the resulting mixture was stirred for 1 h. The reaction mixture was
quenched by the addition of saturated aqueous NH4Cl (2 mL), diluted with
CH2Cl2 (100 mL) and washed with brine (10 mL). The organic layer was
dried (Na2SO4) and the solvents were removed under reduced pressure.
The residue was purified by flash column chromatography (silica gel, 0 !
100% EtOAc in hexanes) to afford FGH trans-diol 116 (105 mg, 98%) as a
white foam. 116: Rf ˆ 0.34 (60% EtOAc in hexanes); [a]2D2 ˆ À22.0 (c ˆ
0.24, CHCl3); IR (thin film): nÄ ˆ 3460, 2931, 2884, 1519, 1455, 1373, 1249,
1085, 832, 785, 732 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.38 ± 7.25 (m,
Chem. Eur. J. 2000, 6, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3143 $ 17.50+.50/0
3143

K. C. Nicolaouet al.
FULL PAPER
12H, ArH), 6.88 (d, J ˆ 8.6 Hz, 2H, PMB), 5.31 (d, J ˆ 0.7 Hz, 1H, G1),
4.84, 4.63 (AB, J ˆ 11.6 Hz, 2H, CH2Ar), 4.66 (s, 1H, F1), 4.63, 4.58 (AB,
J ˆ 11.8 Hz, 2H, CH2Ar), 4.61, 4.56 (AB, J ˆ 10.2 Hz, 2H, CH2Ar), 4.46
(ddd, J ˆ 10.6, 10.6, 4.6 Hz, 1H, G4), 4.27 (brs, 1H, G2), 4.12 (dd, J ˆ 9.5,
4.6 Hz, 1H, G5), 3.98 (dd, J ˆ 10.2, 2.4 Hz, 1H, G3), 3.86 (t, J ˆ 9.0 Hz, 1H,
F4), 3.84 ± 3.78 (m, 2H, H3, H5), 3.80 (s, 3H, OMe), 3.79 (t, J ˆ 10.3 Hz,
1H, G5), 3.76 (dd, J ˆ 9.0, 5.5 Hz, 1H, H2), 3.60 (dd, J ˆ 10.0, 1.9 Hz, 1H,
F6), 3.55 (t, J ˆ 10.4 Hz, 1H, H5), 3.54 ± 3.51 (m, 3H, F2, F6, H4), 3.51 (s,
3H, OMe), 3.32 (s, 3H, OMe), 3.30 ± 3.28 (m, 2H, F3, F5), 2.67 (d, J ˆ
2.6 Hz, 1H, OH), 2.34 (d, J ˆ 5.6 Hz, 1H, OH), 0.82 (s, 9H, tBuSi), 0.04,
0.00 (2  s, 2  3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 159.5, 137.9,
137.8, 130.5, 129.8, 129.6, 128.3, 128.3, 127.7, 127.7, 127.7, 127.7, 127.6, 119.2,
114.0, 95.8, 82.1, 81.4, 77.2 76.4, 75.6, 74.8, 73.3, 72.5, 72.3, 71.5, 71.3, 69.5,
67.5, 63.3, 62.5, 61.8, 59.0, 55.2, 29.7, 25.9, 18.1, À3.7, À5.2; HRMS
resulting mixture was stirred for 5 min and then A2 aromatic acyl fluoride 5
(41 mg, 0.118 mmol, dissolved in THF (0.2 mL)), was added dropwise. The
resulting reaction mixture was warmed to 258C and stirred for 2 h. The
reaction mixture was quenched by the addition of saturated aqueous
NH4Cl (1 mL), diluted with CH2Cl2 (100 mL), and washed with brine
(10 mL). The organic layer was dried (Na2SO4), and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 0 ! 100% Et2O in hexanes) to afford FGHA2
ester 119 (83 mg, 96%) as a white foam. 119: Rf ˆ 0.58 (80% Et2O in
hexanes); [a]2D2 ˆ À17.6 (c ˆ 0.25, CHCl3); IR (thin film): nÄ ˆ 3025, 2926,
2872, 1731, 1602, 1449, 1261, 1149, 1102, 1043, 832, 779, 738, 697 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.41 ± 7.24 (m, 20H, ArH), 6.43 (s, 2H,
ArH (A2)), 5.44 (ddd, J ˆ 9.8, 9.8, 5.5 Hz, 1H, H4), 5.35 (s, 1H, G1), 5.18 (s,
1H, OCH2O), 5.05 (s, 1H, OCH2O), 5.03 (s, 2H, CH2Ar), 5.00 (s, 2H,
CH2Ar), 4.80, 4.62 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 4.69 (s, 1H, F1), 4.66,
4.61 (AB, J ˆ 11.8 Hz, 2H, CH2Ar), 4.55 (ddd, J ˆ 10.6, 10.6, 4.6 Hz, 1H,
G4), 4.30 (brs, 1H, G2), 4.16 (dd, J ˆ 9.6, 4.6 Hz, 1H, G5), 4.13 (dd, J ˆ
11.5, 5.6 Hz, 1H, H5), 4.05 (dd, J ˆ 10.2, 2.4 Hz, 1H, G3), 3.95 (t, J ˆ 9.8 Hz,
1H, H3), 3.90 (t, J ˆ 9.1 Hz, 1H, F4), 3.81 (t, J ˆ 10.3 Hz, 1H, G5), 3.63 (dd,
J ˆ 9.1, 1.8 Hz, 1H, F6), 3.62 (d, J ˆ 9.4 Hz, 1H, H2), 3.59 ± 3.52 (m, 3H, F2,
F6, H5), 3.56 (s, 3H, OMe), 3.34 (s, 3H, OMe), 3.33 ± 3.29 (m, 2H, F3, F5),
2.34 (s, 3H, Me (A2)), 0.89 (s, 9H, tBuSi), 0.07 (2 Â s, 2 Â 3H, MeSi);
13C NMR (150 MHz, CDCl3): d ˆ 166.8, 160.6, 157.3, 138.7, 137.8, 137.6,
136.3, 136.3, 128.6, 128.4, 128.3, 128.3, 128.1, 127.8, 127.7, 127.7, 127.4, 127.4,
127.0, 119.0, 115.8, 108.1, 98.2, 96.7, 96.1, 95.9, 82.0, 81.0, 77.4, 77.0, 75.7, 74.9,
73.1, 71.4, 71.3, 70.3, 70.1, 70.0, 69.7, 67.4, 63.4, 63.2, 61.7, 59.0, 31.5, 29.6, 25.9,
22.6, 20.0, 18.1, 14.1, À3.7, À5.2; HRMS (FAB): calcd for C61H74O17SiNa
‡
(MALDI): calcd for C46H64O15SiNa [M‡Na] : 907.3912, found 907.3891.
FGH methylene acetal 117: nBu4NBr (11 mg, 0.033 mmol) was added to a
1:1 mixture of CH2Br2 and 50% aqueous NaOH (4 mL) and the resulting
mixture was heated to 658C and stirred vigorously. A solution of FGH diol
116 (10 mg, 0.011 mmol) in CH2Br2 (1.0 mL) was added very slowly,
dropwise to the CH2Br2/NaOH mixture with vigorous stirring, over 1 h.
After completion of the addition, the resulting mixture was stirred for 1 h
and then the reaction mixture was diluted with CH2Cl2 (100 mL) and
washed with brine (10 mL). The organic layer was dried (Na2SO4) and the
solvents were removed under reduced pressure. The residue was purified
by flash column chromatography (silica gel, 0 ! 100% EtOAc in hexanes)
to afford FGH methylene acetal 117 (9.1 mg, 90%) as a white foam. 117:
Rf ˆ 0.59 (silica gel, 60% Et2O in hexanes); [a]2D2 ˆ À79.2 (c ˆ 0.27, CHCl3);
‡
[M‡Na] : 1129.4695, found 1129.4632.
IR (thin film): nÄ ˆ 2919, 2861, 1461, 1361, 1255, 1091, 1044, 838, 779 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.41 ± 7.25 (m, 12H, ArH), 6.88 (d, J ˆ
8.6 Hz, 2H, PMB), 5.32 (d, J ˆ 1.0 Hz, 1H, G1), 5.12 (s, 1H, OCH2O), 5.10
(s, 1H, OCH2O), 4.83, 4.58 (AB, J ˆ 11.6 Hz, 2H, CH2Ar), 4.78, 4.56 (AB,
J ˆ 11.3 Hz, 2H, CH2Ar), 4.66 (s, 1H, F1), 4.64, 4.62 (AB, J ˆ 11.1 Hz, 2H,
CH2Ar), 4.50 (ddd, J ˆ 10.5, 10.5, 4.5 Hz, 1H, G4), 4.27 (brs, 1H, G2), 4.12
(dd, J ˆ 9.6, 4.6 Hz, 1H, G5), 4.01 (dd, J ˆ 10.2, 2.4 Hz, 1H, G3), 3.96 (dd,
J ˆ 11.3, 5.2 Hz, 1H, H5), 3.91 (t, J ˆ 9.3 Hz, 1H, H3), 3.91 ± 3.89 (m, 1H,
H4), 3.88 (t, J ˆ 10.7 Hz, 1H, F4), 3.80 (s, 3H, OMe), 3.78 (t, J ˆ 10.1 Hz,
1H, G5), 3.61 (dd, J ˆ 10.6, 1.9 Hz, 1H, F6), 3.55 (dd, J ˆ 10.6, 5.5 Hz, 1H,
F6), 3.53 (s, 3H, OMe), 3.53 ± 3.48 (m, 2H, F2, H5), 3.45 (d, J ˆ 9.3 Hz, 1H,
H2), 3.32 (s, 3H, OMe), 3.31 ± 3.26 (m, 2H, F3, F5), 0.86 (s, 9H, tBuSi), 0.05,
0.04 (2  s, 2  3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 159.4, 137.9,
137.7, 129.7, 129.5, 128.3, 127.8, 127.7, 127.7, 127.6, 119.0, 113.9, 96.6, 96.0,
96.0, 82.1, 81.1, 80.2, 77.1, 77.1, 75.7, 75.0, 74.9, 73.3, 72.0, 71.5, 71.3, 69.7, 67.5,
65.8, 64.8, 63.3, 61.8, 59.0, 55.2, 29.7, 25.9, 18.1, 15.2, À3.7, À5.7; HRMS
FGHA2 alcohol 2: nBu4NF (96 mL, 1.0m solution in THF, 0.096 mmol) was
added to a solution of FGH TBS ether 119 (89 mg, 0.080 mmol) in THF
(0.5 mL) at 258C and the resulting mixture was stirred for 1 h. The reaction
mixture was quenched by the addition of saturated aqueous NH4Cl (2 mL),
diluted with CH2Cl2 (150 mL) and washed with brine (10 mL). The organic
layer was dried (Na2SO4), and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 80% EtOAc in hexanes) to afford FGHA2 alcohol 2 (72 mg, 91%)
as a white foam. 2: Rf ˆ 0.21 (60% EtOAc in hexanes); [a]2D2 ˆ À5.7 (c ˆ
0.14, CHCl3); IR (thin film): nÄ ˆ 3448, 2955, 2919, 2872, 1725, 1602, 1449,
1
1378, 1255, 1155, 1108, 1049, 932, 738 cmÀ1; H NMR (600 MHz, CDCl3):
d ˆ 7.39 ± 7.23 (m, 20H, ArH), 6.43 (s, 2H, ArH (A2)), 5.44 (ddd, J ˆ 9.7, 9.7,
5.5 Hz, 1H, H4), 5.33 (d, J ˆ 0.8 Hz, 1H, G1), 5.18 (s, 1H, OCH2O), 5.05 (s,
1H, OCH2O), 5.02 (s, 2H, CH2Ar), 5.00 (s, 2H, CH2Ar), 4.77, 4.61 (AB, J ˆ
11.7 Hz, 2H, CH2Ar), 4.75, 4.66 (AB, J ˆ 11.9 Hz, 2H, CH2Ar), 4.69 (s, 1H,
F1), 4.54 (ddd, J ˆ 10.5, 10.5, 4.5 Hz, 1H, G4), 4.29 (brs, 1H, G2), 4.18 (dd,
J ˆ 9.7, 5.1 Hz, 1H, G5), 4.12 (dd, J ˆ 11.3, 5.4 Hz, 1H, H5), 4.05 (dd, J ˆ
10.2, 5.4 Hz, 1H, G3), 3.94 (t, J ˆ 9.8 Hz, 1H, H3), 3.88 (t, J ˆ 9.5 Hz, 1H,
F4), 3.82 (dd, J ˆ 10.6, 10.6 Hz, 1H, G5), 3.70 (dd, J ˆ 10.5, 3.7 Hz, 1H, F6),
3.63 (dd, J ˆ 10.5, 5.1 Hz, 1H, F6), 3.61 ± 3.59 (m, 2H, F2, H2), 3.60 (s, 3H,
OMe), 3.56 (dd, J ˆ 11.3, 9.7 Hz, 1H, H5), 3.37 (s, 3H, OMe), 3.36 ± 3.34 (m,
2H, F3, F5), 2.32 (s, 3H, Me (A2)), 2.12 (brs, 1H, OH); 13C NMR
(150 MHz, CDCl3): d ˆ 166.8, 160.6, 157.3, 138.7, 137.7, 137.5, 136.3, 136.3,
128.6, 128.4, 128.3, 128.1, 128.0, 127.8, 127.7, 127.5, 127.4, 127.0, 119.1, 115.8,
108.1, 98.2, 96.7, 96.0, 96.0, 81.3, 81.0, 77.4, 75.6, 74.9, 73.2, 72.4, 71.8, 70.3,
70.1, 70.1, 69.6, 67.8, 63.4, 63.4, 61.8, 59.3, 53.8, 29.6, 29.6, 20.0, 14.1, 14.0;
‡
(MALDI): calcd for C47H64O15SiNa [M‡Na] : 919.3912, found 919.3912.
FGH alcohol 118: DDQ (30 mg, 0.134 mmol) was added to a solution of
FGH PMB ether 117 (80 mg, 0.089 mmol) in CH2Cl2/buffer solution (pH 7)
(10:1, 0.5 mL) at 08C and the resulting mixture was warmed to 258C and
stirred for 1 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and
washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The
organic layer was dried (Na2SO4) and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 100% Et2O in hexanes) to afford FGH alcohol 118
(59 mg, 85%) as a white foam. 118: Rf ˆ 0.29 (silica gel, 80% Et2O in
hexanes); [a]2D2 ˆ À11.0 (c ˆ 0.01, CHCl3); IR (thin film): nÄ ˆ 3475, 2928,
2884, 1455, 1373, 1320, 1255, 1108, 1044, 838, 773 cmÀ1; 1H NMR (600 MHz,
CDCl3): d ˆ 7.39 ± 7.26 (m, 10H, ArH), 5.33 (s, 1H, G1), 5.15 (s, 1H,
OCH2O), 5.10 (s, 1H, OCH2O), 4.84, 4.65 (AB, J ˆ 11.6 Hz, 2H, CH2Ar),
4.66 (s, 1H, F1), 4.63, 4.58 (AB, J ˆ 11.8 Hz, 2H, CH2Ar), 4.52 (ddd, J ˆ
10.6, 10.6, 4.6 Hz, 1H, G4), 4.30 (brs, 1H, G2), 4.15 ± 4.10 (m, 2H, G5, H3),
4.01 (dd, J ˆ 10.2, 2.3 Hz, 1H, G3), 3.98 (dd, J ˆ 11.4, 5.5 Hz, 1H, H5), 3.87
(t, J ˆ 9.1 Hz, 1H, F4), 3.79 (d, J ˆ 10.1 Hz, 1H, H2), 3.74 (t, J ˆ 9.6 Hz, 1H,
G5), 3.61 (dd, J ˆ 10.3, 1.3 Hz, 1H, F6), 3.55 (dd, J ˆ 10.3, 5.4 Hz, 1H, F6),
3.53 (s, 3H, OMe), 3.52 ± 3.37 (m, 2H, F2, H4), 3.45 (t, J ˆ 9.6 Hz, 1H, H5),
3.33 (s, 3H, OMe), 3.32 ± 3.27 (m, 2H, F3, F5), 2.73 (brs, 1H, OH), 0.86 (s,
9H, tBuSi), 0.05, 0.04 (2 Â s, 2 Â 3H, MeSi); 13C NMR (150 MHz, CDCl3):
d ˆ 137.8, 137.7, 128.3, 127.7, 127.7, 127.5, 119.1, 96.5, 96.0, 95.9, 82.0, 81.0,
80.2, 77.0, 75.7, 74.6, 73.2, 71.4, 71.3, 69.7, 69.0, 67.4, 66.2, 63.3, 61.7, 59.0, 30.2,
29.6, 25.9, 18.1, À3.7, À5.2; HRMS (MALDI): calcd for C39H56O14SiNa
‡
HRMS (FAB): calcd for C55H60O17Na [M‡Na] : 1015.3728, found
1015.3735.
FGH diol 120: nBu4NF (0.38 mL, 1.0m solution in THF, 0.38 mmol) was
added quickly to a solution of FGH alcohol 42 (0.43 g, 0.36 mmol) and 4 Š
MS in THF (2.5 mL) at 08C. The resulting mixture was stirred at 08C for
15 min. The reaction mixture was quenched by the addition of saturated
aqueous NH4Cl (5 mL), diluted with CH2Cl2 (100 mL) and washed with
brine (2 Â 5 mL). The organic layer was dried (Na2SO4) and the solvents
were removed under reduced pressure. The residue was purified by flash
column chromatography (silica gel, 0 ! 100% Et2O in hexanes) to afford
FGH diol 120 (0.27 g, 70%) as a white foam, and recovered starting
material (0.06 g, 15%). 120: Rf ˆ 0.14 (70% Et2O in hexanes); [a]D22
ˆ
À24.6 (c ˆ 2.31, CHCl3); IR (thin film): nÄ ˆ 3456, 2938, 2865, 1613, 1514,
1454, 1249, 1112, 1036, 742 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.59 ±
‡
[M‡Na] : 799.3337, found 799.3426.
7.57 (m, 2H, ArH), 7.37 ± 7.23 (m, 13H, ArH), 7.21 (d, J ˆ 8.6 Hz, 2H,
PMB), 6.85 (d, J ˆ 8.6 Hz, 2H, PMB), 5.24 (d, J ˆ 2.0 Hz, 1H, G1), 4.91 (d,
J ˆ 6.7 Hz, 1H, H1), 4.79, 4.71 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.72 (s, 1H,
FGHA2 ester 119: NaH (4.0 mg, 0.094 mmol) was added to a solution of
FGH alcohol 118 (61 mg, 0.079 mmol) in THF (0.2 mL) at 08C. The
3144
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3144 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 2
3116±3148
F1), 4.71, 4.41 (AB, J ˆ 11.1 Hz, 2H, CH2Ar), 4.55, 4.47 (AB, J ˆ 11.7 Hz,
2H, CH2Ar), 4.07 (brs, 1H, H3), 4.00 (t, J ˆ 8.7 Hz, 1H, F4), 3.95 (ddd, J ˆ
9.5, 9.5, 5.3 Hz, 1H, G4), 3.93 ± 3.91 (m, 1H, G2), 3.90 (dd, J ˆ 10.5, 2.8 Hz,
1H, H5), 3.87 ± 3.85 (m, 1H, G3), 3.79 (s, 3H, OMe), 3.73 (dd, J ˆ 11.3,
5.5 Hz, 1H, G5), 3.70 (dd, J ˆ 11.3, 2.7 Hz, 1H, F6), 3.68 (dd, J ˆ 6.7, 3.4 Hz,
1H, H2), 3.63 (d, J ˆ 2.7 Hz, 1H, OH), 3.59 (dd, J ˆ 10.5, 6.1 Hz, 1H, F6),
3.56 (brd, J ˆ 3.2 Hz, 1H, H5), 3.50 (s, 3H, OMe), 3.43 (ddd, J ˆ 7.7, 7.7,
4.5 Hz, 1H, H4), 3.38 (t, J ˆ 10.7 Hz, 1H, G5), 3.38 ± 3.34 (m, 2H, F3, F5),
3.32 (s, 3H, OMe), 2.28 (brs, 1H, OH), 1.03 ± 0.96 (m, 21H, iPr3Si);
13C NMR (150 MHz, CDCl3): d ˆ 159.3, 138.2, 138.0, 133.6, 129.8, 129.3,
129.2, 128.7, 128.3, 128.1, 127.7, 127.6, 127.5, 127.5, 127.4, 113.9, 100.8, 95.5,
94.8, 82.3, 77.4, 77.3, 76.3, 73.6, 71.9, 71.4, 70.6, 70.0, 69.4, 68.1, 65.8, 62.9,
61.5, 60.6, 59.0, 55.2, 50.5, 30.3, 18.2, 18.1, 13.0; HRMS (FAB): calcd for
FGH cyclic sulfate 123: SOCl2 (7.0 mL, 0.097 mmol) was added to a solution
of FGH diol 122 (60 mg, 0.065 mmol) and Et3N (27.0 mL, 0.194 mmol) in
CH2Cl2 (0.5 mL) at 08C and the reaction mixture was stirred for 5 min. The
reaction mixture was diluted with Et2O (100 mL) and washed with brine
(10 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The residue was dissolved in CCl4/
MeCN/H2O (1:1:1.5, 2.0 mL) and cooled to 08C. NaHCO3 (97 mg,
1.15 mmol) and NaIO4 (308 mg, 1.44 mmol) were added and the resulting
mixture was warmed to 258C and stirred for 1 h. The reaction mixture was
diluted with Et2O (150 mL) and washed with saturated aqueous NH4Cl
(20 mL) and brine (20 mL). The organic layer was dried (Na2SO4), the
solvents were removed under reduced pressure, and the residue was
purified by flash column chromatography (silica gel, 0 ! 100% EtOAc in
hexanes) to afford FGH cyclic sulfate 123 (62 mg, 97% over two steps) as a
white foam. 123: Rf ˆ 0.65 (70% Et2O in hexanes); [a]2D2 ˆ À10.7 (c ˆ 0.41,
CHCl3); IR (thin film): nÄ ˆ 2929, 1618, 1520, 1458, 1400, 1252, 1215,
1116 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.40 ± 7.25 (m, 10H, ArH), 7.26
(d, J ˆ 8.5 Hz, 2H, PMB), 6.90 (d, J ˆ 8.6 Hz, 2H, PMB), 5.33 (d, J ˆ
1.1 Hz, 1H, G1), 5.04 (t, J ˆ 5.8 Hz, 1H, H3), 4.91 (d, J ˆ 5.4 Hz, 1H,
H2), 4.83, 4.64 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 4.80 (s, 1H, F1), 4.73, 4.44
(AB, J ˆ 11.3 Hz, 2H, CH2Ar), 4.67, 4.58 (AB, J ˆ 11.4 Hz, 2H, CH2Ar),
4.32 (brs, 1H, G2), 4.23 (ddd, J ˆ 10.4, 10.4, 4.5 Hz, 1H, G4), 4.14 (dd, J ˆ
10.1, 2.4 Hz, 1H, G3), 4.12 ± 4.08 (m, 2H, G5, H4), 4.05 (t, J ˆ 8.1 Hz, 1H,
F4), 3.94 (dd, J ˆ 12.3, 4.8 Hz, 1H, H5), 3.82 (t, J ˆ 10.7 Hz, 1H, G5), 3.81
(s, 3H, OMe), 3.71 (dd, J ˆ 12.3, 8.0 Hz, 1H, F6), 3.70 ± 3.68 (m, 2H, F2,
H5), 3.59 (dd, J ˆ 10.3, 5.7 Hz, 1H, F6), 3.50 (s, 3H, OMe), 3.43 ± 3.40 (m,
2H, F3, F5), 3.31 (s, 3H, OMe), 1.11 ± 0.98 (m, 21H, iPr3Si); 13C NMR
(150 MHz, CDCl3): d ˆ 159.7, 138.0, 137.5, 129.7, 128.7, 128.4, 128.2, 127.9,
127.8, 127.7, 127.5, 127.3, 125.5, 115.6, 114.0, 96.0, 95.6, 82.9, 81.9, 79.0, 78.7,
77.4, 76.2, 75.6, 73.4, 72.6, 72.1, 71.9, 71.0, 70.6, 68.0, 63.5, 61.6, 61.1, 58.9,
55.3, 30.3, 29.6, 18.2, 18.0, 12.9; HRMS (ESI): calcd for C49H68O17SSiNa
‡
C55H76O14SeSiCs [M‡Cs] : 1201.3224, found 1201.3164.
FGH allylic orthoester 121: NaIO4 (308 mg, 1.44 mmol) and NaHCO3
(97 mg, 1.15 mmol) were added to a solution of FGH diol 120 (154 mg,
0.14 mmol) in MeOH/CH2Cl2/H2O (3:2:1, 2.1 mL) and the resulting
mixture was stirred at 258C for 4 h. The reaction mixture was diluted with
CH2Cl2 (250 mL) and washed with saturated aqueous NH4Cl (20 mL) and
brine (20 mL). The organic layer was dried (Na2SO4) and the solvents were
removed under reduced pressure. The crude selenoxide was dissolved in
toluene (2 mL) and transferred by cannula to a sealed tube. The flask was
washed with toluene (2 Â 2 mL) and the organics were transferred to the
sealed tube. Diisopropylamine (3 mL) and vinyl acetate (6 mL) were
added, and the tube was sealed and heated to 1408C for 12 h. After cooling,
the reaction mixture was concentrated and the residue was purified by flash
column chromatography (silica gel, 0 ! 80% Et2O in hexanes) to afford
the FGH allylic orthoester 121 (95 mg, 74% over two steps) as a white
foam. 121: Rf ˆ 0.76 (50% Et2O in hexanes); [a]2D2 ˆ À26.2 (c ˆ 0.53,
CHCl3); IR (thin film): nÄ ˆ 3020, 2927, 1618, 1519, 1456, 1245, 1100 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.37 ± 7.25 (m, 12H, ArH), 6.86 (d, J ˆ
8.5 Hz, 2H, PMB), 6.17 (dd, J ˆ 11.0, 4.5 Hz, 1H, H3), 5.81 (dd, J ˆ 10.0,
1.0 Hz, 1H, H2), 5.34 (d, J ˆ 1.5 Hz, 1H, G1), 4.78, 4.63 (AB, J ˆ 11.5 Hz,
2H, CH2Ar), 4.78 (s, 1H, F1), 4.72, 4.43 (AB, J ˆ 11.5 Hz, 2H, CH2Ar),
4.55, 4.53 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.27 (t, J ˆ 2.0 Hz, 1H, G2), 4.15
(ddd, J ˆ 10.5, 10.5, 4.5 Hz, 1H, G4), 4.11 ± 4.04 (m, 4H, G3, G5, H5, H5),
4.02 (t, J ˆ 8.5 Hz, 1H, F4), 3.86 (d, J ˆ 3.5 Hz, 1H, H4), 3.85 (t, J ˆ 10.5 Hz,
1H, G5), 3.79 (s, 3H, OMe), 3.69 (dd, J ˆ 10.5, 2.5 Hz, 1H, F6), 3.66 (d, J ˆ
2.5 Hz, 1H, F2), 3.60 (dd, J ˆ 10.5, 6.0 Hz, 1H, F6), 3.51 (s, 3H, OMe),
3.40 ± 3.36 (m, 2H, F3, F5), 3.31 (s, 3H, OMe), 1.02 ± 0.97 (m, 21H, iPr3Si);
13C NMR (125 MHz, CDCl3): d ˆ 159.3, 138.2, 138.0, 130.3, 130.2, 129.3,
128.4, 128.3, 127.5, 125.5, 113.9, 95.9, 95.6, 82.2, 73.1, 72.0, 71.0, 69.3, 68.9,
66.1, 64.0, 58.9, 55.3, 46.3, 30.3, 18.2, 13.0; HRMS (FAB): calcd for
‡
[M‡Na] : 1011, found 1011.
FGH benzoate 124: BzOK (30 mg, 0.188 mmol) was added to a solution of
FGH cyclic sulfate 123 (62 mg, 0.063 mmol) and [18]crown-6 (17 mg,
0.063 mmol) in DMF (0.5 mL) and the resulting mixture was heated to
1208C and was stirred for 1 h. The solvents were removed under reduced
pressure and the residue was dissolved in THF (2.0 mL) and cooled to 08C.
A 0.5n solution of H2O and H2SO4 in THF were added in 25 mL increments
until TLC analysis indicated that no baseline material remained. The
reaction mixture was diluted with CH2Cl2 (150 mL) and washed with
saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer
was dried (Na2SO4), the solvents were removed under reduced pressure,
and the residue was purified by flash column chromatography (silica gel,
0 ! 100% EtOAc in hexanes) to afford FGH benzoate 124 (49 mg, 76%)
as a white foam. 124: Rf ˆ 0.33 (70% Et2O in hexanes); [a]2D2 ˆ À22.3 (c ˆ
0.27, CHCl3); IR (thin film): nÄ ˆ 3476, 2944, 2866, 1716, 1613, 1514, 1454,
‡
C49H68O13SiCs [M‡Cs] : 1025.3484, found 1025.3447.
FGH cis-diol 122: OsO4 (0.30 mL, 2.5% solution in tBuOH) was added to a
solution of FGH allylic orthoester 121 (95 mg, 0.106 mmol), NMO (31 mg,
0.266 mmol), and quinuclidine (12 mg, 0.106 mmol) in acetone/H2O (10:1,
1 mL) and the reaction mixture was stirred for 24 h at 258C. The reaction
mixture was diluted with CH2Cl2 (100 mL) and washed with saturated
aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried
(Na2SO4), the solvents were removed under reduced pressure, and the
residue was purified by flash column chromatography (silica gel, 0 ! 100%
EtOAc in hexanes) to afford FGH cis-diol 122 (64 mg, 65%) as a white
foam. 122: Rf ˆ 0.38 (100% Et2O); [a]2D2 ˆ À38.6 (c ˆ 0.78, CHCl3); IR
1275, 1070, 883, 712 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 8.09 (d, J ˆ
7.1 Hz, 2H, ArH), 7.60 (t, J ˆ 7.4 Hz, 1H, ArH), 7.47 (t, J ˆ 7.9 Hz, 2H,
ArH), 7.37 ± 7.21 (m, 10H, ArH), 7.17 (d, J ˆ 8.6 Hz, 2H, PMB), 6.71 (d, J ˆ
8.6 Hz, 2H, PMB), 5.35 (d, J ˆ 0.7 Hz, 1H, G1), 5.16 (dd, J ˆ 10.5, 3.1 Hz,
1H, H3), 4.80 (s, 1H, F1), 4.74, 4.72 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.74,
4.45 (AB, J ˆ 11.3 Hz, 2H, CH2Ar), 4.59, 4.48 (AB, J ˆ 11.9 Hz, 2H,
CH2Ar), 4.39 (d, J ˆ 7.4 Hz, 1H, H2), 4.33 (ddd, J ˆ 10.5, 10.5, 4.4 Hz, 1H,
G4), 4.31 (brs, 1H, G2), 4.12 (dd, J ˆ 9.5, 4.6 Hz, 1H, G5), 4.06 (dd, J ˆ
10.9, 2.6 Hz, 1H, G3), 4.05 (t, J ˆ 8.5 Hz, 1H, F4), 3.93 (d, J ˆ 2.5 Hz, 1H,
H4), 3.92 (dd, J ˆ 11.7, 2.5 Hz, 1H, H5), 3.82 (t, J ˆ 10.9 Hz, 1H, G5), 3.81
(dd, J ˆ 12.1, 4.0 Hz, 1H, H5), 3.73 (s, 3H, OMe), 3.71 (dd, J ˆ 10.3, 2.1 Hz,
1H, F6), 3.69 (d, J ˆ 2.0 Hz, 1H, F2), 3.64 (dd, J ˆ 10.3, 5.9 Hz, 1H, F6),
3.52 (s, 3H, OMe), 3.43 ± 3.40 (m, 2H, F3, F5), 3.34 (s, 3H, OMe), 1.91 (brs,
1H, OH), 1.08 ± 0.97 (m, 21H, iPr3Si); 13C NMR (150 MHz, CDCl3): d ˆ
166.4, 159.2, 138.1, 137.7, 133.2, 129.9, 129.8, 129.8, 129.2, 128.5, 128.4, 128.2,
127.9, 127.7, 127.5, 125.5, 120.1, 113.7, 95.9, 95.8, 82.3, 77.3, 76.8, 76.4, 76.4,
74.8, 73.2, 73.2, 72.3, 71.9, 71.4, 71.0, 69.8, 68.1, 64.0, 63.5, 61.2, 58.9, 55.1,
(thin film): nÄ ˆ 3360, 2927, 1614, 1514, 1454, 1250, 1105 cmÀ1
;
1H NMR
(600 MHz, CDCl3): d ˆ 7.36 ± 7.26 (m, 10H, ArH), 7.25 (d, J ˆ 8.6 Hz, 2H,
PMB), 6.86 (d, J ˆ 8.6 Hz, 2H, PMB), 5.36 (d, J ˆ 1.1 Hz, 1H, G1), 4.78 (s,
1H, F1), 4.71, 4.68 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.71, 4.44 (AB, J ˆ
11.3 Hz, 2H, CH2Ar), 4.57, 4.51 (AB, J ˆ 11.6 Hz, 2H, CH2Ar), 4.30 (brs,
1H, G2), 4.26 (ddd, J ˆ 10.6, 10.6, 4.5 Hz, 1H, G4), 4.10 (dd, J ˆ 9.6, 4.6 Hz,
1H, G5), 4.06 (dd, J ˆ 10.0, 2.6 Hz, 1H, G3), 4.04 ± 4.02 (m, 3H, F4, H2,
H3), 3.94 (dd, J ˆ 12.6, 2.6 Hz, 1H, H5), 3.79 (s, 3H, OMe), 3.78 (t, J ˆ
10.6 Hz, 1H, G5), 3.74 (dd, J ˆ 12.5, 4.1 Hz, 1H, H5), 3.69 (dd, J ˆ 10.5,
2.5 Hz, 1H, F6), 3.67 (d, J ˆ 2.1 Hz, 1H, F2), 3.62 (dd, J ˆ 10.5, 5.9 Hz, 1H,
F6), 3.61 ± 3.58 (m, 1H, H4), 3.50 (s, 3H, OMe), 3.41 ± 3.38 (m, 2H, F3, F5),
3.33 (s, 3H, OMe), 2.63 (brs, 1H, OH), 2.40 (brs, 1H, OH), 1.07 ± 0.95 (m,
21H, iPr3Si); 13C NMR (150 MHz, CDCl3): d ˆ 138.0, 137.8, 133.8, 129.9,
129.3, 128.5, 128.2, 127.9, 127.5, 127.5, 127.4, 125.5, 119.6, 113.9, 95.7, 95.5,
82.3, 77.4 76.3, 75.0, 73.1, 71.9, 71.3, 70.9, 69.1, 68.1, 64.0, 62.1, 61.3, 58.9, 55.3,
49.2, 30.3, 29.7, 21.2, 18.2, 18.1, 13.0, 11.5; HRMS (FAB): calcd for
‡
46.2, 30.3, 18.2, 18.1, 13.0; HRMS (FAB): calcd for C56H74O16SiCs [M‡Cs] :
1163.3800, found 1163.3854.
FGH bromobenzoate 125: BrBzCl (5.6 mg, 0.026 mmol) was added to a
solution of FGH alcohol 124 (20 mg, 0.019 mmol), Et3N (10.5 mL,
0.076 mmol) and 4-DMAP (1.2 mg, 0.004 mmol) in CH2Cl2 (0.20 mL) at
08C. The resulting mixture was warmed to 258C and stirred for 12 h. The
reaction mixture was quenched by the addition of MeOH (1.0 mL), diluted
with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (5 mL)
‡
C49H70O15SiCs [M‡Cs] : 1059.3538, found 1059.3578.
Chem. Eur. J. 2000, 6, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3145 $ 17.50+.50/0
3145