Total synthesis of everninomicin 13,384-1 - Part 3: Synthesis of the DE fragment and completion of the total synthesis

Article abstract of DOI:10.1002/1521-3765(20000901)6:17<3149::AID-CHEM3149>3.0.CO;2-L

The stereoselective construction of the DE fragment (2) of everninomicin 13,384-1 (1) is reported. From the two possible ways of inserting the DE fragment between the A₁B(A)C and FGHA₂ domains of the natural product, the sequence involving the DEFGHA₂ segment was found to be the most viable. This coupling was followed by attachment of a suitably protected and activated A₁B(A)C fragment which led, after orthoester construction and final deprotection to the targeted everninomicin 13,384-1 (1), completing the total synthesis of this complex naturally occurring substance.

Full text of DOI:10.1002/1521-3765(20000901)6:17<3149::AID-CHEM3149>3.0.CO;2-L

FULL PAPER
Total Synthesis of Everninomicin 13,384-1ÐPart 3:
Synthesis of the DE Fragment and Completion of the Total Synthesis
K. C. Nicolaou,* Helen J. Mitchell, Rosa Maria Rodríguez, Konstantina C. Fylaktakidou,
Hideo Suzuki, and Scott R. Conley[a]
Abstract: The stereoselective construction of the DE fragment (2) of everninomicin
13,384-1 (1) is reported. From the two possible ways of inserting the DE fragment
between the A1B(A)C and FGHA2 domains of the natural product, the sequence
involving the DEFGHA2 segment was found to be the most viable. This coupling was
followed by attachment of a suitably protected and activated A1B(A)C fragment
which led, after orthoester construction and final deprotection to the targeted
everninomicin 13,384-1 (1), completing the total synthesis of this complex naturally
occurring substance.
Keywords: carbohydrates ´ everni-
nomicin ´ orthoester formation ´
phenylseleno glycoside ´ stereocon-
trolled glycosidation
was chosen to ensure the stereoselective coupling of this
fragment with the free hydroxy group of the FGHA2 frag-
ment. Functional group manipulation of 2, followed by further
disconnection of the resulting disaccharide 3, led to carbohy-
drate units 4 and 5. The protecting groups on 3 were carefully
defined with optimum flexibility so as to allow for extension at
either end in order to form the larger fragments A1B(A)CDE
or DEFGHA2, respectively. Eventually, it turned out that the
ensemble illustrated by 2 was found to be the most viable form
of the DE fragment for incorporation into the grand structure
of the target molecule. Careful inspection of structure 3
reveals the following two challenging features: a) the b-
mannoside linkage bridging sugars D and E; and b) the
tertiary center on ring D. We chose the Kahne sulfoxide-based
glycosidation reaction[4] as the procedure for coupling 4 and 5
and, in addition, incorporated a benzylidene ring in 4 in order
to ensure the stereocontrolled formation of the b-mannoside
bond, as reported by Crich.[5] Both the projected reaction
conditions and use of a benzylidene ring suited our protecting
group strategy and we, therefore, considered next the issue of
introducing the branching to ring D. At this juncture it was
postulated that the proper introduction of the methyl group at
C-3 of ring D at the monosaccharide stage would be difficult[6]
and, therefore, the planned nucleophilic attack on a carbonyl
functionality was postponed until after the coupling so as to
avoid any 1,3-diaxial interactions, as will be discussed further
below.
Introduction
In the preceding two papers[1, 2] we described the evolution of
the strategies for the construction of the A1B(A)C and
FGHA2 fragments of everninomicin 13,384-1 (1). These
fragments were produced with appropriate activation and
protecting groups for eventual insertion of the central DE
fragment and with the flexibility of the initial coupling being
carried out with either of the two larger fragments. In this
article, we describe the construction of the remaining DE
segment 2, its union with fragments A1B(A)C and FGHA2,
and the completion of the total synthesis of 1.
Results and Discussion
Retrosynthetic analysis and strategy: Figure 1 depicts the
retrosynthetic analysis of everninomicin 13,384-1 (1) in which
the excision of the appropriately protected and activated DE
fragment 2 is highlighted. Thus, the trichloroacetimidate[3]
group in conjunction with an acetate group at C-2 of ring E
[a] Prof. Dr. K. C. Nicolaou, H. J. Mitchell, Dr. R. M. Rodríguez,
Dr. K. C. Fylaktakidou, Dr. H. Suzuki, Dr. S. R. Conley
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
Construction of building blocks: The construction of the
ring D fragment, compound 4, proceeded from known
intermediate 6[7] as shown in Scheme 1. Thus, regioselective
tin-acetal[8] mediated protection of the C-3 hydroxyl group in
9500 Gilman Drive, La Jolla, California 92093 (USA)
Fax : (‡1) 858-784-2469
E-mail: kcn@scripps.edu
Chem. Eur. J. 2000, 6, No. 17
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3149

K. C. Nicolaou et al.
FULL PAPER
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
Me
OMe
1: everninomicin 13,384-1
Me Me
O
Me
Me
MeO
MeO
O
Me
MeO
HO
O
SPh
O
OTIPS
OTBS
PMBO
HO
O
O
O
O
O
E
E
D
D
E
D
+
HO
O
OTBS
O
OTIPS
Ph
OC(NH)CCl3
Me
Me
OTBS
OPMB
OAc
OAc
OTBS
OH
5
2
3
4
Glycosylation
Figure 1. Retrosynthetic analysis of DE fragment 2. Ac ˆ acetyl; PMB ˆ p-methoxybenzyl; TBS ˆ tbutyldimethylsilyl; TIPS ˆ triisopropylsilyl.
O
R
O
SPh
OH
O
SPh
OH
O
SPh
O
O
RO
RO
O
b) TBSOTf
D
b) TBSOTf, 2,6-lutidine
O
OTBS
Ph
Ph
O
O
OTBS
Ph
OPMB
OR
OR
OPMB
11: R = CHPh
12: R = H
9: R = H
10: R = PMB
8: R = SPh
4: R = S(O)Ph
6: R = H
7: R = PMB
c) Zn(OTf)2,
EtSH
a) nBu2SnO;
PMBCl
a) nBu2SnO;
PMBCl
c) mCPBA
d) TsCl, py
Scheme 1. Synthesis of carbohydrate building block D (4). a) 1.1 equiv
nBu2SnO, toluene, reflux, 3 h; 1.5 equiv PMBCl, 0.2 equiv nBu4NI, 25 !
1108C, 2 h, 83%; b) 1.2 equiv TBSOTf, 1.5 equiv 2,6-lutidine, CH2Cl2, 0 !
258C, 0.5 h, 93%; c) 1.1 equiv mCPBA, CH2Cl2, À20 ! 08C, 2 h, 92% (ca.
4:1 mixture of diastereoisomers). Tf ˆ trifluoromethanesulfonyl;
mCPBA ˆ m-chloroperoxybenzoic acid.
Me
O
O
SPh
SPh
X
E
f) NaH, MeI
MeO
HO
OTBS
OTBS
OPMB
OPMB
13: X = OTs
14: X = H
15
e) LAH
g) NBS, H2O, Me2CO
Me
O
Me
O
OTIPS
OTBS
OH
6 as PMB ether 7 (nBu2SnO; PMBCl, nBu4NI, 83% yield)
followed by silylation at C-2 (TBSOTf, 2,6-lutidine, 93%
yield) to afford 8, and oxidation of the sulfur moiety
(mCPBA, 92% yield) furnished the desired sulfoxide 4 (as a
ca. 4:1 mixture of diastereoisomers).
E
h) TIPSOTf
MeO
MeO
OTBS
RO
OPMB
16
17: R = PMB
5: R = H
i) DDQ
Scheme 2. Synthesis of carbohydrate building block E (5). a) 1.1 equiv
nBu2SnO, toluene, reflux, 3 h; 1.5 equiv PMBCl, 0.2 equiv nBu4NI, 25 !
1108C, 2 h, 87%; b) 1.2 equiv TBSOTf, 1.5 equiv 2,6-lutidine, CH2Cl2, 0 !
258C, 1 h, 97%; c) 2.5 equiv Zn(OTf)2, 20 equiv EtSH, CH2Cl2, 08C, 2 h,
77%; d) 1.1 equiv TsCl, py, 0 ! 258C, 12 h, 97%; e) 1.6 equiv LAH, THF,
0 ! 458C, 3 h, 90%; f) 1.1 equiv NaH, 1.3 equiv MeI, DMF, 0 ! 258C, 1 h,
94%; g) 1.5 equiv NBS, Me2CO/H2O 10:1, 0 ! 258C, 2 h, 95%; h) 1.2 equiv
TIPSOTf, 1.5 equiv 2,6-lutidine, CH2Cl2, 0 ! 258C, 6 h, 97%, a:b ca. 1:2;
i) 1.5 equiv DDQ, CH2Cl2/H2O 10:1 0 ! 258C, 1 h, 98%. LAH ˆ lithium
aluminumhydride; Ts ˆ p-toluenesulfonyl; DDQ ˆ 2,3-dichloro-5,6-dicya-
no-1,4-benzoquinone; NBS ˆ N-bromosuccinimide; py ˆ pyridine.
Scheme 2 summarizes the synthesis of the required ring E
acceptor fragment, compound 5. This construction began with
galactose diol 9[9] whose monoprotection as a C-3 PMB ether
proceeded smoothly under the tin-acetal technology, used
successfully and so often in this project, (nBu2SnO; PMBCl,
nBu4NI, 87% yield). The protection of the C-2 hydroxyl
group as a silyl ether (TBSOTf, 2,6-lutidine, 97% yield) was
followed by cleavage of the benzylidene group (Zn(OTf)2/
EtSH, 77% yield) leading to diol 12 via 11. The next objective
was to deoxygenate at C-6, a task carried out successfully by
first tosylating the primary alcohol (TsCl, py, 97% yield) and
then reducing the resulting tosylate (13) with LAH, leading to
compound 14 (90% yield). Methylation of the remaining
hydroxyl group (at C-4) was effected with MeI in the presence
of NaH to furnish methyl ether 15 in 94% yield, and cleavage
of the thioglycoside with NBS in aqueous acetone led to lactol
16 (95%). Silylation of the latter compound (16) (TIPSOTf,
2,6-lutidine) afforded compound 17 together with its a-
anomer (97% yield, b:a ca. 2:1, both anomers could be taken
though the remainder of the sequence). The PMB group was
removed from 17 by exposure to DDQ furnishing the targeted
building block 5 in 98% yield.
Scheme 3 outlines the coupling of building blocks 4 and 5 to
form the advanced key intermediates 3 and 2. Thus, union of 4
and 5 under the Kahne/Crich conditions (4, Tf2O, DTBMP,
À788C; followed by addition of 5) produced smoothly, via the
transient glycosyl triflate, the b-mannoside 18 in 71% yield. It
was then considered prudent to attempt the C-3 branching at
this stage and before the required exchange of protecting
groups. To this end, the PMB group was removed from ring D
of compound 18 (DDQ, 95% yield) and the resulting alcohol
3150
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Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 3
3149±3165
Ph
Ph
O
O
O
Me
Me
MeO
MeO
Me
O
OTIPS
OTBS
O
SPh
O
O
O
a) Tf2O,
DTBMP
c) TPAP,
NMO
O
O
O
O
O
+
E
D
E
D
E
D
MeO
RO
Ph
O
OTBS
O
OTIPS
O
OTIPS
OH
OPMB
OTBS
OTBS
OTBS
20
OTBS
4
5
18: R = PMB
19: R = H
b) DDQ
d) MeLi
RO
X
Me
Me
Me
Me
MeO
MeO
MeO
HO
HO
HO
HO
RO
h) nBu3SnH
AIBN
O
O
O
O
O
O
E
D
E
D
f) TsCl, py
D
E
3
HO
Me
O
OTIPS
OTBS
O
OTIPS
O
OTIPS
OTBS
Me
Me
OTBS
OTBS
OTBS
OTBS
23: X = OTs
24: X = I
3
21: R, R = CHPh
22: R = H
g) LiI, DMF
e) H2, 10% Pd/C
i) nBu2SnO;
PMBCl
Me
Me
Me
Me
Me
Me
MeO
MeO
O
MeO
PMBO
HO
PMBO
PMBO
O
O
j) nBu4NF
O
O
O
O
l) nBuNH2
E
E
D
E
D
D
HO
Me
HO
Me
O
OTIPS
OTBS
OR
O
OR
Me
OTBS
OR
OR
OAc
OAc
28: R = H
2: R = C(NH)CCl3
25
26: R = H
27: R = Ac
k) Ac2O
m) CCl3CN,
DBU
Scheme 3. Assembly of DE fragment 2. a) 1.3 equiv 4, 1.3 equiv Tf2O, 2.2 equiv DTBMP, CH2Cl2, À788C; 1.0 equiv 5, À78 ! 08C, 2 h, 71%; b) 1.3 equiv
DDQ, CH2Cl2/H2O 10:1, 0 ! 258C, 2 h, 95%; c) 1.5 equiv NMO, 0.05 equiv TPAP, CH2Cl2, 258C, 2 h; d) 1.4 equiv MeLi, Et2O, À788C, 1 h, 88% over two
steps; e) H2, 0.2 equiv 10% Pd/C (w/w), EtOAc, 258C, 2 h, 97%; f) 1.2 equiv TsCl, py, 0 ! 258C, 12 h, 87%; g) 5.0 equiv LiI, DMF, 80 ! 1008C, 2 h, 86%;
h) 3.0 equiv nBu3SnH, 0.05 equiv AIBN, benzene, reflux, 0.5 h, 97%; i) 1.1 equiv nBu2SnO, toluene, reflux, 5 h; 1.5 equiv PMBCl, 0.2 equiv nBu4NI, 25 !
1108C, 8 h, 63%; j) 4.0 equiv nBu4NF, THF, 258C, 6 h; k) 2.5 equiv Ac2O, 4.0 equiv Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 ! 258C,1 h, 90% for two steps;
l) 1.2 equiv nBuNH2, THF, 258C, 5 h, 86%; m) 5.0 equiv CCl3CN, 0.05 equiv DBU, CH2Cl2, 08C, 0.5 h, 89%, a:b ca. 30:1. DBU ˆ 1,8-diazabicyclo[5.4.0]un-
dec-7-ene; DTBMP ˆ di-tert-butyl-4-methylpyridine; AIBN ˆ 2,2'-azobisisobutyronitrile; DMF ˆ dimethylformamide.
(19) was oxidized with TPAP/NMO to afford ketone 20. To
our delight, reaction of this ketone (20) with MeLi in ether at
À788C produced the desired tertiary alcohol (21) in 88%
overall yield from 19. The presumed trajectory leading to the
observed product 21 along with the assumed conformation of
ring D of 20 are depicted in Figure 2.
could remain unprotected throughout the remainder of the
sequence without much interferenceÐa prediction that was
proven both correct and fortunate. The next task was to
deoxygenate the C-6 position of ring D, and to this end, the
benzylidene group of 21 was removed by mild hydrogenolysis
(H2, 10% Pd/C, 97% yield) to afford primary alcohol 22
which was converted to its tosylate 23 (TsCl, py, 87% yield).
Initial attempts to reduce this compound 23 resulted in
decomposition, prompting us to exchange the tosylate group
for an iodide (LiI, 86% yield) furnishing derivative 24 whose
reduction with nBu3SnH/AIBN cat. proceeded smoothly to
afford the desired compound 3 in 97% yield.
OTBS
O
OTBS
O
Ph
O
Ph
O
O
O
D
O
D
O
HO
H
O
Me
H
H
Me
a: 20
b: 21
Testing of strategies: The availability of intermediate 3 gave
us the early opportunity to test the first of the two approaches
for the attachment of the DE fragment onto the growing
backbone of the final target, namely the coupling of 3 to the
A1B(A)C glycosyl fluoride 29.[1] Scheme 4 summarizes the
progress made following this strategy. Thus, coupling of donor
29 (see Part 1 in this series)[1] with diol acceptor 3 in Et2O and
in the presence of SnCl2 afforded pentasaccharide 30 in 62%
yield. Although no product resulting from coupling at the
tertiary alcohol on ring D was observed, a by-product with a
double bond across the C-2/C-3 of ring C (i.e., loss of BnOSe-
Ph) was formed on long reaction times and/or exposure to
excessive amounts of Lewis acid catalyst. The next stage
involved testing orthoester formation, and to this end, the
selenium moiety in 30 was oxidized[11] [NaIO4 in MeOH/
CH2Cl2/H2O 3:2:1] followed by heating in a sealed tube at
1408C [toluene/vinyl acetate/diisopropylamine 2:2:1] where-
by the resulting syn-elimination product was encouraged to
cyclize. Pleasantly, this sequence afforded A1B(A)CDE
Figure 2. a) Illustration of preferential a-attack of MeLi on the C-3
carbonyl of ring D in ketone 20. b) Illustration of NOEs used to confirm the
structure of compound 21.
Apparently, the equatorially orientated b-mannoside bond
and the bulky, axially orientated TBS group at C-2 of
compound 20 provided a decisively biased encounter for the
incoming MeLi reagent, as opposed to the monosaccharide
unit D carrying a 1a-substituent in which the reagent would
have encountered opposing 1,2- and 1,3-interactions. Illus-
1
trated in Figure 2 are also the observed NOEs by H-NMR
studies and which served to assign the configuration of the
newly generated stereocenter in 21. The stereochemistry of
the b-mannoside linkage was also confirmed by measuring the
13C ± 1H spin coupling constant[10] which was consistent with
literature values (159.8 Hz). The resulting tertiary alcohol in
21 was found to be highly hindered and difficult to protect
under standard conditions, leading to the conviction that it
Chem. Eur. J. 2000, 6, No. 17
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K. C. Nicolaou et al.
FULL PAPER
second strategy of incorporation, which called for coupling 2
with the FGHA2 fragment 32 (see Scheme 5). Thus, reaction
of 2 with 32 in CH2Cl2 and in the presence of BF3 ´ Et2O at
À208C furnished oligosaccharide 33 with the desired b-
glycoside bond (between rings E and F) and in 55% yield.
This reaction also produced a small amount of the corre-
sponding a-glycoside (between rings E and F, 5% yield) and
Me
Me
OMe O
O
B
O
Cl
O
O
C
F
A1
Me
BnO
Me
Me
BnO
O
SePh
HO
MeO
O
Cl
NO2
Me
O
A
O
E
D
HO
O
OTIPS
Me
Me
OMe
OTBS
OTBS
29
3
a) SnCl2, Et2O
Me
Me
Me
Me
Me
OMe O
Me
OMe
OBn
O
O
O
Me
MeO
O
O
B
O
MeO
O
PMBO
HO
Cl
O
O
O
O
O
O
O
O
C
O
E
D
H
O
A1
F
G
E
D
A2
O
O
HO
SePh
O
Me
O
BnO
HO
NH
O
OTIPS
OTBS
OMe
Me
BnO
OBn
BnO
O
O
OAc
OAc
Cl3C
Me
Cl
OBn
OTBS
2
32
NO2
Me
A
30
Me
OMe
a) BF3•Et2O
b) NaIO4, MeOH
c) Heat, sealed tube
Me
Me OMe
OBn
O
O
O
O
Me
Me
Me
Me
Me
MeO
O
O
OMe O
O
O
PMBO
HO
MeO
O
O
O
O
O
O
H
O
BnO
D
E
G
O
O
F
Cl
A2
O
E
O
B
C
D
O
O
O
OMe
A1
OBn
Me
OR
O
OTIPS
OTBS
OR
OBn
Me
BnO
Me
O
O
BnO
OTBS
Cl
33: R = Ac
34: R = H
NO2
Me
b) K2CO3, MeOH
A
c) TBSOTf
31
Me
OMe
Scheme 4. Synthesis of the A1B(A)CDE system 31. a) 1.1 equiv 3,
1.0 equiv 29, 1.3 equiv SnCl2, Et2O, 0 ! 258C, 6 h, 62%; 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, 60% over
two steps. Bn ˆ benzyl.
Me
Me OMe
OBn
O
O
O
Me
A2
MeO
O
O
O
O
RO
HO
O
O
H
O
D
E
G
F
O
O
O
O
OMe
BnO
OBn
Me
OTBS
OTBS
OBn
35: R = PMB
36: R = H
37: R = CA
d) DDQ
e) (CA)2O, Et3N
orthoester 31 in 60% overall yield and as a single stereo-
isomer. The original vision, however, of coupling either 31 or
30 with the FGHA2 fragment was not realized because of
difficulties encountered in attempting to further elaborate
these intermediates. The successful arrival at compound 31,
however, was highly informative in that it confirmed that the
diol system of ring D could indeed be used in the coupling
reaction as a carbohydrate acceptor, and that an orthoester
formation reaction with advanced intermediates was viable.
Recognizing the difficulties with the A1B(A)C‡DE ap-
proach, we then focussed our attention to the alternative
strategy of attaching a suitably activated DE fragment onto
the FGHA2 segment prior to the incorporation of the
A1B(A)C fragment. To describe what followed, we have to
return to Scheme 3 and compound 3. Thus, in order to reach
our second coupling partner, trichloroacetimidate 2, w e
required suitable protection of the C-4 hydroxyl group of
ring D and activation of the C-1 position of ring E. To this end,
regioselective protection at C-4 of ring D was achieved with
nBu2SnO/PMBCl/nBu4NI, providing PMB ether 25 (63%
yield) which was fully desilylated (nBu4NF) and peracetylated
(Ac2O, Et3N, 4-DMAP cat.) to afford triacetate 27 (90% yield
for two steps, a:b anomers ca. 1:1) via triol 26. Exposure of the
latter compound 27 to the mild action of nBuNH2 in THF led
to the selective removal of the anomeric acetate furnishing
lactol 28 (86% yield), whose conversion to trichloroacetimi-
date 2 required treatment with CCl3CN in the presence of
DBU (89% yield, ca. 30:1 a:b anomer ratio).
f) H2, 10% Pd/C
Me
Me OMe
OH
O
O
O
Me
A2
MeO
O
O
O
O
CAO
HO
O
O
H
O
D
E
G
F
O
O
O
O
OMe
HO
OH
Me
OTBS
OTBS
OH
38
g) TBSOTf
OTBS
Me
MeO
O
Me OMe
O
O
O
Me
A2
O
O
O
O
RO
HO
H
O
D
E
G
F
O
O
O
O
O
OMe
OTBS
TBSO
OTBS
Me
OTBS
OTBS
39: R = CA
40: R = H
h) K2CO3, MeOH
Scheme 5. Completion of the synthesis of the DEFGHA2 fragment (40).
a) 1.7 equiv 2, 0.5 equiv BF3 ´ Et2O, CH2Cl2, À208C; 2 h, 55% yield of
desired b-anomer, 18% of unknown compound (b-anomer) and 5% yield
of a-anomer, a:b ca. 1:10; b) 0.5 equiv K2CO3, MeOH/THF 1:1, 258C, 1 h,
93%; c) 2.5 equiv TBSOTf, 4.0 equiv 2,6-lutidine, CH2Cl2, À10 ! 08C, 1 h,
92%; d) 1.5 equiv DDQ, CH2Cl2/H2O 10:1, 0 ! 258C, 1 h, 98 %;
e) 1.5 equiv (CA)2O, 2.0 equiv Et3N, 0.1 equiv 4-DMAP, CH2Cl2, 0 !
258C, 1 h, 99%; f) H2, 0.2 equiv 10% Pd/C (w/w), EtOAc, 258C, 3 h,
94%; g) 6.0 equiv TBSOTf, 8.0 equiv lutidine, CH2Cl2, 0 ! 258C, 2 h, 92%;
h) 0.2 equiv K2CO3, THF/MeOH 2:1, 258C, 15 min, 85%. CA ˆ chloro-
acetyl.
another compound whose complete structure remains unas-
signed but which appears to be isomeric to 33 and possesses
the E/F b-glycoside stereochemistry (18% yield). The lack of
complete structural information of this by-product created the
need to confirm unambiguously the structure of the major
isomer 33, and it was decided that this could be done through
degradation studies with everninomicin 13,384-1 (1). Specif-
Synthesis of the DEFGHA2 fragment: With trichloroaceti-
midate 2 in hand, we were now ready to proceed with the
3152
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Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 3
3149±3165
ically, we set out to prepare a common intermediate (i.e.,
compound 41, Scheme 6) from 33 (Scheme 5) and from 1 (see
Scheme 7), for spectroscopic comparison. Therefore, penta-
saccharide 33 was deacetylated (Scheme 5) with K2CO3 in
MeOH to afford triol 34 (93% yield) which was then cleanly
dibenzylated (see Scheme 6) with NaH/BnBr (95% yield)
leading to hexabenzyl ether 41 in which the tertiary alcohol on
ring D remained free. Hexa-benzyl ether 41 could also be
derived from the natural product (1) by degradation as
illustrated in Scheme 7. Thus, everninomicin 13,384-1 (1)[12]
was benzylated by treatment with excess NaH/BnBr in DMF
affording the fully benzylated everninomicin 49 in 93% yield.
The CD orthoester bridge was then selectively ruptured with
dilute aqueous HCl in THF[13] affording the corresponding
open-chain dihydroxy ester which was treated in situ with
aqueous KOH causing cyclization to d-lactone 51 and release
of diol 42. The C-4 position of ring D in compound 42 was
selectively protected as the PMB ether (NaH/PMBCl, 93%
yield) affording the targeted 41. The latter compound was
found to be identical to that derived from synthetic material,
thus confirming the latterꢁs structural identity. The next task
was to devise and test the best forward scenario involving
coupling of the A1B(A)C and DEFGHA2 fragments and final
drive for completion of the synthesis. Compatibility of
protecting groups during coupling and their ability to promote
such coupling as well as deprotection issues had to be resolved
before a path to the end was found. In all, three sets of
protecting groups on fragment DEFGHA2 were tested before
the final path was opened.
Me
Me OMe
OBn
O
O
O
Me
MeO
O
O
O
O
O
PMBO
HO
O
H
O
E
G
D
F
A2
O
O
O
O
OMe
BnO
OBn
Me
OH
OH
OBn
34
a) BnBr, NaH
OBn
Me
Me OMe
O
O
O
Me
A2
MeO
O
O
O
RO
HO
O
O
H
O
E
G
D
F
O
O
O
O
O
OMe
BnO
OBn
Me
OBn
OBn
OBn
41: R = PMB
42: R = H
43: R = TBS
g) (CA)2O, Et3N
b) DDQ
c) TBSOTf
47: R = CA
We had initially targeted the hexa-benzyl diol 42
(Scheme 6) as a potential partner in the projected final
coupling with the A1B(A)C fragment, therefore, the PMB
group was oxidatively removed (DDQ, 95% yield) from 41 to
give hexabenzyl diol 42. This plan was, however, thwarted by
lowglycosidation yields and rupture of the sensitive CD
orthoester moiety upon attempted debenzylation of the
expected coupling product (49, Scheme 7). We then turned
our attention to the hexa-acetyl counterpart of 42 and
proceeded as summarized in Scheme 6. Thus, treatment of
hexabenzyl diol 42 with TBSOTf/2,6-lutidine allowed selec-
tive protection at C-4 of ring D (43, 96% yield) while
hydrogenolysis of the resulting product followed by acetyla-
tion (Ac2O, Et3N, 4-DMAP cat.) furnished hexa-acetate 45 via
compound 44 in 88% overall yield. Removal of the TBS
group from ring D of 45 (nBu4NF) afforded diol 46 which,
however, upon attempted glycosidation with glycosyl donor
29 [A1B(A)C fragment] revealed its own glycosidation prob-
lems (e.g. sluggish reactivity and lowcoupling yields).
Our third and final strategy involved the adoption of the
hexa-TBS derivative 40 (Scheme 6) as the DEFGHA2 cou-
pling partner. Our initial synthesis of this compound began
with 42 and proceeded as shown in Scheme 6. Thus, selective
formation of the chloroacetate moiety on ring D of 42
[(CA)2O, Et3N, 4-DMAP cat., 98% yield] led to 47 which
was subjected to hydrogenolysis (H2, 10% Pd/C) affording
heptaol 48. Six TBS groups were then installed on 48 by
exposure to excess TBSOTf in the presence of 2,6-di-tert-
butylpyridine providing the TBS derivative 39 (65% yield
over two steps) whose tertiary hydroxy group (ring D)
remained free. The chloroacetate (CA) group was then
removed from the latter compound (K2CO3, MeOH) furnish-
ing the targeted diol 40 in 85% yield. Upon realizing, from
preliminary results, the promising potential of diol 40 as a
coupling partner, we returned to compound 34 (Scheme 5) for
a more efficient route to this compound (40). Thus, triol 34
was silylated with TBSOTf/2,6-lutidine leading to bis-TBS
derivative 35 (92% yield) from which the PMB group was
d) H2, 10% Pd/C, EtOAc
OR
Me
Me OMe
O
O
O
Me
A2
MeO
O
O
O
O
TBSO
HO
O
H
O
E
G
D
F
O
O
O
O
O
OMe
RO
OR
Me
OR
OR
OR
44: R = H
45: R = Ac
e) Ac2O
f) nBu4NF
Me
MeO
O
Me OMe
OAc
O
O
O
O
Me
A2
O
O
O
HO
O
H
O
E
G
O
D
F
O
HO
O
O
OMe
AcO
OAc
Me
OAc
OAc
OAc
46
h) H2, 10% Pd/C
Me
MeO
O
Me OMe
OH
O
O
O
Me
A2
O
O
O
O
CAO
HO
O
H
O
E
G
D
F
O
O
O
O
OMe
HO
OH
Me
OH
OH
OH
48
i) TBSOTf
Me
Me OMe
OTBS
O
O
O
Me
A2
MeO
O
O
O
O
O
RO
HO
H
O
E
G
D
F
O
O
O
O
O
OMe
OTBS
TBSO
OTBS
Me
OTBS
OTBS
39: R = CA
40: R = H
j) K2CO3, MeOH
Scheme 6. Synthesis of DEFGHA2 fragments 40, 42, and 46, initial
strategies. a) 3.0 equiv NaH, 2.5 equiv BnBr, 0.2 equiv nBu4NI, DMF,
0 ! 258C, 2 h, 95%; b) 1.5 equiv DDQ, CH2Cl2/H2O 10:1, 0 ! 258C, 2 h,
95%; c) 1.5 equiv TBSOTf, 3.0 equiv lutidine, CH2Cl2, À10 ! 08C, 1 h,
96%; d) 0.5 equiv 10% Pd/C (w/w), EtOAc, 258C, 6 h; e) 10.0 equiv Ac2O,
20 equiv Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 ! 258C, 2 h, 88% over two
steps; f) 1.5 equiv nBu4NF, 1.5 equiv AcOH, THF, 0 ! 258C, 2 h, 90%;
g) 1.5 equiv (CA)2O, 3.0 equiv Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 ! 258C,
1 h, 98%; h) 0.5 equiv 10% Pd/C (w/w), EtOAc, 258C, 4 h; i) 8.0 equiv
TBSOTf, 20 equiv 2,6-di-tert-butylpyridine, CH2Cl2, 0 ! 258C, 8 h, 65%
over two steps; j) 0.2 equiv K2CO3, MeOH, 258C,15 min, 85%.
Chem. Eur. J. 2000, 6, No. 17
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3153

K. C. Nicolaou et al.
FULL PAPER
derivative 54 in 65% yield and
as a single stereoisomer. The
remaining task for the genera-
tion of everninomicin from 54
was the removal of the protect-
ing groups which was accom-
plished by the following two-
step sequence. Upon extensive
experimentation with different
catalysts, solvents and buffer
systems, it was discovered that
the optimum conditions for re-
moval of the two benzyl
ethersÐwithout damaging the
chlorine, nitro or orthoester
sitesÐrequired exposure to H2
in the presence of 10% Pd/C
and NaHCO3 in tBuOMe. The
resulting hexa-TBS derivative
was then fully deprotected
through the action of nBu4NF
in THF furnishing the targeted
molecule (1) in 75% overall
yield from 54. Synthetic ever-
Me
Me OMe
OH
O
O
Me
Me
O
Me
OMe O
MeO
O
O
O
O
O
O
O
O
O
O
Cl
H
O
O
E
G
O
B
C
D
F
A2
A1
O
O
O
O
OMe
HO
OH
Me
HO
Me
O
O
HO
OH
OH
OH
Cl
NO2
Me
A
1: everninomicin 13,384-1
Me
OMe
a) i) NaH, BnBr, DMF, or
ii) TBSOTf, 2,6-lutidine
Me
Me OMe
OR
O
O
Me
Me
O
Me
OMe O
MeO
O
O
O
O
O
O
O
O
O
O
Cl
H
O
O
E
G
O
Me
B
C
D
F
A2
A1
O
O
O
O
OMe
RO
OR
Me
RO
O
O
RO
OR
OR
OR
Cl
NO2
Me
A
49: R = Bn
50: R = TBS
Me
Me
OMe
Me
b) HCl, H2O, THF;
KOH, H2O, THF
OMe O
O
B
O
Cl
O
O
C
O
A1
Me
Me OMe
OR
+
O
O
O
Me
Me
RO
MeO
O
RO
R1O
O
O
O
O
O
O
Cl
H
O
E
G
D
F
NO2
Me
A2
O
A
O
O
HO
O
O
OMe
RO
OR
Me
OR
OR
OR
Me
OMe
42: R = Bn, R1 = H
41: R = Bn, R1 = PMB
40: R = TBS, R1 = H
c) NaH, PMBCl
51: R = Bn
52: R = TBS
Scheme 7. Degradation studies with everninomicin 13,384-1 (1). a) i) 15 equiv NaH, 20 equiv BnBr, 0.1 equiv
nBu4NI, DMF, 0 ! 258C, 2 h, 93%; ii) 15 equiv TBSOTf, 30 equiv lutidine, CH2Cl2, 0 ! 258C, 3 h, 64%;
b) i) R ˆ Bn: 5% aq HCl, THF, 258C; then 1n aq KOH, THF, 258C, 85% of 51, 90% of 42; ii) R ˆ TBS: 5% aq
HCl, THF, 258C; then 1n aq KOH, THF, 258C, 83% of 52, 91% of 40; c) 1.2 equiv NaH, 1.5 equiv PMBCl,
0.1 equiv nBu4NI, DMF, 0 ! 258C, 1 h, 93 %.
ninomicin 13,384-1 (1)
w as
identical by the usual criteria
1
(TLC, H NMR, 13C NMR, IR,
MS, [a]) with an authentic
sample.[12]
removed (DDQ, 98% yield) and replaced with a chloroace-
tate protecting group [(CA)2O, Et3N, 4-DMAP cat., 99%
yield] to afford chloroacetate 37 via diol 36. In a subsequent
sequence, the four benzyl groups were removed from 37 (H2,
10% Pd/C, 94% yield) furnishing pentaol 38 onto which four
TBS groups were installed (TBSOTf, 2,6-lutidine, 92% yield)
to afford 39, and finally the chloroacetate was cleaved from
the latter compound (K2CO3, MeOH, 85% yield) leading to
the desired hexa-TBS diol system 40. The overall yield for the
conversion of 40 from 34 (as depicted in Scheme 5) was 66%
over six steps; in comparison, the six-step conversion of 34 to
40 as shown in Scheme 6, proceeded in 49% overall yield.
Later on, and after the completion of the described
synthesis of 1, we found that hexa-TBS derivative 40 could
also be obtained via a degradative route from the natural
product (1) following an analogous sequence as that em-
ployed for the generation of the benzylated derivative 42
(Scheme 7). Thus, exposure of everninomicin (1) to TBSOTf
in the presence of 2,6-lutidine furnished the fully silylated
everninomicin 50 in 64% yield. Treatment of 50 with dilute aq
HCl followed by subsequent addition of aq KOH furnished
the bis-silylated d-lactone 52 (83%) and the targeted hexa-
silylated diol 40 (91% yield). This degradative route provides
ample quantities of the rather complex DEFGHA2 fragment
40, which could potentially be useful for the semisynthesis of
analogs and libraries thereof.
Final stages of the total synthesis of everninomicin 13,384-1:
The final stages of the total synthesis of everninomicin 13,384-
1 (1) beginning with the union of the two advanced
intermediates described above is shown in Scheme 8. Thus,
coupling of the A1B(A)C glycosyl fluoride donor 29 with the
DEFGHA2 hexa-TBS diol acceptor 40 in the presence of
SnCl2 in Et2O proceeded smoothly and with complete stereo-
control leading to the 2-phenylseleno glycoside 53 in 70%
yield. No problems arising from elimination of the BnO and
PhSe groups were in evidence this time, as was for the case in
our initial attempts to bring about the union of 29 and 3 (vide
supra). Formation of the remaining orthoester site was then
accomplished with equal facility upon exposure of 53 to the
SinayÈ conditions [NaIO4 oxidation to the selenoxide in
MeOH/CH2Cl2/H2O 3:2:1 followed by heating in a sealed
tube at 1408C in toluene/vinyl acetate/diisopropylamine
2:2:1] to afford the fully protected everninomicin 13,384-1
Conclusion
The described program culminating in the total synthesis of
everninomicin 13,384-1 (1) served as an opportunity to
develop a number of novel synthetic reactions and strategies,
explore their scope and generality, and apply them to complex
situations. Some of these explorations will be described in
more detail in the following article.[14] Furthermore, the
reported total synthesis constituted an adventure in which the
power of new synthetic reactions both from our own and from
other laboratories was demonstrated. Most notable of these
methods are the stereocontrolled construction of 1,1'-disac-
charides,[14±15] the 1,2-phenylthio-[16] and the 1,2-phenylseleno-
[2, 14]
migrations on carbohydrate templates and their use in
3154
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Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 3
3149±3165
mixture was refluxed again for 2 h, and
then the reaction mixture was
quenched by the addition of H2O
(2 mL). The solvents were removed
under reduced pressure and the resi-
due was purified by flash column
chromatography (silica gel, 0 ! 80%
Et2O in hexanes) to afford PMB ether
7 (10.85 g, 83%) as a white solid. 7:
Rf ˆ 0.30 (70% Et2O in hexanes);
[a]2D2 ˆ ‡186.6 (c ˆ 2.89, CHCl3); IR
(thin film): nÄ ˆ 3434, 3060, 2950, 1511,
Me
O
Me
OMe O
Me
Me OMe
OTBS
O
O
O
Me
O
B
O
Cl
MeO
O
O
O
O
HO
HO
O
O
C
F
O
A1
H
O
D
E
G
F
A2
O
Me
O
BnO
O
O
O
OMe
BnO
SePh
TBSO
OTBS
Me
Cl
OTBS
OTBS
OTBS
NO2
Me
A
O
29
40
Me
OMe
a) SnCl2 , Et2O
Me OMe
Me
Me
OMe O
Me
MeO
O
OTBS
O
O
O
Me
A2
O
B
O
Cl
O
O
O
O
O
O
O
C
H
O
A1
E
G
D
F
1248, 1090, 1028, 786, 747, 698 cmÀ1
;
O
HO
SePh
O
Me
O
BnO
O
O
OMe
OTBS
BnO
O
TBSO
OTBS
1H NMR (600 MHz, CDCl3): d ˆ
7.54 ± 7.27 (m, 12H, ArH), 6.90 (d,
J ˆ 8.6 Hz, 2H, PMB), 5.63 (s, 1H,
CHAr), 5.59 (s, 1H, D1), 4.83, 4.68
(AB, J ˆ 11.4 Hz, 2H, CH2Ar), 4.34
(ddd, J ˆ 9.8, 9.8, 4.9 Hz, 1H, D5), 4.23
(t, J ˆ 1.8 Hz, 1H, D2), 4.22 (dd, J ˆ
10.3, 4.9 Hz, 1H, D6), 4.17 (t, J ˆ
9.5 Hz, 1H, D4), 3.95 (dd, J ˆ 9.6,
3.3 Hz, 1H, D3), 3.86 (t, J ˆ 10.3 Hz,
1H, D6), 3.82 (s, 3H, OMe), 2.97 (d,
J ˆ 1.3 Hz, 1H, OH); 13C NMR
(150 MHz, CDCl3): d ˆ 159.5, 137.4,
133.3, 131.6, 129.7, 129.6, 129.2, 128.9,
128.2, 127.6, 126.0, 113.9, 101.5, 87.8,
78.9, 75.3, 72.9, 71.3, 68.5, 64.6, 55.2;
Me
Cl
OTBS
OTBS
NO2
Me
A
O
53
Me
OMe
b) NaIO4, MeOH
c) Heat - sealed tube
Me
Me OMe
OTBS
O
O
Me
Me
O
O
Me
OMe O
MeO
O
O
O
O
O
O
O
O
O
Cl
H
D
E
G
O
O
B
C
F
A2
A1
O
O
O
O
O
OMe
OTBS
TBSO
OTBS
Me
BnO
Me
O
O
BnO
OTBS
OTBS
Cl
NO2
Me
A
54
d) H2, 10% Pd/C, NaHCO3
e) nBu4NF
Me
OMe
Me
Me OMe
OH
O
O
Me
Me
O
Me
OMe O
MeO
O
O
O
O
O
O
O
O
O
Cl
H
O
D
B
O
E
G
O
C
F
HRMS
(MALDI):
calcd
for
A2
A1
O
O
O
O
O
OMe
‡
C27H28O6SNa [M‡Na] : 503.1504,
HO
OH
Me
OH
HO
Me
O
O
HO
OH
OH
found 503.1505.
Cl
NO2
Me
A
TBS ether 8: TBSOTf (5.73 mL,
25.0 mmol) was added to a solution
1: everninomicin 13,384-1
Me
OMe
of PMB ether 7 (10.00 g, 20.8 mmol)
and 2,6-lutidine (3.64 mL, 31.0 mmol)
in CH2Cl2 (110 mL) at 08C and the
resulting mixture was warmed to 258C
Scheme 8. Final stages of the total synthesis of everninomicin 13,384-1 (1). a) 2.4 equiv 29, 2.0 equiv SnCl2, Et2O,
0 ! 258C, 6 h, 70%; 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, 65% over two steps; d) H2, 0.2 equiv 10% Pd/C
(w/w), 4.0 equiv NaHCO3, tBuOMe, 258C, 1 h; e) 10.0 equiv nBu4NF, THF, 258C, 10 h, 75% for two steps.
and stirred for 0.5 h. The reaction
mixture was diluted with CH2Cl2
stereocontrolled glycosidation reactions. Other processes
explored and championed in these investigations include the
selective silylation of carbohydrate diols in different solvents,
the use of acyl fluorides for the formation of sterically
hindered esters, the SinayÈ orthoester formation protocol,[11]
the Kahne sulfoxide b-mannoside forming glycosidation,[4, 5]
the Schmidt trichloroacetimidate glycosidation method,[3] the
Mukaiyama glycosyl fluoride methodology,[17] and the tin-
acetal technology[8] for differentiating 1,2-diols. In addition, a
considerable body of knowledge regarding selectivity in
protective group chemistry was accumulated, and light was
shed on conformational effects on selective functionalization
of carbohydrate substrates. Significantly, the stage is nowset
for further studies in the field, including semisynthesis of
designed analogues of everninomicin 13,384-1 (1), solid-phase
synthesis, combinatorial chemistry, and chemical biology
studies.
(800 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 ! 80% Et2O in hexanes) to afford TBS ether
8 (11.51 g, 93%) as a white foam. 8: Rf ˆ 0.76 (50% Et2O in hexanes);
[a]2D2 ˆ ‡142.9 (c ˆ 0.41, CHCl3); IR (thin film): nÄ ˆ 2930, 2857, 1613, 1515,
1
1471, 1372, 1250, 1101, 1034, 837, 780, 741, 696 cmÀ1; H NMR (600 MHz,
CDCl3): d ˆ 7.53 ± 7.28 (m, 12H, ArH), 6.87 (d, J ˆ 8.5 Hz, 2H, PMB), 5.64
(s, 1H, CHAr), 5.33 (d, J ˆ 0.9 Hz, 1H, D1), 4.76, 4.66 (AB, J ˆ 11.6 Hz,
2H, CH2Ar), 4.29 (ddd, J ˆ 9.7, 9.7, 4.8 Hz, 1H, D5), 4.23 (brs, 1H, D2),
4.21 (dd, J ˆ 10.2, 4.5 Hz, 1H, D6), 4.20 (t, J ˆ 9.3 Hz, 1H, D4), 3.87 (dd,
J ˆ 9.7, 2.8 Hz, 1H, D3), 3.86 (t, J ˆ 10.4 Hz, 1H, D6), 3.82 (s, 3H, OMe),
0.90 (s, 9H, tBuSi), 0.09 (s, 3H, MeSi), 0.05 (s, 3H, MeSi); 13C NMR
(150 MHz, CDCl3): d ˆ 159.1, 137.7, 133.8, 131.9, 130.5, 129.5, 129.1, 128.8,
128.1, 127.6, 126.1, 113.6, 101.5, 90.3, 79.2, 75.5, 72.7, 72.6, 68.6, 65.5, 55.2,
25.8, 18.2, À4.4, À5.0; HRMS (MALDI): calcd for C33H42O6SSiNa
‡
[M‡Na] : 617.2369, found 617.2358.
Ring D sulfoxide 4: mCPBA (3.19 g, 18.5 mmol) was added to a solution of
TBS ether 8 (10.00 g, 16.8 mmol) in CH2Cl2 (85 mL) at À208C and the
resulting mixture was warmed to 08C and stirred for 2 h. The reaction
mixture was quenched by the addition of saturated aqueous NaHCO3
(20 mL), diluted with CH2Cl2 (800 mL), and washed with brine (80 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 ring D sulfoxide 4
(9.52 g, 92%, ca. 4:1 mixture of diastereoisomers) as a white foam. 4: Rf ˆ
0.19 (30% Et2O in hexanes); [a]2D2 ˆ À41.8 (c ˆ 3.03, CHCl3); IR (thin
film): nÄ ˆ 3060, 2931, 2857, 1613, 1586, 1515, 1467, 1381, 1251, 1119, 1030,
834, 752 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.62 ± 7.36 (m, 10H, ArH),
7.35 (d, J ˆ 8.6 Hz, 2H, PMB), 6.88 (d, J ˆ 8.6 Hz, 2H, PMB), 5.65 (s, 1H,
CHAr), 4.82, 4.72 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.68 (d, J ˆ 1.0 Hz, 1H,
Experimental Section
General: For general procedures and techniques, see Part 1[1] in this series.
PMB ether 7: nBu2SnO (7.44 g, 29.9 mmol) was added to a solution of
mannose diol 6[7] (9.80 g, 27.2 mmol) in toluene (130 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 PMBCl (5.53 mL,
40.8 mmol) and nBu4NI (2.01 g, 5.4 mmol) were added. The reaction
Chem. Eur. J. 2000, 6, No. 17
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3155 $ 17.50+.50/0
3155

K. C. Nicolaou et al.
FULL PAPER
D1), 4.23 (d, J ˆ 0.8 Hz, 1H, D2), 4.24 ± 4.21 (m, 1H, D3), 4.23 (t, J ˆ
7.2 Hz, 1H, D4), 4.21 (dd, J ˆ 10.3, 4.8 Hz, 1H, D6), 4.12 ± 4.08 (m, 1H, D5),
3.82 (s, 3H, OMe), 3.75 (t, J ˆ 10.1 Hz, 1H, D6), 0.84 (s, 9H, tBuSi), 0.04 (s,
3H, MeSi), À0.08 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 160.1,
142.3, 138.2, 134.0, 132.6, 131.3, 131.0, 130.7, 130.3, 129.8, 129.1, 127.0, 125.4,
114.5, 102.5, 101.4, 79.0, 76.5, 73.8, 71.2, 69.1, 68.2, 56.1, 26.6, 19.0, À3.6,
Tosylate 13: Recrystallized TsCl (5.20 g, 27.3 mmol) was added to a
solution of diol 12 (12.60 g, 24.8 mmol) in pyridine (55 mL) at 08C and the
resulting mixture was warmed to 258C and stirred for 12 h. The reaction
mixture was diluted with CH2Cl2 (500 mL) and washed with saturated
aqueous NH4Cl (100 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 tosylate 13 (15.92 g, 97%) as a white foam. 13:
Rf ˆ 0.53 (70% Et2O in hexanes); [a]2D2 ˆ À50.3 (c ˆ 0.29, CHCl3); IR (thin
film): nÄ ˆ 3433, 2928, 2855, 1612, 1513, 1363, 1250, 1176, 1130, 1095, 1034,
‡
À4.5; HRMS (MALDI): calcd for C33H42O7SSiNa [M‡Na] : 633.2318,
found 633.2327.
PMB ether 10: nBu2SnO (11.45 g, 46.0 mmol) was added to a solution of
galactose diol 9[9] (15.00 g, 41.6 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 PMBCl
(8.46 mL, 62.4 mmol) and nBu4NI (3.07 g, 8.3 mmol) were added. The
reaction mixture was refluxed again for 2 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 PMB ether
10 (17.41 g, 87%) as a white solid. 10: Rf ˆ 0.31 (100% Et2O); [a]2D2 ˆ ‡32.9
(c ˆ 0.85, CHCl3); IR (thin film): nÄ ˆ 3440, 3071, 2928, 2873, 1612, 1513,
983 837 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.74 (d, J ˆ 8.2 Hz, 2H,
ArH), 7.49 ± 7.24 (m, 9H, ArH), 6.89 (d, J ˆ 8.6 Hz, 2H, PMB), 4.59, 4.48
(AB, J ˆ 11.3 Hz, 2H, CH2Ar), 4.52 (d, J ˆ 9.6 Hz, 1H, E1), 4.21 (dd, J ˆ
10.4, 5.1 Hz, 1H, E6), 4.17 (dd, J ˆ 10.4, 7.2 Hz, 1H, E6), 3.88 (dd, J ˆ 3.0,
0.8 Hz, 1H, E4), 3.82 (s, 3H, OMe), 3.75 (dd, J ˆ 9.3, 8.5 Hz, 1H, E2),
3.70 ± 3.68 (m, 1H, E5), 3.36 (dd, J ˆ 8.4, 3.3 Hz, 1H, E3), 2.41 (s, 3H,
OMe), 1.43 (s, 1H, OH), 0.93 (s, 9H, tBuSi), 0.14 (s, 3H, MeSi), 0.08 (s, 3H,
MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 159.5, 144.9, 134.5, 132.4, 131.1,
129.8, 129.6, 129.3, 128.8, 128.0, 127.2, 114.0, 89.6, 82.7, 75.2, 71.6, 69.8, 68.6,
65.6, 55.2, 30.3, 26.1, 21.6, 18.3, À3.7, À4.3; HRMS (ESI): calcd for
1
1248, 1173, 1102, 1078, 1030, 996, 817, 747, 697 cmÀ1; H NMR (600 MHz,
‡
C33H44O8S2SiNa [M‡Na] : 683, found 683.
CDCl3): d ˆ 7.69 (d, J ˆ 7.0 Hz, 2H, ArH), 7.43 ± 7.23 (m, 10H, ArH), 6.85
(d, J ˆ 8.5 Hz, 2H, PMB), 5.44 (s, 1H, CHAr), 4.68, 4.63 (AB, J ˆ 11.5 Hz,
2H, CH2Ar), 4.52 (d, J ˆ 9.5 Hz, 1H, E1), 4.35 (d, J ˆ 12.0, Hz, 1H, E6),
4.12 (d, J ˆ 3.5 Hz, 1H, E4), 3.97 (d, J ˆ 12.0, Hz, 1H, E6), 3.93 (t, J ˆ
9.5 Hz, 1H, E2), 3.78 (s, 3H, OMe), 3.49 (dd, J ˆ 9.9, 3.5 Hz, 1H, E3), 3.42
(s, 1H, E5), 2.55 (s, 1H, OH); 13C NMR (150 MHz, CDCl3): d ˆ 159.6,
137.8, 133.6, 129.4, 128.9, 128.8, 128.0, 127.9, 126.5, 113.8, 101.0, 87.0, 79.9,
73.2, 71.1, 70.0, 69.3, 67.1, 55.2; HRMS (MALDI): calcd for C27H28O6SNa
Alcohol 14: LAH (0.50 g, 13.1 mmol) was added slowly to a solution of
tosylate 13 (5.41 g, 8.2 mmol) in THF (40 mL) at 08C. The resulting mixture
was heated to 458C and stirred for 3 h. The reaction mixture was cooled to
08C and carefully quenched by the addition of saturated aqueous NH4Cl
(10 mL), diluted with Et2O (500 mL), and stirred for 1 h. The mixture was
diluted with Et2O (200 mL) and washed with 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 ! 80% Et2O in hexanes) to afford alcohol 14 (3.61 g, 90%) as a white
foam. 14: Rf ˆ 0.37 (50% Et2O in hexanes); [a]2D2 ˆ À6.2 (c ˆ 0.86, CHCl3);
IR (thin film): nÄ ˆ 3495, 2931, 2856, 1613, 1585, 1515, 1469, 1366, 1250, 1130,
‡
[M‡Na] : 503.1504, found 503.1491.
TBS ether 11: TBSOTf (9.75 mL, 42.4 mmol) was added to a solution of
PMB ether 10 (17.00 g, 35.4 mmol) and 2,6-lutidine (6.18 mL, 53.1 mmol) in
CH2Cl2 (175 mL) at 08C and the resulting mixture was warmed to 258C and
stirred for 1 h. The reaction mixture was diluted with CH2Cl2 (800 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 chromatog-
raphy (silica gel, 0 ! 80% Et2O in hexanes) to afford TBS ether 11
(20.41 g, 97%) as a white foam. 11: Rf ˆ 0.61 (50% Et2O); [a]2D2 ˆ ‡57.2
(c ˆ 0.32, CHCl3); IR (thin film): nÄ ˆ 2954, 2856, 1613, 1585, 1514, 1471,
1
1089, 1042, 998, 872, 789, 779, 744 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ
7.50 (d, J ˆ 7.1 Hz, 2H, ArH), 7.29 ± 7.20 (m, 5H, ArH), 6.88 (d, J ˆ 8.6 Hz,
2H, PMB), 4.57, 4.54 (AB, J ˆ 11.2 Hz, 2H, CH2Ar), 4.53 (d, J ˆ 9.6 Hz,
1H, E1), 3.81 (s, 3H, OMe), 3.79 (t, J ˆ 9.4 Hz, 1H, E2), 3.76 (d, J ˆ 3.2 Hz,
1H, E4), 3.55 (brq, J ˆ 6.5 Hz, 1H, E5), 3.37 (dd, J ˆ 8.5, 3.3 Hz, 1H, E3),
2.00 (s, 1H, OH), 1.34 (d, J ˆ 6.5 Hz, 3H, E6), 0.93 (s, 9H, tBuSi), 0.15 (s,
3H, MeSi), 0.08 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 159.4,
135.1, 131.1, 129.6, 128.7, 126.9, 113.9, 89.7, 83.4, 73.9, 71.1, 69.8, 68.6, 55.2,
30.3, 26.1, 18.3, 16.8, À3.6, À4.3; HRMS (MALDI): calcd for C26H38O5S-
1
1363, 1249, 1172, 1100, 1048, 1001, 909, 865, 838, 818, 735 cmÀ1; H NMR
(500 MHz, CDCl3): d ˆ 7.63 ± 7.19 (m, 10H, ArH), 7.32 (d, J ˆ 8.6 Hz, 2H,
PMB), 6.86 (d, J ˆ 8.6 Hz, 2H, PMB), 5.39 (s, 1H, CHAr), 4.61, 4.58 (AB,
J ˆ 11.5 Hz, 2H, CH2Ar), 4.59 (d, J ˆ 9.5 Hz, 1H, E1), 4.33 (dd, J ˆ 12.0,
1.5 Hz, 1H, E6), 4.09 (d, J ˆ 2.5 Hz, 1H, E4), 4.08 (t, J ˆ 9.0 Hz, 1H, E2),
3.95 (dd, J ˆ 12.0, 1.5 Hz, 1H, E6), 3.81 (s, 3H, OMe), 3.43 (dd, J ˆ 8.5,
3.5 Hz, 1H, E3), 3.37 (brs, 1H, E5), 0.96 (s, 9H, tBuSi), 0.06 (s, 3H, MeSi),
0.05 (s, 3H, MeSi); 13C NMR (125 MHz, CDCl3): d ˆ 159.1, 138.1, 134.4,
131.1, 130.4, 129.3, 128.8, 128.6, 128.0, 126.6, 126.4, 113.5, 101.0, 88.9, 81.9,
72.8, 70.6, 69.7, 69.4, 68.9, 55.2, 26.1, 18.4, À3.7, À4.7; HRMS (MALDI):
‡
SiNa [M‡Na] : 513.2107, found 513.2129.
Methyl ether 15: NaH (0.29 g, 7.2 mmol) was added to a solution of alcohol
14 (3.22 g, 6.5 mmol) in DMF (30 mL) at 08C and the resulting mixture was
stirred for 5 min. MeI (0.53 mL, 8.5 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 (5 mL), diluted with
Et2O (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 ! 70%
Et2O in hexanes) to afford methyl ether 15 (3.12 g, 94%) as a white foam.
15: Rf ˆ 0.47 (50% Et2O in hexanes); [a]2D2 ˆ À19.2 (c ˆ 0.63, CHCl3); IR
(thin film): nÄ ˆ 2931, 2855, 1612, 1514, 1463, 1365, 1249, 1130, 1056, 1038,
‡
calcd for C33H42O6SSiNa [M‡Na] : 617.2369, found 617.2395.
Diol 12: Zn(OTf)2 (22.90 g, 63.0 mmol) was added to a solution of TBS
ether 11 (15.00 g, 25.2 mmol) and EtSH (40.00 mL, 500 mmol) in CH2Cl2
(150 mL) at 08C and the resulting mixture was stirred at 08C for 2 h. The
reaction mixture was quenched by the careful addition of saturated
aqueous NaHCO3 (200 mL), diluted with CH2Cl2 (800 mL) and washed
with 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
837, 779 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.51 ± 7.16 (m, 7H, ArH),
6.87 (d, J ˆ 8.6 Hz, 2H, PMB), 4.62, 4.57 (AB, J ˆ 11.5 Hz, 2H, CH2Ar),
4.50 (d, J ˆ 9.5 Hz, 1H, E1), 3.91 (dd, J ˆ 9.4, 8.2 Hz, 1H, E2), 3.81 (s, 3H,
OMe), 3.57 (s, 3H, OMe), 3.48 (brq, J ˆ 6.3 Hz, 1H, E5), 3.31 (dd, J ˆ 8.1,
2.9 Hz, 1H, E3), 3.30 (brs, 1H, E4), 1.29 (d, J ˆ 6.3 Hz, 3H, E6), 0.91 (s, 9H,
tBuSi), 0.17 (s, 3H, MeSi), 0.06 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3):
d ˆ 159.1, 135.7, 131.1, 130.2, 129.3, 129.1, 128.6, 126.7, 113.7, 91.9, 84.5, 78.7,
74.4, 71.7, 70.3, 61.7, 55.2, 26.2, 18.3, 17.0, À3.6, À4.2; HRMS (MALDI):
diol 12 (9.86 g, 77%) as a white solid. 12: Rf ˆ 0.41 (100% Et2O); [a]D22
ˆ
À39.2 (c ˆ 1.07, CHCl3); IR (thin film): nÄ ˆ 3418, 2929, 2855, 1514, 1472,
1244, 1132, 1084, 1035, 872, 779 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.47
(d, J ˆ 8.3 Hz, 2H, ArH), 7.31 ± 7.19 (m, 5H, ArH), 6.88 (d, J ˆ 8.6 Hz, 2H,
PMB), 4.58, 4.53 (AB, J ˆ 11.3 Hz, 2H, CH2Ar), 4.57 (d, J ˆ 9.5 Hz, 1H,
E1), 3.95 (d, J ˆ 3.0 Hz, 1H, E4), 3.93 (dd, J ˆ 11.8, 7.1 Hz, 1H, E6), 3.85 (t,
J ˆ 9.0 Hz, 1H, E2), 3.80 (s, 3H, OMe), 3.73 (dd, J ˆ 11.8, 4.3 Hz, 1H, E6),
3.47 (dd, J ˆ 7.6, 4.1 Hz, 1H, E5), 3.38 (dd, J ˆ 8.5, 3.3 Hz, 1H, E3), 2.33
(brs, 2H, OH), 0.94 (s, 9H, tBuSi), 0.15 (s, 3H, MeSi), 0.10 (s, 3H, MeSi);
13C NMR (150 MHz, CDCl3): d ˆ 159.4, 134.8, 130.9, 129.5, 128.8, 126.9,
113.9, 89.5, 83.0, 77.9, 71.1, 70.0, 66.3, 62.4, 55.2, 30.0, 26.0, 18.3, À3.7, À4.3;
‡
calcd for C27H40O5SSiNa [M‡Na] : 527.2263, found 527.2284.
Lactol 16: NBS (1.70 g, 9.5 mmol) was added to a solution of methyl ether
15 (3.21 g, 6.4 mmol) in acetone/H2O (10:1, 33 mL) at 08C and the resulting
mixture warmed to 258C and stirred for 2 h. The reaction mixture was
quenched by the addition of saturated aqueous NaHCO3 (20 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 the lactol 16 (2.49 g, 95%) as a
white foam. 16: Rf ˆ 0.26, 0.41 (70% Et2O in hexanes); [a]2D2 ˆ ‡22.9 (c ˆ
‡
HRMS (MALDI): calcd for C26H38O6SSiNa [M‡Na] : 529.2056, found
529.2062.
3156
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3156 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 3
3149±3165
0.17, CHCl3); IR (thin film): nÄ ˆ 3416, 2931, 2862, 1612, 1513, 1465, 1250,
1088, 837 cmÀ1; 1H NMR (500 MHz, CDCl3 (ca. 3:1 a:b ratio)): d ˆ 7.29 (d,
J ˆ 8.6 Hz, 2.6H, PMB), 6.87 (d, J ˆ 8.6 Hz, 2.6H, PMB), 5.12 (d, J ˆ
3.8 Hz, 1H, E1), 4.68 ± 4.57 (m, 2.6H, CH2Ar), 4.43 (t, J ˆ 7.3 Hz, 0.3H,
E1), 4.09 (brq, J ˆ 6.5 Hz, 1H, E5), 4.04 (dd, J ˆ 9.5, 3.8 Hz, 1H, E2), 3.81
(s, 4H, OMe), 3.67 (dd, J ˆ 9.4, 7.3 Hz, 0.3H, E2), 3.60 ± 3.55 (m, 5H, E3,
OMe), 3.52 (brq, J ˆ 6.5 Hz, 0.3H, E5), 3.31 (d, J ˆ 2.1 Hz, 1H, E4), 3.24
(dd, J ˆ 9.4, 2.9 Hz, 0.3H, E3), 3.21 (d, J ˆ 2.6 Hz, 0.3H, E-4), 3.07 (brs, 1H,
OH), 2.87 (d, J ˆ 7.3 Hz, 0.3H, OH), 1.27 (d, J ˆ 6.5 Hz, 1H, E6), 1.24 (d,
J ˆ 6.5 Hz, 3H, E6), 0.90 (s, 10H, tBuSi), 0.10 (s, 1H, MeSi), 0.09 (s, 3H,
MeSi), 0.08 (s, 3H, MeSi), 0.05 (s, 1H, MeSi); 13C NMR (150 MHz, CDCl3):
d ˆ 159.1, 130.5, 129.3, 129.1, 113.7, 98.0, 93.5, 82.6, 79.8, 79.2, 78.9, 73.7,
72.3, 72.2, 70.7, 70.1, 66.7, 61.7, 55.2, 25.9, 25.8, 18.2, 18.0, 16.7, 16.5, À4.3,
foam. 18: Rf ˆ 0.45 (10% Et2O in hexanes); [a]2D2 ˆ À17.7 (c ˆ 0.90,
CHCl3); IR (thin film): nÄ ˆ 2960, 2855, 1613, 1515, 1469, 1383, 1303, 1252,
1072, 777, 699 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.52 ± 7.35 (m, 5H,
ArH), 7.27 (d, J ˆ 8.6 Hz, 2H, PMB), 6.85 (d, J ˆ 8.6 Hz, 2H, PMB), 5.60 (s,
1H, CHAr), 4.70, 4.64 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.49 (s, 1H, D1), 4.46
(d, J ˆ 7.5 Hz, 1H, E1), 4.25 (dd, J ˆ 10.0, 4.5 Hz, 1H, D6), 4.22 (d, J ˆ
2.5 Hz, 1H, D2), 4.04 (t, J ˆ 9.0 Hz, 1H, D4), 3.83 (t, J ˆ 10.0 Hz, 1H, D6),
3.81 (s, 3H, OMe), 3.61 (dd, J ˆ 9.5, 7.5 Hz, 1H, E2), 3.54 (s, 3H, OMe),
3.51 (brq, J ˆ 6.5 Hz, 1H, E5), 3.42 (dd, J ˆ 10.0, 3.0 Hz, 1H, D3), 3.37 (dd,
J ˆ 9.5, 3.5 Hz, 1H, E3), 3.29 (d, J ˆ 3.5 Hz, 1H, E4), 3.28 (ddd, J ˆ 10.0,
10.0, 4.5 Hz, 1H, D5), 1.25 (d, J ˆ 6.5 Hz, 3H, E6), 1.09 ± 1.04 (m, 21H,
iPr3Si), 0.92 (s, 9H, tBuSi), 0.84 (s, 9H, tBuSi), 0.16 (s, 3H, MeSi), 0.13 (s,
3H, MeSi), 0.12 (s, 6H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 159.0,
137.6, 130.3, 129.6, 129.1, 128.8, 128.1, 128.0, 126.4, 126.1, 113.5, 104.3, 101.5,
98.8, 84.7, 82.4, 79.2, 76.7, 74.8, 73.3, 72.3, 71.4, 70.4, 68.9, 67.6, 62.3, 55.0,
26.0, 18.0, 17.8, 16.1, 12.7, À3.2, À3.9, À4.1, À4.3; HRMS (FAB): calcd for
‡
À4.4, À4.5, À4.9; HRMS (MALDI): calcd for C21H36O6SiNa [M‡Na] :
435.2179, found 435.2168.
TIPS ether 17: TIPSOTf (1.77 mL, 6.57 mmol) was added to a solution of
lactol 16 (2.26 g, 5.48 mmol) and 2,6-lutidine (0.96 mL, 8.22 mmol) in
CH2Cl2 (27 mL) at 08C and the resulting mixture was warmed to 258C and
stirred for 6 h. 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) and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 40% Et2O in hexanes) to afford TIPS ether 17 (3.02 g,
97%) as a white foam. 17: Rf ˆ 0.56 (15% Et2O in hexanes); IR (thin film):
‡
C49H84O11Si3Cs [M‡Cs] : 1065.4376, found 1065.4326.
DE alcohol 19: DDQ (0.26 g, 1.13 mmol) was added to a solution of DE
disaccharide 18 (0.81 g, 0.87 mmol) in CH2Cl2/H2O (10:1, 5.2 mL) at 08C
and the resulting mixture was warmed to 258C and stirred for 2 h. The
reaction mixture was diluted with CH2Cl2 (250 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 ! 30% Et2O in hexanes) to afford DE alcohol 19 (0.67 g, 95%) as a
white foam. 19: Rf ˆ 0.54 (20% Et2O in hexanes); [a]2D2 ˆ À39.9 (c ˆ 6.53,
CHCl3); IR (thin film): nÄ ˆ 3472, 2932, 2862, 1467, 1384, 1253, 1181, 1095,
nÄ ˆ 2937, 2865, 1514, 1466, 1250, 1106, 838 cmÀ1
;
1H NMR (500 MHz,
CDCl3 (1:2.3 a:b ratio)): d ˆ 7.28 (d, J ˆ 8.6 Hz, 3H, PMB), 6.87 (d, J ˆ
8.6 Hz, 3H, PMB), 5.17 (d, J ˆ 3.5 Hz, 1H, E1), 4.63 ± 4.55 (m, 6H, CH2Ar),
4.49 (d, J ˆ 7.5 Hz, 2H, E1), 4.06 (dd, J ˆ 9.5, 3.0 Hz, 1H, E2), 4.01 (brq,
J ˆ 6.5 Hz, 1H, E5), 3.81 (s, 10H, OMe), 3.73 (dd, J ˆ 10.0, 2.5 Hz, 2H, E3),
3.67 (dd, J ˆ 9.0, 7.0 Hz, 2H, E2), 3.58 (s, 3H, OMe), 3.54 (s, 6H, OMe),
3.45 (brq, J ˆ 6.5 Hz, 2H, E5), 3.27 (brs, 1H, E4), 3.24 (dd, J ˆ 9.0, 3.0 Hz,
2H, E3), 3.22 (dd, J ˆ 3.0, 0.5 Hz, 2H, E4), 1.23 (d, J ˆ 6.5 Hz, 6H, E6), 1.17
(d, J ˆ 6.5 Hz, 3H, E6), 1.10 ± 1.05 (m, 63H, iPr3Si), 0.89 (s, 9H, tBuSi), 0.87
(s, 18H, tBuSi), 0.09 (s, 6H, MeSi), 0.07 (s, 3H, MeSi), 0.06 (s, 9H, MeSi);
13C NMR (150 MHz, CDCl3): d ˆ 130.6, 129.2, 113.6, 98.9, 94.5, 83.4, 80.7,
79.1, 78.1, 73.5, 72.2, 70.6, 70.4, 66.3, 61.6, 61.4, 55.2, 26.1, 18.2, 18.1, 16.5,
16.3, 12.7, 12.3, À3.9, À4.2, À4.3, À4.5; HRMS (MALDI): calcd for
1018, 837, 779 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.51 ± 7.35 (m, 5H,
ArH), 5.55 (s, 1H, CHAr), 4.62 (s, 1H, D1), 4.48 (d, J ˆ 7.5 Hz, 1H, E1),
4.27 (dd, J ˆ 10.5, 5.0 Hz, 1H, D6), 4.25 (d, J ˆ 3.5 Hz, 1H, D2), 3.81 (t, J ˆ
10.0 Hz, 1H, D6), 3.78 (t, J ˆ 9.0 Hz, 1H, D4), 3.70 (ddd, J ˆ 10.0, 7.0,
3.0 Hz, 1H, D3), 3.63 (dd, J ˆ 9.5, 7.0 Hz, 1H, E2), 3.54 (s, 3H, OMe), 3.52
(q, J ˆ 6.5 Hz, 1H, E5), 3.43 (dd, J ˆ 9.5, 3.5 Hz, 1H, E3), 3.35 (ddd, J ˆ 9.5,
9.5, 5.0 Hz, 1H, D5), 3.30 (d, J ˆ 3.0 Hz, 1H, E4), 2.15 (d, J ˆ 6.5 Hz, 1H,
OH), 1.25 (d, J ˆ 6.5 Hz, 3H, E6), 1.14 ± 1.06 (m, 21H, iPr3Si), 0.95 (s, 9H,
tBuSi), 0.89 (s, 9H, tBuSi), 0.25 (s, 3H, MeSi), 0.17 (s, 3H, MeSi), 0.14 (s,
3H, MeSi), 0.13 (s, 3H, MeSi); 13C NMR (125 MHz, CDCl3): d ˆ 137.2,
129.2, 128.3, 126.3, 103.9, 102.2, 98.9, 84.6, 79.2, 73.5, 72.0, 71.7, 70.4, 68.8,
67.2, 62.3, 26.1, 26.0, 18.2, 18.0, 16.2, 12.8, À3.4, À3.8, À4.6; HRMS (FAB):
‡
C30H56O6Si2Na [M‡Na] : 591.3513, found 591.3535.
Ring E alcohol 5: DDQ (1.65 g, 7.3 mmol) was added to a solution of TIPS
ether 17 (2.75 g, 4.8 mmol) in CH2Cl2/H2O (10:1, 33 mL) at 08C and the
resulting mixture was warmed to 258C and stirred for 1 h. The reaction
mixture was diluted with CH2Cl2 (250 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 ! 50%
Et2O in hexanes) to afford ring E alcohol 5 (2.13 g, 98%) as a white foam.
5: Rf ˆ 0.49 (15% Et2O in hexanes); [a]2D2 ˆ À1.15 (c ˆ 0.33, CHCl3); IR
(thin film): nÄ ˆ 3488, 2943, 2865, 1465, 1252, 1090, 1046, 886, 837, 778,
684 cmÀ1; 1H NMR (500 MHz, CDCl3 (b only)): d ˆ 4.44 (d, J ˆ 6.7 Hz, 1H,
E1), 3.56 (s, 3H, OMe), 3.52 (brq, J ˆ 6.6 Hz, 1H, E5), 3.43 (ddd, J ˆ 7.0,
7.0, 3.4 Hz, 1H, E3), 3.40 (t, J ˆ 6.8 Hz, 1H, E2), 3.25 (d, J ˆ 3.4 Hz, 1H,
E4), 2.13 (d, J ˆ 7.7 Hz, 1H, OH), 1.27 (d, J ˆ 6.6 Hz, 3H, E6), 1.10 ± 0.99
(m, 21H, iPr3Si), 0.88 (s, 9H, tBuSi), 0.10 (s, 3H, MeSi), 0.08 (s, 3H, MeSi);
13C NMR (150 MHz, CDCl3): d ˆ 98.2, 82.2, 75.6, 75.3, 70.6, 62.3, 25.9, 17.9,
16.5, 12.5, À3.9, À4.5; HRMS (MALDI): calcd for C22H48O5Si2Na
‡
calcd for C41H76O10Si3Cs [M‡Cs] : 945.3801, found 945.3825.
DE ketone 20: DE alcohol 19 (0.49 g, 0.61 mmol), NMO (0.11 g,
0.91 mmol), and 4 Š MS (0.1 g) were dissolved in CH2Cl2 (4 mL) and the
reaction mixture was stirred for 5 min. TPAP (11 mg, 0.03 mmol) was
added and the reaction mixture was stirred at 258C for 2 h. The reaction
mixture was diluted with Et2O (30 mL), filtered through a short pad of
silica gel, and then the solvents were removed under reduced pressure to
afford ketone 20 (ca. 0.46 g) as a white foam. 20: Rf ˆ 0.32 (10% Et2O in
hexanes); [a]2D2 ˆ À33.8 (c ˆ 3.69, CHCl3); IR (thin film): nÄ ˆ 2930, 2864,
1750, 1472, 1384, 1254, 1180, 1096, 1017, 838, 778 cmÀ1; 1H NMR (400 MHz,
CDCl3): d ˆ 7.53 ± 7.36 (m, 5H, ArH), 5.60 (s, 1H, CHAr), 4.82 (d, J ˆ
10.0 Hz, 1H, D4), 4.76 (s, 1H, D1), 4.49 (d, J ˆ 7.1 Hz, 1H, E1), 4.42 (dd,
J ˆ 10.3, 4.6 Hz, 1H, D6), 4.34 (s, 1H, D2), 3.96 (t, J ˆ 10.0 Hz, 1H, D6),
3.66 (dd, J ˆ 9.4, 7.1 Hz, 1H, E2), 3.61 (s, 3H, OMe), 3.55 (dd, J ˆ 9.2,
3.0 Hz, 1H, E3), 3.51 ± 3.34 (m, 2H, D5, E5), 3.33 (d, J ˆ 2.9 Hz, 1H, E4),
1.26 (d, J ˆ 6.5 Hz, 3H, E6), 1.16 ± 1.03 (m, 21H, iPr3Si), 0.90 (s, 9H, tBuSi),
0.87 (s, 9H, tBuSi), 0.16 (s, 3H, MeSi), 0.12 (s, 3H, MeSi), 0.11 (s, 3H,
MeSi), 0.10 (s, 3H, MeSi); 13C NMR (100 MHz, CDCl3): d ˆ 198.5, 136.4,
129.4, 128.3, 126.4, 104.7, 102.2, 98.8, 84.5, 82.4, 80.7, 78.2, 73.3, 70.3, 69.3,
67.4, 65.8, 62.1, 26.1, 25.7, 18.2, 18.0, 16.1, 12.8, À3.5, À3.8, À4.6, À5.0;
‡
[M‡Na] : 471.2938, found 471.2940.
DE disaccharide 18: Ring D sulfoxide 4 (2.23 g, 3.65 mmol) and di-tert-
butyl-4-methylpyridine (1.27 g, 6.18 mmol) were azeotroped with benzene,
dissolved in CH2Cl2 (7 mL) and cooled to À788C. 4 Š MS (0.3 g) were
added and the reaction mixture was stirred for 5 min. Tf2O (0.614 mL,
3.65 mmol) was added dropwise and the reaction mixture was stirred for
5 min. Ring E alcohol 5 (1.26 g, 2.81 mmol) was dissolved in CH2Cl2 (4 mL)
and added to the reaction mixture by cannula. The flask was rinsed with
CH2Cl2 (2 Â 2 mL) and this was also transferred to the reaction mixture.
The reaction mixture was stirred at À788C for 30 min, followed by gradual
warming to 08C over 2 h. The reaction mixture was then quenched by the
addition of saturated aqueous NaHCO3 (50 mL), diluted with CH2Cl2
(500 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 ! 50%
Et2O in hexanes) to afford b-DE disaccharide 18 (1.86 g, 71%) as a white
‡
HRMS (FAB): calcd for C41H74O10Si3Cs [M‡Cs] : 943.3644, found
943.3677.
DE alcohol 21: Crude DE ketone 20 (ca. 0.46 g, 0.61 mmol) was dissolved
in Et2O (4 mL) and cooled to À788C. MeLi (0.61 mL, 0.85 mmol, 1.8m
solution in Et2O) was added dropwise and the reaction mixture was stirred
for 1 h. The reaction mixture was quenched by the addition of saturated
aqueous NH4Cl (10 mL), diluted with Et2O (150 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 ! 50% Et2O in hexanes) to afford DE
alcohol 21 (0.44 g, 88% over two steps) as a white foam. 21: Rf ˆ 0.56 (10%
Et2O in hexanes); [a]2D2 ˆ À54.6 (c ˆ 0.33, CHCl3); IR (thin film): nÄ ˆ 3500,
Chem. Eur. J. 2000, 6, No. 17
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3157 $ 17.50+.50/0
3157

K. C. Nicolaou et al.
FULL PAPER
2929, 2864, 1463, 1383, 1253, 1183, 1092, 1017, 835, 779 cmÀ1
;
1H NMR
(dd, J ˆ 9.4, 3.6 Hz, 1H, E3), 3.25 ± 3.19 (m, 2H, D5, D6), 2.50 (s, 1H, OH),
2.12 (d, J ˆ 2.4 Hz, 1H, OH), 1.26 (d, J ˆ 6.5 Hz, 3H, E6), 1.16 (s, 3H, Me
(D3)), 1.15 ± 1.06 (m, 21H, iPr3Si), 0.93 (s, 9H, tBuSi), 0.89 (s, 9H, tBuSi),
0.31 (s, 3H, MeSi), 0.14 (s, 3H, MeSi), 0.13 (s, 3H, MeSi), 0.12 (s, 3H,
MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 102.0, 99.1, 85.5, 82.3, 76.2, 75.2,
74.8, 74.2, 74.1, 73.5, 70.5, 62.4, 26.2, 26.0, 18.2, 18.1, 17.2, 16.1, 15.3, 12.9, 7.6,
(600 MHz, CDCl3): d ˆ 7.51 ± 7.31 (m, 5H, ArH), 5.56 (s, 1H, CHAr), 4.80
(s, 1H, D1), 4.48 (d, J ˆ 7.1 Hz, 1H, E1), 4.26 (dd, J ˆ 10.2, 4.9 Hz, 1H, D6),
3.87 (s, 1H, D2), 3.75 (t, J ˆ 10.1 Hz, 1H, D6), 3.71 (d, J ˆ 9.5 Hz, 1H, D4),
3.62 (dd, J ˆ 9.3, 7.1 Hz, 1H, E2), 3.53 ± 3.51 (m, 1H, E5), 3.52 (s, 3H,
OMe), 3.43 (ddd, J ˆ 9.8, 9.8, 5.0 Hz, 1H, D5), 3.42 (dd, J ˆ 9.4, 3.4 Hz, 1H,
E3), 3.31 (d, J ˆ 3.3 Hz, 1H, E4), 2.48 (s, 1H, OH), 1.32 (s, 3H, Me (D3)),
1.26 (d, J ˆ 6.4 Hz, 3H, E6), 1.16 ± 1.03 (m, 21H, iPr3Si), 0.96 (s, 9H, tBuSi),
0.91 (s, 9H, tBuSi), 0.30 (s, 3H, MeSi), 0.17 (s, 3H, MeSi), 0.15 (s, 3H,
MeSi), 0.14 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 137.5, 129.0,
128.2, 126.3, 125.5, 102.7 (JC1,H1 ˆ 159.8 Hz), 102.2 (JC1,H1 ˆ 157.5 Hz), 99.1,
85.3, 82.7, 82.2, 76.8, 73.6, 72.3, 70.5, 69.2, 66.3, 62.3, 30.3, 26.2, 26.2, 18.2,
18.1, 16.2, 13.0, À3.3, À3.4, À3.9, À4.7; HRMS (FAB): calcd for
‡
À3.3, À3.5, À4.0, À5.0; HRMS (FAB): calcd for C35H73IO9Si3Cs [M‡Cs] :
981.2662, found 981.2645.
DE diol 3: AIBN (5.0 mg, 0.01 mmol) was added to a solution of DE iodide
24 (0.16 g, 0.19 mmol) and nBu3SnH (0.16 mL, 0.60 mmol) in benzene
(3.0 mL) at 258C and the resulting mixture was immediately refluxed for 0.5 h.
The reaction mixture was cooled 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 DE diol 3 (0.13 g,
97%) as a white foam. 3: Rf ˆ 0.45 (50% Et2O in hexanes); [a]2D2 ˆ À21.2
(c ˆ 0.43, CHCl3); IR (thin film): nÄ ˆ 3432, 2931, 2857, 1463, 1301, 1248,
‡
C42H78O10Si3Cs [M‡Cs] : 959.3957, found 959.3997.
DE triol 22: 10% Pd/C (40 mg) was added to a solution of DE benzylidene
21 (0.22 g, 0.26 mmol) in EtOAc (3.0 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 (50 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 DE triol 22 (0.19 g, 97%) as a white foam. 22: Rf ˆ 0.27
(70% Et2O in hexanes); [a]2D2 ˆ À70.7 (c ˆ 0.44, CHCl3); IR (thin film):
nÄ ˆ 3422, 2928, 2864, 1463, 1382, 1254, 1178, 1090, 836, 779 cmÀ1; 1H NMR
(600 MHz, CDCl3): d ˆ 4.79 (s, 1H, D1), 4.47 (d, J ˆ 7.1 Hz, 1H, E1), 3.85
(dd, J ˆ 11.6, 3.9 Hz, 1H, D6), 3.84 (d, J ˆ 3.3 Hz, 1H, D2), 3.78 (dd, J ˆ
11.4, 3.9 Hz, 1H, D6), 3.77 (d, J ˆ 9.7 Hz, 1H, D4), 3.60 (dd, J ˆ 9.3, 7.1 Hz,
1H, E2), 3.51 (s, 3H, OMe), 3.50 (q, J ˆ 6.5 Hz, 1H, E5), 3.40 (dd, J ˆ 9.3,
3.5 Hz, 1H, E3), 3.34 (ddd, J ˆ 9.6, 9.6, 3.9 Hz, 1H, D5), 3.31 (d, J ˆ 3.4 Hz,
1H, E4), 2.33 (s, 1H, OH), 2.02 (s, 1H, OH), 1.43 (s, 3H, Me (D3)), 1.24 (d,
J ˆ 6.4 Hz, 3H, E6), 1.17 ± 1.04 (m, 21H, iPr3Si), 0.92 (s, 9H, tBuSi), 0.90 (s,
9H, tBuSi), 0.29 (s, 3H, MeSi), 0.15 (s, 3H, MeSi), 0.13 (s, 3H, MeSi), 0.13
(s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 102.0, 99.1, 85.3, 83.0, 76.1,
74.2, 74.1, 73.6, 71.8, 70.4, 63.2, 62.3, 31.5, 26.2, 26.0, 18.2, 17.2, 16.2, 13.0,
1175, 1073, 818 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 4.70 (s, 1H, D1),
4.46 (d, J ˆ 6.5 Hz, 1H, E1), 3.80 (s, 1H, D2), 3.58 (d, J ˆ 8.5 Hz, 1H, E2),
3.52 (s, 3H, OMe), 3.50 (q, J ˆ 6.5 Hz, 1H, E5), 3.41 ± 3.31 (m, 4H, D4, D5,
E3, E4), 2.00 (s, 1H, OH), 1.43 (d, J ˆ 0.5 Hz, 1H, OH), 1.28 (d, J ˆ 5.5 Hz,
3H, D6), 1.24 (d, J ˆ 5.5 Hz, 3H, E6), 1.16 (s, 3H, Me (D3)), 1.14 ± 1.06 (m,
21H, iPr3Si), 0.92 (s, 9H, tBuSi), 0.89 (s, 9H, tBuSi), 0.30 (s, 3H, MeSi), 0.14
(s, 3H, MeSi), 0.13 (s, 3H, MeSi), 0.12 (s, 3H, MeSi); 13C NMR (150 MHz,
CDCl3): d ˆ 119.0, 101.6, 99.1, 85.1, 82.5, 76.6, 76.3, 74.0, 73.6, 70.5, 63.3,
26.2, 26.0, 18.4, 18.2, 17.1, 16.2, 12.9, À3.4, À3.6, À4.1, À4.8; HRMS
‡
(MALDI): calcd for C35H74O9Si3Na [M‡Na] : 745.4538, found 745.4520.
DE PMB ether 25: nBu2SnO (45.0 mg, 0.18 mmol) was added to a solution
of DE diol 3 (0.12 g, 0.17 mmol) in toluene (10 mL) and the resulting
mixture was refluxed with removal of H2O using a Dean Stark apparatus
for 5 h. The reaction mixture was cooled to 258C and PMBCl (34.0 mL,
0.25 mmol) and nBu4NI (12 mg, 0.03 mmol) were added. The reaction
mixture was refluxed again for 8 h, and then the reaction mixture was
quenched by the addition of H2O (0.5 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 DE PMB
ether 25 (88 mg, 63%) as a white foam. 25: Rf ˆ 0.62 (30% Et2O in
hexanes); [a]2D2 ˆ À10.0 (c ˆ 0.11, CHCl3); IR (thin film): nÄ ˆ 3450, 2932,
‡
À3.4, À3.4, À3.9, À4.9; HRMS (FAB): calcd for C35H74O10Si3Cs [M‡Cs] :
871.3644, found 871.3610.
Tosylate 23: Recrystallized TsCl (0.06 g, 0.31 mmol) was added to a
solution of DE triol 22 (0.19 g, 0.26 mmol) in pyridine (1.0 mL) at 08C and
the resulting mixture was warmed to 258C and stirred for 12 h. The reaction
mixture was diluted with CH2Cl2 (150 mL) and washed with saturated
aqueous NH4Cl (20 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 DE tosylate 23 (0.20 g, 87%) as a white foam.
23: Rf ˆ 0.42 (70% Et2O in hexanes); [a]2D2 ˆ À25.9 (c ˆ 0.27, CHCl3); IR
(thin film): nÄ ˆ 3542, 3436, 2931, 2851, 1595, 1461, 1361, 1249, 1179, 1085,
985, 838, 779, 720 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.77 (d, J ˆ 8.3 Hz,
2H, ArH), 7.34 (d, J ˆ 8.3 Hz, 2H, ArH), 4.71 (s, 1H, D1), 4.46 (d, J ˆ
7.1 Hz, 1H, E1), 4.29 (dd, J ˆ 10.6, 1.4 Hz, 1H, D6), 4.22 (dd, J ˆ 10.6,
6.2 Hz, 1H, D6), 3.81 (s, 1H, D2), 3.59 (dd, J ˆ 9.3, 7.1 Hz, 1H, E2), 3.57 (d,
J ˆ 3.9 Hz, 1H, E4), 3.53 ± 3.48 (m, 3H, D4, D5, E5), 3.50 (s, 3H, OMe),
3.40 (dd, J ˆ 9.4, 3.6 Hz, 1H, E3), 2.43 (s, 3H, ArMe), 2.27 (s, 1H, OH), 2.02
(d, J ˆ 1.9 Hz, 1H, OH), 1.26 (d, J ˆ 6.2 Hz, 3H, E6), 1.25 (s, 3H, Me (D3)),
1.13 ± 1.05 (m, 21H, iPr3Si), 0.91 (s, 9H, tBuSi), 0.88 (s, 9H, tBuSi), 0.30 (s,
3H, MeSi), 0.13 (s, 3H, MeSi), 0.12 (s, 3H, MeSi), 0.11 (s, 3H, MeSi);
13C NMR (150 MHz, CDCl3): d ˆ 144.7, 133.3, 129.8, 127.6, 101.7, 99.0, 85.5,
82.1, 75.8, 74.1, 73.5, 72.5, 71.0, 70.5, 70.1, 62.1, 26.2, 26.0, 21.6, 18.4, 18.1,
18.0, 16.9, 16.0, 12.8, À3.4, À3.5, À4.0, À4.9; HRMS (FAB): calcd for
2861, 1519, 1249, 1185, 1091, 844, 773 cmÀ1 1H NMR (600 MHz, CDCl3):
;
d ˆ 7.28 (d, J ˆ 8.5 Hz, 2H, PMB), 6.87 (d, J ˆ 8.5 Hz, 2H, PMB), 4.84, 4.55
(AB, J ˆ 10.9 Hz, 2H, CH2Ar), 4.64 (s, 1H, D1), 4.47 (d, J ˆ 7.1 Hz, 1 H,
E1), 3.80 (s, 3H, OMe), 3.74 (s, 1H, D2), 3.58 (dd, J ˆ 9.2, 7.2 Hz, 1H, E2),
3.51 (s, 3H, OMe), 3.48 (q, J ˆ 7.3 Hz, 1H, E5), 3.40 (d, J ˆ 3.3 Hz, 1H, E4),
3.34 (dd, J ˆ 9.4, 3.5 Hz, 1H, E3), 3.29 (dd, J ˆ 9.4, 6.0 Hz, 1H, D5), 3.18 (d,
J ˆ 9.4 Hz, 1H, D4), 2.55 (s, 1H, OH), 1.25 (d, J ˆ 6.9 Hz, 6H, D6, E6), 1.21
(s, 3H, Me (D3)), 1.14 ± 1.04 (m, 21H, iPr3Si), 0.93 (s, 9H, tBuSi), 0.89 (s,
9H, tBuSi), 0.29 (s, 3H, MeSi), 0.14 (s, 3H, MeSi), 0.13 (s, 3H, MeSi), 0.11
(s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 159.2, 130.6, 129.9, 113.7,
101.6, 99.1, 85.1, 83.6, 82.5, 75.0, 74.8, 73.5, 70.6, 70.4, 62.3, 55.3, 29.7, 26.2,
26.1, 18.8, 18.5, 18.2, 18.1, 18.1, 16.2, 12.9, À3.3, À3.5, À3.9, À4.9; HRMS
‡
(MALDI): calcd for C43H82O10Si3Na [M‡Na] : 865.5113, found 865.5104.
DE triacetate 27: nBu4NF (0.81 mL, 0.81 mmol) was added to a solution of
DE alcohol 25 (0.17 g, 0.20 mmol) in THF (1.0 mL) and the resulting
mixture was stirred at 258C for 6 h. The reaction mixture was diluted with
CH2Cl2 (1.0 mL) and Et3N (0.112 mL, 0.81 mmol) and 4-DMAP (5.0 mg,
0.01 mmol) were added. The resulting mixture was cooled to 08C and Ac2O
(51.0 mL, 0.50 mmol) was added. The reaction mixture was warmed to 258C
and stirred for 1 h. 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) 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 DE triacetate 27
(0.106 g, 90% over two steps) as a white foam. 27: Rf ˆ 0.30 (100% Et2O);
IR (thin film): nÄ ˆ 3452, 2934, 1754, 1613, 1513, 1371, 1245, 1091, 919,
732 cmÀ1; 1H NMR (600 MHz, CDCl3, ca. 1:1 mixture of anomers): d ˆ 7.28
(d, J ˆ 8.6 Hz, 2H, PMB), 7.27 (d, J ˆ 8.6 Hz, 2H, PMB), 6.87 (d, J ˆ 8.6 Hz,
4H, PMB), 6.26 (d, J ˆ 3.7 Hz, 1H, E1), 5.53 (d, J ˆ 8.3 Hz, 1H, E1), 5.29
(dd, J ˆ 10.3, 8.3 Hz, 1H, E2), 5.26 (dd, J ˆ 10.3, 3.7 Hz, 1H, E2), 4.96 (s,
1H, D1), 4.93 (s, 1H, D1), 4.81, 4.55 (AB, J ˆ 10.8 Hz, 4H, CH2Ar), 4.79 (s,
1H, D2), 4.72 (s, 1H, D2), 4.03 (brq, J ˆ 6.3 Hz, 1H, E5), 3.99 (dd, J ˆ 10.6,
2.8 Hz, 1H, E3), 3.80 (s, 6H, OMe), 3.75 (dd, J ˆ 10.2, 2.8 Hz, 1H, E3), 3.68
(brq, J ˆ 6.4 Hz, 1H, E5), 3.52 (d, J ˆ 2.0 Hz, 1H, E4), 3.45 (d, J ˆ 2.7 Hz,
‡
C42H80O12SSi3Cs [M‡Cs] : 1025.3733, found 1025.3783.
DE iodide 24: LiI (0.15 g, 1.12 mmol) was added to a solution of DE
tosylate 23 (0.20 g, 0.22 mmol) in DMF (2.0 mL) at 258C and the resulting
mixture was heated from 808C to 1008C over 2 h. The reaction mixture was
cooled, diluted with Et2O (150 mL) and washed with saturated aqueous
NH4Cl (20 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 ! 80% Et2O in
hexanes) to afford DE iodide 24 (0.16 g, 86%) as a white foam. 24: Rf ˆ
0.46 (50% Et2O in hexanes); [a]2D2 ˆ À10.5 (c ˆ 0.20, CHCl3); IR (thin
film): nÄ ˆ 3554, 3460, 2931, 1861, 1467, 1373, 1302, 1255, 1178, 1085, 861, 826,
1
773, 732 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 4.75 (s, 1H, D1), 4.47 (d,
J ˆ 7.1 Hz, 1H, E1), 3.82 (s, 1H, D2), 3.73 (d, J ˆ 3.5 Hz, 1H, E4), 3.62 ±
3.60 (m, 2H, E2, D4), 3.55 (s, 3H, OMe), 3.53 ± 3.50 (m, 2H, D6, E5), 3.41
3158
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
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Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 3
3149±3165
1H, E4), 3.44 ± 3.23 (m, 4H, D4, D4, D5, D5), 2.14 (s, 3H, OAc), 2.13 (s,
3H, OAc), 2.11 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.03 (s, 3H, OAc), 2.01 (s,
3H, OAc), 1.37 (s, 6H, Me (D3)), 1.36 (d, J ˆ 6.1 Hz, 3H, D6), 1.34 (d, J ˆ
6.1 Hz, 3H, D6), 1.30 (d, J ˆ 6.1 Hz, 3H, E6), 1.23 (d, J ˆ 6.1 Hz, 3H, E6);
13C NMR (150 MHz, CDCl3): d ˆ 170.9, 170.8, 169.6, 169.6, 169.2, 168.8,
159.3, 135.7, 130.4, 129.6, 125.5, 113.8, 99.0, 98.8, 92.4, 90.4, 82.6, 82.5, 81.3,
80.8, 80.4, 75.9, 75.9, 75.0, 73.8, 71.6, 70.9, 70.9, 69.7, 69.0, 68.5, 61.4, 61.3,
55.2, 30.3, 29.3, 21.0, 20.9, 20.9, 20.8, 20.7, 20.6, 19.9, 18.6, 18.5, 16.2; HRMS
Me), 2.30 (ddd, J ˆ 12.3, 4.8, 1.9 Hz, 1H, B2), 2.03 (dd, J ˆ 13.7, 1.7 Hz, 1H,
A2), 1.69 (s, 3H, Me (A3)), 1.63 (dt, J ˆ 12.2, 12.2 Hz, 1H, B2), 1.33 (d, J ˆ
6.2 Hz, 3H, B6), 1.31 (d, J ˆ 6.2 Hz, 3H, C6), 1.25 (s, 3H, Me (D3)), 1.24 (d,
J ˆ 6.4 Hz, 3H, D6), 1.24 (d, J ˆ 5.4 Hz, 3H, E6), 1.14 ± 1.04 (m, 21H,
iPr3Si), 0.88 (s, 9H, tBuSi), 0.86 (s, 9H, tBuSi), 0.83 (d, J ˆ 6.2 Hz, 3H, A6),
0.26 (s, 3H, MeSi), 0.11 (s, 6H, MeSi), 0.09 (s, 3H, MeSi); 13C NMR
(150 MHz, CDCl3): d ˆ 165.6, 153.3, 153.2, 138.2, 135.9, 134.8, 134.5, 129.0,
128.6, 128.5, 128.2, 127.6, 127.5, 126.4, 126.0, 121.7, 102.3, 101.5, 100.1, 99.1,
92.4, 89.9, 85.1, 84.2, 82.5, 80.0, 78.0, 76.1, 74.9, 74.5, 73.5, 72.3, 71.1, 71.0,
70.5, 70.0, 67.6, 66.2, 65.8, 62.2, 62.0, 60.8, 48.5, 40.1, 36.3, 29.7, 26.2, 26.1,
25.1, 19.4, 19.3, 18.5, 18.4, 18.1, 18.0, 17.8, 16.2, 15.3, 12.8, À3.4, À3.5, À3.9,
‡
(MALDI): calcd for C28H40O13Na [M‡Na] : 607.2367, found 607.2352.
DE lactol 28: nBuNH2 (15.0 mL, 0.21 mmol) was added to a solution of DE
triacetate 27 (100 mg, 0.17 mmol) in THF (1.0 mL) and the resulting
mixture was stirred at 258C for 5 h. The reaction mixture was diluted with
CH2Cl2 (150 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 residue was purified by flash column
chromatography (silica gel, 0 ! 100% EtOAc in hexanes) to afford DE
lactol 28 (80 mg, 86%) as a white foam. 28: Rf ˆ 0.30 (100% EtOAc); IR
‡
À4.9; HRMS (FAB): calcd for C84H129Cl2NO22SeSi3Cs [M‡Cs] :
1870.5911, found 1870.6012.
A1B(A)CDE orthoester 31: NaIO4 (41 mg, 0.19 mmol) and NaHCO3
(13 mg, 0.15 mmol) were added to a solution of A1B(A)CDE pentasac-
charide 30 (33 mg, 0.019 mmol) in MeOH/CH2Cl2/H2O (3:2:1, 1.0 mL) and
the resulting mixture was stirred at 258C for 4 h. The reaction mixture was
diluted with CH2Cl2 (150 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 (1 mL) and transferred by cannula to a sealed tube.
The flask was washed with toluene (2 Â 0.5 mL) and the organics were
transferred to the sealed tube. Diisopropylamine (1 mL) and vinyl acetate
(2 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 preparative TLC (silica gel, 50% Et2O in hexanes) to afford
A1B(A)CDE orthoester 31 (18 mg, 60% over two steps) as a white foam.
31: Rf ˆ 0.21 (30% Et2O in hexanes); [a]2D2 ˆ À8.0 (c ˆ 0.64, CHCl3); IR
(thin film): nÄ ˆ 2934, 2863, 1737, 1543, 1457, 1388, 1251, 1128, 1095, 1043,
907, 840, 778, 735 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.57 (d, J ˆ 7.3 Hz,
2H, ArH), 7.43 ± 7.27 (m, 8H, ArH), 5.05, 5.02 (AB, J ˆ 10.1 Hz, 2H,
CH2Ar), 4.94 (brd, J ˆ 3.2 Hz, 1H, A1), 4.88 (t, J ˆ 9.4 Hz, 1H, B4), 4.87 (s,
1H, D1), 4.75 (dd, J ˆ 9.8, 1.6 Hz, 1H, B1), 4.68, 4.55 (AB, J ˆ 11.0 Hz, 2H,
CH2Ar), 4.45 (d, J ˆ 7.1 Hz, 1H, E1), 4.11 (s, 1H, D2), 3.94 ± 3.79 (m, 6H,
B3, C3, C4, C5, D4, E5), 3.82 (s, 3H, OMe), 3.73 (dq, J ˆ 10.0, 6.4 Hz, 1H,
D5), 3.64 (d, J ˆ 9.4 Hz, 1H, A4), 3.59 (dd, J ˆ 9.2, 7.2 Hz, 1H, E2), 3.54 (s,
3H, OMe), 3.53 ± 3.46 (m, 1H, A5), 3.43 (dd, J ˆ 9.4, 3.4 Hz, 1H, E3), 3.35
(s, 3H, OMe), 3.34 ± 3.31 (m, 2H, B5, E4), 2.51 (dd, J ˆ 12.8, 5.1 Hz, 1H,
C2), 2.44 (dd, J ˆ 13.8, 5.0 Hz, 1H, A2), 2.38 (s, 3H, Me (A1)), 2.29 (dd, J ˆ
10.7, 3.3 Hz, 1H, B2), 2.01 (dd, J ˆ 13.7, 1.8 Hz, 1H, A2), 1.90 (t, J ˆ 12.1 Hz,
1H, C2), 1.69 (dt, J ˆ 12.2, 12.2 Hz, 1H, B2), 1.69 (s, 3H, Me (A3)), 1.34 (s,
3H, Me (D3)), 1.32 (d, J ˆ 6.2 Hz, 3H, C6), 1.30 (d, J ˆ 6.0 Hz, 3H, B6),
1.27 (d, J ˆ 6.3 Hz, 3H, D6), 1.23 (d, J ˆ 6.4 Hz, 3H, E6), 1.19 ± 1.06 (m,
21H, iPr3Si), 0.94 (s, 9H, tBuSi), 0.89 (s, 9H, tBuSi), 0.82 (d, J ˆ 6.2 Hz, 3H,
A6), 0.20 (s, 3H, MeSi), 0.13 (s, 3H, MeSi), 0.13 (s, 3H, MeSi), 0.12 (s, 3H,
MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 165.6, 153.3, 153.2, 151.5, 138.7,
135.9, 134.8, 128.7, 128.6, 128.2, 127.5, 127.3, 126.4, 126.0, 121.7, 120.1, 102.4,
100.2, 99.2, 92.4, 90.0, 84.7, 84.3, 82.9, 82.5, 81.6, 79.1, 77.2, 76.2, 74.9, 74.1,
73.9, 72.5, 71.8, 71.1, 70.4, 70.1, 68.3, 66.2, 65.9, 62.3, 62.0, 60.8, 45.5, 40.1,
38.9, 36.4, 29.7, 26.3, 24.0, 21.0, 20.6, 19.4, 19.2, 18.4, 18.3, 18.1, 17.6, 16.2,
15.3, 13.0, À3.5, À3.8, À3.9, À4.5; HRMS (ESI): calcd for C78H125Cl2NO23-
(thin film): nÄ ˆ 3366, 2931, 2872, 1737, 1649, 1549, 1515, 1372, 1247, 1088 cmÀ1
;
1H NMR (600 MHz, CDCl3 (a:b ca. 10:1)): d ˆ 7.26 (d, J ˆ 8.5 Hz, 2H,
PMB), 6.86 (d, J ˆ 8.5 Hz, 2H, PMB), 5.38 (d, J ˆ 3.6 Hz, 1H, E1), 5.04 (dd,
J ˆ 10.6, 3.7 Hz, 1H, E2), 4.93 (s, 1H, D1), 4.80 (s, 1H, D2), 4.78, 4.53 (AB,
J ˆ 10.8 Hz, 2H, CH2Ar), 4.15 (brq, J ˆ 6.4 Hz, 1H, E5), 4.11 (dd, J ˆ 10.6,
2.8 Hz, 1H, E3), 3.78 (s, 3H, OMe), 3.55 (s, 3H, OMe), 3.45 (d, J ˆ 2.1 Hz,
1H, E4), 3.38 (dq, J ˆ 9.5, 6.4 Hz, 1H, D5), 3.30 (d, J ˆ 9.5 Hz, 1H, D4),
2.10 (s, 3H, OAc), 2.07 (s, 3H, OAc), 1.33 (s, 3H, Me (D3)), 1.31 (d, J ˆ
6.4 Hz, 3H, E6), 1.19 (d, J ˆ 6.4 Hz, 3H, D6); 13C NMR (150 MHz, CDCl3):
d ˆ 170.9, 170.1, 159.2, 130.4, 129.6, 113.7, 98.9, 95.9, 90.4, 82.6, 81.9, 76.2,
75.9, 74.9, 73.7, 71.0, 70.7, 65.9, 60.3, 55.2, 39.3, 31.5, 21.1, 19.9, 19.6, 18.5,
‡
16.1; HRMS (MALDI): calcd for C26H38O12Na [M‡Na] : 565.2261, found
565.2282.
DE trichloroacetimidate 2: DBU (1 drop) was added to a solution of DE
lactol 28 (86 mg, 0.16 mmol) and Cl3CCN (0.10 mL, 0.80 mmol) in CH2Cl2
(1.0 mL) at 08C and the resulting mixture was stirred for 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
DE trichloroacetimdiate 2 (97 mg, 89%, a:b ca. 30:1) as a white foam. 2:
Rf ˆ 0.60 (80% EtOAc in hexanes); IR (thin film): nÄ ˆ 3495, 3331, 2978,
2951, 2884, 1743, 1678, 1614, 1508, 1455, 1373, 1243, 1091, 1049, 844,
791 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 8.54 (s, 1H, NH), 7.27 (d, J ˆ
8.5 Hz, 2H, PMB), 6.87 (d, J ˆ 8.5 Hz, 2H, PMB), 6.47 (d, J ˆ 3.7 Hz, 1H,
E1), 5.28 (dd, J ˆ 10.6, 3.7 Hz, 1H, E2), 4.99 (s, 1H, D2), 4.81, 4.56 (AB, J ˆ
11.0 Hz, 2H, CH2Ar), 4.16 ± 4.12 (m, 2H, E3, E5), 3.79 (s, 3H, OMe), 3.59
(s, 3H, OMe), 3.57 (brs, 1H, E4), 3.42 (dq, J ˆ 9.6, 5.9 Hz, 1H, D5), 3.32 (d,
J ˆ 9.6 Hz, 1H, D4), 2.14 (s, 3H, OAc), 2.00 (s, 3H, OAc), 1.37 (s, 3H, Me
(D3)), 1.35 (d, J ˆ 6.0 Hz, 3H, D6), 1.26 (d, J ˆ 6.6 Hz, 3H, E6); 13C NMR
(125 MHz, CDCl3): d ˆ 170.1, 170.0, 161.1, 159.0, 130.5, 129.8, 114.4, 98.5,
94.3, 91.6, 82.5, 81.7, 76.1, 75.0, 74.3, 71.0, 69.4, 65.5, 61.5, 55.5, 30.2, 21.2,
21.0, 20.3, 18.2, 16.3.
A1B(A)CDE pentasaccharide 30: A1B(A)C glycosyl fluoride 29[1] (30 mg,
0.028 mmol) and DE diol 3 (22 mg, 0.030 mmol) were azeotroped with
benzene (3 Â 3 mL) and then dried under high vacuum for 1 h. Et2O
(0.15 mL) and 4 Š MS were added, and the mixture was cooled to 08C and
stirred for 15 min. SnCl2 (6.6 mg, 0.035 mmol) was added in one portion
and the resulting mixture was warmed to 258C and stirred for 6 h. The
reaction mixture was diluted with EtOAc (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 preparative TLC (silica gel, 50%
Et2O in hexanes) to afford A1B(A)CDE pentasaccharide 30 (33 mg, 62%)
as a white foam. 30: Rf ˆ 0.21 (30% Et2O in hexanes); [a]2D2 ˆ À11.1 (c ˆ
0.10, CHCl3); IR (thin film): nÄ ˆ 2934, 2864, 1738, 1548, 1455, 1392, 1252,
‡
Si3Na [M‡H2O‡Na] : 1620, found 1620.
DEFGHA2 b-pentasaccharide 33: DE trichloroacetimidate
2 (82 mg,
0.12 mmol) and FGHA2 alcohol 32[2] (73 mg, 0.07 mmol) were azeotroped
with benzene (3 Â 3 mL) and then dried under high vacuum for 1 h. CH2Cl2
(0.35 mL) and 4 Š MS were added, and the mixture was stirred for 15 min.
The resulting mixture was cooled to À208C and BF3 ´ Et2O (74 mL, 0.5m
solution in CH2Cl2, 0.037 mmol) was added dropwise. The reaction mixture
was stirred at À208C for 2 h. The reaction mixture was diluted with EtOAc
(150 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 preparative
TLC (silica gel, 10% acetone in CH2Cl2) to afford DEFGHA2 b-
1092, 836, 778, 736 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.60 ± 7.17 (m,
15H, ArH), 5.21 (d, J ˆ 1.8 Hz, 1H, C1), 5.05, 5.02 (AB, J ˆ 10.1 Hz, 2H,
CH2Ar), 4.94 (brd, J ˆ 3.2 Hz, 1H, A1), 4.87 (t, J ˆ 9.4 Hz, 1H, B4), 4.80
(brd, J ˆ 8.7 Hz, 1H, B1), 4.66, 4.53 (AB, J ˆ 11.2 Hz, 2H, CH2Ar), 4.60 (s,
1H, D1), 4.46 (d, J ˆ 7.1 Hz, 1H, E1), 4.15 (dd, J ˆ 7.8, 4.4 Hz, 1H, C3), 4.01
(brs, 1H, C2), 3.93 ± 3.88 (m, 1H, C5), 3.86 ± 3.84 (m, 1H, B3), 3.82 (s, 3H,
OMe), 3.69 (s, 1H, D2), 3.64 (d, J ˆ 9.5 Hz, 1H, A4), 3.57 (dd, J ˆ 9.0,
7.6 Hz, 1H, E2), 3.56 (t, J ˆ 7.1 Hz, 1H, C4), 3.53 ± 3.46 (m, 2H, A5, D5),
3.49 (s, 3H, OMe), 3.39 ± 3.30 (m, 3H, B5, D4, E3), 3.35 (s, 3H, OMe),
3.23 ± 3.20 (m, 2H, E4, E5), 2.45 (dd, J ˆ 13.7, 4.9 Hz, 1H, A2), 2.38 (s, 3H,
pentasaccharide 33 (61 mg, 55%) as
a white foam, DEFGHA2 a-
pentasaccharide (6.0 mg, 5%) (a:b ca. 1:10) and a rearranged DEFGHA2
b-pentasaccharide (20 mg, 18%). 33: Rf ˆ 0.15 (100% Et2O); [a]2D2 ˆ À14.0
(c ˆ 0.10, CHCl3); IR (thin film): nÄ ˆ 3422, 2971, 2939, 2895, 1743, 1732,
1600, 1517, 1451, 1369, 1242, 1154, 1088, 1044 cmÀ1 1H NMR (600 MHz,
;
CDCl3): d ˆ 7.44 ± 7.22 (m, 22H, ArH, PMB), 6.87 (d, J ˆ 8.6 Hz, 2H,
PMB), 6.41 (s, 2H, ArH (A2)), 5.41 (dd, J ˆ 9.8, 9.8, 5.6 Hz, 1H, H4), 5.27 (s,
1H, G1), 5.14 (s, 1H, OCH2O), 5.13 (dd, J ˆ 10.2, 8.0 Hz, 1H, E2), 5.01 (s,
Chem. Eur. J. 2000, 6, No. 17
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3159 $ 17.50+.50/0
3159

K. C. Nicolaou et al.
FULL PAPER
‡
2H, CH2Ar), 4.99 (s, 1H, OCH2O), 4.99 (s, 2H, CH2Ar), 4.90 (s, 1H, D1),
4.81, 4.55 (AB, J ˆ 10.8 Hz, 2H, CH2Ar), 4.77, 4.69 (AB, J ˆ 11.8 Hz, 2H,
CH2Ar), 4.74, 4.69 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.66 (s, 1H, D2), 4.63 (s,
1H, F1), 4.61 (d, J ˆ 7.8 Hz, 1H, E1), 4.50 (ddd, J ˆ 10.6, 10.6, 4.6 Hz, 1H,
G4), 4.24 (brs, 1H, G2), 4.14 ± 4.12 (m, 1H, G5), 4.10 (dd, J ˆ 11.6, 5.5 Hz,
1H, H5), 4.00 (dd, J ˆ 10.2, 2.3 Hz, 1H, G3), 3.91 (t, J ˆ 9.8 Hz, 1H, H3),
3.90 (t, J ˆ 8.7 Hz, 1H, F4), 3.80 (s, 3H, OMe), 3.78 (t, J ˆ 10.3 Hz, 1H, G5),
3.59 ± 3.47 (m, 7H, E3, E4, F2, F6, F6, H2, H5), 3.55 (s, 3H, OMe), 3.51 (s,
3H, OMe), 3.38 (dq, J ˆ 9.4, 6.1 Hz, 1H, D5), 3.37 ± 3.30 (m, 4H, D4, E5,
F3, F5), 3.30 (s, 3H, OMe), 2.31 (s, 3H, Me (A2)), 2.13 (s, 3H, OAc), 2.05 (s,
3H, OAc), 1.75 (brs, 1H, OH), 1.35 (s, 3H, Me (D3)), 1.31 (d, J ˆ 6.0 Hz,
3H, D6), 1.17 (d, J ˆ 6.2 Hz, 3H, E6); 13C NMR (125 MHz, CDCl3): d ˆ
170.9, 168.9, 166.8, 160.7, 159.3, 157.3, 138.7, 138.6, 137.6, 136.4, 136.3, 130.4,
129.7, 128.6, 128.4, 128.3, 128.3, 128.1, 127.9, 127.7, 127.5, 127.4, 127.2, 127.1,
119.1, 115.9, 113.8, 108.1, 100.8, 98.8, 98.2, 96.7, 96.0, 95.8, 82.6, 81.5, 81.0,
80.7, 80.5, 77.6, 77.5, 76.0, 75.6, 75.0, 74.9, 74.4, 73.8, 73.1, 72.1, 71.5, 70.8,
70.8, 70.4, 70.3, 70.2, 70.0, 69.7, 65.8, 63.4, 63.3, 61.6, 61.2, 59.1, 55.2, 45.8,
21.0, 20.8, 20.0, 18.5, 16.4, 15.2, 14.2, 8.6; HRMS (MALDI): calcd for
18.5, 18.3, 16.3, 14.2; HRMS (MALDI): calcd for C77H92O26Na [M‡Na] :
1455.5774, found 1455.5704.
DEFGHA2 bis-TBS ether 35: TBSOTf (14.0 mL, 0.05 mmol) was added to a
solution of DEFGHA2 diol 34 (30 mg, 0.02 mmol) and 2,6-lutidine
(10.0 mL, 0.08 mmol) in CH2Cl2 (0.3 mL) at À108C and the resulting
mixture was warmed to 08C and stirred for 1 h. 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)
and the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 0 ! 60% EtOAc in
hexanes) to afford DEFGHA2 bis-TBS ether 35 (32 mg, 92%) as a white
foam. 35: Rf ˆ 0.43 (40% EtOAc in hexanes); [a]2D2 ˆ À30.0 (c ˆ 0.20,
CHCl3); IR (thin film): nÄ ˆ 3403, 2929, 2873, 1732, 1605, 1451, 1374, 1248,
1094, 1050, 841 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.42 ± 7.22 (m, 22H,
ArH, PMB), 6.88 (d, J ˆ 8.6 Hz, 2H, PMB), 6.41 (s, 2H, ArH (A2)), 5.42
(ddd, J ˆ 9.7, 9.7, 5.5 Hz, 1H, H4), 5.28 (d, J ˆ 1.1 Hz, 1H, G1), 5.12 (s, 1H,
OCH2O), 5.02 (s, 2H, CH2Ar), 5.00 (s, 2H, CH2Ar), 4.93 (s, 1H, OCH2O),
4.88, 4.48 (AB, J ˆ 10.6 Hz, 2H, CH2Ar), 4.79 (s, 1H, D1), 4.78, 4.71 (AB,
J ˆ 12.1 Hz, 2H, CH2Ar), 4.78, 4.61 (AB, J ˆ 11.9 Hz, 2H, CH2Ar), 4.78 (d,
J ˆ 7.6 Hz, 1H, E1), 4.66 (s, 1H, F1), 4.51 (ddd, J ˆ 10.5, 10.5, 4.5 Hz, 1H,
G4), 4.20 (brs, 1H, G2), 4.14 ± 4.09 (m, 4H, D2, F4, G5, H3), 4.07 (dd, J ˆ
10.3, 2.4 Hz, 1H, G3), 3.91 (t, J ˆ 9.7 Hz, 2H, H5, G5), 3.80 (s, 3H, OMe),
3.67 (dd, J ˆ 9.3, 7.6 Hz, 1H, E2), 3.61 ± 3.40 (m, 11H, D4, E3, E4, E5, F2,
F6, F6, F3, F5, H2, H5), 3.60 (s, 3H, OMe), 3.47 (s, 3H, OMe), 3.29 (dq, J ˆ
9.3, 7.6 Hz, 1H, D5), 3.26 (s, 3H, OMe), 2.31 (s, 3H, Me (A2)), 1.37 (s, 3H,
Me (D3)), 1.27 (d, J ˆ 7.1 Hz, 3H, D6), 1.17 (d, J ˆ 6.4 Hz, 3H, E6), 0.95 (s,
9H, tBuSi), 0.89 (s, 9H, tBuSi), 0.22 (s, 3H, MeSi), 0.19 (s, 3H, MeSi), 0.10
(s, 3H, MeSi), 0.03 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 166.9,
160.7, 159.2, 157.4, 138.7, 137.8, 136.4, 130.9, 129.4, 128.6, 128.5, 128.3, 128.1,
128.1 127.9, 127.7, 127.5, 127.4, 127.2, 127.1, 119.1, 116.0, 108.2, 102.6, 100.9,
98.3, 95.7, 84.4, 83.6, 82.3, 81.2, 78.1, 75.7, 75.4, 75.3, 75.0, 73.3, 73.0, 72.7,
71.3, 70.5, 70.4, 70.3, 70.1, 69.9, 65.8, 61.9, 58.8, 55.3, 29.7, 26.1, 20.0, 18.6,
18.4, 18.0, 16.4, 15.3, 14.2, À1.7, À2.3, À3.5, À4.5; HRMS (MALDI): calcd
‡
C81H96O28Na [M‡Na] : 1539.5986, found 1539.6047. Rearranged DEF-
GHA2 b-pentasaccharide: Rf ˆ 0.16 (100% Et2O); 1H NMR (600 MHz,
CDCl3): d ˆ 7.43 ± 7.62 (m, 22H, ArH, PMB), 6.87 (d, J ˆ 8.6 Hz, 2H,
PMB), 6.42 (s, 2H, ArH (A2)), 5.37 (ddd, J ˆ 9.4, 9.4, 5.5 Hz, 1H, H4), 5.28
(d, J ˆ 0.8 Hz, 1H, G1), 5.20 (s, 1H, OCH2O), 5.12 (dd, J ˆ 10.2, 8.0 Hz,
1H, E2), 5.09 (s, 1H, OCH2O), 5.02 (s, 4H, CH2Ar), 4.90 (brs, 1H, D1),
4.87, 4.60 (AB, J ˆ 11.6 Hz, 2H, CH2Ar), 4.80, 4.55 (AB, J ˆ 10.8 Hz, 2H,
CH2Ar), 4.75, 4.68 (AB, J ˆ 11.9 Hz, 2H, CH2Ar), 4.66 (d, J ˆ 0.7 Hz, 1H,
D2), 4.63 (s, 1H, F1), 4.59 (d, J ˆ 7.7 Hz, 1H, E1), 4.35 (ddd, J ˆ 10.5, 10.5,
4.5 Hz, 1H, G4), 4.28 (brs, 1H, G2), 4.12 ± 4.08 (m, 3H, G3, G5, H5), 3.91
(t, J ˆ 8.8 Hz, 1H, F4), 3.89 (t, J ˆ 9.8 Hz, 1H, H3), 3.80 (s, 3H, OMe), 3.73
(t, J ˆ 10.4 Hz, 1H, G5), 3.63 (d, J ˆ 9.6 Hz, 1H, H2), 3.59 ± 3.47 (m, 6H,
E3, E4, F2, F6, F6, H5), 3.55 (s, 3H, OMe), 3.52 (s, 3H, OMe), 3.37 (dq, J ˆ
9.4, 6.0 Hz, 1H, D5), 3.35 ± 3.31 (m, 4H, D4, E5, F3, F5), 3.30 (s, 3H, OMe),
2.32 (s, 3H, Me (A2)), 2.12 (s, 3H, OAc), 2.05 (s, 3H, OAc), 1.33 (s, 3H, Me
(D3)), 1.31 (d, J ˆ 6.0 Hz, 3H, D6), 1.17 (d, J ˆ 6.3 Hz, 3H, E6); 13C NMR
(125 MHz, CDCl3): d ˆ 170.9, 169.0, 167.0, 160.7, 159.3, 157.5, 138.9, 138.7,
137.7, 136.4, 136.4, 130.4, 129.7, 128.6, 128.5, 128.3, 128.1, 128.0, 127.8, 127.7,
127.5, 127.4, 127.2, 127.1, 123.9, 119.1, 115.9, 113.8, 108.1, 100.9, 98.8, 98.3,
96.8, 95.8, 94.4, 82.6, 81.5, 80.7, 78.5, 77.6, 76.0, 75.3, 75.2, 75.1, 75.0, 74.4,
73.8, 73.2, 72.2, 72.2, 71.5, 70.9, 70.8, 70.4, 70.1, 65.8, 63.8, 63.5, 61.7, 61.2,
60.4, 59.2, 55.3, 45.8, 29.7, 21.0, 21.0, 20.1, 16.4, 15.3, 14.2, 8.6; HRMS
‡
for C89H120O26Si2Na [M‡Na] : 1683.7504, found 1683.7512.
DEFGHA2 diol 36: DDQ (4.0 mg, 0.03 mmol) was added to a solution of
DEFGHA2 bis-TBS ether 35 (32 mg, 0.02 mmol) in CH2Cl2/H2O (10:1,
0.3 mL) at 08C and the resulting mixture was warmed to 258C and stirred
for 1 h. 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) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 60% EtOAc in hexanes) to afford DEFGHA2 diol 36 (29 mg,
‡
(MALDI): calcd for C81H96O28Na [M‡Na] : 1539.5986, found 1539.6047.
98%) as a white foam. 36: Rf ˆ 0.39 (50% EtOAc in hexanes); [a]D22
ˆ
DEFGHA2 triol 34: K2CO3 (3 mg, 0.02 mmol) was added to a solution of
DEFGHA2 diacetate 33 (34 mg, 0.02 mmol) in THF/MeOH (2:1, 0.3 mL)
and the resulting mixture was stirred at 258C for 1 h. The reaction mixture
was diluted with CH2Cl2 (150 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 residue was
purified by flash column chromatography (silica gel, 100% EtOAc) to
afford DEFGHA2 triol 34 (30 mg, 93%) as a white foam. 34: Rf ˆ 0.21
(100% EtOAc); [a]2D2 ˆ À20.5 (c ˆ 0.22, CHCl3); IR (thin film): nÄ ˆ 3420,
À12.9 (c ˆ 0.21, CHCl3); IR (thin film): nÄ ˆ 3420, 2930, 2895, 2862, 1732,
1605, 1457, 1374, 1154, 1105, 1044, 841 cmÀ1; H NMR (600 MHz, CDCl3):
1
d ˆ 7.42 ± 7.22 (m, 20H, ArH), 6.41 (s, 2H, ArH (A2)), 5.42 (ddd, J ˆ 9.7, 9.7,
5.4 Hz, 1H, H4), 5.28 (s, 1H, G1), 5.12 (s, 1H, OCH2O), 5.02 (s, 2H,
CH2Ar), 5.00 (s, 2H, CH2Ar), 4.93 (s, 1H, OCH2O), 4.79 (s, 1H, D1), 4.78,
4.71 (AB, J ˆ 12.2 Hz, 2H, CH2Ar), 4.78, 4.62 (AB, J ˆ 11.8 Hz, 2H,
CH2Ar), 4.72 (s, 1H, F1), 4.51 (ddd, J ˆ 10.6, 10.6, 4.6 Hz, 1H, G4), 4.20
(brs, 1H, G2), 4.14 ± 4.08 (m, 5H, E1, F4, G5, H2, H3), 4.07 (dd, J ˆ 10.4,
2.4 Hz, 1H, G3), 3.91 (t, J ˆ 9.5 Hz, 2H, H5, G5), 3.80 (s, 1H, D2), 3.67 (dd,
J ˆ 9.3, 7.6 Hz, 1H, E2), 3.60 ± 3.44 (m, 9H, D4, E3, E4, E5, F3, F5, F6, F6,
H5), 3.59 (s, 3H, OMe), 3.51 (s, 3H, OMe), 3.40 (d, J ˆ 3.0 Hz, 1H, F2), 3.37
(dq, J ˆ 9.6, 6.0 Hz, 1H, D5), 3.27 (s, 3H, OMe), 2.31 (s, 3H, Me (A2)), 1.81
(d, J ˆ 2.4 Hz, 1H, OH), 1.30 (d, J ˆ 6.4 Hz, 3H, D6), 1.24 (d, J ˆ 6.4 Hz,
3H, E6), 1.22 (s, 3H, Me (D3)), 0.90 (s, 9H, tBuSi), 0.89 (s, 9H, tBuSi), 0.18
(s, 3H, MeSi), 0.15 (s, 3H, MeSi), 0.09 (s, 3H, MeSi), 0.03 (s, 3H, MeSi);
13C NMR (150 MHz, CDCl3): d ˆ 166.9, 160.7, 157.4, 139.2, 139.0, 138.7,
137.8, 136.4, 136.4, 132.0, 128.7, 128.6, 128.6, 128.5, 128.3, 128.1, 128.1, 127.9,
127.8, 127.7, 127.5, 127.4, 127.1, 126.9, 119.1, 116.0, 114.3, 108.2, 101.0, 98.4,
96.7, 95.7, 95.0, 84.3, 82.3, 81.1, 75.7, 75.6, 74.9, 73.4, 73.0, 72.8, 71.3, 71.2,
70.4, 70.4, 70.3, 70.1, 69.9, 65.8, 63.5, 63.2, 61.9, 60.6, 58.8, 26.1, 19.3, 18.4,
18.3, 18.0, 16.4, 15.3, À2.3, À2.7, À3.5, À4.5; HRMS (MALDI): calcd for
2931, 2884, 1732, 1600, 1512, 1451, 1374, 1253, 1160, 1083, 918, 736 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.41 ± 7.24 (m, 22H, ArH, PMB), 6.87 (d,
J ˆ 8.5 Hz, 2H, PMB), 6.41 (s, 2H, ArH (A2)), 5.42 (ddd, J ˆ 9.7, 9.7, 5.6 Hz,
1H, H4), 5.25 (s, 1H, G1), 5.16 (s, 1H, OCH2O), 5.02 (s, 1H, OCH2O), 5.02
(s, 2H, CH2Ar), 4.99 (s, 2H, CH2Ar), 4.90 (s, 1H, D1), 4.79, 4.59 (AB, J ˆ
10.7 Hz, 2H, CH2Ar), 4.79, 4.58 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 4.72 (s, 2H,
CH2Ar), 4.60 (s, 1H, F1), 4.58 (d, J ˆ 7.7 Hz, 1H, E1), 4.51 (ddd, J ˆ 10.5,
10.5, 4.5 Hz, 1H, G4), 4.25 (brs, 1H, G2), 4.14 (dd, J ˆ 9.2, 4.4 Hz, 1H, G5),
4.13 (t, J ˆ 8.3 Hz, 1H, F4), 4.10 (dd, J ˆ 11.4, 5.2 Hz, 1H, H5), 4.00 (dd, J ˆ
10.2, 2.2 Hz, 1H, G3), 3.92 (t, J ˆ 9.8 Hz, 1H, H3), 3.80 (s, 3H, OMe), 3.77
(t, J ˆ 10.3 Hz, 1H, G5), 3.71 ± 3.67 (m, 3H, D2, E2, H2), 3.62 ± 3.52 (m, 7H,
D4, E3, E4, F2, F6, F6, H5), 3.54 (s, 3H, OMe), 3.52 (s, 3H, OMe), 3.46 (d,
J ˆ 2.6 Hz, 1H, OH), 3.41 ± 3.31 (m, 4H, D5, E5, F3, F5), 3.39 (s, 3H, OMe),
3.28 (d, J ˆ 2.5 Hz, 1H, OH), 2.31 (s, 3H, Me (A2)), 1.35 (s, 3H, Me (D3)),
1.28 (d, J ˆ 5.2 Hz, 3H, D6), 1.17 (d, J ˆ 6.3 Hz, 3H, E6); 13C NMR
(125 MHz, CDCl3): d ˆ 166.8, 160.7, 159.2, 157.3, 138.7, 138.0, 137.6, 136.4,
136.4, 130.7, 129.7, 128.6, 128.4, 128.3, 128.1, 127.9, 127.8, 127.5, 127.4, 127.3,
127.1, 119.1, 115.9, 113.7, 108.2, 104.3, 99.2, 98.3, 96.7, 96.2, 96.1, 83.3, 81.8,
80.9, 80.5, 77.6, 77.5, 75.6, 75.3, 75.0, 74.7, 74.4, 74.2, 74.2, 74.2, 72.1, 71.8,
70.9, 70.7, 70.4, 70.2, 70.1, 69.7, 63.5, 61.9, 61.8, 60.3, 59.4, 55.2, 21.0, 20.0,
‡
C81H112O25Si2Na [M‡Na] : 1563.6929, found 1563.6920.
DEFGHA2 chloroacetate 37: Chloroacetic anhydride (CA2O) (4.5 mg,
0.03 mmol) was added to a solution of DEFGHA2 diol 36 (29 mg,
0.02 mmol), Et3N (5.2 mL, 0.04 mmol) and 4-DMAP (0.2 mg, 0.002 mmol)
in CH2Cl2 (0.3 mL) at 08C and the resulting mixture was warmed to 258C
and stirred for 1 h. The reaction mixture was diluted with CH2Cl2 (150 mL)
and washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL).
3160
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3160 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 3
3149±3165
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 DEFGHA2
chloroacetate 37 (30 mg, 99%) as a white foam. 37: Rf ˆ 0.45 (50% EtOAc
in hexanes); [a]2D2 ˆ À35.0 (c ˆ 0.14, CHCl3); IR (thin film): nÄ ˆ 3500, 2928,
J ˆ 11.1, 5.4 Hz, 1H, H5), 4.09 (d, J ˆ 7.5 Hz, 1H, E1), 4.07 ± 4.02 (m, 1H,
G5), 4.05 (s, 2H, CH2Cl), 3.99 (dd, J ˆ 10.1, 2.3 Hz, 1H, G3), 3.94 (t, J ˆ
9.4 Hz, 1H, H3), 3.93 (t, J ˆ 9.8 Hz, 1H, G5), 3.85 ± 3.83 (m, 2H, F4, E3),
3.79 (s, 1H, D2), 3.67 (dd, J ˆ 9.2, 7.8 Hz, 1H, E2), 3.59 (s, 3H, OMe), 3.53 ±
3.40 (m, 9H, D5, E4, E5, F3, F5, F6, F6, H2, H5), 3.43 (s, 3H, OMe), 3.38 (d,
J ˆ 3.0 Hz, 1H, F2), 3.31 (s, 3H, OMe), 2.23 (s, 3H, Me (A2)), 1.41 (s, 3H,
Me (D3)), 1.26 (d, J ˆ 6.4 Hz, 3H, D6), 1.19 (d, J ˆ 6.8 Hz, 3H, E6), 0.97 (s,
9H, tBuSi), 0.96 (s, 9H, tBuSi), 0.90 (s, 18H, tBuSi), 0.89 (s, 9H, tBuSi), 0.84
(s, 9H, tBuSi), 0.21 (s, 6H, MeSi), 0.18 (s, 6H, MeSi), 0.16 (s, 3H, MeSi),
0.10 (s, 3H, MeSi), 0.09 (s, 6H, MeSi), 0.08 (s, 3H, MeSi), 0.07 (s, 6H,
MeSi), 0.06 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 167.1, 166.2,
157.3, 153.9, 138.0, 135.8, 128.3, 127.7, 125.5, 119.1, 119.0, 114.9, 108.5, 103.3,
100.9, 97.3, 96.5, 84.4, 82.3, 80.9, 77.8, 77.5, 75.6, 75.3, 75.1, 70.9, 70.6, 70.5,
70.4, 69.5, 68.9, 65.8, 63.4, 63.1, 62.0, 58.5, 40.8, 34.2, 30.3, 29.7, 19.9, 19.8,
18.7, 18.6, 18.1, 18.0, 17.9, 16.3, 15.3, À2.2, À2.8, À3.8, À4.2, À4.3, À4.4,
À4.5, À4.6, À4.9, À4.9, À5.0; HRMS (MALDI): calcd for C79H145ClO26-
2855, 1733, 1604, 1458, 1380, 1257, 1150, 1100, 1039, 841 cmÀ1 1H NMR
;
(600 MHz, CDCl3): d ˆ 7.42 ± 7.22 (m, 20H, ArH), 6.41 (s, 2H, ArH (A2)),
5.42 (ddd, J ˆ 9.8, 9.8, 5.5 Hz, 1H, H4), 5.28 (s, 1H, G1), 5.15 (d, J ˆ
10.1 Hz, 1H, D4), 5.12 (s, 1H, OCH2O), 5.02 (s, 2H, CH2Ar), 5.00 (s,
2H, CH2Ar), 4.93 (s, 1H, OCH2O), 4.79 (s, 1H, D1), 4.78, 4.61 (AB, J ˆ
11.8 Hz, 2H, CH2Ar), 4.77, 4.71 (AB, J ˆ 12.1 Hz, 2H, CH2Ar), 4.76 (s, 1H,
F1), 4.51 (ddd, J ˆ 10.6, 10.6, 4.6 Hz, 1H, G4), 4.20 (brs, 1H, G2), 4.13 (t,
J ˆ 7.5 Hz, 1H, F4), 4.12 ± 4.10 (m, 3H, E1, G5, H3), 4.09 (dd, J ˆ 10.8,
2.5 Hz, 1H, G3), 4.06 (s, 2H, CH2Cl), 3.91 (t, J ˆ 10.0 Hz, 2H, H5, G5), 3.80
(s, 1H, D2), 3.68 (dd, J ˆ 8.0, 7.7 Hz, 1H, E2), 3.63 ± 3.44 (m, 10H, D5, E3,
E4, E5, F3, F5, F6, F6, H2, H5), 3.60 (s, 3H, OMe), 3.51 (s, 3H, OMe), 3.38
(d, J ˆ 3.0 Hz, 1H, F2), 3.27 (s, 3H, OMe), 2.31 (s, 3H, Me (A2)), 1.30 (s,
3H, Me (D3)), 1.24 (d, J ˆ 6.4 Hz, 3H, E6), 1.20 (d, J ˆ 6.4 Hz, 3H, D6),
0.89 (s, 9H, tBuSi), 0.84 (s, 9H, tBuSi), 0.17 (s, 3H, MeSi), 0.10 (s, 3H,
MeSi), 0.09 (s, 3H, MeSi), 0.04 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3):
d ˆ 166.9, 166.2, 160.7, 157.3, 155.7, 154.5, 139.1, 138.7, 137.7, 136.4, 128.8,
128.6, 128.6, 128.5, 128.3, 128.1, 128.1, 127.9, 127.7, 127.5, 127.4, 127.2, 127.1,
126.9, 119.1, 116.0, 108.2, 102.5, 100.9, 98.3, 97.8, 96.7, 95.7, 95.0, 84.5, 82.3,
81.1, 77.7, 77.5, 75.7, 75.5, 75.3, 73.3, 73.0, 72.7, 71.3, 70.4, 70.4, 70.3, 70.1, 69.8,
68.9, 63.5, 63.2, 62.0, 60.6, 58.8, 40.8, 29.7, 26.0, 25.7, 20.0, 19.9, 18.0, 18.0,
16.3, À2.2, À2.8, À3.5, À4.5; HRMS (MALDI): calcd for C83H113ClO26-
‡
Si6Na [M‡Na] : 1735.8225, found 1735.8271.
DEFGHA2 hexa-TBS diol 40: K2CO3 (0.6 mg, 0.004 mmol) was added to a
solution of DEFGHA2 hexa-TBS chloroacetate 39 (35 mg, 0.02 mmol) in
THF/MeOH (2:1, 0.3 mL) and the resulting mixture was stirred at 258C for
15 min. The reaction mixture was diluted with CH2Cl2 (150 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 residue was purified by flash column chromatog-
raphy (silica gel, 0 ! 60% Et2O in hexanes) to afford DEFGHA2 hexa-
TBS diol 40 (28 mg, 85%) as a white foam. 40: Rf ˆ 0.27 (40% Et2O in
hexanes); [a]2D2 ˆ À29.1 (c ˆ 0.10, CHCl3); IR (thin film): nÄ ˆ 3495, 2955,
‡
Si2Na [M‡Na] : 1639.6645, found 1639.6676.
DEFGHA2 pentaol 38: 10% Pd/C (5 mg) was added to a solution of
DEFGHA2 alcohol 37 (30 mg, 0.02 mmol) in EtOAc (1.0 mL) and the
resulting mixture was stirred under 1 atm of H2 (balloon) at 258C for 3 h.
The reaction mixture was diluted with EtOAc (50 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% EtOAc in hexanes) to afford DEFGHA2 pentaol 38 (22 mg,
2919, 2861, 1737, 1602, 1467, 1361, 1255, 1073, 838, 779 cmÀ1 1H NMR
;
(600 MHz, CDCl3): d ˆ 6.29 (d, J ˆ 1.7 Hz, 1H, ArH (A2)), 6.16 (d, J ˆ
1.8 Hz, 1H, ArH (A2)), 5.33 (ddd, J ˆ 10.1, 10.1, 5.6 Hz, 1H, H4), 5.18 (s,
1H, OCH2O), 5.06 (s, 1H, OCH2O), 5.05 (brs, 1H, F1), 5.01 (s, 1H, G1),
4.68 (s, 1H, D1), 4.39 (ddd, J ˆ 10.3, 10.3, 2.5 Hz, 1H, G4), 4.24 (brs, 1H,
G2), 4.17 (dd, J ˆ 11.1, 5.4 Hz, 1H, H5), 4.12 (brs, 1H, F3), 4.08 (d, J ˆ
7.4 Hz, 1H, E1), 4.05 (dd, J ˆ 9.4, 4.8 Hz, 1H, G5), 4.00 (dd, J ˆ 10.1, 2.2 Hz,
1H, G3), 3.96 (t, J ˆ 9.4 Hz, 1H, G5), 3.95 (t, J ˆ 9.4 Hz, 1H, H3), 3.89 (t,
J ˆ 8.3 Hz, 1H, F4), 3.77 (s, 1H, D2), 3.64 (dd, J ˆ 8.0, 8.0 Hz, 1H, E2), 3.59
(t, J ˆ 10.0 Hz, 1H, H5), 3.58 (d, J ˆ 9.5 Hz, 1H, H2), 3.53 (s, 3H, OMe),
3.52 ± 3.51 (m, 1H, D5 or E5), 3.49 ± 3.37 (m, 7H, D4, E3, E4, F2, F5, F6.
F6), 3.40 (s, 3H, OMe), 3.33 ± 3.29 (m, 1H, D5 or E5), 3.30 (s, 3H, OMe),
2.44 (s, 1H, OH), 2.24 (s, 3H, Me (A2)), 1.93 (brs, 1H, OH), 1.29 (d, J ˆ
5.9 Hz, 3H, D6 or E6), 1.27 (d, J ˆ 6.5 Hz, 3H, D6 or E6), 1.16 (s, 3H, Me
(D3)), 0.96 (s, 9H, tBuSi), 0.95 (s, 9H, tBuSi), 0.92 (s, 9H, tBuSi), 0.90 (s,
9H, tBuSi), 0.90 (s, 9H, tBuSi), 0.89 (s, 9H, tBuSi), 0.28 (s, 3H, MeSi), 0.21
(s, 3H, MeSi), 0.18 (s, 3H, MeSi), 0.18 (s, 3H, MeSi), 0.14 (s, 3H, MeSi),
0.10 (s, 3H, MeSi), 0.10 (s, 3H, MeSi), 0.10 (s, 3H, MeSi), 0.09 (s, 3H,
MeSi), 0.07 (s, 3H, MeSi), 0.07 (s, 3H, MeSi), 0.07 (s, 3H, MeSi); 13C NMR
(125 MHz, CDCl3): d ˆ 167.4, 157.3, 153.9, 137.9, 119.0, 118.9, 114.9, 108.4,
103.5, 101.6, 97.2, 96.4, 84.8, 82.4, 81.1, 77.3, 76.7, 76.4, 75.1, 73.9, 72.7, 71.3,
70.6, 70.5, 70.0, 69.5, 65.8, 63.3, 63.0, 62.4, 58.4, 29.3, 28.0, 25.8, 25.6, 19.8,
18.4, 18.2, 18.1, 18.0, 17.1, 16.3, 15.3, À3.4, À3.7, À3.9, À4.2, À4.3, À4.4,
À4.6, À4.9, À4.9, À5.0, À5.2; HRMS (FAB): calcd for C77H144O25Si6Na
94%) as a white foam. 38: Rf ˆ 0.14 (70% EtOAc in hexanes); [a]D22
ˆ
À10.0 (c ˆ 0.21, CHCl3); IR (thin film): nÄ ˆ 3463, 2929, 1740, 1651, 1458,
1256, 1043, 840, 779 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 6.28 (d, J ˆ
2.5 Hz, 1H, ArH (A2)), 6.24 (d, J ˆ 2.5 Hz, 1H, ArH (A2)), 5.41 (ddd, J ˆ
9.2, 9.2, 5.5 Hz, 1H, H4), 5.30 (s, 1H, G1), 5.21 (s, 1H, OCH2O), 5.17 (s, 1H,
OCH2O), 5.15 (d, J ˆ 10.0 Hz, 1H, D4), 4.75 (d, J ˆ 8.6 Hz, 2H, CH2Cl),
4.51 (brs, 1H, G2), 4.40 (ddd, J ˆ 10.5, 10.5, 4.6 Hz, 1H, G4), 4.27 (dd, J ˆ
11.7, 5.6 Hz, 1H, H5), 4.17 (brs, 1H, D1), 4.15 (dd, J ˆ 9.6, 4.5 Hz, 1H, G5),
4.10 (d, J ˆ 7.6 Hz, 1H, E1), 4.06 (s, 1H, F1), 4.03 (t, J ˆ 9.8 Hz, 1H, H3),
4.00 (dd, J ˆ 10.1, 2.6 Hz, 1H, G3), 3.91 (t, J ˆ 10.2 Hz, 1H, G5), 3.76 (s, 1H,
D2), 3.74 ± 3.60 (m, 9H, E2, E3, E4, E5, F4, F6, F6, H2, H5), 3.61 (s, 6H,
OMe), 3.52 ± 3.46 (m, 3H, D5, F2, F3), 3.42 ± 3.39 (m, 1H, F5), 3.36 (s, 3H,
OMe), 2.49 (s, 3H, Me (A2)), 2.24 (s, 1H, OH), 1.31 (d, J ˆ 6.4 Hz, 3H, E6),
1.25 (s, 3H, Me (D3)), 1.21 (d, J ˆ 7.0 Hz, 3H, D6), 0.91 (s, 9H, tBuSi), 0.84
(s, 9H, tBuSi), 0.16 (s, 3H, MeSi), 0.11 (s, 3H, MeSi), 0.10 (s, 3H, MeSi),
0.03 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 166.2, 165.8, 161.1,
144.1, 119.1, 111.8, 104.7, 103.3, 101.4, 101.0, 97.0, 97.0, 95.8, 84.3, 81.9, 80.7,
79.4, 75.5, 75.3, 75.1, 75.0, 72.7, 71.0, 71.0, 70.6, 70.3, 69.1, 69.0, 65.9, 63.8,
63.2, 62.0, 59.2, 40.8, 29.7, 26.1, 25.7, 24.6, 19.8, 18.2, 18.0, 17.9, 16.0, 15.2,
14.1, À2.2, À2.8, À3.4, À4.7; HRMS (MALDI): calcd for C55H89ClO26Si2-
‡
[M‡Na] : 1659.8509, found 1659.8452.
DEFGHA2 hexa-benzyl PMB ether 41: NaH (4.0 mg, 0.09 mmol) was
added to a solution of DEFGHA2 triol 34 (40 mg, 0.03 mmol) in DMF
(0.5 mL) at 08C and the resulting mixture was stirred for 5 min. BnBr
(7.4 mL, 0.075 mmol) and nBu4NI (2.0 mg, 0.006 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 (3 mL),
diluted with Et2O (150 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 DEFGHA2 hexa-benzyl PMB
‡
Na [M‡Na] : 1279.4767, found 1279.4761.
DEFGHA2 hexa-TBS chloroacetate 39: TBSOTf (4.8 mL, 0.108 mmol) was
added to a solution of DEFGHA2 pentaol 38 (22 mg, 0.018 mmol) and 2,6-
lutidine (16.0 mL, 0.144 mmol) in CH2Cl2 (1.0 mL) at 08C. 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 chromatography (silica gel, 0 ! 100% Et2O in
hexanes) to afford DEFGHA2 hexa-TBS chloroacetate 39: (28 mg, 92%)
as a white foam. 39: Rf ˆ 0.54 (100% Et2O); [a]2D2 ˆ À30.7 (c ˆ 0.30,
CHCl3); IR (thin film): nÄ ˆ 3421, 3031, 2857, 1737, 1601, 1472, 1256, 1172,
ether 41 (43 mg, 95%) as a white foam. 41: Rf ˆ 0.69 (100% Et2O); [a]D22
ˆ
À37.5 (c ˆ 0.12, CHCl3); IR (thin film): nÄ ˆ 3526, 3026, 2928, 2884, 1732,
1605, 1517, 1451, 1369, 1253, 1094, 912, 736 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d ˆ 7.51 ± 7.20 (m, 32H, ArH, PMB), 6.86 (d, J ˆ 8.6 Hz, 2H,
PMB), 6.42 (s, 2H, ArH (A2)), 5.42 (ddd, J ˆ 9.8, 9.8, 5.5 Hz, 1H, H4), 5.29
(s, 1H, G1), 5.15 (s, 1H, OCH2O), 5.12, 4.57 (AB, J ˆ 11.6 Hz, 2H, CH2Ar),
5.02 (s, 2H, CH2Ar), 5.00 (s, 2H, CH2Ar), 4.98 (s, 1H, OCH2O), 4.86, 4.62
(AB, J ˆ 10.5 Hz, 2H, CH2Ar), 4.84, 4.47 (AB, J ˆ 11.5 Hz, 2H, CH2Ar),
4.83, 4.62 (AB, J ˆ 11.1 Hz, 2H, CH2Ar), 4.81, 4.74 (AB, J ˆ 12.1 Hz, 2H,
1102, 1048, 836, 780 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 6.28 (d, J ˆ
2.0 Hz, 1H, ArH (A2)), 6.16 (d, J ˆ 2.0 Hz, 1H, ArH (A2)), 5.34 (ddd, J ˆ
10.0, 10.0, 5.6 Hz, 1H, H4), 5.17 (s, 1H, G1), 5.14 (d, J ˆ 10.0 Hz, 1H, D4),
5.06 (s, 1H, OCH2O), 5.01 (s, 1H, OCH2O), 4.99 (brs, 1H, F1), 4.75 (s, 1H,
D1), 4.38 (ddd, J ˆ 10.5, 10.5, 6.0 Hz, 1H, G4), 4.26 (brs, 1H, G2), 4.17 (dd,
Chem. Eur. J. 2000, 6, No. 17
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3161 $ 17.50+.50/0
3161

K. C. Nicolaou et al.
FULL PAPER
CH2Ar), 4.80 (s, 1H, D1), 4.74 (s, 1H, F1), 4.52 (ddd, J ˆ 10.4, 10.4, 6.1 Hz,
1H, G4), 4.44 (d, J ˆ 8.3 Hz, 1H, E1), 4.24 (s, 1H, G2), 4.13 (dd, J ˆ 10.9,
4.6 Hz, 1H, H5), 4.11 (dd, J ˆ 11.4, 5.6 Hz, 1H, G5), 4.05 (dd, J ˆ 11.0,
2.5 Hz, 1H, G3), 4.04 (t, J ˆ 8.3 Hz, 1H, F4), 3.92 (t, J ˆ 9.7 Hz, 1H, H3),
3.85 (t, J ˆ 10.0 Hz, 1H, G5), 3.79 (s, 3H, OMe), 3.68 ± 3.41 (m, 12H, D2,
D4, E2, E3, E4, E5, F3, F5, F6, F6, H2, H5), 3.59 (s, 3H, OMe), 3.53 (s, 3H,
OMe), 3.37 (d, J ˆ 2.9 Hz, 1H, F2), 3.24 (dq, J ˆ 9.5, 7.0 Hz, 1H, D5), 3.18
(s, 3H, OMe), 3.00 (brs, 1H, OH), 2.32 (s, 3H, Me (A2)), 1.28 (d, J ˆ 5.8 Hz,
3H, E6), 1.27 (s, 3H, Me (D3)), 1.22 (d, J ˆ 6.3 Hz, 3H, D6); 13C NMR
(125 MHz, CDCl3): d ˆ 166.9, 160.7, 159.2, 157.4, 139.0, 138.7, 138.5, 138.2,
137.7, 137.7, 136.4, 136.4, 130.8, 129.6, 128.6, 128.5, 128.4, 128.4, 128.3, 128.2,
128.1, 128.0, 127.9, 127.9, 127.8, 127.7, 127.7, 127.6, 127.5, 127.4, 127.4, 127.3,
127.1, 119.1, 116.0, 113.7, 108.2, 103.2, 102.1, 98.3, 95.9, 95.4, 84.0, 83.4, 82.8,
81.9, 79.4, 79.2, 77.5, 77.3, 75.7, 75.5, 75.4, 75.2, 75.1, 74.8, 74.0, 73.1, 72.5, 71.1,
70.8, 70.4, 70.3, 70.3, 70.1, 69.8, 63.2, 61.8, 61.2, 58.9, 55.2, 31.5, 20.0, 18.5,
(s, 3H, OMe), 3.62 (s, 3H, OMe), 3.46 (d, J ˆ 2.8 Hz, 1H, F2), 3.40 (d, J ˆ
9.3 Hz, 1H, D4), 3.28 (s, 3H, OMe), 3.27 (dq, J ˆ 9.3, 6.1 Hz, 1H, D5), 2.87
(brs, 1H, OH), 2.40 (s, 3H, Me (A2)), 1.35 (s, 3H, Me (D3)), 1.33 (d, J ˆ
5.8 Hz, 3H, D6), 1.30 (d, J ˆ 7.2 Hz, 3H, E6), 0.95 (s, 9H, tBuSi), 0.19 (s,
3H, MeSi), 0.13 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 166.8,
160.7, 157.3, 138.9, 138.1, 137.6, 136.4, 136.3, 128.6, 128.5, 128.4, 128.4, 128.3,
128.2, 128.1, 128.0 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 127.0, 119.1,
115.9, 108.1, 103.2, 102.1, 98.2, 96.7, 95.3, 95.2, 83.0, 82.6, 81.8, 81.0, 79.8,
78.0, 77.9, 77.4, 75.6, 75.4, 75.3, 75.2, 75.1, 75.0, 73.1, 73.0, 72.5, 71.8, 71.0,
70.3, 70.2, 70.0, 69.8, 67.9, 63.4, 63.2, 61.8, 61.2, 58.8, 53.4, 30.3, 29.5, 26.0,
20.0, 18.7, 18.3, 17.6, 16.3, 15.2, À3.8, À4.8; HRMS (FAB): calcd for
‡
C89H110O25SiCs [M‡Cs] : 1739.6160, found 1739.6267.
DEFGHA2 heptaol 44: 10% Pd/C (20 mg) was added to a solution of
DEFGHA2 hexa-benzyl TBS ether 43 (50 mg, 0.03 mmol) in EtOAc
(1.0 mL) and the resulting mixture was stirred under 1 atm of H2 (balloon)
at 258C for 6 h. The reaction mixture was diluted with EtOAc (50 mL) and
filtered through a short pad of Celite and the solvents were removed under
reduced pressure to afford crude DEFGHA2 heptaol 44 as a white foam;
‡
18.2, 16.3, 14.1; HRMS (MALDI): calcd for C91H104O26Na [M‡Na] :
1635.6713, found 1635.6692.
DEFGHA2 hexa-benzyl diol 42: DDQ (4.0 mg, 0.033 mmol) was added to a
solution of DEFGHA2 hexa-benzyl PMB ether 41 (35 mg, 0.022 mmol) in
CH2Cl2/H2O (10:1, 0.5 mL) at 08C and the resulting mixture was warmed to
258C and stirred for 2 h. 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) 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
DEFGHA2 hexa-benzyl diol 42 (31 mg, 95%) as a as a white foam. 42:
Rf ˆ 0.38 (75% EtOAc in hexanes); [a]2D2 ˆ À24.8 (c ˆ 1.82, CHCl3); IR
‡
HRMS (FAB): calcd for C47H74O25SiCs [M‡Cs] : 1199.3393, found
1199.3396.
DEFGHA2 hexa-acetyl TBS ether 45: Ac2O (31.0 mL, 0.30 mmol) was
added to a solution of the above crude DEFGHA2 heptaol 44 (45 mg),
Et3N (84.0 mL, 0.60 mmol) and 4-DMAP (1.0 mg, 0.006 mmol) in CH2Cl2
(1.0 mL) at 08C and the resulting mixture was warmed to 258C and stirred
for 2 h. 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) 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 DEFGHA2 hexa-acetyl TBS
ether 45 (36 mg, 88% over two steps) as a white foam. 45: Rf ˆ 0.33 (100%
EtOAc); [a]2D2 ˆ À26.0 (c ˆ 0.05, CHCl3); IR (thin film): nÄ ˆ 2955, 2885,
1749, 1362, 1226, 1132, 1049 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 6.88 (d,
J ˆ 1.8 Hz, 1H, ArH (A2)), 6.81 (d, J ˆ 1.8 Hz, 1H, ArH (A2)), 5.50 (brs,
1H, G2), 5.34 (ddd, J ˆ 9.5, 9.5, 5.6 Hz, 1H, H4), 5.22 (s, 1H, G1), 5.17 (s,
1H, OCH2O), 5.08 (s, 1H, OCH2O), 5.06 (dd, J ˆ 10.2, 8.0 Hz, 1H, E2),
4.93 (dd, J ˆ 8.9, 3.3 Hz, 1H, F3), 4.91 (s, 1H, D2), 4.75 (s, 1H, D1), 4.69 (s,
1H, F1), 4.34 (d, J ˆ 7.9 Hz, 1H, E1), 4.29 (ddd, J ˆ 10.6, 10.6, 4.5 Hz, 1H,
G4), 4.17 (dd, J ˆ 11.4, 5.5 Hz, 1H, H5), 4.14 (dd, J ˆ 9.6, 4.3 Hz, 1H, G5),
4.03 (dd, J ˆ 10.2, 2.7 Hz, 1H, G3), 3.95 (t, J ˆ 8.7 Hz, 1H, F4), 3.93 (t, J ˆ
9.7 Hz, 1H, H3), 3.85 (t, J ˆ 10.3 Hz, 1H, G5), 3.65 ± 3.33 (m, 10H, D4, E3,
E4, E5, F2, F5, F6, F6, H2, H5), 3.61 (s, 3H, OMe), 3.48 (s, 3H, OMe), 3.36
(s, 3H, OMe), 3.30 (dq, J ˆ 9.0, 6.1 Hz, 1H, D5), 2.40 (s, 3H, Me (A2)), 2.27
(s, 3H, OAc), 2.25 (s, 3H, OAc), 2.09 (s, 9H, OAc), 2.04 (s, 3H, OAc), 1.42
(s, 3H, Me (D3)), 1.27 (d, J ˆ 6.0 Hz, 3H, D6), 1.26 (d, J ˆ 6.2 Hz, 3H, E6),
0.89 (s, 9H, tBuSi), 0.10 (s, 3H, MeSi), 0.07 (s, 3H, MeSi); 13C NMR
(150 MHz, CDCl3): d ˆ 170.7, 170.0, 169.2, 168.7, 168.7, 168.5, 164.8, 152.0,
149.3, 139.8, 125.5, 122.6, 119.0, 114.2, 101.0, 98.8, 96.8, 95.1, 94.7, 81.2, 80.7,
78.5, 76.6, 75.6, 75.5, 75.1, 74.8, 73.0, 72.8, 72.0, 71.0, 70.7, 70.5, 69.8, 69.6,
63.2, 63.2, 61.3, 61.3, 59.3, 30.3, 26.0, 21.0, 21.0, 20.8, 20.8, 20.6, 20.0, 19.4,
18.8, 18.3, 16.4, À3.9, À4.5; HRMS (FAB): calcd for C59H86O31SiCs
(thin film): nÄ ˆ 3565, 2891, 1732, 1456, 1070, 734, 698 cmÀ1
;
1H NMR
(600 MHz, CDCl3): d ˆ 7.46 ± 7.11 (m, 30H, ArH), 6.42 (s, 2H, ArH (A2)),
5.44 (ddd, J ˆ 9.7, 9.7, 5.5 Hz, 1H, H4), 5.31 (s, 1H, G1), 5.15 (s, 1H,
OCH2O), 5.12, 4.52 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 5.02 (s, 2H, CH2Ar),
5.00 (s, 2H, CH2Ar), 4.99 (s, 1H, OCH2O), 4.87, 4.61 (AB, J ˆ 11.4 Hz, 2H,
CH2Ar), 4.85 (s, 1H, D1), 4.83, 4.76 (AB, J ˆ 12.2 Hz, 2H, CH2Ar), 4.79,
4.61 (AB, J ˆ 11.8 Hz, 2H, CH2Ar), 4.75 (s, 1H, F1), 4.55 (ddd, J ˆ 10.4,
10.4, 6.1 Hz, 1H, G4), 4.47 (d, J ˆ 7.6 Hz, 1H, E1), 4.25 (s, 1H, G2), 4.14
(dd, J ˆ 9.6, 4.6 Hz, 1H, H5), 4.12 (dd, J ˆ 10.8, 8.0 Hz, 1H, G5), 4.07 ± 4.04
(m, 2H, F4, G3), 3.93 (t, J ˆ 9.7 Hz, 1H, H3), 3.86 (t, J ˆ 10.1 Hz, 1H, G5),
3.68 ± 3.43 (m, 11H, D2, E2, E3, E4, E5, F3, F5, F6, F6, H2, H5), 3.58 (s, 3H,
OMe), 3.54 (s, 3H, OMe), 3.38 (d, J ˆ 2.4 Hz, 1H, F2), 3.36 (d, J ˆ 9.6 Hz,
1H, D4), 3.33 (s, 1H, OH), 3.28 (dq, J ˆ 9.6, 5.8 Hz, 1H, D5), 3.20 (s, 3H,
OMe), 2.89 (s, 1H, OH), 2.32 (s, 3H, Me (A2)), 1.30 (d, J ˆ 5.8 Hz, 3H, D6),
1.24 (d, J ˆ 7.2 Hz, 3H, E6), 1.22 (s, 3H, Me (D3)); 13C NMR (125 MHz,
CDCl3): d ˆ 166.8, 160.6, 157.3, 138.9, 138.7, 138.5, 138.0, 137.6, 136.3, 136.3,
128.5, 128.4, 128.4, 128.4, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4,
127.3, 127.0, 127.0, 119.0, 115.8, 108.0, 103.1, 102.0, 98.2, 96.6, 95.8, 95.3, 82.6,
81.7, 81.0, 79.7, 79.1, 77.8, 77.4, 76.5, 75.6, 75.3, 75.2, 75.0, 74.9, 73.0, 72.9, 72.4,
71.0, 70.5, 70.3, 70.2, 70.0, 69.7, 65.7, 63.4, 63.2, 61.8, 61.2, 58.8, 19.9, 18.1,
‡
17.0, 16.3, 15.2; HRMS (MALDI): calcd for C83H96O25Cs [M‡Cs] :
1625.5295, found 1625.5366.
DEFGHA2 hexa-benzyl TBS ether 43: TBSOTf (12.0 mL, 0.05 mmol) was
added to a solution of DEFGHA2 hexa-benzyl diol 42 (52 mg, 0.034 mmol)
and 2,6-lutidine (12.0 mL, 0.10 mmol) in CH2Cl2 (0.5 mL) at À108C and the
resulting mixture was warmed to 08C and stirred for 1 h. 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) 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 DEFGHA2 hexa-benzyl TBS ether 43 (53 mg,
96%) as a white foam. 43: Rf ˆ 0.24 (70% Et2O in hexanes); [a]2D2 ˆ À13.0
(c ˆ 0.10, CHCl3); IR (thin film): nÄ ˆ 3550, 2931, 1735, 1602, 1259, 1075, 912,
734 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.53 ± 7.31 (m, 30H, ArH), 6.51
(s, 2H, ArH (A2)), 5.51 (ddd, J ˆ 9.7, 9.7, 4.2 Hz, 1H, H4), 5.38 (d, J ˆ
1.1 Hz, 1H, G1), 5.23 (s, 1H, OCH2O), 5.17, 4.67 (AB, J ˆ 11.8 Hz, 2H,
CH2Ar), 5.10 (s, 2H, CH2Ar), 5.08 (s, 2H, CH2Ar), 5.07 (s, 1H, OCH2O),
4.94, 4.87 (AB, J ˆ 11.2 Hz, 2H, CH2Ar), 4.91, 4.67 (AB, J ˆ 10.9 Hz, 2H,
CH2Ar), 4.89 (s, 1H, D1), 4.85, 4.69 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.81 (s,
1H, F1), 4.61 (ddd, J ˆ 10.6, 10.6, 4.0 Hz, 1H, G4), 4.54 (d, J ˆ 7.6 Hz, 1H,
E1), 4.33 (brs, 1H, G2), 4.23 (dd, J ˆ 10.0, 4.0 Hz, 1H, G5), 4.21 (dd, J ˆ
10.0, 5.6 Hz, 1H, H5), 4.14 (dd, J ˆ 10.0, 2.6 Hz, 1H, G3), 4.13 (t, J ˆ 7.8 Hz,
1H, F4), 4.01 (t, J ˆ 9.8 Hz, 1H, H3), 3.95 (t, J ˆ 9.8 Hz, 1H, G5), 3.75 (brs,
1H, D2), 3.75 ± 3.57 (m, 10H, E2, E3, E4, E5, F3, F5, F6, F6, H2, H5), 3.67
‡
[M‡Cs] : 1451.3977, found 1451.3911.
DEFGHA2 hexa-acetyl diol 46: nBu4NF (31.0 mL, 0.03 mmol) was added to
a solution of DEFGHA2 hexa-acetyl TBS ether 45 (22 mg, 0.02 mmol) and
AcOH (1.0 mL, 0.03 mmol) in THF (0.3 mL) and the resulting mixture was
stirred at 258C for 2 h. The reaction mixture was diluted with CH2Cl2
(150 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 residue was purified by flash column
chromatography (silica gel, 0 ! 10% MeOH in EtOAc) to afford
DEFGHA2 hexa-acetyl diol 46 (18 mg, 90%) as a white foam. 46: Rf ˆ
0.11 (100% EtOAc); [a]2D2 ˆ À10.0 (c ˆ 0.04, CHCl3); IR (thin film): nÄ ˆ
3390, 2926, 1749, 1650, 1446, 1385, 1319, 1259, 1072 cmÀ1 1H NMR
;
(600 MHz, CDCl3): d ˆ 6.56 (d, J ˆ 1.7 Hz, 1H, ArH (A2)), 6.41 (d, J ˆ
1.7 Hz, 1H, ArH (A2)), 5.50 (brs, 1H, G2), 5.30 (ddd, J ˆ 9.5, 9.5, 5.6 Hz,
1H, H4), 5.22 (s, 1H, G1), 5.16 (s, 1H, OCH2O), 5.08 (s, 1H, OCH2O), 5.06
(dd, J ˆ 10.0, 8.1 Hz, 1H, E2), 4.92 (dd, J ˆ 8.9, 3.2 Hz, 1H, F3), 4.92 (s, 1H,
D2), 4.75 (s, 1H, D1), 4.71 (s, 1H, F1), 4.34 (d, J ˆ 8.0 Hz, 1H, E1), 4.28
(ddd, J ˆ 10.6, 10.6, 4.5 Hz, 1H, G4), 4.16 (dd, J ˆ 11.4, 5.5 Hz, 1H, H5),
4.14 (dd, J ˆ 9.6, 3.7 Hz, 1H, G5), 4.01 (dd, J ˆ 10.1, 2.5 Hz, 1H, G3), 3.95
(t, J ˆ 8.7 Hz, 1H, F4), 3.93 (t, J ˆ 9.7 Hz, 1H, H3), 3.85 (t, J ˆ 10.1 Hz, 1H,
G5), 3.65 ± 3.37 (m, 11H, D4, D5, E3, E4, E5, F2, F5, F6, F6, H2, H5), 3.54
3162
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3162 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 3
3149±3165
(s, 3H, OMe), 3.48 (s, 3H, OMe), 3.36 (s, 3H, OMe), 2.71 (s, 1H, OH), 2.36
(s, 3H, Me (A2)), 2.25 (s, 3H, OAc), 2.09 (s, 6H, OAc), 2.08 (s, 3H, OAc),
2.04 (s, 6H, OAc), 1.42 (s, 3H, Me (D3)), 1.33 (d, J ˆ 5.9 Hz, 3H, D6), 1.26
(d, J ˆ 6.4 Hz, 3H, E6); 13C NMR (150 MHz, CDCl3): d ˆ 170.9, 170.1,
169.4, 168.9, 165.2, 159.2, 154.4, 150.8, 141.2, 119.1, 115.9, 108.2, 101.0, 98.8,
96.8, 95.1, 94.8, 81.4, 80.7, 75.5, 75.2, 75.1, 74.8, 73.0, 72.7, 71.1, 70.8, 70.5,
70.4, 69.6, 65.8, 63.4, 63.1, 61.4, 61.3, 59.3, 30.3, 21.2, 21.0, 20.9, 20.8, 20.7,
20.6, 20.4, 18.7, 18.2, 16.4, 15.2, 13.7; HRMS (MALDI): calcd for
[a]2D2 ˆ À22.0 (c ˆ 3.89, CHCl3); IR (thin film): nÄ ˆ 2935, 1736, 1603, 1542,
1
1454, 1370, 1330, 1253, 1102 cmÀ1; H NMR (500 MHz, CDCl3): d ˆ 7.58 ±
7.06 (m, 40H, ArH), 6.42 (s, 2H, ArH (A2)), 5.43 (ddd, J ˆ 9.7, 9.7,
5.5 Hz, 1H, H4), 5.31 (s, 1H, OCH2O), 5.15 (s, 1H, OCH2O), 5.07 ± 4.97 (m,
8H, 3  CH2Ar, D1, G1), 4.92 (t, J ˆ 9.3 Hz, 1H, B4), 4.86 ± 4.59 (m, 13H,
4.5  CH2Ar, A1, B1, D2, F1), 4.53 (ddd, J ˆ 10.4, 10.4, 4.5 Hz, 1H, G4),
4.45 (brd, J ˆ 7.6 Hz, 1H, E1), 4.33 (d, J ˆ 11.6 Hz, 1H, CH2Ar), 4.25 (brs,
1H, G2), 4.15 ± 4.07 (m, 2H, G5, H5), 4.06 ± 4.03 (m, 3H, F4, G3, G5), 3.95
(d, J ˆ 10.0 Hz, 1H, H2), 3.93 (t, J ˆ 9.9 Hz, 1H, H3), 3.90 ± 3.83 (m, 4H,
B3, C3, C4, C5 or D5 or E5), 3.83 (s, 3H, OMe), 3.71 ± 3.49 (m, 12H, A4,
A5, D4, E2, E3, E4, F3, F5, F6, F6, H5, C5 or D5 or E5), 3.64 (s, 3H, OMe),
3.53 (s, 3H, OMe), 3.47 ± 3.36 (m, 3H, B5, F2, C5 or D5 or E5), 3.37 (s, 3H,
OMe), 3.19 (s, 3H, OMe), 2.49 ± 2.43 (m, 2H, A2, C2), 2.40 (s, 3H, Me
(A1)), 2.35 ± 2.29 (m, 4H, B2, Me), 2.05 ± 2.02 (m, 1H, A2), 1.82 (t, J ˆ
12.0 Hz, 1H, C2), 1.72 (dt, J ˆ 12.1, 12.1 Hz, 1H, B2), 1.71 (s, 3H, Me (A2)),
1.36 (d, J ˆ 6.1 Hz, 3H, B6), 1.34 (s, 3H, Me (D3)), 1.31 (d, J ˆ 6.0 Hz, 6H,
C6 or D6 or E6), 1.24 (d, J ˆ 5.2 Hz, 3H, C6 or D6 or E6), 1.02 (s, 3H, Me
(A3)), 0.84 (d, J ˆ 6.2 Hz, 3H, A6); 13C NMR (125 MHz, CDCl3): d ˆ 171.0,
166.7, 165.5, 160.6, 157.2, 153.2, 153.0, 138.8, 138.6, 138.4, 137.5, 136.3, 136.2,
135.7, 134.7, 128.0, 127.8, 127.6, 127.4, 127.4, 127.3, 127.2, 127.1, 127.0, 126.2,
125.9, 121.6, 119.8, 119.0, 115.8, 108.0, 103.1, 101.4, 99.8, 98.1, 95.8, 95.6,
95.2, 92.3, 89.8, 84.1, 82.6, 82.5, 81.5, 81.0, 80.8, 79.9, 79.6, 79.2, 77.6, 76.5,
76.0, 75.5, 75.2, 75.0, 74.9, 73.8, 73.0, 72.3, 71.3, 71.0, 70.4, 70.2, 70.2, 69.9,
69.7, 68.1, 66.1, 63.4, 63.1, 61.8, 61.7, 61.0, 60.6, 60.2, 58.7, 40.0, 38.3, 36.4, 20.9,
20.0, 19.2, 18.6, 18.2, 18.1, 17.9, 17.5, 16.2, 14.1; HRMS (FAB): calcd for
‡
C53H72O31SiNa [M‡Na] : 1227.3955, found 1227.3943.
DEFGHA2 hexa-benzyl chloroacetate 47: Chloroacetic anhydride (CA2O)
(4.0 mg, 0.022 mmol) was added to a solution of DEFGHA2 hexa-benzyl
diol 42 (22 mg, 0.015 mmol), Et3N (4.4 mL, 0.044 mmol) and 4-DMAP
(0.4 mg, 0.003 mmol) in CH2Cl2 (0.3 mL) at 08C and the resulting mixture
was warmed to 258C and stirred for 1 h. 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), 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 DEFGHA2 hexa-benzyl chloroacetate 47 (23 mg, 98%)
as a white foam. 47: Rf ˆ 0.16 (70% Et2O in hexanes); [a]2D2 ˆ À30.0 (c ˆ
0.11, CHCl3); IR (thin film): nÄ ˆ 2924, 2861, 1731, 1655, 1449, 1361, 1261,
1155, 1072, 1038, 744, 697 cmÀ1; 1H NMR (600 MHz, CDCl3): d ˆ 7.48 ± 7.27
(m, 30H, ArH), 6.43 (s, 2H, ArH (A2)), 5.44 (ddd, J ˆ 9.7, 9.7, 5.6 Hz, 1H,
H4), 5.33 (s, 1H, G1), 5.17 (s, 1H, OCH2O), 5.12, 4.61 (AB, J ˆ 11.6 Hz, 2H,
CH2Ar), 5.03 (s, 2H, CH2Ar), 5.01 (s, 2H, CH2Ar), 5.00 (s, 1H, OCH2O),
4.92 (d, J ˆ 9.8 Hz, 1H, D4), 4.91, 4.61 (AB, J ˆ 11.4 Hz, 2H, CH2Ar), 4.87
(s, 1H, D1), 4.84, 4.77 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.80, 4.62 (AB, J ˆ
11.8 Hz, 2H, CH2Ar), 4.77 (s, 1H, F1), 4.54 (ddd, J ˆ 9.7, 9.7, 4.9 Hz, 1H,
G4), 4.49 (d, J ˆ 7.6 Hz, 1H, E1), 4.26 (brs, 1H, G2), 4.16 (dd, J ˆ 9.6,
4.6 Hz, 1H, G5), 4.14 (dd, J ˆ 11.5, 5.6 Hz, 1H, H5), 4.08 (dd, J ˆ 9.7,
2.0 Hz, 1H, G3), 4.07 (s, 2H, CH2Cl), 3.95 (t, J ˆ 9.7 Hz, 1H, H3), 3.88 (t,
J ˆ 10.1 Hz, 1H, G5), 3.71 ± 3.47 (m, 11H, D2, E2, E3, E4, F3, F4, F5, F6,
F6, H2, H5), 3.60 (s, 3H, OMe), 3.56 (s, 3H, OMe), 3.46 ± 3.41 (m, 2H, D5,
E5), 3.38 (d, J ˆ 2.9 Hz, 1H, F2), 3.32 (s, 1H, OH), 3.22 (s, 3H, OMe), 2.33
(s, 3H, Me (A2)), 1.29 (s, 3H, Me (D3)), 1.25 (d, J ˆ 6.3 Hz, 3H, D6), 1.21
(d, J ˆ 6.1 Hz, 3H, E6); 13C NMR (150 MHz, CDCl3): d ˆ 166.8, 160.6,
157.2, 138.8, 138.6, 138.4, 137.7, 137.6, 136.3, 136.3, 128.5, 128.4, 128.4, 128.2,
128.1, 128.0, 127.9, 127.8, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 127.3, 127.0,
125.4, 119.0, 115.8, 108.1, 103.1, 101.9, 98.2, 96.6, 95.7, 95.2, 82.5, 82.5, 81.7,
79.7, 79.1, 78.3, 77.8, 77.4, 75.5, 75.3, 75.3, 75.1, 75.0, 74.9, 73.0, 72.4, 72.0,
71.0, 70.2, 70.1, 69.9, 69.7, 68.9, 63.4, 63.1, 61.8, 58.8, 40.7, 30.2, 29.6, 19.9, 17.7,
‡
C126H145Cl2NO38Cs [M‡Cs] : 2485, found 2485.
A1B(A)Clactone (benzylated) 51 : A solution of 5% aqueous HCl
(20.0 mL) was added to a solution of the fully benzylated everninomicin
49 (63 mg, 0.027 mmol) in THF (3.0 mL) and the reaction mixture was
stirred at 258C until TLC analysis showed that no starting material
remained, and a more polar spot appeared by TLC. A solution of 1n
aqueous KOH (0.1 ± 0.5 mL) was then added while stirring rapidly, until
TLC indicated the formation of two new spots, one above and one below
the spot from the acidic reaction. The reaction mixture was then quenched
by the addition of saturated aqueous NaHCO3 (5 mL), diluted with CH2Cl2
(150 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 the A1B(A)C lactone 51 (20 mg, 85%) and
hexa-benzyl DEFGHA2 diol 42 (36 mg, 90%) both as white foams. 51: Rf ˆ
0.53 (75% EtOAc in hexanes); [a]2D2 ˆ À43.4 (c ˆ 0.59, CHCl3); IR (thin
film): nÄ ˆ 2978, 2931, 1872, 1760, 1725, 1537, 1449, 1384, 1249, 1090, 903,
‡
17.5, 16.2; HRMS (FAB): calcd for C85H97ClO26Cs [M‡Cs] : 1701.5011,
732 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.57 (d, J ˆ 7.0 Hz, 2H, ArH),
found 1701.5107.
7.43 ± 7.31 (m, 8H, ArH), 5.07, 5.03 (AB, J ˆ 10.1 Hz, 2H, CH2Ar), 4.98 (dd,
J ˆ 4.7, 1.7 Hz, 1H, A1), 4.90 (t, J ˆ 9.4 Hz, 1H, B4), 4.64, 4.57 (AB, J ˆ
11.8 Hz, 2H, CH2Ar), 4.64 (dd, J ˆ 9.5, 1.3 Hz, 1H, B1), 4.23 ± 4.18 (m, 2H,
C3, C5), 3.92 ± 3.87 (m, 1H, B3), 3.89 (s, 3H, OMe), 3.70 (brd, J ˆ 6.7 Hz,
1H, C4), 3.64 (d, J ˆ 10.4 Hz, 1H, A4), 3.48 (dq, J ˆ 9.2, 6.2 Hz, 1H, A5),
3.45 (dq, J ˆ 9.3, 6.3 Hz, 1H, B5), 3.36 (s, 3H, OMe), 2.82 (dd, J ˆ 16.1,
2.8 Hz, 1H, C2), 2.77 (dd, J ˆ 16.1, 4.1 Hz, 1H, C2), 2.47 (dd, J ˆ 13.9,
5.0 Hz, 1H, A2), 2.40 (s, 3H, Me (A1)), 2.32 (dd, J ˆ 11.1, 4.7 Hz, 1H, B2),
2.02 (dd, J ˆ 13.9, 1.9 Hz, 1H, A2), 1.70 (dt, J ˆ 12.2, 12.2 Hz, 1H, B2), 1.69
(s, 3H, Me (A3)), 1.46 (d, J ˆ 6.4 Hz, 3H, C6), 1.37 (d, J ˆ 6.2 Hz, 3H, B6),
0.86 (d, J ˆ 6.2 Hz, 3H, A6); 13C NMR (150 MHz, CDCl3): d ˆ 170.0, 165.6,
153.3, 153.1, 137.5, 135.8, 134.7, 128.6, 128.5, 128.4, 127.8, 127.5, 127.4, 126.4,
125.9, 121.7, 100.6, 92.5, 89.8, 84.2, 81.6, 76.0, 75.8, 75.6, 74.9, 72.1, 71.1, 66.3,
62.0, 60.8, 53.4, 39.8, 36.3, 33.2, 19.4, 18.9, 18.2, 18.0, 17.7; HRMS (FAB):
DEFGHA2 hexa-TBS chloroacetate 39 from 47: 10% Pd/C (20 mg) was
added to a solution of DEFGHA2 hexa-benzyl chloroacetate 47 (70 mg,
0.045 mmol) in EtOAc (3.0 mL) and the resulting mixture was stirred
under 1 atm of H2 (balloon) at 258C for 4 h. The reaction mixture was
filtered through a pad of Celite, the pad was washed with EtOAc (150 mL),
and the solvents were removed under reduced pressure to afford the crude
CA-DEFGHA2 heptaol 48 as a white foam. The crude heptaol was then
dissolved in CH2Cl2 (1.0 mL), 2,6-di-tert-butylpyridine (0.20 mL,
0.89 mmol) was added and the reaction mixture was cooled to 08C.
TBSOTf (820 mL, 0.36 mmol) was added and the resulting mixture was
warmed to 258C and stirred for 8 h. 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) 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
DEFGHA2 hexa-TBS chloroacetate 39 (50 mg, 65% over two steps) as a
white foam, identical to that above.
‡
calcd for C43H53Cl2NO15Cs [M‡H2O‡Cs] : 1026.1847, found 1026.1857.
DEFGHA2 hexa-benzyl PMB ether 41 from hexa-benzyl DEFGHA2 diol
42: NaH (0.3 mg, 0.08 mmol) was added to a solution of DEFGHA2 diol 42
(10 mg, 0.067 mmol) in DMF (0.5 mL) at 08C and the resulting mixture was
stirred for 5 min. PMBCl (1.5 mL, 0.010 mmol) and nBu4NI (0.2 mg,
0.006 mmol) were 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 (3 mL), diluted with Et2O (150 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
DEFGHA2 hexa-benzyl PMB ether 41 (10 mg, 93%) as a white foam,
which was identical to that described above.
Fully benzylated everninomicin 49: NaH (18.4 mg, 0.46 mmol) was added
to a solution of everninomicin 13,384-1 (1)[12] (50 mg, 0.031 mmol) in DMF
(0.5 mL) at 08C and the resulting mixture was stirred for 5 min. BnBr
(72.9 mL, 0.61 mmol) and nBu4NI (1.1 mg, 0.003 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 (3 mL),
diluted with Et2O (150 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 fully benzylated everninomicin
49 (73 mg, 93%) as a white foam. 49: Rf ˆ 0.37 (50% EtOAc in hexanes);
Chem. Eur. J. 2000, 6, No. 17
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3163 $ 17.50+.50/0
3163

K. C. Nicolaou et al.
FULL PAPER
Fully silylated everninomicin 50: TBSOTf (55.0 mL, 0.24 mmol) was added
to a solution of everninomicin 13,384-1 (1)[12] (26 mg, 0.016 mmol) and 2,6-
lutidine (56.0 mL, 0.48 mmol) in CH2Cl2 (0.2 mL) at 08C and the resulting
mixture was warmed to 258C and stirred for 3 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 chromatography (silica gel, 0 ! 50% Et2O in
hexanes) to afford fully silylated everninomicin 50 (26 mg, 64%) as a white
foam. 50: Rf ˆ 0.46 (50% Et2O in hexanes); [a]2D2 ˆ À34.3 (c ˆ 0.70,
CHCl3); IR (thin film): nÄ ˆ 2932, 2861, 1731, 1602, 1549, 1461, 1390, 1355,
A6), 0.29 (s, 3H, MeSi), 0.28 (s, 3H, MeSi), 0.09 (s, 6H, MeSi); 13C NMR
(150 MHz, CDCl3): d ˆ 169.7, 165.9, 153.2, 151.0, 134.5, 125.5, 123.7, 122.7,
118.8, 100.0, 92.5, 89.9, 84.2, 81.1, 77.5, 75.7, 72.1, 71.2, 69.2, 66.2, 61.8, 60.7,
39.9, 36.3, 35.9, 30.3, 25.8, 25.5, 20.2, 19.4, 18.9, 18.2, 17.9, 17.7, 15.2, À3.0,
‡
À4.8, À5.0; HRMS (FAB): calcd for C41H67Cl2NO14Si2Na [M‡Na] :
946.3375, found 946.3391.
A1B(A)CDEFGHA2 2-phenylselenide 53: A1B(A)C glycosyl fluoride 29[1]
(56 mg, 0.054 mmol) and DEFGHA2 hexa-TBS diol 40 (36 mg,
0.022 mmol) were azeotroped with benzene (3 Â 3 mL) and then dried
under high vacuum for 1 h. Et2O (0.15 mL) and 4 Š MS were added, and
the mixture was cooled to 08C and stirred for 15 min. SnCl2 (8.3 mg,
0.043 mmol) was added in one portion and the resulting mixture was
warmed to 258C and stirred for 6 h. The reaction mixture was diluted with
EtOAc (150 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
preparative TLC (silica gel, 50% Et2O in hexanes) to afford A1B(A)C-
DEFGHA2 2-phenylselenide 53 (41 mg, 70%) as a white foam. 53: Rf ˆ
0.43 (50% Et2O in hexanes); [a]2D2 ˆ À13.1 (c ˆ 0.32, CHCl3); IR (thin
film): nÄ ˆ 2930, 2857, 1736, 1599, 1474, 1389, 1253, 1173, 1104, 982, 837, 779,
1255, 1060, 832, 779, 738 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 6.28 (d,
J ˆ 2.0 Hz, 1H, ArH (A2)), 6.16 (d, J ˆ 2.0 Hz, 1H, ArH (A2)), 5.35 (ddd,
J ˆ 10.0, 10.0, 5.6 Hz, 1H, H4), 5.17 (s, 1H, OCH2O), 5.07 (brs, 1H, F1),
5.05 (s, 1H, OCH2O), 5.00 (s, 1H, G1), 4.97 (dd, J ˆ 4.6, 1.5 Hz, 1H, A1),
4.88 (t, J ˆ 9.4 Hz, 1H, B4), 4.85 (s, 1H, D1), 4.66 (d, J ˆ 9.5 Hz, 1H, B1),
4.38 (ddd, J ˆ 10.4, 10.4, 4.6 Hz, 1H, G4), 4.23 (brs, 1H, G2), 4.17 (dd, J ˆ
11.1, 5.5 Hz, 1H, H5), 4.10 (s, 1H, D2), 4.06 (d, J ˆ 7.5 Hz, 1H, E1), 4.04
(dd, J ˆ 9.4, 4.4 Hz, 1H, G5), 4.00 (dd, J ˆ 10.1, 2.3 Hz, 1H, G3), 3.96 (t, J ˆ
10.1 Hz, 2H, F4, G5), 3.93 (t, J ˆ 9.7 Hz, 1H, H3), 3.93 ± 3.80 (m, 3H, B3,
C3, F3), 3.86 (s, 6H, OMe), 3.80 (d, J ˆ 10.0 Hz, 1H, D4), 3.77 (d, J ˆ
6.3 Hz, 1H, E4), 3.69 (dq, J ˆ 9.8, 6.0 Hz, 1H, D5), 3.65 (dd, J ˆ 9.1, 7.5 Hz,
1H, E2), 3.64 (d, J ˆ 9.4 Hz, 1H, A4), 3.58 (d, J ˆ 9.4 Hz, 1H, H2), 3.58 (t,
J ˆ 10.0 Hz, 1H, H5), 3.54 ± 3.41 (m, 8H, A5, B5, C5, E3, E5, F5, F6, F6),
3.39 (s, 3H, OMe), 3.35 (s, 3H, OMe), 3.31 (t, J ˆ 4.2 Hz, 1H, F2), 3.29 (s,
3H, OMe), 3.26 (dd, J ˆ 9.4, 8.2 Hz, 1H, C4), 2.46 (dd, J ˆ 13.6, 4.7 Hz, 1H,
A2), 2.37 (s, 3H, Me (A1)), 2.29 (dd, J ˆ 11.9, 4.2 Hz, 1H, B2), 2.24 (s, 3H,
Me (A2)), 2.24 ± 2.21 (m, 1H, C2), 2.04 (dd, J ˆ 13.6, 1.7 Hz, 1H, A2), 1.92
(dd, J ˆ 13.0, 1.1 Hz, 1H, C2), 1.64 (dt, J ˆ 12.4, 12.4 Hz, 1H, B2), 1.43 (s,
3H, Me (D3)), 1.40 (d, J ˆ 6.2 Hz, 3H, B6), 1.38 (s, 3H, Me (A3)), 1.26 ±
1.24 (m, 9H, C6, D6, E6), 1.05 (s, 9H, tBuSi), 0.96 (s, 9H, tBuSi), 0.95 (s,
9H, tBuSi), 0.93 (s, 9H, tBuSi), 0.90 (s, 9H, tBuSi), 0.89 (s, 9H, tBuSi), 0.88
(s, 9H, tBuSi), 0.88 (s, 9H, tBuSi), 0.85 (d, J ˆ 6.2 Hz, 3H, A6), 0.30 (s, 3H,
MeSi), 0.29 (s, 3H, MeSi), 0.21 (s, 3H, MeSi), 0.21 (s, 3H, MeSi), 0.18 (s,
6H, MeSi), 0.14 (s, 3H, MeSi), 0.14 (s, 3H, MeSi), 0.12 (s, 3H, MeSi), 0.11
(s, 3H, MeSi), 0.09 (s, 3H, MeSi), 0.09 (s, 3H, MeSi), 0.09 (s, 3H, MeSi),
0.07 (s, 3H, MeSi), 0.07 (s, 3H, MeSi), 0.06 (s, 3H, MeSi); 13C NMR
(125 MHz, CDCl3): d ˆ 167.0, 165.8, 157.2, 153.8, 153.2, 150.8, 137.8, 134.4,
125.4, 123.5, 122.8, 120.1, 119.0, 118.9, 118.8, 114.9, 108.3, 103.5, 102.3, 98.7,
97.0, 96.3, 92.4 89.8, 84.2, 84.1, 82.4, 82.3, 81.5, 81.0, 78.8, 76.0, 75.0, 74.2,
73.3, 72.8, 72.4, 71.5, 71.1, 70.5, 70.3, 69.9, 62.4, 61.7, 60.6, 58.2, 42.2, 40.1,
36.2, 34.5, 31.5, 30.2, 29.6, 26.3, 26.0, 25.9, 25.7, 25.5, 25.2, 22.5, 21.1, 20.6,
19.7, 19.3, 19.2, 18.8, 18.4, 18.3, 18.3, 18.2, 18.2, 18.2, 18.0, 18.0, 17.9, 17.5,
16.2, 15.2, 14.0, À3.1, À3.1, À3.8, À3.9, À4.1, À4.2, À4.2, À4.3, À4.4,
À4.5, À4.6, À5.0, À5.1, À5.3; HRMS (FAB): calcd for C118H209Cl2NO38-
734 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.60 (d, J ˆ 7.6 Hz, 2H, ArH),
7.57 (d, J ˆ 7.1 Hz, 2H, ArH), 7.43 ± 7.20 (m, 11H, ArH), 6.29 (d, J ˆ 1.9 Hz,
1H, ArH (A2)), 6.16 (d, J ˆ 1.9 Hz, 1H, ArH (A2)), 5.35 (ddd, J ˆ 9.9, 9.9,
5.6 Hz, 1H, H4), 5.21 (d, J ˆ 1.4 Hz, 1H, C1), 5.06 (s, 2H, OCH2O, G1),
5.05, 5.02 (AB, J ˆ 10.2 Hz, 2H, CH2Ar), 5.01 (s, 2H, F1, OCH2O), 4.94 (dd,
J ˆ 4.7, 1.5 Hz, 1H, A1), 4.87 (t, J ˆ 9.3 Hz, 1H, B4), 4.79 (brd, J ˆ 9.5 Hz,
1H, B1), 4.64, 4.52 (AB, J ˆ 11.3 Hz, 2H, CH2Ar), 4.59 (s, 1H, D1), 4.39
(ddd, J ˆ 10.4, 10.4, 4.4 Hz, 1H, G4), 4.24 (brs, 1H, G2), 4.17 (dd, J ˆ 11.1,
5.5 Hz, 1H, H5), 4.15 (dd, J ˆ 8.1, 4.5 Hz, 1H, C3), 4.11 (brs, 1H, F3), 4.08
(d, J ˆ 7.5 Hz, 1H, E1), 4.04 (dd, J ˆ 9.5, 4.7 Hz, 1H, G5), 4.02 ± 3.97 (m,
2H, C2, G3), 3.96 (t, J ˆ 8.1 Hz, 1H, F4), 3.93 (t, J ˆ 9.8 Hz, 1H, H3), 3.90 ±
3.76 (m, 2H, B3, G5), 3.82 (s, 3H, OMe), 3.67 (s, 1H, D2), 3.64 (d, J ˆ
9.4 Hz, 1H, A4), 3.61 (t, J ˆ 8.8 Hz, 1H, E2), 3.59 (d, J ˆ 10.4 Hz, 1H, H2),
3.57 (t, J ˆ 8.9 Hz, 1H, H5), 3.53 ± 3.46 (m, 8H, A5, C4, C5, D4, D5, F5, F6,
F6), 3.50 (s, 3H, OMe), 3.43 (d, J ˆ 3.1 Hz, 1H, F2), 3.40 (s, 3H, OMe),
3.38 ± 3.28 (m, 2H, B5, E3), 3.35 (s, 3H, OMe), 3.30 (s, 3H, OMe), 3.29 ±
3.18 (m, 2H, E4, E5), 2.45 (dd, J ˆ 13.7, 5.0 Hz, 1H, A2), 2.38 (s, 3H, Me
(A2)), 2.29 (dd, J ˆ 12.3, 6.1 Hz, 1H, B2), 2.26 (s, 3H, Me (A1)), 2.02 (dd,
J ˆ 13.7, 1.6 Hz, 1H, A2), 2.02 (dt, J ˆ 11.9, 11.9 Hz, 1H, B2), 1.68 (s, 3H,
Me (A3)), 1.33 (d, J ˆ 6.2 Hz, 3H, B6), 1.31 (d, J ˆ 6.2 Hz, 3H, C6), 1.27 (d,
J ˆ 6.4 Hz, 3H, D6), 1.25 (s, 3H, Me (D3)), 1.22 (d, J ˆ 5.4 Hz, 3H, E6),
0.97 (s, 9H, tBuSi), 0.96 (s, 9H, tBuSi), 0.90 (s, 9H, tBuSi), 0.90 (s, 9H,
tBuSi), 0.87 (s, 9H, tBuSi), 0.86 (s, 9H, tBuSi), 0.83 (d, J ˆ 6.2 Hz, 3H, A6),
0.25 (s, 3H, MeSi), 0.22 (s, 3H, MeSi), 0.18 (s, 6H, MeSi), 0.11 (s, 3H,
MeSi), 0.09 (s, 6H, MeSi), 0.08 (s, 6H, MeSi), 0.08 (s, 3H, MeSi), 0.07 (s,
3H, MeSi), 0.07 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 167.1,
165.6, 157.3, 153.9, 153.3, 153.2, 138.2, 137.9, 135.9, 134.8, 134.4, 129.0, 128.6,
128.5, 128.5, 128.2, 127.6, 127.5, 126.4, 126.0, 121.7, 119.0, 114.9, 108.4, 103.4,
102.3, 101.5, 100.1, 97.2, 96.4, 92.4, 89.9, 89.9, 84.2, 82.3, 81.1, 80.0, 78.0, 77.3,
76.1, 75.1, 74.9, 74.5, 72.7, 72.3, 71.3, 71.1, 71.0, 70.9, 70.6, 70.5, 70.3, 70.0,
69.5, 67.6, 66.2, 65.8, 63.3, 63.0, 62.4, 62.0, 60.8, 58.4, 48.5, 40.1, 36.3, 29.6,
26.1, 26.0, 25.8, 25.6, 25.3, 19.8, 19.3, 18.7, 18.4, 18.2, 18.1, 18.0, 18.0, 17.6,
16.3, À3.5, À3.7, À4.0, À4.2, À4.3, À4.4, À4.6, À4.9, À4.9, À5.0, À5.2;
‡
Si8Na [M‡Na] : 2565, found 2533.
A1B(A)Clactone (silylated) 52 : A solution of 5% aqueous HCl (10.0 mL)
was added to a solution of the fully silylated everninomicin 50 (30 mg,
0.03 mmol) in THF (1.0 mL) and the reaction mixture was stirred at 258C
until TLC analysis showed that no starting material remained, and a more
polar spot appeared by TLC. A solution of 1n aqueous KOH (0.1 ± 0.5 mL)
was then added while stirring rapidly, until TLC indicated the formation of
two new spots, one above and one below the spot from the acidic reaction.
The reaction mixture was then quenched by the addition of saturated
aqueous NaHCO3 (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% Et2O in hexanes) to afford A1B(A)C
lactone 52 (9.0 mg, 83%) and hexa-TBS DEFGHA2 diol 40 (10 mg, 91%)
both as white foams. 52: Rf ˆ 0.23 (70% Et2O in hexanes); [a]2D2 ˆ À35.7
(c ˆ 0.23, CHCl3); IR (thin film): nÄ ˆ 2935, 2859, 1736, 1544, 1453, 1388,
‡
HRMS (ESI): calcd for C126H199Cl2NO38SeSi6Na [M‡Na] : 2670/2684,
‡
found 2677/2678 [M‡Na] .
Fully protected everninomicin 54: NaIO4 (31 mg, 0.14 mmol) and NaHCO3
(10 mg, 0.11 mmol) were added to a solution of A1B(A)CDEFGHA2
2-phenylselenide 53 (38 mg, 0.014 mmol) in MeOH/CH2Cl2/H2O (3:2:1,
1.0 mL) and the resulting mixture was stirred at 258C for 4 h. The reaction
mixture was diluted with CH2Cl2 (150 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 (1 mL) and transferred by
cannula to a sealed tube. The flask was washed with toluene (2 Â 0.5 mL)
and the organics were transferred to the tube. Diisopropylamine (1 mL)
and vinyl acetate (2 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 preparative TLC (silica gel, 50% Et2O in
hexanes) to afford the fully protected everninomicin 54 (23 mg, 65% over
two steps) as a white foam. Fully protected everninomicin 54: Rf ˆ 0.32
(60% Et2O in hexanes); [a]2D2 ˆ À19.5 (c ˆ 0.20, CHCl3); IR (thin film):
1
1252, 1092, 914, 832, 782, 735 cmÀ1; H NMR (600 MHz, CDCl3): d ˆ 4.96
(brd, J ˆ 4.5 Hz, 1H, A1), 4.90 (t, J ˆ 9.7 Hz, 1H, B4), 4.61 (dd, J ˆ 9.6,
1.7 Hz, 1H, B1), 4.37 (dt, J ˆ 3.5, 3.1 Hz, 1H, C3), 4.29 (dq, J ˆ 6.5, 5.2 Hz,
1H, C5), 3.91 ± 3.85 (m, 1H, B3), 3.85 (s, 3H, OMe), 3.64 (d, J ˆ 9.2 Hz, 1H,
A4), 3.57 ± 3.55 (m, 1H, C4), 3.52 ± 3.48 (m, 2H, A5, B5), 3.34 (s, 3H,
OMe), 2.80 (dd, J ˆ 16.2, 3.5 Hz, 1H, C2), 2.54 (dd, J ˆ 16.2, 2.6 Hz, 1H,
C2), 2.46 (dd, J ˆ 13.6, 4.8 Hz, 1H, A2), 2.36 (s, 3H, Me (A1)), 2.30 (dd, J ˆ
12.7, 4.9 Hz, 1H, B2), 2.02 (dd, J ˆ 13.6, 1.7 Hz, 1H, A2), 1.70 ± 1.65 (m, 1H,
B2), 1.67 (s, 3H, Me (A3)), 1.48 (d, J ˆ 6.5 Hz, 3H, C6), 1.41 (d, J ˆ 6.5 Hz,
3H, B6), 1.04 (s, 9H, tBuSi), 0.87 (s, 9H, tBuSi), 0.85 (d, J ˆ 6.1 Hz, 3H,
3164
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3164 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

Everninomicin 13,384-1: Part 3
3149±3165
nÄ ˆ 2955, 2919, 2861, 1737, 1602, 1543, 1455, 1384, 1255, 1108, 1067, 1038,
6.2 Hz, 3H, C6), 0.77 (d, J ˆ 6.2 Hz, 3H, A6); 13C NMR (150 MHz, CDCl3/
CD3OD 20:1): d ˆ 170.5, 165.8, 165.2, 162.6, 153.2, 151.3, 143.7, 134.4, 120.6,
120.1, 118.8, 118.3, 113.6, 112.1, 104.0, 103.4, 101.0, 100.8, 100.4, 97.5, 96.7,
96.0, 92.3, 89.8, 87.8, 84.1, 82.7, 80.8, 80.7, 80.3, 80.0, 79.3, 78.2, 77.3, 75.2,
75.0, 73.8, 72.6, 72.4, 71.8, 71.8, 71.0, 70.9, 70.6, 69.8, 69.7, 68.9, 68.5, 68.5,
67.9, 66.2, 65.7, 63.6, 63.2, 61.9, 61.8, 61.7, 60.6, 58.9, 39.8, 39.5, 35.8, 24.3,
19.1, 18.5, 18.2, 17.8, 17.7, 17.5, 17.3, 15.9, 14.9; HRMS (ESI): calcd for
838, 779 cmÀ1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.57 (d, J ˆ 7.1 Hz, 2H,
ArH), 7.43 ± 7.31 (m, 8H, ArH), 6.29 (d, J ˆ 1.8 Hz, 1H, ArH (A2)), 6.16 (d,
J ˆ 1.8 Hz, 1H, ArH (A2)), 5.35 (ddd, J ˆ 9.9, 9.9, 5.5 Hz, 1H, H4), 5.18 (s,
1H, OCH2O), 5.07 (brs, 1H, F1), 5.06 (s, 1H, OCH2O), 5.05, 5.02 (AB, J ˆ
10.2 Hz, 2H, CH2Ar), 5.00 (s, 1H, G1), 4.95 (dd, J ˆ 4.6, 1.4 Hz, 1H, A1),
4.88 (t, J ˆ 9.4 Hz, 1H, B4), 4.86 (s, 1H, D1), 4.75 (brd, J ˆ 9.8 Hz, 1H, B1),
4.68, 4.57 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.39 (ddd, J ˆ 10.5, 10.5, 4.8 Hz,
1H, G4), 4.23 (brs, 1H, G2), 4.17 (dd, J ˆ 11.4, 5.7 Hz, 1H, H5), 4.14 (brs,
1H, F3), 4.09 (s, 1H, D2), 4.07 (d, J ˆ 7.4 Hz, 1H, E1), 4.04 (dd, J ˆ 9.2,
4.4 Hz, 1H, G5), 4.01 (dd, J ˆ 10.1, 2.6 Hz, 1H, G3), 3.97 (dd, J ˆ 10.1,
9.2 Hz, 1H, G5), 3.93 (t, J ˆ 9.6 Hz, 1H, H3), 3.89 (brt, J ˆ 8.3 Hz, 1H, C4),
3.86 ± 3.80 (m, 5H, B3, C3, D4, E5, F4), 3.82 (s, 3H, OMe), 3.72 (dq, J ˆ 6.2,
4.0 Hz, 1H, D5), 3.65 (dd, J ˆ 9.2, 7.4 Hz, 1H, E2), 3.64 (d, J ˆ 9.7 Hz, 1H,
A4), 3.59 (t, J ˆ 11.0 Hz, 1H, H5), 3.59 (d, J ˆ 9.2 Hz, 1H, H2), 3.56 (s, 3H,
OMe), 3.53 ± 3.50 (m, 4H, C5, E4, F6, F6), 3.48 ± 3.46 (m, 1H, A5), 3.47 (dd,
J ˆ 9.2, 3.1 Hz, 1H, E3), 3.43 (t, J ˆ 3.5 Hz, 1H, F2), 3.39 (s, 3H, OMe), 3.35
(s, 3H, OMe), 3.34 ± 3.33 (m, 2H, B5, F5), 3.30 (s, 3H, OMe), 2.51 (dd, J ˆ
12.5, 8.5 Hz, 1H, C2), 2.45 (dd, J ˆ 13.7, 4.9 Hz, 1H, A2), 2.38 (s, 3H, Me
(A1)), 2.29 (brdd, J ˆ 12.4, 8.6 Hz, 1H, B2), 2.26 (s, 3H, Me (A2)), 2.01 (dd,
J ˆ 13.7, 1.6 Hz, 1H, A2), 1.90 (t, J ˆ 12.1 Hz, 1H, C2), 1.70 ± 1.66 (m, 1H,
B2), 1.68 (s, 3H, Me (A3)), 1.34 (s, 3H, Me (D3)), 1.32 (d, J ˆ 6.4 Hz, 3H,
B6), 1.31 (d, J ˆ 6.2 Hz, 3H, D6), 1.28 (d, J ˆ 6.6 Hz, 3H, E6), 1.26 (d, J ˆ
6.8 Hz, 3H, C6), 0.96 (s, 9H, tBuSi), 0.95 (s, 9H, tBuSi), 0.94 (s, 9H, tBuSi),
0.90 (s, 9H, tBuSi), 0.89 (s, 18H, tBuSi), 0.83 (d, J ˆ 6.2 Hz, 3H, A6), 0.21 (s,
6H, MeSi), 0.19 (s, 3H, MeSi), 0.18 (s, 6H, MeSi), 0.14 (s, 3H, MeSi), 0.10
(s, 6H, MeSi), 0.10 (s, 3H, MeSi), 0.09 (s, 3H, MeSi), 0.07 (s, 3H, MeSi),
0.06 (s, 3H, MeSi); 13C NMR (125 MHz, CDCl3): d ˆ 167.1, 165.6, 157.3,
153.9, 153.2, 152.3, 138.7, 137.9, 135.9, 134.8, 128.6, 128.6, 128.5, 127.5, 127.2,
126.4, 126.0, 121.7, 120.1, 119.0, 119.0, 114.9, 108.5, 103.5, 102.3, 100.2, 97.2,
96.4, 92.6, 89.9, 84.3, 82.8, 82.4, 81.5, 81.1, 79.0, 77.3, 76.1, 75.1, 74.9, 74.1,
73.5, 72.8, 72.4, 71.8, 71.6, 71.1, 70.5, 70.4, 70.0, 69.1, 68.3, 66.2, 63.3, 63.0,
62.5, 62.0, 60.8, 58.4, 46.2, 40.1, 38.8, 36.4, 29.7, 26.2, 26.0, 25.8, 25.6, 25.6,
19.8, 19.3, 19.2, 18.4, 18.3, 18.3, 18.1, 18.1, 18.0, 18.0, 17.6, 16.2, 11.6, À3.7,
À3.8, À3.9, À4.2, À4.3, À4.4, À4.4, À4.5, À4.5, À4.9, À5.0, À5.2; HRMS
‡
C70H97Cl2NO38Na [M‡Na] : 1653, found 1653.
Acknowledgements
We thank Dr. A. K. Ganguly for helpful discussions and a generous gift of
everninomicin 13,384-1 and Drs. D. H. Huang, G. Siuzdak, and R. Chadha
for NMR spectroscopic, mass spectroscopic and X-ray crystallographic
assistance, respectively. This work was financially supported by the
National Institutes of Health (USA), the Skaggs Institute for Chemical
Biology, postdoctoral fellowships from M.E.C., Spain (R.M.R., Fullbright),
the Japan Society for the Promotion of Science (H.S.) and the George
Hewitt Foundation (K.C.F.), and grants from Schering ± Plough, Pfizer,
Glaxo, Merck, Hoffmann ± LaRoche, DuPont, Bayer, Boehringer Ingel-
heim, and Abbott Laboratories.
[1] K. C. Nicolaou, R. M. Rodríguez, H. J. Mitchell, H. Suzuki, K. C.
Fylaktakidou, O. Baudoin, F. L. van Delft, Chem. Eur. J. 2000, 6, &&,
Part 1 in this series of four papers.
[2] K. C. Nicolaou, H. J. Mitchell, K. C. Fylaktakidou, R. M. Rodríguez,
H. Suzuki, Chem. Eur. J. 2000, 6, &&, Part 2 in this series of four
papers.
[3] R. R. Schmidt, J. Michel, Angew. Chem. 1980, 92, 763 ± 765; Angew.
Chem. Int. Ed. Engl. 1980, 19, 731 ± 733.
[4] D. Kahne, S. Walker, Y. Cheng, D. V. Engen, J. Am. Chem. Soc. 1989,
111, 6881 ± 6882.
‡
(FAB): calcd for C120H193Cl2NO38Si6Na [M‡Na] : 2496/2497, found 2498/
2499.
[5] D. Crich, S. Sun, J. Am. Chem. Soc. 1998, 120, 435 ± 436.
Everninomicin 13,384-1 (1): 10% Pd/C (2.0 mg) was added to a solution of
the fully protected everninomicin 54 (10 mg, 0.004 mmol) and NaHCO3
(1.3 mg, 0.016 mmol) in tBuOMe (1.0 mL) and the resulting mixture was
stirred under 1 atm of H2 (balloon) at 258C for 1 h. The reaction mixture
was filtered through a pad of Celite, the pad was washed with EtOAc
(50 mL), and the solvents were removed under reduced pressure to afford
the crude A1B(A)CDEFGHA2 diol as a white foam. The crude diol was
then dissolved in THF (0.1 mL), nBu4NF (40.01 mL, 0.04 mmol) was added,
and the resulting mixture was stirred at 258C for 10 h. The solvents were
removed under reduced pressure and the residue was purified by flash
column chromatography (silica gel, 0 ! 10% MeOH in EtOAc (1%
Et3N)), followed by preparative TLC (silica gel, 5% MeOH in EtOAc (1%
Et3N)) to afford everninomicin 13,384-1 (1) (5.0 mg, 75% over two steps)
as a white solid. 1: Rf ˆ 0.26 (5% MeOH in EtOAc); [a]2D2 ˆ (syn.) À38.8
(c ˆ 0.08, CHCl3), (nat.) À45.0 (c ˆ 0.10, CHCl3); IR (KBr pellet) nÄ ˆ 3487,
2979, 2939, 1736, 1721, 1652, 1621, 1543, 1457, 1382, 1257, 1200, 1050, 994,
Á
[6] M. Trumtel, P. Tavecchia, A. Veyrieres, P. SinayÈ, Carbohydr. Res. 1990,
202, 257 ± 275.
[7] T. Oshita, M. Shibasaki, T. Yoshizawa, M. Tomita, K. Takao, S.
Kobayashi, Tetrahedron, 1997, 53, 10993 ± 11006.
[8] For a reviewof tin-containing intermediates in carbohydrate chem-
istry, see: T. B. Grindley, Adv. Carbohydr. Chem. Biochem. 1998, 53,
17 ± 142.
[9] K. C. Nicolaou, C. W. Hummel, Y. Iwabuchi, J. Am. Chem. Soc. 1992,
114, 3126 ± 3128.
[10] C. A. Podlasek, J. Wu, W. A. Stripe, P. B. Bondo, A. S. Serianni, J. Am.
Chem. Soc. 1995, 117, 8635 ± 8644.
[11] a) See ref. [6]; b) G. Jaurand, J.-M. Beau, P. SinayÈ, J. Chem. Soc. Chem.
Commun. 1982, 701 ± 703; c) J.-M. Beau, G. Jaurand, J. Esnault, P.
SinayÈ, Tetrahedron Lett. 1987, 28, 1105 ± 1108.
[12] We thank Dr. Ashit Ganguly of Schering-Plough Corp. for a sample of
natural everninomicin 13,384 ± 1 (1).
[13] a) A. K. Ganguly, B. Pramanik, T. C. Chan, O. Sarre, Y.-T. Liu, J.
Morton, V. M. Girijavallabhan, Heterocycles 1989, 28, 83 ± 88; b) A. K.
Ganguly in Topics in Antibiotic Chemistry, Vol. 2 (Part B) (Ed.: P. G.
Sammes), Wiley, NewYork, 1978, pp. 61 ± 96.
[14] K. C. Nicolaou, K. C. Fylaktakidou, H. J. Mitchell, F. L. van Delft,
R. M. Rodríguez, S. R. Conley, Z. Jin, Chem. Eur. J. 2000, 6, &&,
Part 4 in this series of four papers.
600 cmÀ1
;
1H NMR (600 MHz, CDCl3/CD3OD 20:1): d ˆ 6.16 (brs, 2H,
ArH (A2)), 5.32 (ddd, J ˆ 9.4, 9.4, 5.6 Hz, 1H, H4), 5.14 (s, 1H, G1), 5.12 (s,
1H, OCH2O), 5.07 (s, 1H, OCH2O), 4.93 (s, 1H, D1), 4.90 (brd, J ˆ 4.6 Hz,
1H, A1), 4.85 (t, J ˆ 9.4 Hz, 1H, B4), 4.68 (s, 1H, F1), 4.48 (brd, J ˆ 9.7 Hz,
1H, B1), 4.36 (brs, 1H, G2), 4.35 (ddd, J ˆ 10.5, 10.5, 4.6 Hz, 1H, G4), 4.17
(dd, J ˆ 11.7, 5.5 Hz, 1H, H5), 4.12 (d, J ˆ 7.6 Hz, 1H, E1), 4.08 (dd, J ˆ 9.6,
4.5 Hz, 1H, G5), 3.99 (s, 1H, D2), 3.96 (t, J ˆ 9.8 Hz, 1H, H3), 3.88 (dd, J ˆ
10.2, 2.5 Hz, 1H, G3), 3.86 (t, J ˆ 10.6 Hz, 1H, C3), 3.86 ± 3.83 (m, 3H, B3,
C5, D4), 3.79 (s, 3H, OMe), 3.78 ± 3.72 (m, 4H, D5, E5, F6, G5), 3.67 (dd,
J ˆ 9.5, 8.3 Hz, 1H, H5), 3.61 ± 3.50 (m, 7H, A4, E2, E5, F3, F4, F6, H2),
3.54 (s, 3H, OMe), 3.52 (s, 3H, OMe), 3.50 ± 3.36 (m, 6H, A5, B5, E3, E4,
F2, F5), 3.30 (s, 3H, OMe), 3.27 (s, 3H, OMe), 2.99 (t, J ˆ 9.0 Hz, 1H, C4),
2.39 ± 2.37 (m, 1H, A2), 2.32 (dd, J ˆ 12.0, 5.1 Hz, 1H, B2), 2.29 (s, 3H, Me
(A1)), 2.29 ± 2.26 (m, 1H, C2), 2.26 (s, 3H, Me (A2)), 1.96 (dd, J ˆ 13.7,
1.4 Hz, 1H, A2), 1.73 (t, J ˆ 12.3 Hz, 1H, C2), 1.66 (dt, J ˆ 12.3, 12.3 Hz,
1H, B2), 1.59 (s, 3H, Me (A3)), 1.35 (d, J ˆ 6.2 Hz, 3H, B6), 1.30 (s, 3H, Me
(D3)), 1.26 (d, J ˆ 5.9 Hz, 3H, D6), 1.24 (d, J ˆ 5.9 Hz, 3H, E6), 1.24 (d, J ˆ
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b) W. Rosenbrook, Jr., D. A. Riley, P. A. Lartey, Tetrahedron Lett.
1985, 26, 3 ± 4; c) G. H. Posner, S. R. Haines, Tetrahedron Lett. 1985,
26, 5 ± 8.
Received: February 11, 2000 [F2296]
Chem. Eur. J. 2000, 6, No. 17
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