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

Full text of DOI:10.1002/(SICI)1521-3773(19991115)38:22<3340::AID-ANIE3340>3.0.CO;2-2

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target molecule (Figure 1). The novelty of this oligosaccharide
fragment (2), which contains the challenging features of a
1 !1'-disaccharide unit, a highly sensitive orthoester moiety,
and a trans-methylene acetal, forced us into a somewhat
linear, but nevertheless efficient, strategy.
Figure 1 outlines the retrosynthetic analysis upon which the
successful strategy towards subtarget 2 was based. Thus,
disconnection of the ester and orthoester bonds in 2 led to
fragments 3 and 4. Further disconnection of 3 at the indicated
glycoside bond revealed diol 5 and 2-phenylselenoglycosyl
Total Synthesis of Everninomicin 13,384-1Ð
Part 2: Synthesis of the FGHA2 Fragment**
K. C. Nicolaou,* Rosa María Rodríguez,
Konstantina C. Fylaktakidou, Hideo Suzuki, and
Helen J. Mitchell
In the preceding paper,[1] we described the construction of
the A1B(A)C fragment of everninomicin 13,384-1 (1). Herein
we report the synthesis of the FGHA2 fragment (2) of this
Me
Me
OMe
O
OH
O
O
Me
Me
O
Me
OMe
A1
O
MeO
O
O
O
O
O
O
O
O
O
O
Cl
O
H
O
B
A
E
G
O
C
D
F
A2
O
O
O
OMe
HO
OH
Me
HO
Me
O
O
HO
OH
OH
OH
Cl
NO2
Me
Me
OMe
1 everninomicin 13,384-1
Esterification
OMe
OBn
G
OMe
BnO
O
O
OTBS
OPMB
O
Me
PhSe
OH
O
Me
O
O
O
O
O
O
+
F
O
H
H
G
F
F
A2
4
A2
O
O
O
O
O
HO
OMe
TIPSO
OMe
BnO
OBn
BnO
OBn
3
OBn
2
OBn
Glycosylation
Orthoester formation
Glycosylation
OMe
OMe
BnO
O
O
O
O
O
OBz
OH
OH
nBu
OTBS
PhSe
F
Sn
G
F
Cl3C(HN)CO
F
OAllyl
OAllyl
+
+
O
nBu
PMBO
TIPSO
OMe
G
8
OPMB
H
O
OBn
OBn
O
6
7
5
Figure 1. Retrosynthetic analysis of FGHA2 fragment (2). Bn ˆ benzyl; Bz ˆ benzoyl; PMB ˆ p-methoxybenzyl; TBS ˆ tert-butyldimethylsilyl; TIPS ˆ
triisopropylsilyl.
[*] Prof. K. C. Nicolaou, Dr. R. M. Rodríguez,
fluoride 6 as potential precursors. A selenium-assisted cou-
pling of 5 with 6 was expected to furnish regio- and stereo-
Dr. K. C. Fylaktakidou, Dr. H. Suzuki, H. J. Mitchell
Department of Chemistry and
selectively trisaccharide 3, which would be poised for the
formation of a SinayÈ-type orthoester.[2] The success of this
scheme depended on the stereoselectivity of this reaction (see
Figures 2 and 3). Final disassembly of 5 led to tin acetal 7 and
trichloroacetimidate 8 as starting building blocks for this
disaccharide. The stereoselective construction of the 1 !1'-
disaccharide bridge of 5 from 7 and 8 was assured from our
previous studies on model systems that culminated in an
efficient new method[3] for accomplishing this task.
The construction of the individual building blocks are
presented in Schemes 1 ± 4. Building block F (7) was synthe-
sized from the readily available phenylthioglycoside 9[4] as
follows (Scheme 1). Selective silylation of the primary hy-
droxyl group of 9 (TBSOTf/2,6-lutidine, 97%) gave silyl ether
10, which was sequentially exposed to NaH/PMBCl/nBu4NI
(95% yield) and nBu4NF (95% yield) to afford primary
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (‡ 1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] 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., Fulbright), 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-Wellcome, Merck, Hoff-
mann-La Roche, DuPont, and Abbott Laboratories.
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Angew. Chem. Int. Ed. 1999, 38, No. 22

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OR
OAllyl
O
F
SePh
EtO
TPSO
b
O
OEt
O
OH
O
F
ROH
O
c
O
O
OR
OAllyl
18
RO
SePh
16: R = H
17: R = Allyl
OR
SePh
a
III
IV: R = PG
V: R = H
I: R = H
II:R = SF2NEt2
d
DAST
[O]
O
OR
AllylO
OR
O
O
G
TPSO
N
O
O
O
O
O
O
O
∆
f
AllylO
OBz
AllylO
HO
S
HO
AllylO
g
O
SePh
21: R = H
8: R = C(NH)CCl3
19: R = H
20: R = Bz
VIII
VII
VI
e
H
h
O
Figure 2. Orthoester formation via 1,2-migration of the phenylseleno
group followed by glycosylation (I !II !III !IV)[10] and ring closure after
syn-elimination (V!VI !VII !VIII).[2] DASTˆ diethylaminosulfur tri-
fluoride; [O] ˆ oxidant; PG ˆ protecting group.
Scheme 2. Synthesis of carbohydrate building block G (8). a) 2.1 equiv
NaH, 2.1 equiv allylBr, 0.1 equiv nBu4NI, 0.1 equiv [18]crown-6, THF,
0 !258C, 4 h, 93%; b) 2.6 equiv LAH, Et2O, 25 !358C; 93%; c) 1.0 equiv
NaH, 1.1 equiv TPSCl, 0.1 equiv nBu4NI, THF, 0 !258C, 4 h, 90%;
d) 1. 2.0 equiv (COCl)2, 2.5 equiv DMSO, 788C, 2 h; 2. 4.0 equiv Et3N,
78 ! 408C, 2 h; 3. TMS/thiazole,
40 !08C; 4. 1.5 equiv PPTS,
O
O
SPh
O
O
O
SPh
O
MeOH, 0 !258C, 91% (1:1 mixture of diastereoisomers); e) 1.1 equiv
BzCl, 1.5 equiv Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 !258C, 2 h, 98%;
f) 1. 1.2 equiv MeOTf, MeCN, 258C, 0.5 h; 2. 2.4 equiv NaBH4, MeOH,
0 !258C, 0.5 h; 3. 1.2 equiv CuCl2, 8.0 equiv CuO, MeCN/H2O (5/1), 258C,
2 h; g) 1.5 equiv nBu4NF, THF, 258C, 2 h, 81% over four steps; h) 5.0 equiv
CCl3CN, 0.05 equiv DBU, CH2Cl2, 0 !258C, 0.5 h, 85%. DBU ˆ 1,8-
diazabicyclo[5.4.0]undec-7-ene; 4-DMAP ˆ 4-(dimethylamino)pyridine;
DMSO ˆ dimethylsulfoxide; LAH ˆ lithium aluminum hydride; PPTS ˆ
pyridinium p-toluene sulfonate; TMS ˆ trimethylsilyl; TPS ˆ tert-butyldi-
phenylsilyl.
RO
HO
RO
b
c
PMBO
9: R = H
10: R = TBS
11: R = H
12: R = Me
a
d
e
O
OR
O
SPh
OH
MeO
PMBO
MeO
exposed to TMS/thiazole according to the method of Dondoni
et al.[7] to afford, after acidic workup (PPTS/MeOH), the
homologated chain 19 (91% yield, approximate 1:1 ratio of
epimeric alcohols). It is interesting to note here that when we
used the acetonide counterpart of the bis-allyl aldehyde
derived from 18 we observed a ratio of more than 10:1 of the
desired:undesired alcohols in the Dondoni reaction. How-
ever, subsequent difficulties with protecting group manipu-
lation led to the adoption of the less selective sequence
described above, whose efficiency was improved by recycling
the wrong isomer (oxidation/reduction). Benzoylation of the
chromatographically pure alcohol 19 (BzCl/Et3N/4-DMAP,
98%), followed by thiazole rupture (MeOTf; NaBH4 ; CuO;
one-pot reaction)[7] and desilylation (nBu4NF) led to lactol 21
(81% overall yield) via benzoate 20. Finally, formation of the
trichloroacetimidate 8[8] was easily accomplished by exposure
to CCl3CN in the presence of DBU (85% yield).
Scheme 3 presents the synthesis of ring H as the 2-phenyl-
selenoglycosyl fluoride 6 from d-xylose (22). Peracetylation
of 22 (Ac2O/Et3N/4-DMAP, 98% yield) followed by treat-
ment with PhSeH/BF3 ´ Et2O[9] led to a mixture of a- and b-
glycosides (a:b approximately 1:5, 93% yield). The desired b-
glycoside was subjected to basic methanolysis (K2CO3/
MeOH) and the resulting triol was exposed to
g
F
OR
PMBO
OBn
OR
15: R = H
7: R = Sn(nBu)2
13: R = H
14: R = Bn
h
f
Scheme 1. Synthesis of carbohydrate building block F (7). a) 1.2 equiv
TBSOTf, 1.5 equiv 2,6-lutidine, CH2Cl2, 0 !258C, 1 h, 97%; b) 1.1 equiv
NaH, 1.3 equiv PMBCl, 0.2 equiv nBu4NI, DMF, 0 !258C, 4 h, 95%;
c) 1.2 equiv nBu4NF, THF, 258C, 1 h, 95%; d) 1.1 equiv NaH, 1.3 equiv
MeI, DMF, 0 !258C, 1 h, 95%; e) 0.2 equiv TsOH, 2.5 equiv (CH2OH)2,
MeOH, 258C, 5 h, 85%; f) 1.1 equiv nBu2SnO, toluene, 1108C, 3 h;
1.5 equiv BnBr, 0.2 equiv nBu4NI, 25 !1108C, 5 h, 89%; g) 1.5 equiv
NBS, Me2CO/H2O (10/1), 0 !258C, 2 h, 97%; h) 1.1 equiv nBu2SnO,
MeOH, 908C, 3 h, 100%. NBS ˆ N-bromosuccinimide; Tf ˆ trifluorome-
thanesulfonyl; Ts ˆ p-toluenesulfonyl.
alcohol 11. Methylation of 11 (NaH/MeI) then furnished
methoxy compound 12 in 95% yield. Acidic methanolysis
(TsOH/MeOH) of the acetonide group from 12 led to diol 13
(85% yield), which was selectively benzylated at C3 using the
tin acetal technology[5] (nBu2SnO/BnBr/nBu4NI, 89%) to
afford 14. Rupture of the thiophenyl group from 14 with NBS/
H2O furnished lactol 15 (97% yield), which was converted
into the desired tin acetal 7 by exposure to nBu2SnO in
refluxing MeOH (100% yield).
ˆ
Scheme 2 summarizes the synthesis of the ring G trichloro-
acetimidate 8 starting from diethyl-l-tartrate (16). Thus, bis-
allylation of 16 was effected by treatment with NaH/allyl
bromide to afford 17 (93% yield). Reduction of both ester
groups of 17 with LAH in refluxing diethyl ether (93%) was
followed by monosilylation (NaH/TPSCl) to furnish hydroxy
silyl ether 18 in 90% yield. Swern oxidation ((COCl)2/DMSO/
Et3N)[6] of 18 led to the corresponding aldehyde, which was
CH3(CH3O)C CH2/TFA to afford predominantly the 2,3-
acetonide 24 (74% yield over two steps). The remaining
hydroxyl group in 24 was then protected as a PMB ether
(NaH/PMBCl/nBu4NI, 95% yield) and the acetonide was
removed under acidic conditions (PPTS/MeOH) to furnish
diol 26 (96% yield). The next task was to protect the C3
hydroxyl group of 26, an objective that was achieved by
exposure of the latter compound to TBSOTf/2,6-lutidine in
Angew. Chem. Int. Ed. 1999, 38, No. 22
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O
OR
O
O
SePh
O
observation that has to await an explanation. Having set the
stage for the 1,2-migration,[10] the targeted 2-phenylseleno-
glycosyl fluoride 6 was then formed by simple treatment of 27
with DAST (100% yield). This maneuver represents a new
reaction[11] in carbohydrate chemistry and played a crucial
role in the success of this total synthesis.
b, c, d
RO
OR
RO
OR
22: R = H
23: R = Ac
24: R = H
25: R = PMB
e
a
f
The construction of the aromatic fragment A2 (4) is
depicted in Scheme 4. Thus, benzylation of 28[1] (K2CO3/
BnBr, 92%) followed by oxidation (NaClO2, 80% yield)
and fluorination of the resulting carboxylic acid
O
F
O
SePh
OH
H
h
PMBO
SePh
PMBO
g
‡
((Me2N)2CF PF6 , 80% yield)[12] furnished the desired acyl
OTBS
OR
26: R = H
27: R = TBS
6
fluoride 4 in high overall yield.
Scheme 3. Synthesis of carbohydrate building block H (6). a) 5.0 equiv
Ac2O, 8.0 equiv Et3N, 0.2 equiv 4-DMAP, CH2Cl2, 0 !258C, 2 h, 98%;
b) ca. 2.0 equiv PhSeH, 0.2 equiv BF3 ´ Et2O, CH2Cl2, 0 !258C, 4 h, 93%
(a:b ca. 1:5); c) 0.3 equiv K2CO3, MeOH, 258C, 5 h; d) 1.5 equiv
O
Me
O
Me
A2
4
a, b, c
H
F
ˆ
CH3(CH3O)C CH2, 0.2 equiv TFA, DMF, 458C, 3 h, 74% over two steps;
HO
OH
BnO
OBn
e) 1.1 equiv NaH, 1.3 equiv PMBCl, 0.2 equiv nBu4NI, DMF, 0 !258C, 2 h,
95%; f) 0.2 equiv PPTS, MeOH, 0 !258C, 2 h, 96%; g) 1.1 equiv TBSOTf,
1.5 equiv 2,6-lutidine, CH2Cl2, 0 !258C, 0.5 h, 91%; h) 1.5 equiv DAST,
CH2Cl2, 08C, 20 min, 100%. DMF ˆ dimethylformamide; TFA ˆ tri-
fluoroacetic acid.
28
Scheme 4. Synthesis of aromatic ring A2 (4). a) 2.5 equiv BnBr, 4.0 equiv
K2CO3, Me2CO, 708C, 92%; b) 2.4 equiv NaClO2, 2.5 equiv NaH2PO4,
DMSO, 08C, 12 h, 80%; c) 1.5 equiv (Me2N)2CF PF6 , 2.0 equiv iPr2NEt,
CH2Cl2, 0 !258C, 2 h, 80%.
‡
THF at 788C to give 27 in 91% yield. Parenthetically, and
interestingly, treatment of 26 with the same silylating reagent
in CH2Cl2, instead of THF, led to the C2 derivative (96%), an
The assembly of building blocks 4 ± 8 to form the targeted
intermediate 2 is presented in Schemes 5 and 6. The first task
was to construct stereoselectively the 1 !1'-trehalose-type
NH
OMe
OBz
O
O
O
O
O
CCl3
nBu
nBu
O
O
OAllyl
OAllyl
MeO
PMBO
a
+
Sn
G
G
F
F
O
AllylO
OBz
PMBO
OH
OBn
OAllyl
OBn
b, c
7
8
29
OMe
OBn
OMe
OBn
OMe
OR
[Bz]
OCA
O
O
O
O
O
O
3
OR
OR
OAllyl
OAllyl
h
e
f
F
F
F
G
G
G
O
O
O
4
OH
TIPSO
TIPSO
PMBO
OMe
OMe
OMe
OBn
OBn
OBn
33
32: R = Allyl
5: R = H
30: R = H
31: R = Bn
O
F
g
d
H
PMBO
SePh
i
OTBS
6
OTBS
OMe
OBn
OMe
OBn
OTBS
OPMB
PhSe
OR
OPMB
O
O
O
O
O
3
3
G
H
H
F
G
k
l
F
O
O
O
4
4
O
O
O
TIPSO
RO
OMe
OMe
OBn
OBn
34: R = CA [Bz]
35: R = H
36: R = TIPS
37: R = H
38: R = Bz
m
n
j
Scheme 5. Assembly of FGH fragment 38. a) 1. 0.3 equiv TMSOTf, CH2Cl2, 0 !258C, 8 h; 2. 0.3 equiv PPTS, MeOH, 258C, 1 h, 74% over two steps;
b) 1.1 equiv NaH, 1.3 equiv MeI, DMF, 0 !258C, 1 h, 87%; c) 0.3 equiv NaOH, MeOH, 258C, 1 h, 95%; d) 1.1 equiv NaH, 1.3 equiv BnBr, 0.2 equiv nBu4NI,
DMF, 0 !258C, 4 h, 90%; e) 1.5 equiv DDQ, CH2Cl2/H2O (10/1), 0 !258C, 1 h, 91%; f) 1.2 equiv TIPSOTf, 1.5 equiv 2,6-lutidine, CH2Cl2, 0 !258C, 1 h,
97%; g) 1. 2.5 equiv DABCO, 0.1 equiv [(Ph3P)3RhCl], EtOH/H2O (10/1), 908C, 2 h; 2. 2.2 equiv NMO, 0.05 equiv OsO4, Me2CO/H2O (10/1), 258C, 8 h,
81%; h) 1.1 equiv nBu2SnO, toluene, 1108C, 3 h; 1.5 equiv CACl, 0 !258C, 1 h, 97% (1:1 mixture of regioisomers); i) 2.0 equiv 6, 1.8 equiv SnCl2, 0 !258C,
Et2O, 3 h, 92%; j) 0.2 equiv K2CO3, MeOH, 258C, 1 h, 98%; k) 10.0 equiv NaIO4, 8.0 equiv NaHCO3, MeOH/CH2Cl2/H2O (3/2/1), 258C, 2 h; l) vinyl acetate/
toluene/diisopropylamine (2/2/1), sealed tube, 1408C, 16 h, 81%; m) 1.1 equiv nBu4NF, THF, 08C, 2 h, 95%; n) 1.2 equiv BzCl, 1.8 equiv Et3N, 0.2 equiv
4-DMAP, CH2Cl2, 0 !258C, 2 h, 97%. CA ˆ chloroacetyl; DABCO ˆ 1,4-diazabicyclo[2.2.2]octane; DDQ ˆ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone;
NMO ˆ N-methylmorpholine N-oxide.
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Table 1. Selected physical and spectroscopic data of compounds 35, 44, and
2.
linkage between rings F and G, a challenge that was solved by
applying our recently developed methodology for 1 !1'-
disaccharide construction. Thus, the coupling of tin acetal 7
with trichloroacetimidate 8 (Scheme 5) proceeded smoothly
under the catalytic influence of TMSOTf in CH2Cl2 leading,
after PPTS-induced cleavage of the intermediate TMS ether,
to disaccharide 29 in 74% overall yield. As expected from our
previous findings[3] the 1 !1'-disaccharide linkage was formed
in a completely stereocontrolled fashion, furnishing 29 as a
single isomer. The free hydroxyl group in 29 was methylated
(NaH/MeI, 87% yield) and the benzoyl group at C2 of ring G,
which played a crucial role in directing the stereochemical
outcome of the glycoslylation reaction, was removed by
treatment with NaOH in MeOH to afford alcohol 30 (95%
yield). For strategic reasons, a benzyl group was installed on
the hydroxyl group of 30 (NaH/BnBr/nBu4NI, 90% yield) to
afford 31, and the PMB group of ring F was replaced with a
TIPS group (DDQ, 91% yield; TIPSOTf/2,6-lutidine, 97%
yield) to furnish compound 32. Removal of the allyl protect-
ing groups from 32 required initial treatment with Wilkinsonꢁs
catalyst and DABCO, followed by cleavage of the resulting
enol ethers with OsO4/NMO, to furnish 5 in 81% overall
yield. Despite the nonselective differentiation of the two
hydroxyl groups of 5Ðeven with the tin acetal technology,[5]
which led to hydroxychloroacetate 33 (nBu2SnO/CACl, 97%
yield) and its regioisomer (approximately 1:1 ratio)Ðan
efficient pathway to the next stage was secured. Thus, while
the indicated regioisomer (33) was used directly as a
carbohydrate acceptor in a glycosidation reaction with
glycosyl fluoride 6 (SnCl2, Et2O) to give trisaccharide 34
(92% yield) stereoselectively, its regioisomer required further
manipulation prior to being used in the forward sequence.
Specifically, the C4 regioisomer of 33, was benzoylated (BzCl/
Et3N/4-DMAP, 94%) and the chloroacetate group was re-
moved (Et3N/MeOH (1/3), 90% yield) leading to the C3
benzoate counterpart of 33. This compound was then sub-
jected to the same coupling procedure with 6 to afford the
benzoate analogue of trisaccharide 34 (90% yield). Cleavage
of the ester group from 34 (or its benzoate analogue) with
K2CO3 in MeOH led to alcohol 35 in 98% yield (Table 1),
which was now poised for a SinayÈ orthoester formation.[2]
Thus, having assisted in the construction of the glycoside
bond linking rings G and H, the 2-phenylseleno group was
now utilized to prepare the ground for the formation of the
second C O bond between these two rings. To ensure the
stereochemistry of the expected orthoester bond between
rings G and H, we had to rely on the anomeric effect,[13] which
is maximized in the sequence adopted for the formation of the
two C O bonds (see Figure 3). Extensive model studies
demonstrated that the correct orthoester stereochemistry
could only be obtained by first attaching the H ring to the C4
oxygen atom of ring G and then constructing the second
oxygen bridge (C3), rather than the other way around (which
leads to the opposite orthoester stereochemistry, see Fig-
ure 3). Thus, oxidation of the phenylseleno group with NaIO4
followed by heating the crude selenoxide in a mixture of vinyl
acetate/toluene/diisopropylamine (2/2/1) in a sealed tube at
1408C effected sequential syn-elimination at the anomeric
position and ring closure[2] to furnish orthoester 36 in 81%
35: Rf ˆ 0.18 (silica gel, 50% EtOAc in hexanes); aD22
ˆ
22.7 (c ˆ 2.7,
CHCl3); IR (thin film): nÄmax ˆ 3451, 3051, 2930, 2863, 1612, 1582, 1513, 1463,
1383, 1357, 1304, 1251, 1110, 1031, 942, 885, 883 cm 1; 1H NMR (600 MHz,
CDCl3): d ˆ 7.55 (d, J ˆ 7.1, 2H, ArH), 7.39 ± 7.25 (m, 12H, ArH), 7.15 (t,
J ˆ 7.8 Hz, 2H, ArH), 7.06 (t, J ˆ 7.3 Hz, 1H, ArH), 6.86 (d, J ˆ 8.6, 2H,
ArH (PMB)), 5.16 (d, J ˆ 1.7, 1H, G-1), 4.87 and 4.69 (AB, J ˆ 12.2 Hz, 2H,
CH2Ar), 4.80 (d, J ˆ 9.1, 1H, H-1), 4.69 and 4.40 (AB, J ˆ 11.1 Hz, 2H,
CH2Ar), 4.66 (s, 1H, F-1), 4.61 and 4.47 (AB, J ˆ 12.1 Hz, 2H, CH2Ar), 4.30
(brs, 1H, H-3), 4.01 ± 3.92 (m, 5H, G-4, F-4, H-5, H-5, G-2), 3.83 ± 3.79 (m,
1H, G-3), 3.80 (s, 3H, OMe (PMB)), 3.71 ± 3.68 (m, 2H, G-5, F-6), 3.61 (dd,
J ˆ 9.1, 2.7 Hz, 1H, H-2), 3.56 (dd, J ˆ 10.5, 6.1 Hz, 1H, F-6), 3.51 (d, J ˆ
2.6 Hz, 1H, F-2), 3.47 (s, 3H, OMe (F-2)), 3.33 ± 3.31 (m, 2H, F-3, F-5), 3.32
(s, 3H, OMe (F-6)), 3.22 (brs, 1H, H-4), 3.15 (t, J ˆ 10.9 Hz, 1H, G-5),
1.02 ± 0.96 (m, 21H, (iPr)3Si), 0.90 (s, 9H, tBuSi), 0.14 (s, 3H, MeSi), 0.07
(s, 3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 159.4, 138.4, 138.0, 131.6,
131.6, 129.6, 129.4, 128.5, 128.4, 128.2, 128.1, 127.6, 127.5, 127.4, 127.4, 127.2,
126.0, 113.9, 102.8, 95.6, 95.2, 82.2, 78.9, 77.4, 76.8, 76.3, 74.4, 73.6, 72.9, 71.9,
70.8, 70.5, 70.1, 68.0, 63.4, 61.5, 60.3, 59.0, 55.2, 48.4, 25.7, 18.2, 18.0, 18.0,
18.0, 13.2, 13.0, 4.4, 4.8; HR-MS (FAB), calcd for C61H90O14SeSi2Cs
[M ‡ Cs]: 1315.4089, found: 1315.4022
44: Rf ˆ 0.34 (silica gel, 50% EtOAc in hexanes); aD22
ˆ
19.2 (c ˆ 0.12,
CHCl3); IR (thin film): nÄmax ˆ 3448, 2943, 2861, 1725, 1614, 1514, 1455, 1372,
1
1308, 1255, 1108, 1079, 1032, 843, 779 cm 1; H NMR (600 MHz, CDCl3):
d ˆ 8.04 (d, J ˆ 7.1, 2H, ArH), 7.61 (t, J ˆ 7.4 Hz, 1H, ArH), 7.47 (t, J ˆ
7.9 Hz, 2H, ArH), 7.37 ± 7.29 (m, 10H, ArH), 7.12 (d, J ˆ 8.6, 2H, PMB),
6.75 (d, J ˆ 8.6, 2H, PMB), 5.42 (t, J ˆ 9.2 Hz, 1H, H-3), 5.34 (s, 1H, G-1),
4.87 and 4.66 (AB, J ˆ 11.6 Hz, 2H, CH2Ar), 4.67 (s, 1H, F-1), 4.63 and 4.56
(AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.53 and 4.50 (AB, J ˆ 11.0 Hz, 2H,
CH2Ar), 4.48 (ddd, J ˆ 10.5, 10.5, 4.5 Hz, 1H, G-4), 4.33 (brs, 1H, G-2),
4.11 (dd, J ˆ 9.6, 4.5 Hz, 1H, G-5), 4.00 (dd, J ˆ 10.2, 2.3 Hz, 1H, G-3), 3.90
(dd, J ˆ 11.4, 5.4 Hz, 1H, H-5), 3.87 (t, J ˆ 9.0 Hz, 1H, F-4), 3.82 ± 3.76 (m,
3H, H-2, H-4, G-5), 3.76 (s, 3H, OMe (PMB)), 3.69 (t, J ˆ 10.7 Hz, 1H,
H-5), 3.62 (dd, J ˆ 10.4, 1.8 Hz, 1H, F-6), 3.55 (dd, J ˆ 10.8, 5.3 Hz, 1H,
F-6), 3.52 (s, 3H, OMe (F-2)), 3.49 (brs, 1H, F-2), 3.33 (s, 3H, OMe (F-6)),
3.29 ± 3.27 (m, 2H, F-3, F-5), 2.49 (d, J ˆ 8.3 Hz, 1H, OH), 0.86 (s, 9H,
tBuSi), 0.04 (s, 3H, MeSi), 0.03 (s, 3H, MeSi); 13C NMR (150 MHz, CDCl3):
d ˆ 167.1, 159.4, 137.9, 137.8, 133.4, 129.9, 129.5, 129.5, 128.4, 128.3, 128.3,
127.8, 127.7, 127.7, 127.6, 119.3, 113.8, 95.7, 82.0, 81.7, 77.1, 76.7, 75.8, 73.6,
73.4, 72.7, 71.9, 71.4, 71.4, 69.7, 67.5, 63.3, 62.5, 61.8, 59.0, 55.2, 29.7, 25.9,
‡
18.1, 3.7, 5.1; HR-MS (FAB), calcd for C53H68O16SiNa [M ‡ Na ]:
1011.4174, found: 1011.4205
2: Rf ˆ 0.21 (silica gel, 60% EtOAc in hexanes); aD22
ˆ
5.7 (c ˆ 0.14,
CHCl3); IR (thin film): nÄmax ˆ 3448, 2955, 2919, 2872, 1725, 1602, 1449, 1378,
1
1255, 1155, 1108, 1049, 932, 738 cm
;
1H NMR (600 MHz, CDCl3): d ˆ
7.39 ± 7.23 (m, 20H, ArH), 6.43 (s, 2H, ArH (A2)), 5.44 (ddd, J ˆ 9.7, 9.7,
5.5 Hz, 1H, H-4), 5.33 (d, J ˆ 0.8 Hz, 1H, G-1), 5.18 (s, 1H, OCH2O), 5.05
(s, 1H, OCH2O), 5.02 (s, 2H, CH2Ar (A2)), 5.00 (s, 2H, CH2Ar (A2)), 4.77
and 4.61 (AB, J ˆ 11.7 Hz, 2H, CH2Ar), 4.75 and 4.66 (AB, J ˆ 11.9 Hz, 2H,
CH2Ar), 4.69 (s, 1H, F-1), 4.54 (ddd, J ˆ 10.5, 10.5, 4.5 Hz, 1H, G-4), 4.29
(brs, 1H, G-2), 4.18 (dd, J ˆ 9.7, 4.6 Hz, 1H, G-5), 4.12 (dd, J ˆ 11.3, 5.4 Hz,
1H, H-5), 4.05 (dd, J ˆ 10.2, 2.4 Hz, 1H, G-3), 3.94 (t, J ˆ 9.8 Hz, 1H, H-3),
3.88 (t, J ˆ 9.5 Hz, 1H, F-4), 3.82 (dd, J ˆ 10.6, 10.6 Hz, 1H, G-5), 3.70 (dd,
J ˆ 10.5, 3.7 Hz, 1H, F-6), 3.63 (dd, J ˆ 10.5, 5.1 Hz, 1H, F-6), 3.61 ± 3.59
(m, 2H, F-2, H-2), 3.60 (s, 3H, OMe (F-2)), 3.56 (dd, J ˆ 11.3, 9.7 Hz, 1H,
H-5), 3.37 (s, 3H, OMe (F-6)), 3.36 ± 3.34 (m, 2H, F-3, F-5), 2.72 (brs, 1H,
OH), 2.32 (s, 3H, Me (A2)); 13C NMR (150 MHz, CDCl3): d ˆ 166.8, 160.6,
157.3, 138.7, 137.7, 137.5, 136.3, 136.3, 128.6, 128.4, 128.3, 128.1, 128.0, 127.8,
127.7, 127.5, 127.4, 127.0, 119.1, 115.8, 108.1, 98.2, 96.7, 96.0, 96.0, 81.3, 81.0,
77.4, 75.6, 74.9, 73.2, 72.4, 71.8, 70.3, 70.1, 70.1, 69.6, 67.8, 63.4, 63.4, 61.8,
59.3, 53.8, 29.6, 29.6, 27.7, 20.0, 14.1, 14.0; HR-MS (FAB), calcd for
‡
C55H60O17Cs [M ‡ Na ]: 1015.3728, found: 1015.3735
yield and with a diastereoselectivity of approximately 8:1. The
stereochemistry of the orthoester linkage in this series of
compounds was determined by NMR spectroscopic techni-
ques and correlation with a structure of one such isomer
determined unambiguously by X-ray crystallographic analysis
Angew. Chem. Int. Ed. 1999, 38, No. 22
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3822-3343 $ 17.50+.50/0
3343

COMMUNICATIONS
OR
O
O
H
RO
RO
H
RO
RO
OR5
2
G
4
O
O
1
4
G
2
3
O
O
3
1
OR5
HO
HO
H
H
OR
5
5
4
4
O
O
O
O
O
O
O
1
O
1
H
H
G
G
PMBO
TBSO
PMBO
3
3
OMe
OMe
2
2
TBSO
undesired stereoisomer
OBn
desired stereoisomer
OBn
Figure 3. Transition states illustrating the stereoselective formation of the
GH orthoester. The joining of rings G and H through the C4 oxygen atom
followed by ring closure was crucial for the formation of the desired
orthoester stereoisomer. A C3 linked disaccharide leads predominantly to
the undesired orthoester stereoisomer.
(Figure 4). Subsequent findings dictated a need for an ex-
change of protecting group at this stage for the C4 hydroxyl
group of ring F. Thus, exposure of 36 to nBu4NF in THF led
exclusively to alcohol 37 (95% yield). It is worth noting here
that whereas treatment of 35 with nBu4NF removed the TBS
group selectively, the same
Figure 4. ORTEP drawing of orthoester
crystallographic analysis.[20]
A
derived from an X-ray
OMe
OBn
OMe
OBn
O
OTBS
OPMB
O
O
O
O
O
reagent proved selective for
the removal of the TIPS group
from 36, presumably as a con-
sequence of a conformational
change and/or the absence of
the free OH group in going
from 35 to 36. A benzoate
group was then installed on
the free hydroxyl group of
ring F of 37 (BzCl/Et3N/4-
DMAP) to furnish 38 (97%
yield).
The next task was the in-
stallment of an a-hydroxyl
group at the C2 position of
ring H. To this end, the TBS
group of 38 (Scheme 6) was
H
a
b
H
OPMB
F
G
G
F
O
O
O
O
O
O
BzO
RO
OMe
OMe
OBn
OBn
c
38
39: R = Bz
40: R = H
d
OMe
OBn
OMe
OBn
HO
OR
O
O
O
O
O
O
e
H
OPMB
H
O
OPMB
F
F
G
G
O
OMe
O
O
O
O
TBSO
TBSO
OMe
OBn
OBn
41
42: R = H
43: R = Bz
f
g
h
OMe
OBn
OMe
OBn
HO
OR
O
O
O
O
O
O
O
O
j
removed
from
ring H
H
OPMB
H
OR
G
F
G
F
O
OMe
O
(nBu4NF/AcOH/THF, 95%
yield) and the resulting alcohol
was dehydrated by treatment
with Martin sulfurane[14] in the
presence of catalytic amounts
of Et3N to give olefin 39 (85%
yield), thus setting the stage
for a dihydroxylation reaction.
Before that operation, howev-
er, it was found necessary to
exchange the benzoate group
on ring F for a TBS group to
ensure the success of subse-
quent steps. Thus, compound
39 was debenzoylated with
K2CO3/MeOH (90% yield)
and the resulting alcohol was
exposed to TBSCl in the pres-
O
O
O
O
TBSO
TBSO
OMe
OBn
OBn
k
44: R = Bz
45: R = H
46: R = PMB
47: R = H
i
O
Me
OMe
HO
OBn
O
O
O
Me
O
O
O
F
A2
4
H
O
F
G
l
A2
O
O
BnO
OBn
O
OMe
BnO
OBn
m
OBn
2
Scheme 6. Completion of the synthesis of the FGHA2 fragment 2. a) 1.5 equiv nBu4NF, 0.2 equiv AcOH, THF,
258C, 1 h, 95%; b) 4.0 equiv Martin sulfurane, 0.05 equiv Et3N, CHCl3, 508C, 2 h, 85%; c) 0.5 equiv K2CO3,
MeOH, 258C, 6 h, 90%; d) 6.0 equiv of NaH, 12 equiv TBSCl, 1.0 equiv [18]crown-6, THF, 0 !258C, 4 h, 80%;
e) 2.2 equiv NMO, 0.5 equiv OsO4, 1.0 equiv quinuclidine, Me2CO/H2O (10/1), 258C, 36 h, 70% (8:1 mixture of
diastereoisomers); f) 1.1 equiv nBu2SnO, MeOH, reflux, 3 h; 1.5 equiv BzCl, 1,4-dioxane, 158C, 0.5 h, 97% (5:1
mixture of regioisomers); g) 4.0 equiv Dess ± Martin periodinane, 20 equiv NaHCO3, CH2Cl2, 258C,1 h;
h) 1.1 equiv Li(tBuO)3AlH, Et2O, 108C, 1 h, 80% over two steps; i) 0.2 equiv NaOH, MeOH, 258C, 1 h,
98%; j) 3.0 equiv nBu4NBr, CH2Br2/50% aqueous NaOH (1/1), 658C, 2 h, 90%; k) 1.5 equiv DDQ, CH2Cl2/
H2O (10/1), 0 !258C, 1 h, 85%; l) 1.0 equiv NaH, THF, 0 !258C; then 1.5 equiv 4, 2 h, 96%; m) 1.2 equiv
nBu4NF, THF, 258C, 1 h, 90%.
3344
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1433-7851/99/3822-3344 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1999, 38, No. 22

COMMUNICATIONS
Ã
[13] a) P. Deslongschamps, R. Chenevert, R. J. Taillefer, C. Moreau, J. K.
ence of NaH and [18]crown-6 (80% yield), to furnish
compound 41 via alcohol 40. Reaction of the highly sensitive
olefinic orthoester 41 with NMO/OsO4 in the presence of
quinuclidine led to 1,2-diol 42 as the major product (70%
yield, in an approximate 8:1 ratio with its diastereoisomer).
The chromatographically purified diol 42 was then regiose-
lectively converted into the monobenzoate 43 by treatment
with nBu2SnO/BzCl (97% yield, in an approximate 5:1 ratio
with its regioisomer).[15] After chromatographic separation 43
was oxidized (Dess ± Martin periodinane)[16] and reduced with
Li(tBuO)3AlH to afford, via the corresponding ketone, the
desired hydroxy compound 44 (80% overall yield for the last
two steps). Having successfully installed the required a-
hydroxy group at C2 of ring H, it was now time to remove
the benzoate group from the C3 oxygen atom of ring H and to
transform the resulting trans-1,2-diol system into the desired
methylene acetal functionality. To accomplish this goal,
benzoate 44 was treated with NaOH in MeOH and the
resulting diol (45, 98% yield) was converted into methylene
acetal 46, in 90% yield, by slowly adding it to a mixture of
aqueous NaOH, CH2Br2, and nBu4NBr at 658C.[17] The
remaining steps for the completion of the synthesis of the
FGHA2 fragment 2 involved the DDQ-induced removal of the
PMB group from ring H of 46 to afford 47 (85% yield),
esterification of the latter compound with acyl fluoride 4 in the
presence of NaH in THF (96% yield), and removal of the TBS
group from ring F of the obtained ester (nBu4NF, 90% yield;
Scheme 6). The following communication[18] describes the
construction of the required DE fragment and the completion
of the total synthesis of everninomicin 13,384-1 (1).[19]
Saunders, Can. J. Chem. 1975, 53, 1601 ± 1615; b) P. Deslongschamps,
Stereoelectronic Effects in Organic Chemistry, Pergamon, New York,
1983.
[14] J. C. Martin, R. J. Arhart, J. Am. Chem. Soc. 1971, 93, 4327 ± 4329.
[15] X. Wu, F. Kong, Carbohydr. Res. 1987, 162, 166 ± 169.
[16] a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155 ± 4157; b) D. B
Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277 ± 7279; c) S. D.
Meyer, S. L. Schreiber, J. Org. Chem. 1994, 59, 7549 ± 7552.
[17] K. S. Kim, W. A. Szarek, Synthesis 1978, 48 ± 50.
[18] K. C. Nicolaou, H. J. Mitchell, R. M. Rodríguez, K. C. Fylaktakidou,
H. Suzuki, Angew. Chem. 1999, 111, 3535 ± 3540; Angew. Chem. Int.
Ed. 1999, 38, 3345 ± 3350.
[19] All new compounds exhibited satisfactory spectral and exact mass
data.
[20] Further details will be reported in a full account of this total synthesis.
Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-134793. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: (‡44) 1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
Total Synthesis of Everninomicin 13,384-1Ð
Part 3: Synthesis of the DE Fragment and
Completion of the Total Synthesis**
K. C. Nicolaou,* Helen J. Mitchell, Rosa María
Rodríguez, Konstantina C. Fylaktakidou, and
Hideo Suzuki
In the preceding communications,[1, 2] we described the
synthesis of the A1B(A)C and FGHA2 fragments of ever-
ninomicin 13,384-1 (1, Figure 1). Herein, we report the
construction of the remaining DE fragment and the comple-
tion of the total synthesis of 1. Figure 1 depicts the retro-
synthetic excision of the DE fragment from 1 as the
appropriately functionalized key intermediate 2, and its
further disconnection to building blocks 3 and 4. The
protecting groups on 2 were carefully defined so as to be
compatible not only with its assembly, but also with its
incorporation into the structure of the final target. The two
main issues that had to be addressed for the synthesis of 2
Received: August 6, 1999 [Z13842IE]
German version: Angew. Chem. 1999, 111, 3529 ± 3534
Keywords: antibiotics ´ carbohydrates ´ everninomicin ´
glycosylations ´ total synthesis
[1] K. C. Nicolaou, H. J. Mitchell, H. Suzuki, R. M. Rodríguez, O.
Baudoin, K. Fylaktakidou, Angew. Chem. 1999, 111, 3523 ± 3528;
Angew. Chem. Int. Ed. 1999, 38, 3334 ± 3339.
[2] a) G. Jaurand, J.-M. Beau, P. SinayÈ, J. Chem. Soc. Chem. Commun.
1982, 701 ± 703; b) J.-M. Beau, G. Jaurand, J. Esnault, P. SinayÈ,
Tetrahedron Lett. 1987, 28, 1105 ± 1108; c) M. Trumtel, P. Tavecchia, A.
[*] Prof. K. C. Nicolaou, H. J. Mitchell, Dr. R. M. Rodríguez,
Dr. K. C. Fylaktakidou, Dr. H. Suzuki
Department of Chemistry and
Á
Veyrieres, P. SinayÈ, Carbohydr. Res. 1990, 202, 257 ± 275.
[3] K. C. Nicolaou, F. L. van Delft, S. C. Conley, H. J. Mitchell, Z. Jin, M.
Rodríguez, J. Am. Chem. Soc. 1997, 119, 9057 ± 9058.
[4] A. Y. Chemyak, K. V. Antonov, N. K. Kochetkov, Biorg. Khim. 1989,
15, 1113 ± 1127.
[5] For a review on the chemistry of tin-containing intermediates in
carbohydrate chemistry, see T. B. Grindley, Adv. Carbohydr. Chem.
Biochem. 1998, 53, 16 ± 142.
[6] a) R. E. Ireland, D. W. Norbeck, J. Org. Chem. 1985, 50, 2198 ± 2200;
b) A. J. Mansuco, D. Swern, Synthesis 1981, 165 ± 185.
[7] a) A. Dondoni, G. Fantink, M. Fogagnolo, A. Medici, P. Pedrini, J.
Org. Chem. 1988, 53, 1748 ± 1761; b) A. Dondoni, A. Marra, D.
Perrone, J. Org. Chem. 1993, 58, 275 ± 277.
[8] R. R. Schmidt, J. Michel, Angew. Chem. 1980, 92, 763 ± 765; Angew.
Chem. Int. Ed. Engl. 1980, 19, 731 ± 733.
[9] S. Mehta, B. M. Pinto, J. Org. Chem. 1993, 58, 3269 ± 3276.
[10] K. C. Nicolaou, T. Ladduwahetty, J. L. Randall, A. Chucholowski, J.
Am. Chem. Soc. 1986, 108, 2466 ± 2467.
[11] The scope of this 1,2-phenylseleno migration reaction and its
application to stereoselective glycosidations will be described in a
full account of this total synthesis.
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (‡1) 858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] 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., Fulbright), 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-
La Roche, DuPont, and Abbott Laboratories.
[12] L. A. Carpino, A. El-Faham, J. Am. Chem. Soc. 1995, 117, 5401 ± 5402.
Angew. Chem. Int. Ed. 1999, 38, No. 22
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