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

Full text of DOI:10.1002/(SICI)1521-3773(19991115)38:22<3345::AID-ANIE3345>3.0.CO;2-9

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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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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
O
Me
Me
MeO
O
Me
O
SPh
O
OTIPS
OTBS
PMBO
HO
O
O
E
D
D
E
+
MeO
O
OTBS
Ph
O
OC(NH)CCl3
Me
OPMB
OAc
OAc
OH
4
2
3
Glycosylation
Figure 1. Retrosynthetic analysis of the DE fragment 2. Ac ˆ acetyl; PMB ˆ p-methoxybenzyl; TBS ˆ tert-butyldimethyl-
silyl; TIPS ˆ triisopropylsilyl.
were the following: 1) construction of the b-mannoside link-
O
SPh
OH
O
SPh
RO
O
age and 2) installment of the tertiary center on ring D. We
chose the sulfoxide-based glycosidation reaction of Kahne
et al.[3] as the coupling procedure for 3 and 4 and designed the
benzylidene ring[4] in 3 to ensure the stereocontrolled
formation of the b-mannoside bond. The introduction of the
methyl group at C3 of ring D was postponed until after the
coupling to avoid unfavorable 1,3-diaxial interactions[5] during
the planned nucleophilic attack (see below).
Scheme 1 summarizes the construction of building block D
(3), which proceeded smoothly from the known intermediate
5.[6] Thus, the regioselective tin acetal mediated monoprotec-
tion of 5 as a PMB ether (nBu2SnO-PMBCl/nBu4NI, 83%
yield) was followed by TBS introduction at the C2 hydroxyl
group (TBSOTf/2,6-lutidine, 93% yield) and oxidation of the
sulfur group with mCPBA (92% yield) to afford the desired
sulfoxide 3 (approximate 4:1 mixture of separable dia-
stereoisomers).
b
c
O
HO
OTBS
Ph
OR
OPMB
6: R = H
7: R = PMB
8: R = H
9: R = Ts
a
d
e
Me
Me
RO
O
SPh
O
OTIPS
OTBS
E
g
h
MeO
OTBS
OPMB
OR
10: R = H
11: R = Me
12: R = PMB
4: R = H
f
i
Scheme 2. Synthesis of carbohydrate building block E (4). a) 1.1 equiv
nBu2SnO, toluene, 1108C, 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, 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%.
DDQ ˆ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DMF ˆ dimethylfor-
mamide; LAH ˆ lithium aluminum hydride; NBS ˆ N-bromosuccinimide;
py ˆ pyridine; THF ˆ tetrahydrofuran; Ts ˆ p-toluenesulfonyl.
O
O
SPh
O
SPh
OH
O
O
a, b, c
D
Ph
O
OTBS
Ph
O
OPMB
OH
5
3
Scheme 1. Synthesis of carbohydrate building block D (3). a) 1.1 equiv
nBu2SnO, toluene, 1108C, 3 h; 1.5 equiv PMBCl, 0.2 equiv nBu4NI,
25 !1108C, 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, 20 !08C, 2 h, 92%
(ca. 4:1 mixture of diastereoisomers). mCPBA ˆ m-chloroperoxybenzoic
acid; Tf ˆ trifluoromethanesulfonyl.
primary hydroxyl group of 8 (TsCl/py, 97%) followed by
LAH reduction led to derivative 10 (90%), which was
methylated (NaH/MeI, 94% yield) at C4 to afford methoxy
compound 11. Finally, cleavage of the thiophenyl group from
11 with NBS/H2O (95% yield) followed by silylation (TIPS-
OTf/2,6-lutidine, 97%) afforded compound 12 (b:a ratio
approximately 2:1), from which the PMB group was oxida-
tively removed (DDQ, 98% yield) to furnish the desired
building block 4.
The construction of key intermediate 2 from fragments 3
and 4 is summarized in Scheme 3. This assembly began with
the stereoselective coupling of sulfoxide 3 with acceptor 4 in
the presence of Tf2O and di-tert-butyl-4-methyl pyridine
(DTBMP) to afford the b-mannoside 13 (glycosidation with
The synthesis of the other requisite fragment, ring E (4), is
shown in Scheme 2. The tin acetal technology[7] was again
used to facilitate the PMB monoprotection of the starting
material 6[8] (nBu2SnO/PMBCl/nBu4NI, 87% yield) and
furnish the C3 protected intermediate 7. TBS protection of
the C2 hydroxyl group (TBSOTf/2,6-lutidine, 97% yield)
followed by cleavage of the benzylidene group with Zn(OTf)2/
EtSH (77%) afforded diol 8. Selective tosylation of the
3346
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mation of ring D of 14 and the trajectory of
the reagent leading to the desired product.
Thus, in contrast to a monosaccharide
unit D carrying a 1-a substituent in which
the reagent would have encountered repul-
sive 1,2- or 1,3-interactions, the b-manno-
side disaccharide system containing the
bulky and axially orientated TBS group at
C2 proved ideal for setting the tertiary
stereocenter on ring D. Difficulties with
protecting the highly hindered tertiary
alcohol in 15 led us to the conviction that
we could leave it free for the rest of the
sequence without much interferenceÐa
prediction that turned out both correct
and fortunate. The next task was to deoxy-
genate the C6 position of ring D, suitably
protect the C4 hydroxyl group of ring D,
and activate the C1 carbon atom of ring E.
To this end, the benzylidene group of 15
was removed by hydrogenolysis (H2/10%
Pd/C, 97% yield) and the primary hydroxyl
group so generated was tosylated selective-
ly over the secondary hydroxyl group
(TsCl/py, 87% yield) to afford 16. Difficul-
ties with the direct reduction of this tosylate
forced us to proceed through iodide 17 (LiI,
86% yield), which was smoothly reduced
with nBuSnH/AIBN to afford the desired
compound 18 in 97% yield. Protection at
C4 of ring D was effected with nBu2SnO/
PMBCl/nBu4NI leading to 19 (63% yield),
O
Ph
O
Me
Me
O
OTIPS
OTBS
O
SPh
MeO
O
O
O
+
E
D
a
O
E
D
MeO
O
OTBS
Ph
RO
O
OTIPS
OH
OPMB
OTBS
OTBS
3
4
13: R = PMB
14: R = H
b
c
d
Ph
X
O
Me
Me
MeO
MeO
O
HO
HO
O
O
O
O
D
E
e
f
D
E
3
HO
Me
O
OTIPS
O
OTIPS
Me
OTBS
OTBS
OTBS
OTBS
16: X = OTs
17: X = I
18: X = H
15
g
h
i
Me
D
Me
Me
Me
MeO
O
MeO
PMBO
HO
PMBO
HO
O
O
O
E
D
E
OR2
l
O
OR
O
Me
Me
OR1
OR1
OAc
OAc
19: R1 = TBS, R2 = TIPS
20: R1 = R2 = H
21: R1 = R2 = Ac
22: R = H
2: R = C(NH)CCl3
m
j
k
Scheme 3. Assembly of DE fragment 2. a) 1.3 equiv 3, 1.3 equiv Tf2O, 2.2 equiv DTBMP,
CH2Cl2, 788C; 1.0 equiv 4, 78 !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, 788C, 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, 0.01 equiv AIBN, PhH, 808C, 0.5 h, 97%; i) 1.1 equiv nBu2SnO,
toluene, 1108C, 10 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% over two steps; l) 1.3 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). AIBN ˆ 2,2'-azobisisobu-
tyronitrile; DBU ˆ 1,8-diazabicyclo[5.4.0]undec-7-ene; 4-DMAP ˆ 4-dimethylaminopyridine;
DTBMP ˆ di-tert-butyl-4-methylpyridine; NMO ˆ N-methylmorpholine N-oxide; TPAP ˆ
tetrapropylammonium perruthenate.
which
was
completely
desilylated
(nBu4NF) and tris-acetylated (Ac2O/Et3N/
4-DMAP) to afford triacetate 21 in 90%
overall yield (ratio of a- and b-anomers
approximately 1:1) via the tetraol 20.
Finally, the anomeric acetate was selective-
ly removed from the latter compound (22)
by the mild action of nBuNH2 in THF to
give lactol 22, whose conversion into tri-
chloroacetimidate 2 was accomplished by
exposure to CCl3CN and DBU (89%, a:b ratio approximately
30:1).
The coupling of the key intermediates 2 and 23 and the
elaboration of the resulting fragment to the next advanced
key intermediate, 30 is shown in Scheme 4. Thus, reaction of
the trichloroacetimidate 2 with hydroxy fragment 23 in the
SN2 inversion)[3, 4] in 71% yield. The PMB group was then
removed from ring D (DDQ, 95% yield), the resulting
alcohol was oxidized to the corresponding ketone with the
aid of TPAP/NMO, and the latter compound was treated with
MeLi in Et2O at 788C. To our delight, the latter reaction
produced the desired tertiary alcohol 15 in 88% overall yield
(from 14) and as a single stereoisomer (determined by NOE/
NMR experiments). Figure 2 depicts the presumed confor-
presence of BF3 ´ Et2O in CH2Cl2 at
208C furnished
oligosaccharide 24 with the desired b-glycoside linkage
(between rings E and F) and in 55% yield. In addition to
24, this reaction also produced a small amount of the
corresponding a-glycoside (5% yield) and an as of yet
unidentified isomer of 24 (b-glycosidic linkage between rings
E and F, 18% yield). The sensitivity of these advanced
intermediates and our intention to prepare them in a suitable
form for their pending union with the A1B(A)C fragment as
well as for the overall strategy towards the final target
molecule prompted a number of protecting group exchanges
MeO
OTBS
O
Me
O
Ph
O
O
E
D
OTIPS
O
OTBS
O
H
H
Me
Figure 2. Illustration of the preferenial a-attack of MeLi on the C3
carbonyl group of ring D during the formation of compound 15.
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compound 24 was deacetylated (K2CO3/
MeOH) to furnish triol 25 (85% yield),
which was then cleanly dibenzylated with
NaH/BnBr in THF (90% yield) to give
hexabenzyl ether 26[9] in which the tertiary
alcohol on ring D remained free. The remov-
al of the PMB group from 26 with DDQ
proceeded in 95% yield to furnish the desired
diol 27. This compound, however, proved
unsuitable for further elaboration. Problems
associated with 27 included low glycosidation
yields with the A1B(A)C fragment and rup-
ture of the highly sensitive C-D orthoester
moiety upon attempted debenzylation. We
then opted for the hexaacetylated counter-
part of 27 (details will be reported in a later
paper), but again we encountered poor
coupling yields with the same A1B(A)C
partner. Our third generation strategy in-
volved the adoption of the hexa-TBS deriv-
ative 30 (Scheme 4) as the DEFGHA2 cou-
pling partner, and this time we were success-
ful. To reach 30 we proceeded from 27 as
follows: Selective formation of the secondary
chloroacetate on ring D (CA2O/Et3N/4-
DMAP, 98% yield) led to 28, which was
subjected to hydrogenolysis (H2/10% Pd/C)
to afford heptaol 29 (85% yield). Six TBS
groups were then installed on 29 through
exposure to excess TBSOTf in the presence
of 2,6-di-tert-butylpyridine to afford a hexa-
TBS derivative (with a free tertiary OH
group on ring D, 65% yield), from which
the chloroacetate group was removed with
K2CO3 in MeOH to give the targeted inter-
mediate 30 (85% yield; Table 1).
Me
Me
OMe
OBn
O
O
O
Me
MeO
O
PMBO
HO
O
O
O
O
E
D
O
H
F
G
A2
O
O
O
O
O
HO
OMe
Me
BnO
OBn
OAc
OAc
Cl3C
OBn
a
NH
2
23
Me
Me
OMe
O
OBn
O
O
O
Me
MeO
O
O
O
O
PMBO
HO
O
O
BnO
H
E
G
D
F
A2
O
O
O
O
OMe
OBn
Me
OR
OR
OBn
24: R = Ac
25: R = H
b
c
Me
Me
OMe
OBn
O
O
O
Me
MeO
O
O
O
O
RO
HO
O
O
H
E
G
D
F
A2
O
O
O
O
O
OMe
BnO
OBn
Me
OBn
OBn
OBn
26: R = PMB
27: R = H
28: R = CA
d
e
f
Me
Me
OMe
O
OH
O
O
O
Me
MeO
O
O
O
O
CAO
HO
O
O
HO
H
E
G
D
F
A2
O
O
O
O
OMe
OH
Me
OH
OH
OH
29
g
h
The final assembly of the everninomi-
cin 13,384-1 (1) skeleton and the final stages
of the total synthesis are shown in Scheme 5.
Thus, coupling of the A1B(A)C glycosyl
fluoride donor 31[1] with the DEFGHA2
hexa-TBS diol acceptor 30 in the presence
of SnCl2 in Et2O proceeded smoothly, and
with complete stereocontrol,[10] to afford the
2-phenylseleno glycoside 32 (70% yield).
Formation of the remaining orthoester site
was then accomplished with equal facility
under the SinayÈ conditions[11] (NaIO4 oxida-
tion to the selenoxide in MeOH/CH2Cl2/H2O
(3/2/1) followed by heating in a sealed tube at
1408C in toluene/vinyl acetate/diisopropyl-
amine (2/2/1)) to afford the fully protected
everninomicin 13,384-1 derivative 33 in 65%
Me
Me
OMe
O
OTBS
O
O
O
Me
MeO
O
O
O
O
HO
HO
O
O
O
H
E
G
D
F
A2
O
O
O
OMe
TBSO
OTBS
Me
OTBS
OTBS
OTBS
30
Scheme 4. Completion of the synthesis of the DEFGHA2 fragment (30). a) 1.6 equiv 2,
0.5 equiv BF3 ´ Et2O, CH2Cl2, 208C; 2 h, 55% yield of desired b-anomer, 18% of unknown
compound (b-anomer) and 5% yield of a-anomer (a:b ca. 1:9); b) 0.5 equiv K2CO3, MeOH,
258C, 2 h, 85%; c) 2.5 equiv NaH, 3.0 equiv BnBr, THF, 0 !258C, 2 h, 95%; d) 1.3 equiv
DDQ, CH2Cl2/H2O (10/1), 0 !258C, 2 h, 95%; e) 1.5 equiv (CA)2O, 3.0 equiv Et3N, 0.2 equiv
4-DMAP, CH2Cl2, 0 !258C, 1 h, 98%; f) 0.5 equiv 10% Pd/C (w/w), EtOAc, 258C, 4 h, 85%;
g) 8.0 equiv TBSOTf, 20 equiv 2,6-di-tert-butylpyridine, CH2Cl2, 0 !258C, 8 h, 65%;
h) 0.2 equiv K2CO3, MeOH, 258C, 15 min, 85%. CA ˆ chloroacetyl.
yield and as a single stereoisomer. Generation of evernino-
micin 13,384-1 (1) from 33 entailed the following two steps:
a) hydrogenolysis (H2/ 10% Pd/C, NaHCO3, tBuOMe) to
remove the two benzyl ethers and b) desilylation (nBu4NF/
THF) to cleave all six TBS groups (75% overall yield).
Synthetic everninomicin 13,384-1 (1) was identical by the
at this stage. Three sets of protecting groups on fragment
DEFGHA2 were tested before a final forward path was
found.
We initially targeted the hexabenzylated diol 27 (Scheme 4)
as a potential partner in the projected final coupling reaction
with the A1B(A)C fragment. With this objective in mind,
3348
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Angew. Chem. Int. Ed. 1999, 38, No. 22

COMMUNICATIONS
Table 1. Selected physical and spectroscopic data of compounds 2, 30, and 33.
2: Rf ˆ 0.60 (silica, 80% EtOAc in hexanes); IR (thin film): nÄmax ˆ 3495,
3331, 2928, 2951, 2884, 1743, 1678, 1614, 1508, 1455, 1373, 1243, 1091, 1049,
844, 791 cm 1; 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, E-1), 5.28 (dd, J ˆ 10.6, 3.7 Hz, 1H, E-2), 4.99 (s, 1H, D-2), 4.81 (s, 1H,
D1), 4.81 and 4.56 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.16 ± 4.12 (m, 2H, E-3,
E-5), 3.79 (s, 3H, OMe (PMB)), 3.59 (s, 3H, OMe (E-4)), 3.57 (brs, 1H,
E-4), 3.42 (dq, J ˆ 9.6, 5.9 Hz, 1H, D-5), 3.32 (d, J ˆ 9.6 Hz, 1H, D-4), 2.14
(s, 3H, OAc), 2.00 (s, 3H, OAc), 1.37 (s, 3H, Me (D-3)), 1.35 (d, J ˆ 6.0 Hz,
3H, D-6), 1.26 (d, J ˆ 6.6 Hz, 3H, E-6); 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
33: Rf ˆ 0.32 (silica, 60% Et2O in hexanes); aD22
ˆ
19.5 (c ˆ 0.20, CHCl3);
IR (thin film): nÄmax ˆ 2955, 2919, 2861, 1737, 1602, 1543, 1455, 1384, 1255,
1
1108, 1067, 1038, 838, 779 cm 1; H 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, ArH
(A2)), 6.16 (d, J ˆ 1.8 Hz, ArH(A2)), 5.35 (dt, J ˆ 9.9, 9.9, 5.5 Hz, 1H, H-4),
5.18 (s, 1H, OCH2O), 5.07 (brs, 1H, F-1), 5.06 (s, 1H, OCH2O), 5.05 and
5.02 (AB, J ˆ 10.2 Hz, 2H, CH2Ar), 5.00 (s, 1H, G-1), 4.95 (dd, J ˆ 4.6,
1.4 Hz, 1H, A-1), 4.88 (t, J ˆ 9.4 Hz, 1H, B-4), 4.86 (s, 1H, D-1), 4.75 (brd,
J ˆ 9.8 Hz, 1H, B-1), 4.68 and 4.57 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.39 (dt,
J ˆ 10.5, 10.5, 4.8 Hz, 1H, G-4), 4.23 (brs, 1H, G-2), 4.17 (dd, J ˆ 11.4,
5.7 Hz, 1H, H-5), 4.14 (brs, 1H, F-3), 4.09 (s, 1H, D-2), 4.07 (d, J ˆ 7.4 Hz,
1H, E-1), 4.04 (dd, J ˆ 9.2, 4.4 Hz, 1H, G-5), 4.01 (dd, J ˆ 10.1, 2.6 Hz, 1H,
G-3), 3.97 (dd, J ˆ 10.1, 9.2 Hz, 1H, G-5), 3.93 (t, J ˆ 9.6 Hz, 1H, H-3), 3.89
(brt, J ˆ 8.3 Hz, 1H), 3.86 ± 3.80 (m, 5H, B-3, C-3, D-4, E-5, F-4), 3.82 (s,
3H, OMe (A1)), 3.72 (dq, J ˆ 6.2, 4.0 Hz, 1H, D-5), 3.65 (dd, J ˆ 9.2, 9.2 Hz,
1H, E-2), 3.64 (d, J ˆ 9.7 Hz, 1H, A-4), 3.59 (t, J ˆ 11.0 Hz, 1H, H-5), 3.59
(d, J ˆ 9.2 Hz, 1H, H-2), 3.56 (s, 3H, OMe (E-4)), 3.53 ± 3.50 (m, 4H, C-5),
3.48 ± 3.46 (m, 1H, A-5), 3.47 (dd, J ˆ 9.2, 3.1 Hz, 1H, E-3), 3.43 (t, J ˆ
3.5 Hz, 1H, F-2), 3.39 (s, 3H, OMe (F-2)), 3.35 (s, 3H, OMe (A-4)), 3.34 ±
3.33 (m, 2H, B-5, F-5), 3.30 (s, 3H, OMe), 2.51 (dd, J ˆ 12.5, 8.5 Hz, 1H,
C-2), 2.45 (dd, J ˆ 13.7, 4.9 Hz, 1H, A-2), 2.38 (s, 3H, Me (A1), 2.29 (brdd,
J ˆ 12.4, 8.6 Hz, 1H, B-2), 2.26 (s, 3H, Me (A2)), 2.01 (dd, J ˆ 13.7, 1.6 Hz,
1H, A-2), 1.90 (t, J ˆ 12.1 Hz, 1H, C-2), 1.70 ± 1.66 (m, 1H, B-2), 1.68 (s,
3H, Me, A-3), 1.34 (s, 3H, Me, D-3), 1.32 (d, J ˆ 6.4 Hz, 3H, B-6), 1.31 (d,
J ˆ 6.2 Hz, 3H, D-6), 1.28 (d, J ˆ 6.6 Hz, 3H, E-6), 1.26 (d, J ˆ 6.8 Hz, 3H,
C-6), 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, Me (A-6)), 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,
152.3, 153.2, 138.7, 137.9, 135.9, 134.8, 128.6, 128.6, 128.5, 127.5, 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, 3.7, 3.8, 3.9,
4.2, 4.3, 4.4, 4.4, 4.5, 4.5, 4.9, 5.0, 5.2; MS (electrospray
30: Rf ˆ 0.27 (silica, 40% Et2O in hexanes); aD22
ˆ
29.1 (c ˆ 0.10, CHCl3);
IR (thin film): nÄmax ˆ 3495, 2955, 2919, 2861, 1737, 1602, 1467, 1361, 1255,
1
1073, 838, 779 cm
;
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 (dt, J ˆ 10.1, 10.1,
5.6 Hz, 1H, H-4), 5.18 (s, 1H, OCH2O), 5.06 (s, 1H, OCH2O), 5.05 (brs,
1H, F-1), 5.01 (s, 1H, G-1), 4.68 (s, 1H, D-1), 4.39 (dt, J ˆ 10.3, 10.3, 2.5 Hz,
1H, G-4), 4.24 (brs, 1H, G-2), 4.17 (dd, J ˆ 11.1, 5.4 Hz, 1H, H-5), 4.12
(brs, 1H, F-3), 4.08 (d, J ˆ 7.4 Hz, 1H, E-1), 4.05 (dd, J ˆ 9.4, 4.8 Hz, 1H,
G-5), 4.00 (dd, J ˆ 10.1, 2.2 Hz, 1H, G-3), 3.96 (dd, J ˆ 9.4, 9.4 Hz, 1H,
G-5), 3.95 (t, J ˆ 9.4 Hz, 1H, H-3), 3.89 (dd, J ˆ 8.3 Hz, 1H), 3.84 (brs, 1H),
3.78 ± 3.76 (m, 1H), 3.77 (s, 1H, D-2), 3.64 (dd, J ˆ 8.0, 8.0 Hz, 1H, E-2),
3.59 (dd, J ˆ 10.0, 10.0 Hz, 1H, H-5), 3.58 (d, J ˆ 9.5 Hz, 1H, H-2), 3.53 (s,
3H, OMe (E-4)), 3.52 ± 3.51 (m, 1H, D-5 or E-5), 3.49 ± 3.37 (m, 4H, F-2),
3.40 (s, 3H, OMe (F-2)), 3.33 ± 3.29 (m, 2H, D-5 or E-5), 3.30 (s, 3H, OMe
(F-6)), 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, D-6 or E-6), 1.27 (d, J ˆ 6.5 Hz, 3H, D-6 or E-6), 1.16 (s,
3H, Me (D-3)), 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, 3.4, 3.7, 3.9, 4.2,
4.3, 4.4, 4.6, 4.9, 4.9, 5.0, 5.2; HR-MS (FAB): calcd for
‡
ionization): calcd for C120H193O38Cs [M ‡ Cs ]: 2496/2497, found: 2498/
‡
2499
C77H144O25Si6Na [M ‡ Na ]: 1659.8509, found: 1659.8452
usual criteria (TLC, 1H NMR, 13C NMR, IR, MS, a2D2† with an
authentic sample.[12]
phase synthesis, combinatorial chemistry, and chemical biol-
ogy studies.[16]
The reported total synthesis of everninomicin 13,384-1 (1)
constituted an adventurous journey during which we have
demonstrated the power of novel synthetic reactions both
from our own and other laboratories. Most notable of these
methods are the 1,2-phenylthio[10] and the 1,2-phenylseleno
migrations on carbohydrate templates and their use in
stereocontrolled glycosidation reactions; the tin acetal based
stereocontrolled construction of 1 !1'-disaccharides;[13] the
use of acyl fluorides for the formation of sterically hindered
esters; the SinayÈ orthoester protocol formation;[11] the sulf-
oxide-based b-mannoside forming glycosidation by Kahne
et al.;[3, 4] the trichloroacetimidate glycosidation method of
Schmidt and Michel;[14] the glycosyl fluoride methodology of
Mukaiyama et al.;[15] and the tin acetal technology[7] for
differentiating 1,2-diols. Furthermore, a great deal of knowl-
edge regarding selectivity in manipulating protective groups
was gathered and considerable light was shed on conforma-
tional effects on selective functionalization of carbohydrate
templates. Most importantly and as a result of this synthesis,
the stage is now set for further advances in the antibiotics
field, including semisynthesis of designed analogues, solid-
Received: August 6, 1999 [Z13843IE]
German version: Angew. Chem. 1999, 111, 3535 ± 3540
Keywords: antibiotics ´ carbohydrates ´ everninomicin ´
glycosylations ´ total synthesis
[1] K. C. Nicolaou, H. J. Mitchell, H. Suzuki, R. M. Rodríguez, O.
Baudoin, K. C. Fylaktakidou, Angew. Chem. 1999, 111, 3523 ± 3528;
Angew. Chem. Int. Ed. 1999, 38, 3334 ± 3339.
[2] K. C. Nicolaou, R. M. Rodríguez, K. C. Fylaktakidou, H. Suzuki, H. J.
Mitchell, Angew. Chem. 1999, 111, 3529 ± 3534; Angew. Chem. Int. Ed.
1999, 38, 3340 ± 3345.
[3] D. Kahne, S. Walker, Y. Cheng, D. V. Engen, J. Am. Chem. Soc. 1989,
111, 6881 ± 6882.
[4] D. Crich, S. Sun, J. Am. Chem. Soc. 1998, 120, 435 ± 436.
Á
[5] M. Trumtel, P. Tavecchia, A. Veyrieres, P. SinayÈ, Carbohydr. Res. 1990,
202, 257 ± 275.
[6] T. Oshitar, M. Shibasaki, T. Yoshizawa, M. Tomita, K. Takao, S.
Kobayashi, Tetrahedron, 1997, 53, 10993 ± 11006.
[7] 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.
Angew. Chem. Int. Ed. 1999, 38, No. 22
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3822-3349 $ 17.50+.50/0
3349

COMMUNICATIONS
Me
Me
OMe
O
Me
Me
OMe
O
OTBS
O
O
O
Me
O
O
Cl
MeO
O
O
O
O
HO
HO
O
O
B
C
F
O
O
A1
O
H
E
G
D
F
A2
O
Me
BnO
O
O
OMe
BnO
O
SePh
TBSO
OTBS
Me
Cl
OTBS
OTBS
OTBS
NO2
Me
O
A
31
30
Me
OMe
a
Me
O
Me
OMe
A1
O
Me
Me
OMe
OTBS
O
O
O
Me
O
O
MeO
Cl
O
O
O
O
O
O
O
O
O
B
C
O
H
E
G
D
F
A2
O
HO
SePh
Me
O
BnO
O
O
OMe
BnO
TBSO
OTBS
Me
Cl
OTBS
OTBS
OTBS
NO2
Me
O
A
32
Me
OMe
b
c
Me
Me
OMe
O
OTBS
O
O
Me
Me
O
O
Me
OMe
O
MeO
O
O
O
O
O
O
O
O
O
Cl
H
O
E
G
O
B
A
C
D
F
A2
O
A1
O
O
O
OMe
TBSO
OTBS
Me
BnO
Me
O
BnO
OTBS
OTBS
OTBS
Cl
NO2
Me
O
33
Me
OMe
d
e
Me
Me
OMe
O
OH
O
O
Me
Me
O
Me
OMe
O
MeO
O
O
O
O
O
O
O
O
O
Cl
O
H
O
B
E
G
O
C
D
F
A2
A1
O
O
O
O
OMe
HO
OH
Me
HO
Me
O
HO
OH
OH
OH
Cl
NO2
Me
O
A
1 everninomicin 13,384-1
Me
OMe
Scheme 5. Completion of the total synthesis of everninomicin 13,384-1 (1). a) 2.0 equiv 31, 1.8 equiv SnCl2, Et2O, 0 !258C, 6 h, 70%;
b) 10 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, 16 h, 65% over two steps; d) H2, 0.1 equiv 10% Pd/C (w/w), 4.0 equiv NaHCO3, tBuOMe, 258C, 1 h; e) 10.0 equiv
nBu4NF, THF, 258C, 10 h, 75% over two steps.
[8] K. C. Nicolaou, C. W. Hummel, Y. Iwabuchi, J. Am. Chem. Soc. 1992,
114, 3126 ± 3128.
[14] R. R. Schmidt, J. Michel, Angew. Chem. 1980, 92, 763 ± 765; Angew.
Chem. Int. Ed. Engl. 1980, 19, 731 ± 733.
[15] T. Mukaiyama, Y. Murai, S. Shoda, Chem. Lett. 1981, 431 ± 433.
[16] All new compounds exhibited satisfactory spectral and exact mass
data.
[9] Compound 26 was identical with an authentic sample obtained by
degradation of everninomicin 13,384-1 (1). Details of this and other
degradation studies will be reported in later publications.
[10] K. C. Nicolaou, T. Ladduwahetty, J. L. Randall, A. Chucholowski, J.
Am. Chem. Soc. 1986, 108, 2466 ± 2467.
[11] a) Ref. [5]; 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. A. K. Ganguly of Schering Plough Corp. for a sample of
natural everninomicin 13,384-1 (1).
[13] 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.
3350
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3822-3350 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1999, 38, No. 22