Total synthesis of everninomicin 13,384-1 - Part 1: Synthesis of the A1B(A)C fragment

Article abstract of DOI:10.1002/(SICI)1521-3773(19991115)38:22<3334::AID-ANIE3334>3.0.CO;2-H

The powerful antibiotic everninomicin 13,384-1 (1, Ziracin) has been prepared for the first time through a total synthesis. The (1 → 1-disaccharide and the two orthoesters of this target molecule were introduced by new methodologies using a tin acetal and 1,2-phenylseleno migrations. The reaction sequence also relies on stereoselective glycosidations and subtle manipulations of protecting groups. In addition to the introduction of new synthetic methodologies, this total synthesis should allow the preparation of combinatorial libraries of semisynthetic analogues of this highly promising antibiotic for biological screening purposes.

Full text of DOI:10.1002/(SICI)1521-3773(19991115)38:22<3334::AID-ANIE3334>3.0.CO;2-H

COMMUNICATIONS
[6] K. Piepgrass, M. T. Pope, J. Am. Chem. Soc. 1989, 111, 753 ± 754.
[7] W. F. Maier, K. Bergmann, W. Bleicher, P. von R. Schleyer, Tetrahe-
dron Lett. 1981, 22, 4227 ± 4230.
[8] A. M. Khenkin, A. Rosenberger, R. Neumann, J. Catal. 1999, 182, 82 ±
91.
[9] G. A. Tsigdinos, C. J. Hallada, Inorg. Chem. 1968, 7, 437 ± 441.
[10] T. J. R. Weakley, S. A. Malik, J. Inorg. Nucl. Chem. 1967, 29, 2935 ±
2946.
The integrity of the Keggin polyoxometalates K4SiW12O40
and K5PV2Mo10O40 under the reaction conditions was also
proven by IR spectroscopy and X-ray diffraction studies. A
finely powdered sample of the polyoxometalate was treated
under the reaction conditions (0.5 g of benzophenone, 50 mg
of polyoxometalate, 23 atm H2, Tˆ 3008C, t ˆ 200 min). After
cooling, the autoclave was opened and the polyoxometalate
was isolated by filtration. The catalyst first appeared brown-
blue, but after exposure to air the color turned lighter. The IR
spectra and X-ray powder patterns before and after the
reaction were identical, indicating that the structure of the
polyoxometalates was unchanged. A room-temperature ESR
Total Synthesis of Everninomicin 13,384-1Ð
Part 1: Synthesis of the A1B(A)C Fragment**
5
spectrum of the PV2Mo10O40 catalyst after reaction showed
the typical eight-line spectrum of the two-electron-reduced
compound.[8] That no leaching of the polyoxometalate from
the support occurred was indicated by atomic absorption
measurements of the organic phase after extraction with water.
We have demonstrated a new application of Keggin
polyoxometalates as deoxygenation and hydrogenation cata-
lysts for the reduction of carbonyl compounds. The
[PV2Mo10O40]5 polyoxometalate, which is most active for
the activation (oxidation) of H2, is the most active catalyst.
The product selectivity shows that the reduced polyoxometa-
lates deoxygenate ketones and aldehydes; carbinols are not
intermediates. Use of [PV2Mo10O40]5 tends to lead to
formation of saturated compounds, whereas for [SiW12O40]4
alkenes are preferred initial products.
K. C. Nicolaou,* Helen J. Mitchell, Hideo Suzuki,
Rosa Maria Rodríguez, Olivier Baudoin, and
Konstantina C. Fylaktakidou
Dedicated to Dr. A. K. Ganguly
on the occasion of his 65th birthday
Drug-resistant bacteria are currently causing considerable
concern because of the serious and constant threat they pose
to human health and their potential to cause widespread
epidemics. Even vancomycin,[1] whose effectiveness against
such resistant bacterial strains provided the last line of
defense, is showing signs of weakness in the face of the
evolution of aggressive bacteria. Everninomicin 13,384-1
(Ziracin) (1),[2] a member of the orthosomicin class of
antibiotics[3] and currently in clinical trials, is a promising
new weapon against drug-resistant bacteria, including methi-
cillin-resistant staphylococci and vancomycin-resistant strepto-
cocci and enterococci.[4] Isolated from Micromonospora
carbonacea var. africana (found in a soil sample collected
from the banks of the Nyiro River in Kenya), everninomi-
cin 13,384-1 (1) possesses a novel oligosaccharide structure
containing two sensitive orthoester moieties and terminating
with two highly substituted aromatic esters. In addition, 1
contains a 1 !1'-disaccharide bridge, a nitrosugar (everni-
Experimental Section
[9]
Solutions of H3PW12O40, H3PMo12O40, H4SiW12O40, and H5PV2Mo10O40
‡
were treated on an Amberlyst 120 (K form) ion-exchange column to
prepare the polyoxometalates K3PW12O40, K3PMo12O40, K4SiW12O40, and
K5PV2Mo10O40. K6SiM(H2O)W11O39 (M ˆ CoII, CuII, NiII) and K5SiCrIII
-
(H2O)W11O3 were prepared by the literature procedure.[10] The poly-
oxometalates were wet impregnated from water on g-alumina at a 5 wt%
loading and dried at 1008C overnight. Reactions were run in a stirred Parr
autoclave at 3008C and 23 ± 54 atm H2. Specific conditions are given in the
Table legends. The reaction products were analyzed by GC and GC-MS
using an apolar methylsilicone column.
Received: February 19, 1999
Revised version: June 24, 1999 [Z13061IE]
German version: Angew. Chem. 1999, 111, 3551 ± 3554
[*] Prof. K. C. Nicolaou, H. J. Mitchell, Dr. H. Suzuki,
Dr. R. M. Rodríguez, Dr. O. Baudoin, Dr. K. C. Fylaktakidou
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
Keywords: deoxygenations
hydrogenations ´ polyoxometalates ´ reductions
´
heterogeneous catalysis
´
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (‡ 1)858-784-2469
E-mail: kcn@scripps.edu
and
[1] a) N. Mizuno, M. Misono, Chem. Rev. 1998, 98, 199 ± 217; b) I. V.
Kozhevnikov, Chem. Rev. 1998, 98, 171 ± 198; c) I. V. Kozhevnikov,
Catal. Rev. Sci. Eng. 1995, 37, 311 ± 352.
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[2] a) R. Neumann, Prog. Inorg. Chem. 1998, 47, 317 ± 390; b) T. Okuhara,
N. Mizuno, M. Misono, Adv. Catal. 1996, 41, 113 ± 252; c) C. L. Hill,
C. M. Prosser-McCartha, Coord. Chem. 1995, 143, 407 ± 455.
[3] a) M. Misono, Catal. Rev. Sci. Eng. 1987, 23, 269 ± 321; b) N. Mizuno, K.
Katamura, Y. Yoneda, M. Misono, J. Catal. 1983, 83, 384 ± 392.
[4] a) Y. Yoshinaga, K. Seki, T. Nakato, T. Okuhara, Angew. Chem. 1997,
109, 2946 ± 2948; Angew. Chem. Int. Ed. Engl. 1997, 36, 2833 ± 2835;
b) Y. Izumi, Y. Satoh, H. Kondoh, K. Urabe, J. Mol. Catal. 1992, 72,
37 ± 45; c) D. K. Lyon, R. G. Finke, Inorg. Chem. 1990, 29, 1787 ± 1789;
d) K. Urabe, Y. Tanaka, Y. Izumi, Chem. Lett. 1985, 1595 ± 1596.
[5] M. Misono, H. Igarashi, K. Katamura, T. Okuhara, N. Mizuno, Stud.
Surf. Sci. Catal. 1993, 77, 105 ± 110.
[**] 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.), the George Hewitt Foundation (K.C.F.), and Ligue
Nationale contre le Cancer (O.B.), and grants from Schering Plough,
Pfizer, Glaxo, Merck, Hoffmann-La Roche, DuPont, and Abbott
Laboratories.
3334
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3822-3334 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1999, 38, No. 22

COMMUNICATIONS
extreme sensitivity to
Me
Me
OMe
O
OH
O
O
acidic conditions[2] the
Me
Me
HO
O
Me
OMe
A1
O
MeO
O
O
O
O
O
O
O
O
O
O
Cl
CD orthoester moiety
was disassembled first,
leading to phenyl-
seleno fluoride 2 (the
A1B(A)C fragment)
and diol 3 (the DEF-
GHA2 fragment). The
larger fragment 3 was
O
H
O
B
A
E
G
O
C
D
F
A2
O
O
O
OMe
HO
OH
Me
HO
Me
O
OH
OH
OH
Cl
NO2
Me
O
Me
OMe
1 everninomicin 13,384-1
trose), thirteen rings, and thirty five stereogenic centers within
its structure.[5] Certainly, 1 constitutes a formidable challenge
to organic synthesis[6] because of its unusual connectivity and
polyfunctional and sensitive nature. In this and the following
two communications[7, 8] we report the total synthesis of
everninomicin 13,384-1 (1) through a number of novel
synthetic strategies and methods. Herein we lay out the
overall strategy and describe the construction of the A1B(A)C
fragment of the target molecule.
further disconnected at the EF glycosidic bond to give
fragments 4 (DE) and 5 (FGHA2) as potential key inter-
mediates for its construction. Returning to fragment 2,
disconnection at the indicated sites (two glycosidic and one
ester bonds) defined building blocks 6 ± 9 as the requisite
starting materials. Crucial to this plan were the 1,2-phenyl-
seleno and 1,2-phenylthio migrations[9] that set the stage for
the stereocontrolled constructions of the CD and GH
orthoesters and b-2-deoxy B-C glycoside bonds. The stereo-
controlled synthesis of building blocks 6 ± 9 and their assembly
to the A1B(A)C fragment 2 is described below.
Figure 1 outlines, in retrosynthetic format, the strategy
utilized in the present total synthesis. As a consequence of its
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
Orthoester formation
1
Me
OMe
Esterification
Glycosylation
Glycosylation
Me
O
Me
O
Me
Me
OMe
OTBS
O
O
OMe
A1
O
O
Me
O
MeO
O
O
O
O
Cl
HO
HO
O
O
O
O
B
F
C
O
H
E
G
D
F
+
A2
O
O
O
O
OMe
BnO
Me
TBSO
OTBS
BnO
SePh
Me
Me
OTBS
OTBS
OTBS
Cl
2
3
NO2
Me
OMe
O
A
Me
Glycosylation
Me
OMe
OBn
O
O
O
Me
MeO
O
O
O
BMBO
HO
O
O
+
O
H
D
E
G
F
A2
O
O
O
O
OC(NH)CCl3
HO
OMe
BnO
OBn
Me
OAc
OAc
OBn
4
5
F
O
Me
Me
OMe
O
O
O
NO2
Me
Cl
A
F
HO
BnO
TBSO
TBSO
F
OPMB
B
C
A1
+
+
+
BnO
Me
OMe
Me
SPh
OPMB
Cl
9
6
7
8
Figure 1. Retrosynthetic analysis of everninomicin 13,384-1 (1). Ac ˆ acetyl; Bn ˆ benzyl; PMB ˆ p-methoxybenzyl; TBS ˆ tert-butyldimethylsilyl.
Angew. Chem. Int. Ed. 1999, 38, No. 22 ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999 1433-7851/99/3822-3335 $ 17.50+.50/0
3335

COMMUNICATIONS
The construction of the evernitrose donor 9 (Scheme 1)
involved an improved sequence along the lines of our original
synthesis[10] of both evernitrose and vancosamine. Thus,
methylation of alcohol 10 with NaH and MeI gave, in 96%
yield, the methoxy compound 11, which was hydrolyzed to the
17 (Scheme 2) and glucal 25 (Scheme 3), respectively. The
synthesis of building block 7 is summarized in Scheme 2.
Thus, tosylation of the primary hydroxyl group of the known
intermediate 17[13] with TsCl/py furnished tosylate 18 (93%),
which was silylated (TIPSOTf/2,6-lutidine, 90%) and reduced
with LAH (90%) to afford compound 19. Acidic methanoly-
sis (TsOH/MeOH) of the acetonide group in 19 gave diol
20 (80%), whose exposure to nBu2SnO[14] and subsequent
OR
OMe
b
c
TIPSO
OEt
TIPSO
N
O
SPh
O
O
SPh
O
OBn
RO
HO
12
10: R = H
11: R = Me
a
b
c
TIPSO
d
O
O
OMe
OMe
19
17: R = H
18: R = Ts
a
f
d
Me NH
OBn
Me NH
RO
TMSO
OBn
O
SPh
OR
O
SPh
15
13: R = TIPS
14: R = H
f
e
TIPSO
e
HO
OPMB
g
OH
OH
22
20: R = H
21: R = PMB
Me
O
OH
Me
O
F
g
A
h
MeO
MeO
Me NO2
Me NO2
O
F
O
SPh
OR
16
9
B
i
Scheme 1. Synthesis of nitrosugar A (9). a) 1.1 equiv NaH, 1.3 equiv MeI,
THF, 0 !258C, 4 h, 96%; b) 0.1n HCl, THF/H2O (4/1), 258C, 0.5 h, 100%;
c) 1.1 equiv BnONH2 ´ HCl, py, 0 !258C, 2 h, 91% (E:Z ca. 4:1);
d) 2.5 equiv allylMgBr, Et2O, 358C, 1 h, 87%; e) 1.1 equiv nBu4NF,
THF, 258C, 1 h, 92%; f) 5.0 equiv (TMS)2NH, 0.1 equiv TMSCl, 258C,
0.5 h, 100%; g) 1. O3, iC8H8/CCl4 (2/1), 788C, 1 h; 2. 2.0 equiv TFA,
78 !258C, 1 h; 3. 2.0 equiv Ph3P, 78 !258C, 12 h, 82% over three steps
(a:b ca. 1.8:1); h) 1.5 equiv DAST, CH2Cl2, 08C, 20 min, 100%. DASTˆ
(diethylamino)sulfur trifluoride; py ˆ pyridine; TFA ˆ trifluoroacetic acid;
TIPS ˆ triisopropylsilyl; TMS ˆ trimethylsilyl.
TBSO
SPh
TBSO
OTBS
OTBS
23: R = PMB
24: R = H
7
h
Scheme 2. Synthesis of carbohydrate building block B (7). a) 1.1 equiv
TsCl, py, 0 !258C, 12 h, 93%; b) 1.1 equiv TIPSOTf, 1.5 equiv 2,6-lutidine,
CH2Cl2, 0 !258C, 0.5 h, 90%; c) 2.5 equiv LAH, THF, 0 !458C, 6 h, 90%;
d) 0.5 equiv TsOH, 2.5 equiv (CH2OH)2, MeOH, 258C, 10 h, 80%;
e) 1.1 equiv nBu2SnO, toluene, 1108C, 3 h; 1.5 equiv PMBCl, 0.2 equiv
nBu4NI, 25 !1108C, 83%; f) 2.5 equiv nBu4NF, THF, 258C, 2 h, 91%;
g) 2.2 equiv TBSOTf, 4.0 equiv 2,6-lutidine, CH2Cl2, 0 !258C, 0.5 h, 93%;
h) 1.5 equiv DDQ, CH2Cl2/H2O (10/1) 0 !258C, 1 h, 91%; i) 1.5 equiv
DAST, CH2Cl2, 08C, 20 min, 100% (a:b ca. 10:1). DDQ ˆ 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone; LAH ˆ lithium aluminum hydride; Tf ˆ tri-
fluoromethanesulfonyl; Ts ˆ p-toluenesulfonyl.
corresponding ketone with aqueous HCl and converted into
oxime 12 by condensation with O-benzylhydroxylamine (ratio
of E:Z isomers approximately 4:1; 91% over 2 steps).
Addition of allylmagnesium bromide to 12 in diethyl ether
at 358C afforded 13 (87% yield), which after an exchange of
silyl groups (nBu4NF, 92%; (TMS)2NH, TMSCl, 100%) gave
the more labile trimethylsilyl ether 15 via the hydroxy
compound 14. Ozonolysis of 15 followed by sequential
exposure to TFA and Ph3P resulted in aldehyde and nitro
group formation, desilylation, and ring closure and the
generation of lactol 16. Finally, treatment of lactol 16 with
DAST[11] led to its rapid conversion into glycosyl fluoride 9 in
quantitative yield (an approximate 8:1 mixture of a- and b-
anomers).
Despite our original model studies[12] and success in
constructing rings B and C from a common intermediate, we
now required a more demanding orchestration of protecting
groups and glycosylation tactics for an eventual total syn-
thesis. After considerable design and experimentation, we
finally discovered the winning combination of TBS and PMB
groups on rings B and C, respectively.
reaction with PMBCl/nBu4NI furnished 21 in 83% overall
yield. Removal of the TIPS group was induced by nBu4NF to
give diol 22 (91%), whose treatment with TBSOTf and 2,6-
lutidine furnished the bis-TBS derivative 23 (93%). Finally,
DDQ deprotection of 23 gave hydroxy compound 24 (91%),
which on exposure to DAST resulted in the desired 1,2-
migration[9] of the thiophenyl group (with inversion of the C2
stereochemistry) and inplantation of the fluoride group at C1
(100%, approximate 10:1 mixture of a- and b-anomers)
leading to the targeted glycosyl fluoride 7.
Building block 8 was constructed in five steps from the
readily available glucal 25[15] as shown in Scheme 3. Thus, tin
acetal mediated benzylation of 25 (nBu2SnO, BnBr/nBu4NI)
resulted in the selective protection at C3 in 83% yield.
Further protection, now at C4, with TBSCl/imidazole led to
compound 27 whose exposure to OsO4/NMO furnished diol
28 in 97% yield (approximate 1:1 mixture of anomers).
Protection of both hydroxyl groups of 28 as PMB ethers
Furthermore, the adopted constructions of rings B (7) and
C (8) took independent paths and started from thioglycoside
3336
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3822-3336 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1999, 38, No. 22

COMMUNICATIONS
orcinol (30) with Zn(CN)2/AlCl3 gave aldehyde 31 (92%),
which was oxidized to the corresponding carboxylic acid
(NaClO2, 80%) and methylated (MeOH/NaHCO3) to give
methyl ester 32 (90%). Chlorination of 32 with SO2Cl2 led to
dichloride 33 in 95% yield, while sequential protection of the
phenolic groups proceeded smoothly and regioselectively
upon treatment with TIPSOTf/2,6-lutidine (90%) and Ag2O/
MeI (91%) to furnish compound 34. The TIPS group was then
exchanged for a Bn group (nBu4NF, 96%; K2CO3/BnBr,
92%) to give 36 via 35. The resistance of the methyl ester in 36
towards hydrolysis led to a three-step protocol for its
conversion into carboxylic acid 38 (DIBAL reduction, 90%;
PDC oxidation, 90%; NaClO2 oxidation, 95%) involving
aldehyde 37 as an intermediate. Finally, exposure[16] of 38 to
O
O
b
HO
TBSO
OR
OBn
25: R = H
26: R = Bn
a
27
c
O
OR
OR
O
OPMB
C
e
TBSO
HO
OPMB
OBn
OBn
28: R = H
29: R = PMB
8
d
Scheme 3. Synthesis of carbohydrate building block C (8). a) 1.1 equiv
nBu2SnO, toluene, 1108C, 3 h, 1.5 equiv BnBr, 0.2 equiv nBu4NI,
25 !1108C, 5 h, 83%; b) 1.5 equiv TBSCl, 2.5 equiv imidazole, 0 !258C,
3 h, 93%; c) 1.1 equiv NMO, 0.05 equiv OsO4, Me2CO/H2O (10/1), 258C,
8 h, 97%; d) 2.4 equiv NaH, 3.0 equiv PMBCl, 0.2 equiv nBu4NI, DMF,
0 !258C, 3 h, 95%; e) 1.1 equiv nBu4NF, THF, 258C, 1 h, 95% (a:b
ca. 1:1). NMO ˆ N-methylmorpholine N-oxide.
‡
(Me2N)2CF PF6 gave the desired acyl fluoride 6, which
withstood chromatographic purification on silica gel (97%
yield).
Having constructed all four requisite building blocks (6 ± 9),
their assembly became the next task at hand. Scheme 5
summarizes their stereoselective coupling to form the
A1B(A)C fragment 2. Thus, the SnCl2-mediated coupling of
glycosyl fluoride 7 with alcohol 8 under mild conditions (4 Š
MS, CH2Cl2/Et2O/Me2S (1/1/1), 108C)[9] gave disaccharide
39 in 71% yield and as a single stereoisomer. Having
performed its b-directing duty, thus ensuring the desired
stereochemical outcome in this glycosylation reaction, the
2-thiophenyl group was now ready for reductive cleavage with
Raney-nickel. This procedure led smoothly from 39 to 40. The
latter intermediate (40) was then modified for its coupling
with acyl fluoride 6 by bis-desilylation (nBu4NF, 78% over
two steps) and selective monoallylation (nBu2SnO/allyl
bromide, 93%) to convert it into 41 (Table 1). Upon
activation of the hydroxyl group of 41 (nBuLi, THF,
78 !08C) followed by addition of acyl fluoride 6, the
corresponding ester was formed in 99% yield, from which the
allyl group was removed with Wilkinsonꢁs catalyst/DABCO
and OsO4/NMO to afford 42 (81% yield). A TIPS group was
then installed on ring B (TIPSOTf/2,6-lutidine, 93%) to
afford compound 43. These particular choices of protecting
groups were necessary for optimum esterification yields and
subsequent chemistry. Experimentation with future steps in
the total synthesis dictated the introduction of the selenium
group before the attachment of the evernitrose fragment,
and therefore the following sequence was adopted. Thus, the
PMB groups were removed from 43 by exposure to PhSH and
BF3 ´ Et2O (83%) and acetate groups were installed in their
place (Ac2O/Et3N/4-DMAP, 98%) to afford diacetate 44.
Exposure of 44 to nBuNH2 led to the selective cleavage of the
C1 acetate and the liberation of lactol 45 (91%), which was
then converted into trichloroacetimidate 46[17] by treatment
with CCl3CN in the presence of DBU. Addition of PhSeH[18]
to 46 in the presence of BF3 ´ Et2O gave the desired b-
phenylseleno glycoside as expected with participation of the
C2 acetate (a:b approximately 1:9, 78% over two steps).
Removal of the TIPS group from this product with nBu4NF
furnished the phenylseleno glycoside 47 (91% yield), which
was ready for the next coupling. Indeed, attachment of the
evernitrose fragment 9 onto the A1BC chain 47 proceeded
smoothly under the influence of SnCl2 to furnish the desired
(NaH/PMBCl/nBu4NI, 95%) led to 29 (approximate 1:1
mixture of anomers) and exposure to nBu4NF generated the
desired building block 8 in 95% yield. The stereochemistry at
C1 is inconsequential as it will be destroyed at a later stage.
A more efficient synthesis than the one previously report-
ed[12] for the aromatic fragment 6 was developed and is
summarized in Scheme 4. Thus, Gatterman formylation of
OH
O
OH
X
R
OMe
b
c
HO
HO
Me
Me
X
30: R = H
32: X = H
33: X = Cl
a
d
31: R = CHO
e, f
OMe
O
OMe
O
Cl
Cl
OMe
R
A1
i
RO
BnO
Me
Me
j
Cl
Cl
37: R = H
38: R = OH
6: R = F
34: R = TIPS
35: R = H
36: R = Bn
k
l
g
h
Scheme 4. Synthesis of aromatic ring A1 (6). a) 1. 1.5 equiv Zn(CN)2,
2.4 equiv AlCl3, HCl(g), 08C, 3 h; 2. H2O, 0 !1008C, 30 min, 92%;
b) 2.4 equiv NaClO2, 2.5 equiv NaH2PO4, DMSO, 08C, 12 h, 80%;
c) 2.0 equiv MeI, 1.2 equiv NaHCO3, CH2Cl2, 258C, 12 h, 90%;
d) 2.5 equiv SO2Cl2, CH2Cl2, 358C, 3 h, 95%; e) 1.1 equiv TIPSOTf,
1.3 equiv 2,6-lutidine, CH2Cl2, 788C, 0.5 h, 90%; f) 4.0 equiv Ag2O,
4.0 equiv MeI, Et2O, 308C, 12 h, 91%; g) 1.3 equiv nBu4NF, THF, 258C, 2 h,
96%; h) 1.5 equiv BnBr, 3.0 equiv K2CO3, Me2CO, 708C, 92%; i) 1.2 equiv
DIBAL, CH2Cl2, 788C, 1 h, 90%; j) 3.0 equiv PDC, 3 Š MS, CH2Cl2,
258C, 3 h, 90%; k) 3.0 equiv NaClO2, 3.0 equiv NaH2PO4, 2-methyl-2-
butene (2.0m in THF, 4.0 equiv), tBuOH, H2O, 258C, 3 h, 95%; l) 1.5 equiv
‡
(Me2N)2CF PF6
,
2.0 equiv iPr2NEt, CH2Cl2, 0 !258C, 2 h, 97%.
DIBAL ˆ diisobutylaluminum
hydride;
DMSO ˆ dimethylsulfoxide;
PDC ˆ pyridinium dichromate.
Angew. Chem. Int. Ed. 1999, 38, No. 22
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3822-3337 $ 17.50+.50/0
3337

COMMUNICATIONS
Me
Me
Me
Me
O
O
O
O
HO
C
8
a
TBSO
TBSO
F
OPMB
OPMB
TBSO
TBSO
O
OPMB
OPMB
B
B
C
+
SPh
BnO
R
BnO
7
39: R = SPh
40: R = H
b
OMe
O
Cl
c, d
F
A1
BnO
Me
Me
RO
Me
Me
Me
OMe
A1
O
Cl
6
O
O
O
O
Cl
O
O
C
HO
AllylO
O
B
OPMB
OPMB
B
OPMB
OPMB
C
e
f
BnO
Me
BnO
BnO
Cl
41
42: R = H
43: R = TIPS
g
h, i
Me
Me
Me
Me
OMe
O
OMe
A1
O
O
O
O
O
Cl
Cl
O
O
C
OR
OAc
O
O
C
SePh
OAc
B
B
A1
l
BnO
Me
BnO
Me
HO
OTIPS
BnO
BnO
m
Cl
Cl
47
44: R = Ac
45: R = H
46: R = C(NH)CCl3
j
F
k
n
NO2
Me
OMe
O
A
Me
9
Me
Me
Me
O
Me
OMe
O
OMe
A1
O
O
O
O
O
Cl
Cl
O
O
B
F
O
O
B
SePh
C
C
A1
p
BnO
Me
BnO
Me
O
BnO
NO2
Me
SePh
BnO
OR
Cl
Cl
NO2
Me
O
A
O
A
Me
OMe
Me
OMe
48: R = Ac
49: R = H
2
o
Scheme 5. Construction of A1B(A)C fragment 2. a) 1.0 equiv 7, 1.1 equiv 8, 1.8 equiv SnCl2, 4 Š MS, CH2Cl2/Et2O/Me2S (1/1/1), 108C, 3 h, 71%;
b) ca. 1.0 equiv Raney-Ni (w/w), EtOH/THF (1/1), 908C, 8 h; c) 2.2 equiv nBu4NF, 258C, 2 h, 78% over two steps; d) 1.1 equiv nBu2SnO, toluene, 1108C, 3 h;
1.5 equiv allylBr, 0.2 equiv nBu4NI, 25 !1108C, 93%; e) 1.1 equiv nBuLi, THF, 78 !08C, 1 h; 1.2 equiv 6, THF, 258C, 99%; f) 1. 1.5 equiv DABCO,
0.05 equiv [(Ph3P)3RhCl], EtOH/H2O (10/1), 908C, 2 h; 2. 1.1 equiv NMO, 0.05 equiv OsO4, Me2CO/H2O (10/1), 258C, 8 h, 81%; g) 1.2 equiv TIPSOTf,
1.5 equiv 2,6-lutidine, CH2Cl2, 0 !258C, 1 h, 93%; h) 8.0 equiv PhSH, 4.0 equiv BF3 ´ Et2O, CH2Cl2, 308C, 2 h, 83%; i) 2.5 equiv Ac2O, 4.0 equiv Et3N,
0.2 equiv 4-DMAP, CH2Cl2, 0 !258C, 1 h, 98%; j) 1.3 equiv nBuNH2, THF, 258C, 5 h, 91%; k) 5.0 equiv CCl3CN, 0.05 equiv DBU, CH2Cl2, 08C, 0.5 h;
l) ca. 2.0 equiv PhSeH, 0.2 equiv BF3 ´ Et2O, CH2Cl2, 78 !08C, 1 h, 78% over two steps (a:b ca. 1:9); m) 1.2 equiv nBu4NF, THF, 258C, 1 h, 91%;
n) 2.0 equiv 9, 1.2 equiv SnCl2, CH2Cl2/Et2O (1/1), 0 !258C, 1 h, 80%; o) 0.3 equiv NaOH, MeOH, 258C, 1 h, 91%; p) 1.5 equiv DAST, CH2Cl2, 08C, 20 min,
90% (a:b ca. 8:1). DABCO ˆ 1,4-diazabicyclo[2.2.2]octane; DBU ˆ 1,8-diazabicyclo[5. 4.0]undec-7-ene; 4-DMAP ˆ 4-dimethylaminopyridine.
assembly 48 (80%) in which the newly formed glycoside bond
(A !B, a-anomer) was fully controlled by the anomeric
effect.
the following communication[7] we describe the construc-
tion of the desired FGHA2 fragment of everninomicin 13,384-
1 (1).
Finally, basic hydrolysis (NaOH/MeOH) of the acetate
group from 48 led to the C2 hydroxy compound 49 (91%
yield), whose treatment with DAST produced the targeted
2-phenylselenoglycosyl fluoride 2 in excellent yield (90%)
and with an inversion of the stereochemistry at C2 of ring C
(approximate 8:1 mixture of a- and b-fluoride anomers).[19] In
Received: August 6, 1999 [Z13841IE]
German version: Angew. Chem. 1999, 111, 3523 ± 3528
Keywords: antibiotics ´ carbohydrates ´ everninomicin ´
glycosylations ´ total synthesis
3338
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3822-3338 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1999, 38, No. 22

COMMUNICATIONS
Table 1. Selected physical and spectroscopic data of compounds 41, 42, and
49.
[2] 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, New York, 1978, pp. 61 ± 96; c) A. K. Ganguly, V. M.
Girijavallabhan, O. Sarre (Schering Plough), WO 87/02366, 1987; d) P.
Mahesh, V. P. Gullo, H. Roberta, D. Loebenberg, J. B. Morton, G. H.
Miller, H. Y. Kwon (Schering Plough), EP 0538011A1, 1992; e) A. K.
Ganguly, J. L. McCormick, L. Jinping, A. K. Saksena, P. R. Das, R.
Pradip, T. M. Chan, Bioorg. Med. Chem. Lett. 1999, 9, 1209 ± 1214.
[3] D. E. Wright, Tetrahedron 1979, 35, 1207 ± 1237.
[4] a) J. A. Maertens, Curr. Opin. Anti-Infect. Invest. Drugs 1999, 1, 49 ±
56; b) J. A. Maertens, Drugs 1999, 2, 446 ± 453.
[5] a) A. K. Ganguly, J. L. McCormick, T. M. Chan, A. K. Saksena, P. R.
Das, Tetrahedron Lett. 1997, 38, 7989 ± 7991; b) T. M. Chan, R. M.
Osterman, J. B. Morton, A. K. Ganguly, Magn. Reson. Chem. 1997, 35,
529 ± 532.
41: Rf ˆ 0.25 (silica, 70% Et2O in hexanes); aD22
ˆ
23.4 (c ˆ 0.80, CHCl3);
IR (thin film): nÄmax ˆ 3387, 2955, 2908, 2861, 1608, 1584, 1455, 1355, 1302,
1
1249, 1173, 1091, 1044, 926, 814, 732 cm
;
1H NMR (500 MHz, CDCl3):
d ˆ 7.41 ± 7.24 (m, 7H, ArH), 7.17 (d, J ˆ 8.5 Hz, 2H, PMB), 6.88 (d, J ˆ
8.5 Hz, 2H, PMB), 6.79 (d, J ˆ 8.5 Hz, 2H, PMB), 5.90 (dddd, J ˆ 17.0, 10.5,
6.0, 5.5 Hz, 1H, OCH2CHCH2), 5.28 (dd, J ˆ 17.0, 1.5 Hz, 1H,
OCH2CHCH2), 5.19 (dd, J ˆ 10.5, 1.0 Hz, 1H, OCH2CHCH2), 4.92 and
4.83 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.88 and 4.59 (AB, J ˆ 11.5 Hz, 2H,
CH2Ar), 4.81 and 4.61 (AB, J ˆ 10.5 Hz, 2H, CH2Ar), 4.70 (dd, J ˆ 9.5,
2.0 Hz, 1H, B-1), 4.47 (d, J ˆ 8.0 Hz, 1H, C-1), 4.11 (dd, J ˆ 12.5, 5.5 Hz,
1H, OCH2CHCH2), 3.94 (dd, J ˆ 12.5, 6.0 Hz, 1H, OCH2CHCH2), 3.80 (s,
3H, OMe (PMB)), 3.77 (s, 3H, OMe (PMB)), 3.54 (t, J ˆ 8.5 Hz, 1H, C-3),
3.44 (t, J ˆ 8.5 Hz, 1H, C-2), 3.41 ± 3.35 (m, 2H, C-4, C-5), 3.30 ± 3.22 (m,
1H, B-3), 3.21 ± 3.10 (m, 2H, B-4, B-5), 2.64 (d, J ˆ 2.0 Hz, 1H, OH), 2.30
(ddd, J ˆ 12.5, 4.5, 2.0 Hz, 1H, B-2), 1.46 (td, J ˆ 12.5, 9.5 Hz, 1H, B-2), 1.35
(d, J ˆ 5.0 Hz, 3H, C-6), 1.24 (d, J ˆ 5.5 Hz, 3H, B-6); 13C NMR (125 MHz,
CDCl3): d ˆ 159.2, 159.0, 138.9, 134.5, 130.5, 130.0, 129.7, 129.7, 129.5, 129.5,
129.4, 128.1, 127.5, 127.2, 117.3, 113.7, 113.5, 102.1, 100.0, 94.8, 83.1, 82.0,
81.8, 81.6, 80.4, 79.4, 78.5, 75.4, 75.2, 71.8, 70.8, 69.8, 55.1, 36.2, 18.0, 17.8;
[6] For synthetic studies within the orthosomicin class, see a) P. Juetten, C.
Zagar, H. D. Scharf, Recent Prog. Chem. Synth. Antibiot. Relat.
Microb. Prod. 1993, 475 ± 549, and references therein; b) P. Juetten,
H. D. Scharf, G. Raabe, J. Org. Chem. 1991, 56, 7144 ± 7149; c) M.
Á
Trumtel, P. Tavecchia, A. Veyrieres, P. SinayÈ, Carbohydr. Res. 1990,
202, 257 ± 275.
‡
HR-MS (FAB), calcd for C38H48O10Cs [M ‡ Cs ]: 797.3202, found:
[7] 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.
[8] 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.
[9] K. C. Nicolaou, T. Ladduwahetty, J. L. Randall, A. Chucholowski, J.
Am. Chem. Soc. 1986, 108, 2466 ± 2467.
[10] K. C. Nicolaou, H. J. Mitchell, F. L. van Delft, F. Rübsam, R. M.
Rodríguez, Angew. Chem. 1998, 110, 1972 ± 1974; Angew. Chem. Int.
Ed. 1998, 37, 1871 ± 1874.
[11] a) W. Rosenbrook, Jr., D. A. Riley, P. A. Lartey, Tetrahedron Lett.
1985, 26, 3 ± 4; b) G. H. Posner, S. R. Haines, Tetrahedron Lett. 1985,
26, 5 ± 8; c) T. Mukaiyama, Y. Murai, S. Shoda, Chem. Lett. 1981, 431 ±
433.
[12] K. C. Nicolaou, R. M. Rodríguez, H. J. Mitchell, F. L. van Delft,
Angew. Chem. 1998, 110, 1975 ± 1977; Angew. Chem. Int. Ed. 1998, 37,
1874 ± 1876.
[13] A. Y. Chemyak, K. V. Antonov, N. K. Kochetkov, Biorg. Khim. 1989,
15, 1113 ± 1127.
[14] 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.
797.2287
42: Rf ˆ 0.24 (silica, 70% Et2O in hexanes); a2D2 ˆ ‡12.0 (c ˆ 0.20, CHCl3);
IR (thin film): nÄmax ˆ 3425, 2931, 2884, 1731, 1614, 1544, 1138, 1326, 1302,
1249, 1120, 1073, 938, 820, 749 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.57
(d, J ˆ 6.9 Hz, 2H, ArH), 7.43 ± 7.28 (m, 10H, ArH), 7.16 (d, J ˆ 8.6 Hz,
2H, PMB), 6.88 (d, J ˆ 8.6 Hz, 2H, PMB), 6.79 (d, J ˆ 8.6 Hz, 2H, PMB),
5.03 (brs, 2H, CH2Ar (A1)), 4.93 and 4.83 (AB, J ˆ 10.9 Hz, 2H, CH2Ar),
4.88 and 4.59 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.81 and 4.59 (AB, J ˆ
11.5 Hz, 2H, CH2Ar), 4.78 (t, J ˆ 9.4 Hz, 1H, B-4), 4.74 (dd, J ˆ 9.7,
1.8 Hz, 1H, B-1), 4.47 (d, J ˆ 7.9 Hz, 1H, C-1), 3.87 (s, 3H, OMe), 3.85 ±
3.72 (m, 1H, B-3), 3.81 (s, 3H, OMe), 3.78 (s, 3H, OMe), 3.55 (brt, J ˆ
9.0 Hz, 1H, C-3), 3.43 (dd, J ˆ 9.0, 7.9 Hz, 1H, C-2), 3.41 ± 3.36 (m, 2H, C-4,
C-5), 3.33 (dq, J ˆ 9.4, 6.2 Hz, 1H, B-5), 2.66 (d, J ˆ 4.4 Hz, 1H, OH), 2.36
(s, 3H, Me (A1)), 2.40 ± 2.30 (m, 1H, B-2), 1.72 (td, J ˆ 12.2, 9.7 Hz, 1H,
B-2), 1.35 (d, J ˆ 5.3 Hz, 3H, C-6), 1.23 (d, J ˆ 6.2 Hz, 3H, B-6); 13C NMR
(150 MHz, CDCl3): d ˆ 166.4, 159.3, 159.1, 153.0, 151.8, 139.0, 138.9, 133.2,
130.5, 130.1, 129.8, 129.7, 129.6, 129.5, 129.2, 128.5, 128.2, 127.5, 127.3, 126.4,
125.5, 121.4, 113.8, 113.6, 102.2, 100.3, 84.2, 82.9, 81.9, 79.5, 75.3, 74.9, 74.5,
70.9, 70.8, 69.8, 69.6, 65.8, 62.4, 55.2, 39.3, 34.2, 30.3, 29.5, 21.1, 18.0, 17.6,
‡
17.4, 15.2; HR-MS (FAB), calcd for C51H56Cl2O13Na [M ‡ Na ]: 969.2995,
found: 969.2998
49: Rf ˆ 0.20 (silica, 50% Et2O in hexanes); aD22
ˆ
36.1 (c ˆ 0.40, CHCl3);
IR (thin film): nÄmax ˆ 3476, 2939, 1732, 1542, 1453, 1391, 1251, 1128, 1032,
[15] S. Czernecki, K. Vijayakumaran, G. Ville, J. Org. Chem. 1986, 51,
5472 ± 5474.
[16] L. A. Carpino, A. El-Faham, J. Am. Chem. Soc. 1995, 117, 5401 ± 5402.
[17] R. R. Schmidt, J. Michel, Angew. Chem. 1980, 92, 763 ± 765; Angew.
Chem. Int. Ed. Engl. 1980, 19, 731 ± 733.
[18] S. Mehta, B. M. Pinto, J. Org. Chem. 1993, 58, 3269 ± 3276.
[19] All new compounds exhibited satisfactory spectral and exact mass
data.
1
911, 736 cm
;
1H NMR (600 MHz, CDCl3): d ˆ 7.64 (d, J ˆ 7.0 Hz, 2H,
ArH), 7.57 (d, J ˆ 7.0 Hz, 2H, ArH), 7.45 ± 7.27 (m, 11H, ArH), 5.06 and
5.03 (AB, J ˆ 10.2 Hz, 2H, CH2Ar), 4.98 and 4.83 (AB, J ˆ 11.3 Hz, 2H,
CH2Ar), 4.94 (brdd, J ˆ 5.0, 1.8 Hz, 1H, A-1), 4.89 (t, J ˆ 9.4 Hz, 1H, B-4),
4.72 (d, J ˆ 9.6 Hz, 1H, C-1), 4.67 (dd, J ˆ 9.7, 1.8 Hz, 1H, B-1), 3.89 ± 3.83
(m, 1H, B-3), 3.86 (s, 3H, OMe (A)), 3.65 (d, J ˆ 9.4 Hz, 1H, A-4), 3.53 ±
3.32 (m, 6H, A-5, B-5, C-2, C-3, C-4, C-5), 3.36 (s, 3H, OMe (A1)), 2.49
(brs, 1H, OH), 2.46 (dd, J ˆ 13.8, 5.0 Hz, 1H, A-2), 2.39 (s, 3H, Me (A1)),
2.29 (ddd, J ˆ 12.9, 5.1, 1.8 Hz, 1H, B-2), 2.02 (dd, J ˆ 13.8, 1.8 Hz, 1H,
A-2), 1.72 ± 1.65 (m, 1H, B-2), 1.68 (s, 3H, Me (A-3)), 1.34 (d, J ˆ 5.9 Hz,
3H, B-6 or C-6), 1.33 (d, J ˆ 6.2 Hz, 3H, B-6 or C-6), 0.84 (d, J ˆ 6.2 Hz,
3H, A-6); 13C NMR (150 MHz, CDCl3): d ˆ 165.5, 153.2, 153.1, 138.7,
135.8, 135.1, 134.7, 129.0, 128.6, 128.5, 128.3, 128.2, 127.6, 127.5, 126.3, 125.9,
125.4, 99.7, 99.0, 92.4, 89.9, 84.3, 84.2, 83.0, 81.7, 76.7, 76.1, 75.0, 74.9, 73.1,
72.3, 71.0, 66.2, 61.9, 90.7, 40.0, 36.4, 31.5, 30.2, 22.6, 19.3, 18.3, 18.2, 18.0,
‡
17.6, 14.1; HR-MS (FAB), calcd for C49H57Cl2NO14SeCs [M ‡ Cs ]:
1166.1378, found: 1166.1319
[1] For a review on the chemistry and biology of vancomycin and other
glycopeptide antibiotics, see K. C. Nicolaou, C. N. C. Boddy, S. Bräse,
N. Winssinger, Angew. Chem. 1999, 109, 1518 ± 1519; Angew. Chem.
Int. Ed. 1999, 38, 2096 ± 2152; see also D. H. Williams, B. Bardsley,
Angew. Chem. 1999, 111, 1264 ± 1286; Angew. Chem. Int. Ed. 1999, 38,
1172 ± 1193.
Angew. Chem. Int. Ed. 1999, 38, No. 22
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3822-3339 $ 17.50+.50/0
3339