Benzylidene acetal fragmentation route to 6-deoxy sugars: Direct reductive cleavage in the presence of ether protecting groups, permitting the efficient, highly stereocontrolled synthesis of β-D-rhamnosides from D-mannosyl glycosyl donors

Article abstract of DOI:10.1021/ja048070j

An approach to the stereocontrolled synthesis of β-D-rhamnopyranosides is described in which 2,3-O-benzyl or related 4,6-O-[α-(2-(2-iodophenyl) ethylthiocarbonyl)benzylidene]-mannosyl thioglycosides are first used to introduce the β-D-mannopyranoside link

Full text of DOI:10.1021/ja048070j

Published on Web 06/11/2004
Benzylidene Acetal Fragmentation Route to 6-Deoxy Sugars:
Direct Reductive Cleavage in the Presence of Ether Protecting
Groups, Permitting the Efficient, Highly Stereocontrolled
Synthesis of â-D-Rhamnosides from D-Mannosyl Glycosyl
Donors. Total Synthesis of r-D-Gal-(1f3)-r-D-Rha-(1f3)-
â-D-Rha-(1f4)-â-D-Glu-OMe, the Repeating Unit of the
Antigenic Lipopolysaccharide from Escherichia hermannii
ATCC 33650 and 33652
David Crich* and Qingjia Yao
Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
Received April 3, 2004; E-mail: Dcrich@uic.edu
Abstract: An approach to the stereocontrolled synthesis of â-D-rhamnopyranosides is described in which
2,3-O-benzyl or related 4,6-O-[R-(2-(2-iodophenyl)ethylthiocarbonyl)benzylidene]-mannosyl thioglycosides
are first used to introduce the â-D-mannopyranoside linkage in high yield and stereoselectivity. Following
glycosylation, treatment with tributyltin hydride in toluene at reflux brings about reductive radical fragmentation
directly to the 6-deoxy sugar in high yield. A variation of these donors bearing a carboxylated donor on O3
is a highly R-selective mannosyl and, after radical fragmentation, R-D-rhamnosyl donor. Using this
stereoselective glycosylation/radical-fragmentation approach, a concise synthesis of the title tetrasaccharide
is realized in which both the â-D- and R-D-rhamnopyranosyl units are obtained in a single step by a double
radical fragmentation of the modified benzylidene acetals.
Introduction
located in the form of R- and â-glycosidic linkages. In terms
of chemical synthesis, the two enantiomeric series present very
Rhamnopyranosides are frequent components of antigenic
bacterial capsular polysaccharides and exopolysaccharides. As
such, they play important roles in the propagation of disease
states and may be viewed as components of vaccines against
pneumococcal infections.1 While the L-rhamnopyranosides are
the most common of the two antipodes in bacterial polysac-
charides, increasing numbers of the D-modification2 are being
different problems, with the readily available L-rhamnose being
the obvious starting point for both the R- and â-L-rhamnopy-
ranosides and the lack of a facile, large-scale source of
D-rhamnose3,4 dictating an indirect approach to the D-rhamno-
sides. This paper concentrates on the synthesis of the D-
rhamnopyranosides, with particular focus on the â-D-series,
while ongoing work in our laboratory addresses the problem of
the â-L-family.5 The effectiveness of the method developed here
is illustrated by a concise synthesis of the tetrasaccharide
repeating unit 1 of the antigenic lipopolysaccharide from
Escherichia hermannii ATCC 33650 and 33652, an atypical
biogroup of Escherichia coli, isolated from human wounds,
lungs, and stools.2l The synthetic challenge of 1 is heightened
by the presence of a total of four different types of glycosidic
bond, including an R-D-rhamnopyranoside directly linked to the
(1) (a) Jennings, H. J. AdV. Carbohydr. Chem. Biochem. 1983, 41, 155-208.
(b) Fedson, D. S.; Shapiro, E. D.; Laforce, F. M.; Mufson, M. A.; Spika,
J. S.; Breiman, R. F.; Broome, C. V.; Musher, D. M. Arch. Intern. Med.
1994, 154, 2531-2535. (c) Goldblatt, D. J. Med. Microbiol. 1998, 47, 563-
567. (d) Djuretic, T.; Ryan, M. J.; Millar, E.; Fairley, C. K.; Goldblatt, D.
J. Infection 1998, 37, 54-58.
(2) (a) Hirooka, M.; Yoshimura, A.; Saito, I.; Ikawa, F.; Uemoto, Y.; Koto,
S.; Takabatake, A.; Taniguchi, A.; Shinoda, Y.; Morinaga, A. Bull. Chem.
Soc. Jpn. 2003, 76, 1409-1421. (b) Spitali, M.; Smith, A. R. M. J.
Phytopathol. 2000, 148, 563-568. (c) Knirel, Y. A.; Shashkov, A. S.;
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360-366. (e) Winn, A. M.; Wilkinson, S. Q. Carbohydr. Res. 1996, 294,
109-115. (f) Senchenkova, S. N.; Shashkov, A. S.; Keckes, M. L.;
Ahohuendo, B. C.; Knirel, Y. A.; Rudolph, K. Carbohydr. Res. 2000, 329,
831-838. (g) Vinogradov, E. V.; Shashkov, A. S.; Knirel, Y. A. Carbohydr.
Res. 1991, 212, 307-311. (h) Vinogradov, E. V.; Campos-Portuguez, S.;
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A.; Silipo, A.; Lanzetta, R.; Newman, M.-A.; Dow, J. M.; Parrilli, M.
Carbohydr. Res. 2003, 338, 277-281. (j) Perry, M. B.; Richards, J. C.
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(4) Bundle has previously developed a synthesis of S-ethyl 2-O-acetyl-3,4-di-
O-benzyl-â-D-thiorhamnopyranoside from D-mannose as an R-rhamnosyl
donor: Kihlberg, J.; Eichler, E.; Bundle, D. R. Carbohydr. Res. 1991, 211,
59-75.
(5) Crich, D.; Picione, J. Org. Lett. 2003, 5, 781-784.
9
8232
J. AM. CHEM. SOC. 2004, 126, 8232-8236
10.1021/ja048070j CCC: $27.50 © 2004 American Chemical Society

6-Deoxy Sugars from Benzylidene Acetal Fragmentation
A R T I C L E S
â-D-rhamnopyranoside, all of which must be assembled with a
high degree of stereocontrol.
be less than ideal owing (i) to the facile cleavage of benzyl
ethers, important components of many oligosaccharide synthe-
ses, on exposure to N-bromosuccinimide11 and (ii) to the
requirement of the extra debromination step after glycosylation.
A more direct reductive fragmentation route from benzylidene
acetals to 6-deoxy sugars, developed by Roberts and co-workers,
12
following earlier work by Pedersen,12f also suffers from the
problem of competing benzyl ether cleavage.13 With this
background, the initial goal of the research described here
became the development of an alternative approach to the
fragmentation of 4,6-O-benzylidene acetals, leading directly to
6-deoxy sugars, that is fully compatible with the presence of
benzyl and other ethers.14
The obvious approach to â-D-rhamnosides in terms of both
directness and availability of starting materials is the selective
deoxygenation of D-mannose derivatives at position 6. This
deoxygenation might conceivably be achieved either prior to
or after glycosylation. Deoxygenation prior to glycosylation is
effectively a synthesis of a D-rhamnosyl donor and brings the
problem in line with that of the L-rhamnosides. Deoxygenation
after glycosylation simplifies the problem to one of stereocon-
trolled â-mannoside synthesis and regioselective protection.
Both approaches are associated with the considerable problem
of the stereoselective synthesis of the 1,2-cis-equatorial-type
glycosidic bond6 for which the 4,6-O-benzylidene â-directed
glycosylations initially developed in this laboratory,7,8 which
are finding increasing application in complex oligosaccharide
synthesis,9 provide effective solutions, at least in the mannose
series. The obvious solution to the â-D-rhamnopyranoside then
becomes one of employing a 4,6-O-benzylidene-protected â-D-
mannosyl donor followed by a Hanessian-type10 fragmentation
of the benzylidene acetal leading to a 4-O-benzoyl-6-bromo-
6-deoxy-â-D-mannoside, that is, a 4-O-benzoyl-6-bromo-â-D-
rhamnoside, followed by removal of the extraneous bromine
atom. Closer examination, however, reveals this approach to
Results and Discussion
Regioselective Fragmentation of Benzylidene Acetals. The
incompatibility of the Hanessian N-bromosuccinamide (NBS)-
mediated benzylidene acetal fragmentation and benzyl and
similarly protected carbohydrates stems from the intermolecular
hydrogen-atom abstraction, which is insufficiently discrimina-
tory between a single benzylidene C-H bond and the typical
multiplicity of benzyl C-H bonds.10 Roberts’s method, employ-
ing a thiyl radical as an intermolecular hydrogen-abstracting
species, fails similarly.12,13 This leads to the notion that
chemoselectivity might be enforced by the application of an
intramolecular hydrogen-abstraction step. Accordingly, substrate
2 was prepared and subjected to treatment with tributylstannane
under conditions likely to permit 1,5-hydrogen-atom abstraction.
Surprisingly, despite repeated attempts, only traces of the desired
abstraction and ensuing fragmentation were observed, with the
majority of the product being that of simple reductive deiodi-
nation. The contrast between these failures and the highly
successful radical translocations achieved by Curran and others15
with related but less constrained systems calls to mind the
difficulties experienced earlier by this16 and the Curran group17
in the intramolecular abstraction of anomeric hydrogens with
radical-bearing protecting groups on O2. Apparently, the
transition state for 1,5-hydrogen-atom abstraction by aryl
(6) (a) Barresi, F.; Hindsgaul, O. In Modern Methods in Carbohydrate
Synthesis; Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic Publish-
ers: Amsterdam, 1996; pp 251-276. (b) Demchenko, A. V. Synlett 2003,
1225-1240. (c) Pozsgay, V. In Carbohydrates in Chemistry and Biology;
Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, Germany,
2000; Vol. 1, pp 319-343. (d) Gridley, J. J.; Osborn, H. M. I. J. Chem.
Soc., Perkin Trans. 1 2000, 1471-1491.
(7) (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506-4507. (b) Crich, D.;
Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223. (c) Crich, D.; Sun,
S. Tetrahedron 1998, 54, 8321-8348. (d) Crich, D.; Smith, M. J. Am.
Chem. Soc. 2001, 123, 9015-9020. (e) Crich, D.; Smith, M. J. Am. Chem.
Soc. 2002, 124, 8867-8869. (f) Crich, D.; Li, H. J. Org. Chem. 2000, 65,
801-805.
(8) For developmental work in other laboratories see: (a) Yun, M.; Shin, Y.;
Chun, K. H.; Jen, S. Bull. Chem. Soc. Kor. 2000, 21, 562-566. (b)
Weingart, R.; Schmidt, R. R. Tetrahedron Lett. 2000, 41, 8753-8758. (c)
Tsuda, T.; Sato, S.; Nakamura, S.; Hashimoto, S. Hetereocycles 2003, 59,
509-515. (d) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. J. Am.
Chem. Soc. 2001, 123, 8477-8481. (e) Litjens, R. E. J. N.; Leeuwenburgh,
M. A.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 2001, 42,
8693-8696. (f) Code´e, J. D. C.; van den Bos, L. J.; Litjens, R. E. J. N.;
Overkleeft, H. S.; van Boeckel, C. A. A.; van Boom, J. H.; van der Marel,
G. A. Tetrahedron 2004, 60, 1057-1064. (g) Duro´n, S. G.; Polat, T.; Wong,
C.-H. Org. Lett. 2004, 6, 839-841.
(9) (a) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2002, 124, 2263-2266. (b)
Dudkin, V. Y.; Crich, D. Tetrahedron Lett. 2003, 44, 1787-1789. (c)
Dudkin, V. Y.; Miller, J. S.; Danishefsky, S. J. Tetrahedron Lett. 2003,
44, 1791-1793. (d) Kim, K. S.; Kang, S. S.; Seo, Y. S.; Kim, H. J.; Jeong,
K.-S. Synlett 2003, 1311-1314. (e) Crich, D.; de la Mora, M. A.; Cruz, R.
Tetrahedron 2002, 58, 35-44. (f) Crich, D.; Dai, Z. Tetrahedron 1999,
55, 1569-1580. (g) Nicolaou, K. C.; Mitchell, H. J.; Rodriguez, R. M.;
Fylaktakidou, K. C.; Suzuki, H.; Conley, S. R. Chem. Eur. J. 2000, 6,
3149-3165. (h) Crich, D.; Li, H.; Yao, Q.; Wink, D. J.; Sommer, R. D.;
Rheingold, A. L. J. Am. Chem. Soc. 2001, 123, 5826-5828. (i) Crich, D.;
Li, H. J. Org. Chem. 2002, 67, 4640-4646. (j) Dudkin, V. K.; Miller, J.
S.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 736-738. (k) Mandal,
M.; Dudkin, V. Y.; Geng, X.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2004, 43, 2557-2561. (l) Wu, X.; Schmidt, R. R. J. Org. Chem. 2004, 69,
1853-1857.
(10) (a) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035-1044. (b)
Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1045-1053. (c)
Hanessian, S. Org. Synth. 1987, 65, 243-247. (d) Hullar, T. L.; Siskin, S.
B. J. Org. Chem. 1970, 35, 225-227. (e) Hanessian, S. AdV. Chem. Ser.
1968, 74, 159-201. (f) Szarek, W. A. AdV. Carbohydr. Chem. Biochem.
1973, 28, 225-306. (g) Paulsen, H. AdV. Carbohydr. Chem. Biochem. 1971,
26, 127-195. (h) Gelas, J. AdV. Carbohydr. Chem. Biochem. 1981, 39,
71-156. (i) Chana, J. S.; Collins, P. M.; Farnia, F.; Peacock, D. J. J. Chem.
Soc., Chem. Commun. 1988, 94-96. (j) McNulty, J.; Wilson, J.; Rochon,
A. C. J. Org. Chem. 2004, 69, 563-565.
(11) The majority of NBS-mediated cleavage of carbohydrate-based benzylidene
acetals has been conducted with the residual alcohols either unprotected
or protected as esters. Reports occasionally surface on the application of
the reaction in the presence of benzyl-type ethers, but yields are generally
low and difficult to reproduce: Liotta, L. J.; Dombi, K. L.; Kelley, S. A.;
Targontsidis, S.; Morin, A. M. Tetrahedron Lett. 1997, 38, 7833-7834.
(12) (a) Roberts, B. P.; Smits, T. M. Tetrahedron Lett. 2001, 42, 3663-3666.
(b) Roberts, B. P.; Smits, T. M. Tetrahedron Lett. 2001, 42, 137-140. (c)
Dang, H.-S.; Roberts, B. P.; Sekhon, J.; Smits, T. M. Org. Biomol. Chem.
2003, 1, 1330-1341. (d) Fielding, A. J.; Franchi, P.; Roberts, B. P.; Smits,
T. M. J. Chem. Soc., Perkin Trans. 2 2002, 155-163. (e) Cai, Y.; Dang,
H. S.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 1 2002, 2449-2458. (f)
Jeppesen, L. M.; Lundt, I.; Pedersen, C. Acta Chem. Scand. 1973, 27, 3579-
3585.
(13) There are no published reports of this chemistry in the presence of benzyl
ethers. Certainly, in our hands, benzyl ether cleavage is competitive with
benylidene acetal fragmentation.
(14) For a preliminary communication see: Crich, D.; Yao, Q. Org. Lett. 2003,
5, 2189-2191.
(15) (a) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem. Soc. 1988,
110, 5900-5902. (b) Curran, D. P.; Xu, J. J. Am. Chem. Soc. 1996, 118,
3142-3147. (c) Robertson, J.; Pillai, J.; Lush, R. K. Chem. Soc. ReV. 2001,
30, 94-103.
9
J. AM. CHEM. SOC. VOL. 126, NO. 26, 2004 8233

A R T I C L E S
Crich and Yao
Scheme 1. Synthesis of Glycosyl Donors 8 and 9
Scheme 2. Stereocontrolled Glycosylation
Table 1. Glycosylation and Cleavage in the Mannose Series
â-mannoside
â-rhamnoside
acetal
donor
acceptor
(% yield)
(% yield)
(% yield)
8
10 (94)
14 (78)
18 (8)
radicals from acetals is not sufficiently flexible to enable
juxtaposition with a rigid cyclic acetal.
8
9
8
11 (71)
12 (77)
13 (84)
15 (74)
16 (78)
17 (80)
19 (13)
20 (8)
21 (9)
Attention was therefore refocused on a fragmentation ap-
proach to a benzylidene radical, in particular one based on the
decarbonylation of an acyl radical. Among the available methods
for acyl radical generation,18 the use of a 2-(2-iodophenyl)-
ethylthio ester19 was the method of choice, as preliminary
experiments demonstrated this functionality to be stable under
the conditions intended for the activation of thioglycosides in
the eventual synthesis of 1.
Reaction of known diol 37e with the dimethyl acetal 420
afforded the carbohydrate acetals 5 and 6 in 85% yield in the
form of a 3/1 mixture favoring the less polar isomer (Scheme
1). Analytical quantities of the two pure isomers were obtained
by preparative TLC for characterization purposes and the less-
polar major isomer was tentatively assigned as having the
carbomethoxy group in the less-exposed axial position. Some
support for this assignment was gleaned from parallels between
the spectroscopic data and those of crystallographically assigned,
carbohydrate-based pyruvate acetals.21 Analogous to methodol-
ogy from the Gennari group,22 the mixture of methyl esters 5
and 6 was treated with a reagent preformed from 2-(2-
iodophenyl)ethanethiol, 719, and trimethylaluminum to give the
desired thiol esters 8 and 9; the optimized conditions for this
transesterification required heating to reflux in toluene, reflective
of the hindered nature of the substrate, to give a yield of 90%
(Scheme 1). Although not strictly necessary, the isomers were
separated chromatographically and used pure in the subsequent
glycosylations to facilitate subsequent spectral interpretation.
Following our standard thioglycoside activation protocol,
isomers 8 and 9 were coupled to a selection of primary,
secondary, and tertiary alcohols with the aid of 1-benzenesulfinyl
piperidine (BSP)7d and the hindered base 2,4,6-tri-tert-butylpy-
rimidine (TTBP)23 to give the corresponding â-mannosides
(Scheme 2, Table 1). Two points are of note in these coupling
reactions. First, as expected on the basis of simple exploratory
experiments, the thiol ester is stable under the conditions of
the thioglycoside activations. Second, in line with expectations
from previous 4,6-O-benzylidene directed mannosylations,7,8 the
couplings are highly â-selective, with only the one anomer being
observed. The assignment of anomeric stereochemistry reposes
on the characteristic, somewhat upfield chemical shift (typically
δ 3.0-3.2 in CDCl3) of the mannose H5 in the â-series,7c which
we have consistently found to be a reliable diagnostic and which
has been independently verified by means of nuclear Overhauser
measurements and anomeric 1JCH coupling constants24 on many
occasions.
As expected, dropwise addition of tributyltin hydride and
AIBN to mannosides 10-13 in toluene at reflux afforded the
corresponding â-D-rhamnosides 14-17 in good yield, as well
as the simple 4,6-O-benzylidene-protected mannosides 18-21
(Scheme 3, Table 1). In each reaction, the sole fragmentation
product was the 6-deoxy sugar, with none of the alternative
4-deoxy products being observed in the crude reaction mixtures.
The benzylidene acetal byproducts, arising from premature
quenching of the benzylidene radical intermediates, were formed
as single isomers with the depicted stereochemistry. Stereo-
chemical assignment of the acetals was made by comparison
with the spectral data of authentic standards and is consistent
with axial quenching of the intermediate σ-radical.25
(16) (a) Brunckova, J.; Crich, D.; Yao, Q. Tetrahedron Lett. 1994, 35, 6619-
6622. (b) Crich, D.; Sun, S.; Brunckova, J. J. Org. Chem. 1996, 61, 605-
615.
(17) Yamazaki, N.; Eichenberger, E.; Curran, D. P. Tetrahedron Lett. 1994,
35, 6623-6626.
(18) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99,
1991-2070.
(19) Crich, D.; Yao, Q. J. Org. Chem. 1996, 61, 3566-3570.
(20) Chan, T. H.; Brook, M. A.; Chaly, T. Synthesis 1983, 203-205.
(21) (a) Garegg, P. J.; Janesson, P.-E.; Lindberg, B.; Lindh, F.; Lonngren, J.;
Kvarnstrom, I.; Nimmich, W. Carbohydr. Res. 1980, 78, 127-132. (b)
Garegg, P. J.; Lindberg, B.; Kvarnstrom, I. Carbohydr. Res. 1979, 77, 171-
178.
Tetrasaccharide Synthesis. In designing the synthesis of
tetrasaccharide 1, as its â-methyl glycoside, emphasis was placed
(23) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-326.
(24) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293-297.
(25) (a) Crich, D.; Ritchie, T. J. J. Chem. Soc., Chem. Commun. 1988, 1461-
1463. (b) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: Weinheim, 1996.
(22) Gennari, C.; Carcano, M.; Donghi, M.; Mongelli, N.; Vanotti, E.; Vulpetti,
A. J. Org. Chem. 1997, 62, 4746-4755.
9
8234 J. AM. CHEM. SOC. VOL. 126, NO. 26, 2004

6-Deoxy Sugars from Benzylidene Acetal Fragmentation
A R T I C L E S
Scheme 3. Reductive Radical Fragmentation
Scheme 4. Preparation of Donors 26 and 27
on using, as closely as possible, a set of standard glycosylation
conditions for the formation of all glycosidic bonds, for which
the BSP/triflic anhydride activation of thioglycosides was
selected,7d,9i,26 and on obtaining the â-D- and R-D-rhamnopy-
ranosidic units with a minimum of steps from a common
building block. Toward this end, diol 229f was converted to the
3-O-(2-naphthyl)methyl ether27 by treatment with dibutyltin
oxide28 and then 2-naphthylmethyl bromide. Standard benzyl-
ation with benzyl bromide and sodium hydride then afforded
the fully protected thioglycoside 23. The benzylidene acetal was
selectively removed by treatment with neopentyl glycol and
camphor sulfonic acid in methylene chloride, giving diol 24.
Exposure to acetal 4 in the presence of camphorsulfonic acid
enabled introduction of the modified benzylidene acetal 25 as
a mixture of stereoisomers, of which only the less polar isomer,
presumed to have an equatorial phenyl group (vide supra), was
employed in the subsequent work to facilitate spectral inter-
pretation. Treatment of 25 with thiol 7 and trimethylaluminum
then gave the â-D-rhamnosyl donor 26 (Scheme 4). This
substance was converted in two steps: selective naphthylmethyl
ether removal with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) and esterification to the presumed R-D-rhamnosyl donor
27 (Scheme 4). The 3-O-chloroacetate 27 was selected as the
R-rhamnosyl donor on the basis of previous observations,
whereby an ester at the 3-position was found to be strongly
R-directing and to overcome the strong â-directing influence
of the 4,6-O-benzylidene acetal in the mannose series,29 and
the presumption that it could be selectively removed in the
presence of the hindered thiol ester function.
7% yield of the R-anomer 30 (Scheme 5). The stereochemistry
of 29 is readily apparent from the characteristic upfield chemical
shift of the mannose H5 residue (δ 3.20), which is shifted
considerably downfield in the R-anomer. Exposure to wet DDQ
then removed the naphthylmethyl ether, providing alcohol 31
for the next coupling. Interestingly, attempts at the activation
of donor 27 with BSP and Tf2O failed, and we therefore turned
to the even more potent combination of diphenyl sulfoxide and
Tf2O, subsequently developed by van Boom and co-workers8e,31
following initial work by Gin on the activation of hemiacetals.32
This reagent combination performed excellently and permitted
coupling of 27 with disaccharide acceptor 31, giving trisaccha-
ride 32 in 75% yield. As anticipated,29 only R-glycoside 32 was
formed in this reaction. In this trisaccharide, only one mannose
H5 resonance was found in the region δ 3.0-3.2, consistent
with the presence of only one of two possible â-mannosides;
moreover, in the gated CH coupled 13C NMR spectrum, three
1
anomeric carbon resonances were located with JCH coupling
constants of 154.6, 153.3, and 175.1 Hz, in agreement with the
presence of two equatorial and one axial glycosidic linkages.24
Removal of the chloroacetate protecting group with ethylene-
diamine33,34 provided alcohol 33 (Scheme 5) and set the stage
for the conversion of the two mannoside groups to the
corresponding rhamnosides.
Dropwise addition of tributyltin hydride and AIBN to a
solution of 33 at reflux in toluene provided bis rhamnosyl
trisaccharide 34 in 54% isolated yield. The final coupling was
accomplished by the standard BSP/Tf2O activation protocol,
using galactosyl donor 35, whose R-selectivity under similar
conditions had been previously established.26 In this coupling,
tetrasaccharide 36 was formed as a single R-anomer, as was
clear from the gated CH coupled 13C NMR spectrum, which
Methyl 2,3,4-tri-O-benzyl-â-D-glucopyranoside 28, obtained
by reduction of the corresponding 4,6-O-benzylidene acetal with
sodium cyanoborohydride in the presence of HCl,30 was coupled
to donor 26 on a 2 g scale, following preactivation with BSP
and Tf2O in the presence of TTBP in dichloromethane at -60
°C to give an 85% yield of the â-mannoside 29 along with a
1
exhibited four anomeric carbon signals with JCH coupling
constants of 160.4, 159.1, 173.1, and 168.9 Hz, consistent with
the presence of two equatorial and two axial glycosidic linkages,
(26) Crich, D.; de la Mora, M.; Vinod, A. U. J. Org. Chem. 2003, 68, 8142-
8148.
(27) (a) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63, 4172-
4173. (b) Wright, J. A.; Yu, J.; Spencer, J. B. Tetrahedron Lett. 2001, 42,
4033-4036. (c) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; Alderfer,
J. L. Tetrahedron Lett. 2000, 41, 169-173.
(31) Code´e, J. D. C.; Litjens, R. E. J. N.; den Heeten, R.; Overkleeft, H. S.; van
Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1519-1522.
(32) (a) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997, 119,
7597-7598. (b) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122,
4269-4279.
(33) Cook, A. F.; Maichuk, D. T. J. Org. Chem. 1970, 35, 1940-1943.
(34) Note that it was necessary to remove the chloroacetate group prior to the
radical reaction to prevent competitive reduction of the relatively weak
chloroacetate C-Cl bond by the stannane.
(28) (a) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643-663. (b) David,
S. In PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Dekker:
New York, 1997; pp 69-83.
(29) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291-1297.
(30) (a) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97-
101. (b) Garegg, P. J. In PreparatiVe Carbohydrate Chemistry; Hanessian,
S., Ed.; Dekker: New York, 1993; pp 53-67.
9
J. AM. CHEM. SOC. VOL. 126, NO. 26, 2004 8235

A R T I C L E S
Crich and Yao
Scheme 5. Stereocontrolled Trisaccharide Formation
Scheme 6. Double Radical Fragmentation and Completion of the Synthesis
respectively. Saponification of the two benzoate esters provided
diol 37, which finally was converted to the target 38, the methyl
glycoside of 1, by hydrogenolysis over Pearlman’s catalyst
(Scheme 6). The fully deprotected tetrasaccharide displayed a
molecular ion in the high-resolution ESIMS, consistent with
step reductive radical fragmentation to the 6-deoxy sugar.
Operation of the method in the presence of a 3-O-carboxylate
ester in the donor permits the equally direct and stereocontrolled
synthesis of R-D-rhamnopyranosides. The single-step radical-
fragmentation method has been conducted in the presence of
up to five benzyl ethers without detriment. In the synthesis of
the tetrasaccharide repeating unit of the Escherichia hermannii
ATCC 33650 and 33652, both the R-D- and â-D-rhamnopyra-
nosidic units were obtained in a single step by a double radical
fragmentation of the corresponding mannosides.
1
the assigned structure. In the H NMR spectrum, four clearly
resolved anomeric hydrogen signals were present at δ 4.20 (d,
J ) 8.0 Hz, â-Glu), 4.64 (br s, â-Rha), 4.99 (br s, R-Rha), and
5.17 (d, J ) 3.5 Hz, R-Gal), while the 13C NMR spectrum
presented four anomeric carbon resonances at δ 103.9 (d, 1JCH
) 157.3 Hz, â-Glu), 100.0 (d, 1JCH ) 158.8 Hz, â-Rha), 102.8
Acknowledgment. We thank the NIH (GM 57335) for
support of this work.
1
1
(d, JCH ) 169.5 Hz, R-Rha), and 100.8 (d, JCH ) 167.2 Hz,
R-Gal), in complete agreement with structure 38.
Supporting Information Available: Full experimental and
characterization details. This material is available free of charge
via the Internet at http://pubs.acs.org.
In summary, a method for the stereocontrolled synthesis of
â-D-rhamnopyranosidic linkages has been developed. This
method consists of a stereocontrolled â-mannoside synthesis,
directed by a modified benzylidene acetal, followed by a single-
JA048070J
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8236 J. AM. CHEM. SOC. VOL. 126, NO. 26, 2004