Synthesis and stereoselective glycosylation of D- and L-glycero-β-D- manno-heptopyranoses

Article abstract of DOI:10.1021/ol050224s

(Chemical Equation Presented) A method for the direct stereocontrolled synthesis of D- and L-glycero-β-D-manno-heptopyranosides such as those found in the repeating unit of the O-specific polysaccharide from the CNCTC 113/92 LPS (serotype 54) is described

Full text of DOI:10.1021/ol050224s

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1395-1398
Synthesis and Stereoselective
Glycosylation of - and
-glycero- -manno-Heptopyranoses
D
L
â
-D
David Crich* and Abhisek Banerjee
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received February 2, 2005
ABSTRACT
A method for the direct stereocontrolled synthesis of
D- and L-glycero-â-D-manno-heptopyranosides such as those found in the repeating unit
of the O-specific polysaccharide from the CNCTC 113/92 LPS (serotype 54) is described. The method relies on the presence of a 4,6-O-
benzylidene acetal to effect stereocontrol at the anomeric center; the configuration at C6 (
L
- or
D-glycero) is of minimal importance.
1
Well-defined syntheses of complex oligosaccharides and
glycoconjugates corresponding to native bacterial structures
are essential tools for investigation of the immunological
response against polysaccharides.1 Heptoses of the L-glycero-
D-manno and D-glycero-D-manno configurations are common
constituents of the inner and outer core regions of li-
popolysaccharides (LPS) and are found in many pathogenic
bacteria.2 The synthesis of higher carbon sugars has been
investigated for more than a century,3 and several methods
have been developed;2-4 however, less attention has been
devoted to their stereocontrolled incorporation into glycosidic
bonds. Most LPS heptosides have the R-anomeric configu-
ration,2 and syntheses of several complex oligosaccharides
containing R-L,D- or R-D,D-heptopyranosides (Hepp) have
been achieved by Oscarson and co-workers.1,5
by a combination of H and 13C NMR spectroscopy, mass
spectrometry, monosaccharide analysis, and immunological
methods.6 Interestingly, the O-specific polysaccharide of this
strain was found to be composed of a hexasaccharide
repeating unit (Figure 1) containing two unusual â-linked
Figure 1. Repeating unit of the O-specific polysaccharide from
CNCTC 113/92 LPS (serotype 54).
The structure of the core LPS from Plesimonas shigel-
loides O54 (strain CNCTC 113/92) was recently elucidated
heptose units. The presence of the two â-linkages in this
immunological lipopolysaccharide prompted the investigation
(1) Oscarson, S. Carbohydr. Polym. 2001, 44, 305.
(2) Zamyatina, A.; Gronow, S.; Puchberger, M.; Graziani, A.; Hofinger,
A.; Kosma, P. Carbohydr. Res. 2003, 338, 2571.
(3) Gyo¨rgydea´k, Z.; Pelyva´s, I. F. Monosaccharide SugarssChemical
Synthesis by Chain Elongation, Degradation and Epimerization; Academic
Press: San Diego, 1998.
(4) (a) Brimacombe, J. S.; Kabir, A. B. K. M. S. Carbohydr. Res. 1986,
152, 329 and references therein. (b) Boons, G. J. P. H.; van der Marel, G.
A.; van Boom, J. H. Tetrahedron Lett. 1989, 30, 229. (c) Jørgensen, M.;
Iversen, E. H.; Madsen, R. J. Org. Chem. 2001, 66, 4625 and references
therein. (d) Read, J. A.; Ahmed, R. A.; Morrison, J. P.; Coleman, W. G.,
Jr.; Tanner, M. E. J. Am. Chem. Soc. 2004, 126, 8878.
(5) (a) Oscarson, S.; Ritzen, H. Carbohydr. Res. 1994, 254, 81. (b)
Ekeloef, K.; Oscarson, S. J. Carbohydr. Chem. 1995, 14, 299. (c) Bernlind,
C.; Oscarson, S. Carbohydr. Res. 1997, 297, 251. (d) Bernlind, C.; Oscarson,
S. J. Org. Chem. 1998, 63, 7780. (e) Bernlind, C.; Bennett, S.; Oscarson,
S. Tetrahedron: Asymmetry 2000, 11, 481. (f) Segerstedt, E.; Manerstedt,
K.; Johansson, M.; Oscarson, S. J. Carbohydr. Chem. 2004, 23, 443.
(6) (a) Niedziela, T.; Lukasiewicz, J.; Jachymek, W.; Dzieciatkowska,
M.; Lugowski, C.; Kenne, L. J. Biol. Chem. 2002, 277, 11653. (b) Czaja,
J.; Jachymek, W.; Niedziela, T.; Lugowski, C.; Aldova, E.; Kenne, L. Eur.
J. Biochem. 2000, 267, 1672.
10.1021/ol050224s CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/03/2005

which we now report into stereocontrolled â-glycosidation
in D,D-heptoses and the related L,D-epimers.
Scheme 1. Synthesis of Heptoses 5 and 6
Our interest in these molecules was further spurred by the
insight that their study might yield into the underlying
reasons for the beneficial influence of the 4,6-O-benzylidene
acetal on the stereocontrolled preparation of â-mannosides.7
Originally, working in the gluco series, Fraser-Reid and co-
workers suggested that trans-fused 4,6-O-benzylidene pro-
tecting groups restrict the flexibility of the pyranose ring,
resulting in an oxacarbenium ion intermediate with a com-
puted (PM3) 20° twist in the ideally syn coplanar C5-O5-
C1-C2 system.8a In a subsequent paper, differential solvation
was also computed to be of significance in these so-called
torsional disarming effects.8b More recently, Bols and co-
workers provided experimental evidence in support of the
notion that the disarming effect of the 4,6-O-acetal group is
mainly due to the locking of the C5-C6 bond in the deacti-
vated tg-conformation.9 We hypothesized that the inclusion
of either an extra axial C-6 substituent, as in the 4,6-O-benzyl-
idene-protected L-glycero-D-manno-heptoses, or a correspond-
ing equatorial substituent, as in the D-glycero-D-manno series,
would influence both torsional and solvation considerations
differently, whereas the tg conformation of the C5-C6 bond
would be unchanged. Comparisons of either reactivity or
stereoselectivity between the two diastereomeric series might
therefore provide support for one or other of the two
conflicting rationales for the 4,6-O-benzylidene group effect.
the corresponding unstable15 aldehyde, which was carried
on to the next step, Wittig olefination,14 without purification.
The yield (65%) of the olefination product 3 was com-
promised by the concomitant formation of diene 4 in 14%
yield.16 Use of the Nysted reagent17 for this transformation
also generated compound 4, along with compound 3,
however, in higher yield, whereas the Petasis reagent18 gave
predominantly decomposition products. Treatment of olefin
3 with OsO4 (5 mol %) and NMNO at 0 °C and room
temperature furnished diols 5 and 6 in 5:1 and 3:1 diaster-
eomeric ratios and in 79 and 81% yields, respectively. The
stereochemical outcome of this dihydroxylation follows
Kishi’s empirical rule;19 the relatively poor diastereoselec-
tivity starting from the sugar with 2,3-erythro configuration
is also consistent with literature precedent.4c Asymmetric
dihydroxylation was also unsatisfactory for this transforma-
tion in our hands.15,20 Silylation of 5 gave the primary silyl
ether 7, which, when subjected to the Mitsunobu protocol,15
afforded the inverted ester 8. Removal of the ester function
then gave more significant quantities of the L,D-series in the
form of the silyl ether 9 (Scheme 2).
Figure 2. L- and D-glycero-D-manno-heptopyranosides.
The synthesis of a diastereomeric glycosyl donor pair
(Scheme 1) began with the known 4,6-O-p-methoxybenzyl-
idene-protected thiomannoside 1,10 which was regioselec-
tively opened to the primary alcohol 2 exclusively in 90%
yield with DIBAL-H in dichloromethane.11 Comparable
results were obtained with scandium triflate-catalyzed, BH3-
THF-mediated reduction;12 all other standard protocols13 gave
mixtures of isomers and considerable cleavage of the acid-
labile p-methoxybenzyl group. Swern oxidation14 of 2 gave
Scheme 2. Inversion of Configuration at C6
(7) (a) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9051. (b)
Crich, D.; Lim, L. B. L. Org. React. 2004, 64, 115.
(8) (a) Fraser-Reid, B.; Wu, Z.; Andrews, C. W.; Skowronski, E.; Bowen,
J. P. J. Am. Chem. Soc. 1991, 113, 1434. (b) Andrews, C. W.; Rodebaugh,
R. Fraser-Reid, B. J. Org. Chem. 1996, 61, 5280.
(9) Jensen, H. H.; Nordstrøm, L. U.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205.
(10) Crich, D.; Li, W.; Li, H. J. Am. Chem. Soc. 2004, 126, 15081.
(11) (a) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett.
1983, 1593. (b) Mikami, T.; Asano, H.; Mitsunobu, O. Chem. Lett. 1987,
2033.
(12) Wang, C.-C.; Luo, S.-Y.; Shie, C.-R.; Hung, S.-C. Org. Lett. 2002,
4, 847. Note: This method gave 84% yield but generated more diol compared
to the DIBAL-H reaction.
Compound 7 was converted uneventfully to the D-glycero-
D-manno-heptothioglycoside 10 by oxidative ring closure
with DDQ in 84% yield (Scheme 3).21
In the diasteromeric series, however, cyclization of silyl
ether 9 was comparatively slow due to the developing 1,3-
1396
Org. Lett., Vol. 7, No. 7, 2005

Scheme 3. Preparation of Glycosyl Donors 10 and 11
Figure 3. Diagnostic NOE correlations for donors 10 and 11.
A series of glycosylation reactions were then conducted
with donors 10 and 11 with thioglycoside activation by
means of 1-benzenesulfinyl piperidine and trifluoromethane-
sulfonic anhydride (BSP/Tf2O)7a in the presence of the
hindered base 2,4,6-tri-tert-butylpyrimidine (TTBP)22 in
dichloromethane at -60 °C prior to the addition of the
acceptor alcohols (Scheme 4).
diaxial interaction in the acetal ring. As a consequence,
oxidative cleavage of the PMB group was a competing
reaction, resulting in the formation of diol 12 in 48% yield
along with the desired L-glycero-D-manno-heptothioglycoside
11 in 43% yield. In the face of this difficulty, a protocol
was devised whereby the crude reaction mixture from
treatment of 9 with DDQ was treated with p-methoxyben-
zylaldehyde dimethyl acetal and catalytic CSA to give 11
in 80% yield over two steps (Scheme 3).
Scheme 4. Glycosylation with the BSP/Tf2O Couple
At this stage, the NOE correlations indicated in Figure 3
served to confirm both the configuration at C6 in compounds
10 and 11, as well as the equatorial nature of the p-
methoxyphenyl group in the two acetals.
All couplings were highly â-selective and proceeded in
high yields (Table 1). A minor exception to the otherwise
Table 1. Diastereoselective Glycosidation Reactions
Org. Lett., Vol. 7, No. 7, 2005
1397

1
exclusive â-selectivity was observed in the coupling of donor
11 to the glucose-4-OH acceptor 13 (Table 1, entry 2). This
may represent a small difference in reactivity between the
two donors, which only becomes apparent with less reactive
acceptors such as 13.23 The assignment of anomeric stereo-
again confirmed by determination of the JCH coupling
constants.
In summary, a method for the stereocontrolled synthesis
of both â-D-glycero-D-manno- and â-L-glycero-D-manno-
heptopyranosides has been established. We anticipate that
this work will open the way for the synthesis of most
â-linked heptopyranosides, including those in the polysac-
charide repeating unit illustrated in Figure 1. Furthermore,
it has been established that the stereochemistry of substitution
at the 6-position has little effect on the stereoselectivity of
these 4,6-O-alkylidene acetal-controlled glycosidation reac-
tions. This observation is most consistent with Bols’ inter-
pretation of the benzylidene acetal effect, namely, the locking
of the C5-C6 bond in the tg conformation.
1
chemistry in all glycosides was made on the basis of JCH
coupling constants.24 Furthermore, in all products arising
from donors 10 and 11, a relatively upfield chemical shift
(δ 3.25 to 3.50 in CDCl3) of the heptose H5 resonance was
observed, as is characteristic of 4,6-O-benzylidene-protected
â-mannosides.25
Finally, attention was turned to deprotection (Table 2).
Thus, glycosides 17, 18â, and 19 were first exposed to TBAF
in THF. This was followed by benzylidene acetal and acet-
Acknowledgment. We thank the NIGMHS for financial
support (GM 57335).
Table 2. Final Deprotections
Supporting Information Available: Full experimental
details and charcterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL050224S
(13) (a) Johansson, R.; Samuelsson, B. J. Chem. Soc., Chem. Commun.
1984, 201. (b) Liptak, A.; Jodal, I.; Nasai, P. Carbohydr. Res. 1975, 44, 1.
(c) Sakagami, M.; Hamana, H. Tetrahedron Lett. 2000, 41, 5547. (d) Jiang,
L.; Chan, T.-K. Tetrahedron Lett. 1998, 39, 355. (e) Garegg, P. J. In
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S.; van der Marel, G. A.; van Boom, J. H. Tetrahedron 1999, 55, 8253.
(15) Dong, L.; Roosenberg, J. M., II; Miller, M. J. J. Am. Chem. Soc.
2002, 124, 15001.
(16) Note: epimerization at C5 was also observed but was substantially
eliminated by carrying out the reaction at low temperature.
(17) (a) Nysted, L. N. U.S. Pat. 3,865,848, 1975. (b) Matsubara, S.;
Sugihara, M.; Utimoto, K. Synlett 1998, 313.
(18) Petasis, N. A.; Bzowei, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(19) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247.
(b) Cha, J. K.; Kim, N.-S. Chem. ReV. 1995, 95, 1761.
(20) Gurjar, M. K.; Talukdar, A. Tetrahedron 2004, 60, 3267.
(21) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron. Lett.
1982, 23, 889. (b) Lergenmu¨ller, M.; Nukada, T.; Kuramochi, K.; Dan, A.;
Ogawa, T.; Ito, Y. Eur. J. Org. Chem. 1999, 1367. (c) Mulzer, J.; Berger,
M. J. Org. Chem. 2004, 69, 891.
a Treatment with TBAF in THF followed by camphorsulfonic acid in
methanol, both at room temperature. b Hydrogenolysis over Pd/C in
methanol.
(22) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323.
(23) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155.
(24) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293.
(25) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321.
onide removal with catalytic CSA in refluxing methanol.
Finally, hydrogenolysis over Pd/C afforded the fully depro-
tected disaccharides, whose anomeric stereochemistry was
1398
Org. Lett., Vol. 7, No. 7, 2005