Synthesis of some biologically relevant β-C-glycoconjugates

Article abstract of DOI:10.1021/ol034363q

(Matrix presented) An esterification-RCM approach to a variety of biologically relevant β-C-glycoconjugates is reported herein. A range of carboxylic acids were coupled with several different olefin alcohols 1 to provide esters 3. The esters were then con

Full text of DOI:10.1021/ol034363q

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1721-1723
Synthesis of Some Biologically Relevant
â-C-Glycoconjugates
Maarten H. D. Postema* and Jared L. Piper
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202
mpostema@chem.wayne.edu
Received February 28, 2003
ABSTRACT
An esterification−RCM approach to a variety of biologically relevant â-C-glycoconjugates is reported herein. A range of carboxylic acids were
coupled with several different olefin alcohols 1 to provide esters 3. The esters were then converted to the final ring-closed product 6 in three
steps in 49−60% overall yield. The formed compounds are biologically relevant and serve as stable carbohydrate mimics of the corresponding
O-glycosides.
The replacement of the interglycosidic oxygen atom in
O-glycosides leads to stable C-glycoside analogues that
exhibit increased stability toward hydrolysis.1 There have
been a wealth of synthetic approaches2 toward this class of
carbohydrate mimics,3 and in recent years, biological data
on these compounds have started to appear. Recently, several
C-glycoside derivatives have been found to possess binding
constants and biological properties very similar to those of
their oxygen counterparts.4
Our laboratory has been involved in the synthesis of a
variety of C-saccharide5 mimics via a ring-closing metathesis-
based6 (RCM) approach,7 and in this letter, we communicate
our results toward the synthesis of a variety of â-C-
glycoconjugates.8
Our generic approach to C-glycosides is outlined in
Scheme 1 and shows the esterification-RCM protocol to
Scheme 1. RCM Approach to â-C-Glycosides
(1) (a) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca
Raton, 1995, p 379. (b) Levy, D. E.; Tang, C. The Chemistry of
C-Glycosides; Elsevier Science: Oxford, 1995; Vol. 13, 290p.
(2) For reviews on C-glycoside synthesis, see: (a) Postema, M. H. D.;
Calimente, D. In Glycochemistry: Principles, Synthesis and Applications;
Wang, P. G., Bertozzi, C., Eds.; Marcel Dekker: New York, 2000; Chapter
4, pp 77-131. (b) Du, Y.; Lindhardt, R. J. Tetrahedron 1998, 54, 9913-
9959. (c) Beau, J.-M.; Gallagher, T. Top. Curr. Chem. 1997, 187, 1-54.
(d) Nicotra, F. Top. Curr. Chem. 1997, 187, 55-83. (e) Togo, H.; He, W.;
Waki, Y.; Yokoyama, M. Synlett 1998, 700-717. (f) Jaramillo, C.; Knapp,
S. Synthesis 1994, 1-20. (g) Herscovici, J.; Antonakis, K. In Studies in
Natural Product Chemistry, StereoselectiVe Synthesis; Rahman, A., Ed.;
Elsevier: Amsterdam, 1992; Vol. 10, Part F, pp 337-403.
(3) For some recent approaches to C-glycosides, see: (a) Chiara, J. L.;
Sesmilo, E. Angew. Chem., Int. Ed. 2002, 41, 3242-3246. (b) Liu, H.;
Smoliakova, I. P.; Koikov, L. N. Org. Lett. 2002, 4, 3895-3898. (c) Larrosa,
I.; Romea, P.; Urpi, F.; Balsells, D.; Vilarrasa, J.; Font-Bardia, M.; Solans,
X. Org. Lett. 2002, 4, 4651-4654. (d) Paterson, D. E.; Griffin, F. K.;
Alcaraz, M. L.; Taylor, R. J. K. Eur. J. Org. Chem. 2002, 1323-1336. (e)
Cheng, X. H.; Khan, N.; Mootoo, D. R. J. Org. Chem. 2000, 65, 2544-
2547.
furnish C-glycoside 6. Implied within is the fact that a large
number of â-C-glycosides are readily accessible by simply
employing the appropriate carboxylic acid in the esterification
step.
10.1021/ol034363q CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/09/2003

Accordingly, known olefin alcohol 1a9 was coupled with
acid 2a10 to give ester 3a in good yield.11 Takai methylena-
tion12 of ester 3a to acyclic enol ether 4a was followed by
exposure of crude 4a to 20 mol % of the second generation
Grubbs catalyst 713 in hot toluene to give an intermediate
glycal 5a that was not isolated but regioselectively hydrobo-
rated14 with an excess of BH3‚THF. Oxidative quench (H2O2,
NaOH) of the intermediate borane then afforded the target
â-C-glycoside 6a in 55% yield15 over three steps, Scheme
2. The stereochemistry of hydroboration was verified by
This three-step protocol efficiently provided the target
C-glycoside 6a, a carbon mimic of an O-phenyl glycoside,16
in good overall yield.
To explore the use of different protecting groups on the
olefin alcohol fragment, compound 1b was targeted for
synthesis. Deacetylation of tri-O-acetyl-D-glucal (8) was
followed by p-methoxybenzylation to deliver 9. Oxidative
cleavage of the olefin17 then gave aldehydo-formate ester
10 that was isolable but instable and, therefore, directly
converted to lactol 11 by exposure to basic methanol. Wittig
reaction of the lactol with an excess of Ph3PdCH2 then
provided olefin alcohol 1b, Scheme 3.
Scheme 2. Synthesis of a Benzylic â-C-Glycoside
Scheme 3. Synthesis of Olefin Alcohol 1b
A variety of diverse C-glycoconjugates (6a-i) were then
prepared as outlined in Table 1. The esterifications (1 + 2
f 3), mediated by DCC and 4-DMAP, proceeded in
excellent yield, and application of the three-step protocol to
the formed esters 3a-i served to deliver the target â-C-
glycosides 6a-i, respectively, in 49-60% overall yield for
the three steps. Entry 2 represents a C-glycoside that carries
a very lipophilic group at the anomeric center.
Entries 3 and 4 are stable mimics of sterol glycosides,
while compounds 6e and 6f are C-glycoside analogues of
O-linked amino acid glycosides based on serine and ty-
rosine.18
acetylation of 6a and examination of proton NMR data (J1,2
) J2,3 ) 8.9 Hz).
(4) (a) Wei, A.; Boy, K. M.; Kishi, Y. J. Am. Chem. Soc. 1995, 117,
9432-9436. (b) Wang, J.; Ko´vac, P.; Sinay¨, P.; Glaudemans, C. P. J.
Carbohydr. Res. 1998, 308, 191-193. (c) Tsuruta, O.; Yuasa, H.; Kurono,
S.; Hashimoto, H. Bioorg. Med. Chem. Lett. 1999, 9, 807-810. (d) Yang,
G.; Franck, R. W.; Bittman, R.; Samadder, P.; Arthur, G. Org. Lett. 2001,
3, 197-200. (e) Cheng, X. H.; Khan, N.; Mootoo, D. R. J. Org. Chem.
2000, 65, 2544-2547.
(5) For a comprehensive review on the synthesis of C-saccharides, see:
Liu, L.; McKee, M.; Postema, M. H. D. Curr. Org. Chem. 2001, 5, 1133-
1167.
In these latter two examples, the Boc group on the nitrogen
was found to be compatible with the methylenation chemistry
(6) For reviews on olefin metathesis chemistry, see: (a) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (b) Fu¨rstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3012-3043. (c) Wright, D. L. Curr. Org. Chem.
1999, 3, 211-240. (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413-4450. (e) Ivin, K. J. J. Mol. Catal. A.: Chem. 1998, 133, 1-16. (f)
Randall, M. L.; Snapper, M. L. J. Mol. Catal. A: Chem. 1998, 133, 29-
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(h) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-
2056. (i) Fu¨rstner, A. Top. Catal. 1997, 4, 285-299. (j) Grubbs, R. H.;
Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-452. (k) Schmalz,
H.-G. Angew. Chem., Int. Ed. 1995, 34, 1833-1836.
(7) (a) Postema, M. H. D.; Calimente, D. J. Org. Chem. 1999, 64, 1770-
1771. (b) Postema, M. H. D.; Calimente, D.; Liu, L.; Behrmann, T. L. J.
Org. Chem. 2000, 65, 6061-6068. (c) Liu, L.; Postema, M. H. D. J. Am.
Chem. Soc. 2001, 123, 8602-8603. (d) Postema, M. H. D.; Piper, J. L.;
Liu, L.; Shen, J.; Faust M.; Andreana, P. R. J. Org. Chem. 2003, in press.
(8) For a review on the use of olefin metathesis in carbohydrate chemistry,
see: Jo¨rgensen, M.; Hadwiger, P.; Madsen, R.; Stutz, A. E.; Wrodnigg, T.
M. Curr. Org. Chem. 2000, 4, 565-588.
(12) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem.
1994, 59, 2668-2670.
(13) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
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Tetrahedron Lett. 1987, 28, 6591-6594.
(15) Yields refer to chromatographically and spectroscopically homo-
geneous materials.
(16) There are a large number of natural products that contain this type
of linkage, e.g., vancomycin.
(17) Darrow, J. W.; Drueckhammer, D. G. J. Org. Chem. 1994, 59,
2976-2985.
(18) For a review on carbon-linked amino acids, see: Dondoni, A.; Marra,
A. Chem ReV. 2000, 100, 4395-4422.
(19) Nagatsu, A.; Watanabe, M.; Ikemoto, K.; Hashimoto, M.; Murakami,
N.; Sakakibara, J.; Tokuda, H.; Nishino, H.; Iwashima, A.; Yazawa, K.
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(10) See Supporting Information.
(11) All new compounds were fully characterized by extensive one- and
two-dimensional NMR techniques, IR and high-resolution mass spectrom-
etry, and optical rotation.
(20) See, for example: (a) Cipolla, L.; Nicotra, F.; Vismara, E.; Guerrini,
M. Tetrahedron 1997, 53, 6163-6170. (b) Gujar, M. K.; Reddy, R.
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Org. Lett., Vol. 5, No. 10, 2003

of O-glycoglycerolipids. Certain O-glycoglycerolipids have
been found to possess antitumor activity,19 and the corre-
sponding C-glycoside analogues4d,20 would provide stable
mimics of these compounds.
Table 1. Synthesis of â-C-Glycoconjugatesa
Scheme 4 shows the conversion of 6g to a representative
C-glucoglycerolipid 13. Benzylation of O-2 on 6g was
Scheme 4. Synthesis of â-C-Glucoglycerolipid
followed by removal of the acetonide protecting group and
acylation with stearic anhydride of the resulting diol yielding
12 in 60% overall yield. Hydrogenolysis of the benzyl groups
then completed the sequence to produce the C-glucoglyc-
erolipid 13. The use of p-methoxybenzyl groups, as in 6h,
should allow for the introduction of double bonds in the long-
chain fatty acid.
We have shown that our convergent RCM-based approach
to â-C-glycosides is flexible and allows for the synthesis of
a variety of functionalized â-C-glycoconjugates such as
C-glucoglycerolipids, C-glycosyl amino acids, and C-gly-
cosyl steroids in good overall yield.
Acknowledgment. We thank Mr. Anuj Prasher for
preliminary technical assistance, Professor Christopher Hadad
(The Ohio State University) for HRMS spectra, and Dr. M.
K. Ksebati (Wayne State University) for assistance with
NMR data. Acknowledgment is gratefully made to the NSF
(CHE-0132770) for support of this research.
Supporting Information Available: Representative pro-
cedures for the preparation of 3a, 6a, 11, 1b, 3g, 6g, 12,
and 13 along with spectral data listings and copies of NMR
spectra for 3a, 6a, 11, 1b, 3g, 6g, 12, and 13. This material
is available free of charge via the Internet at http://pubs.acs.org.
a All compounds have been fully characterized by standard spectral
methods. b Formed by RCM with 20 mol % 7 followed by hydroboration
(BH3‚THF) and oxidative quench (NaOH, H2O2). c Yields are over three
steps (methylenation, RCM, and hydroboration and oxidative quench).
even in the presence of an excess of the Takai reagent.
Compounds 6g-i are precursors to C-glycoside analogues
OL034363Q
Org. Lett., Vol. 5, No. 10, 2003
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