A unified approach to differentially linked β-C-disaccharides by ring-closing metathesis [5]

Full text of DOI:10.1021/ja010641+

8602
J. Am. Chem. Soc. 2001, 123, 8602-8603
Scheme 1. Metathesis Approach to C-Saccharide Synthesis
A Unified Approach to Differentially Linked
â-C-Disaccharides by Ring-Closing Metathesis
Lei Liu and Maarten H. D. Postema*
Department of Chemistry
Wayne State UniVersity
Detroit, Michigan 48202
ReceiVed March 12, 2001
C-Glycosides, compounds in which the interglycosidic oxygen
atom has been replaced by a carbon atom, are an important class
of stable carbohydrate mimics.1 These compounds have received
considerable attention from both a synthetic2 and biological3 point
of view, and the debate regarding their validity as conformational
mimics of the parent O-glycosides is ongoing.4
Scheme 2. Preparation of C-4 Acid 12a
The preparation of C-saccharides,5 whether they are C-
disaccharides or higher homologues, is considerably more chal-
lenging than the synthesis of simple C-glycosides. Any linkage,
other than (1f6), consists of only one carbon atom separating
the two monosaccharide units. Although there have been several
approaches to the synthesis of a variety of differentially linked
C-disaccharides,6 no single method provides a unified and versatile
strategy for a convergent and efficient synthesis of (1f1), (1f2),
(1f3), (1f4), and (1f6) linked-C-disaccharides. In this com-
munication, we report that a Keck allylation-ring-closing me-
tathesis (RCM) approach delivers a variety of differentially linked
â-C-disaccharides in an efficient manner and provides the first
unified entry to this important class of carbohydrate mimics.7
The general approach begins with dehydrative coupling of a
suitable carbohydrate-based acid such as 2 with olefin alcohol 1
to give ester 3, Scheme 1. Methylenation of 3 is followed by
RCM to then give glycal 5. Functionalization of the double bond
then delivers the â-C-disaccharides 6 or 7.
Alcohol 88 was converted to iodide 9 and exposure to
allyltributyltin and AIBN9 gave the equatorially allylated product
10a in 75% yield. Some of the inseparable axial isomer (15%)
was also formed. The acetates were exchanged for benzyl groups
(75% over two steps), and oxidative cleavage of the mixture of
olefins 11a gave the corresponding aldehydes which were
separated.10 The major aldehyde was then oxidized to acid 12a,
Scheme 2.
DCC-mediated coupling of acid 12a with alcohol 13 gave ester
14a in good yield. Methylenation11 of 14a and subsequent ring-
closing metathesis of acyclic enol ether 15a mediated by catalyst
1912 furnished the (1f4)-C-disaccharide glycal 16a (41%). This
low yield was puzzling, since TLC analysis of the reaction showed
clean conversion of 15a to the cyclized material 16a. We reasoned
that the glycal was decomposing or hydrolyzing during purifica-
tion, and this prompted us to explore a one-pot approach. Once
the RCM reaction was deemed complete by TLC analysis, an
excess of BH3‚THF13 was added to the reaction mixture. Oxidative
workup then furnished the (1f4)-â-C-disaccharide 17a in 64%
over two steps. Hydrogenolysis of the benzyl groups on 17a and
peracetylation then afforded the known14 (1f4)-â-C-disaccharide
18a, Scheme 3. This one-pot protocol not only improved the yield
of the final product but also removed the need for purification of
the sensitive C-disaccharide glycal 16a.
For the preparation of the various carbohydrate-based carboxy-
lic acids, we relied upon a radical allylation-oxidative cleavage
approach. The chemistry is illustrated with the preparation of the
C-4 gluco acid 12a, Scheme 2.
(1) (a) Postema, M. H. D. C-Glycoside Synthesis, 1st ed.; CRC Press: Boca
Raton, 1995; p 379. (b) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides,
1st ed.; Elsevier Science: Oxford, 1995; Vol. 13, p 291.
(2) For reviews on C-glycoside synthesis, see: (a) Postema, M. H. D.;
Calimonte, D. In Glycochemistry Principles, Synthesis and Applications;
Bertozzi, C., Wang, P. G., Eds.; Marcel Dekker: New York, 2000; pp 77-
131. (b) Du, Y.; Lindhart, R. J.; Vlahov, I. R. 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.
(3) Bertozzi, C.; Bednarski, M. In Modern Methods in Carbohydrate
Synthesis; Khan, S. H., O’Neil, R. A. O., Eds.; Harwood Academic
Publishers: Amsterdam, 1996; pp 316-351.
(4) (a) Wei, A.; Haudrechy, A.; Audin, C.; Jun, H.-S.; Haudrechy-Bretel,
N.; Kishi, Y. J. Org. Chem. 1995, 60, 2160-2169 (b) Asensio, J. L.; Espinosa,
J. F.; Dietrich, H.; Can˜ada, F. J.; Schmidt, R. R.; Mart´ın-Lomas, M.; Andre´,
S.; Gabius, H.-J.; Jime´nez-Barbero, J. J. Am. Chem. Soc. 1999, 121, 8995-
9000. (c) Rubinstenn, G.; Sinay¨, P.; Berthault, P. J. Chem. Phys. A 1997,
101, 2536-2540 and references therein.
Acids 12c-12e (not shown) were prepared using the same
general approach outlined in Scheme 2.15 The stereochemistry of
the allylation step was ascertained by Noe and 1H NMR
decoupling experiments on the corresponding aldehydes and was
(5) For a review of C-saccharide synthesis, see: McKee, M., Liu, L.
Postema, M. H. D. Curr. Org. Chem. 2001, 5, in press.
(8) Koch, K.; Chambers, R. J. Carbohydr. Res. 1993, 241, 295-299.
(9) Keck, G. E.; Enholm, E. J.; Yates, J. B.; Wiley: M. R. Tetrahedron
1985, 41, 4079-4094.
(10) All new compounds were fully characterized by extensive 1-D and
2-D NMR techniques, IR, and high-resolution mass spectrometry.
(11) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 1994,
59, 2668-2670.
(12) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886.
(13) (a) Hanessian, S.; Martin, M.; Desai, R. C. J. Chem. Soc., Chem.
Commun. 1986, 926-927. (b) Schmidt, R. R.; Preuss, R.; Betz, R. Tetrahedron
Lett. 1987, 28, 6591-6594.
(14) Khan, A. T.; Sharma, P.; Schmidt, R. R. J. Carbohydr. Chem. 1995,
14, 1353-1367.
(15) See Supporting Information.
(6) For some synthetic approaches to C-disaccharides, see: (a) Postema,
M. H. D.; D. Calimente, D.; Liu, L.; Behrmann, T. L. J. Org. Chem. 2000,
65, 6061-6068. (b) Griffin, F. K.; Paterson, D. E.; Taylor, R. J. K. Angew
Chem. Int. Ed. 1999, 38, 2939-2942. (c) Khan, N.; Cheng, X.; Mootoo, D.
R. J. Am. Chem. Soc. 1999, 121, 4918-4919. (d) Leeuwenburgh, M. A.;
Timmers, C. M.; van der Marel, G.; van Boom, J. H.; Mallet, J. M.; Sinay¨, P.
Tetrahedron Lett. 1997, 38, 6251-6254. (e) Dondoni, A.; Zuurmond, H.;
Boscarato, A. J. Org. Chem. 1997, 62, 8114-8124. (f) Mallet, A.; Mallet,
J.-M.; Sinay, P. Tetrahedron Asymmetry 1994, 5, 2593-2608. (g) Sutherlin,
D. P.; Armstrong, R. W. J. Org. Chem. 1997, 62, 5267-5283. (h) Martin, O.
R.; Lai, W. J. Org. Chem. 1993, 58, 176-185.
(7) For a review on the use of olefin metathesis in carbohydrate chemistry,
see: Jorgensen, M.; Hadwiger, P.; Madsen, R.; Stutz, A. E.; Wrodnigg, T.
M. Curr. Org. Chem. 2000, 4, 565-588.
10.1021/ja010641+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/08/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 35, 2001 8603
Table 1. Synthesis of â-C-Disaccharides by RCMa
Scheme 3. RCM-Based Synthesis of â-C-Disaccharides
(14f15) proceeded in reasonable yield, although a large excess
of the methylenating reagent was required for reactions to be
driven to completion. The one-pot RCM-hydroboration protocol
works well, and the results in Table 1 (entries 1 and 2) contrast
the difference between the one-pot procedure and simple isolation
of the glycal. The C-disaccharide 17 was consistently isolated in
∼60% yield over two steps. Significantly, the one-pot protocol
works efficiently with the easily handled catalyst 2018 (entries
2-5). It was necessary to add 20-30 mol % of metathesis catalyst
portion-wise over the course of the reaction (toluene, 60 °C) to
drive the cyclization to completion.19
The above results show that the RCM approach to C-saccharide
synthesis is a viable route to a variety of differentially linked
â-C-disaccharides in good overall yield starting from readily
available starting materials. This approach should allow access
to a host of other biologically relevant glycosidic linkages.
a Yields refer to chromatographically homogeneous material. b Acid
12b was prepared from the corresponding known20 ethyl ester.15 c Acid
12f was prepared from the known21 allyl derivative.15 d The corre-
sponding olefin alcohol is known.22 e Yields are for two steps; RCM
and hydroboration-oxidative workup. f Stereochemistry at C-1 and C-2
determined by acetylation and analysis of H-2 coupling constant in 1H
NMR.15 g Reaction carried out with 20-30 mol % of 19 in a glovebox
followed by hydroboration. h Reaction carried out with 20-30 mol %
of 20 on an argon manifold followed by hydroboration. i RCM with
20-30 mol % of 19 gave a 34% yield of the corresponding glycal.
Acknowledgment. We thank Wayne State University for partial
support. Acknowledgment is also made to the donors of the Petroleum
Research Fund, administered by the American Chemical Society, for
partial support of this research, (No. 33075-G1).
Supporting Information Available: Experimental procedures for the
preparation of compounds 9, 10a-12a, and 14a-18a, spectral data listing
1
for 14a-g, 15a-g, 17a-g, 18a and copies of H NMR spectra for 9,
10a, 14a, 15a, 17a, 16b, 18a, and Schemes showing the preparation of
acids 12b-f (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
found to favor equatorial allylation at C-3 and C-4, but not at
C-2 (entries 4 and 5).15 In this case, the adjacent OBn and OMe
groups exert opposing steric effects on the course of the allylation
to give a mixture (R: â, 2:3) of allylated products.
JA010641+
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
Olefin alcohol 13 was prepared by Wittig reaction16 of 3,4,6-
tri-O-benzyl-D-arabinofuranose17 with Ph3PdCH2.
(19) Upon completion of this work, the RCM of an enol ether-olefin
mediated by 20 appeared: Rainier, J. D.; Cox, J. M.; Allwein, S. P.
Tetrahedron Lett. 2001, 42, 179-181.
Ester formation (12+13f14), mediated by DCC and 4-DMAP,
proved to be routine. Methylenation of the resulting esters
(20) Lourens, G. J.; Koekemoer, J. M. Tetrahedron Lett. 1975, 3719-
3722.
(21) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984, 25, 2383-
2386.
(16) Freeman, F.; Robarge, K. D. Carbohydr. Res. 1986, 154, 270-274.
(17) Commercially available from Sigma.
(22) Haudrechy, A.; Sinay¨, P. J. Org. Chem. 1992, 57, 4142-4151.