We therefore selected the bicyclo[3.1.0]hexane derivatives
5 and 6 (Figure 3) as targets. Compounds of this type predict-
Figure 1. Structures of UDP-R-D-galactofuranose (1) and deca-
prenyl â-D-arabinofuranosyl phosphate (2).
Figure 3. Target molecules 5 and 6.
as the donor species.8 The biosynthesis of the arabinan
domain is less well understood, but it appears that a number
of enzymes, which use decaprenyl â-D-arabinofuranosyl
phosphate (2) as the donor species, are involved.4,7,9
Computational and NMR studies10 have suggested that 1
and 2 adopt an envelope conformer in which C2 is either
above or below the plane formed by the other ring atoms (3
and 4, respectively, Figure 2). As part of our continuing
ably11 adopt a conformation in which the cyclopentane
carbon forming the flap of the envelope is on the same side
of the ring as the cyclopropane methylene group (Figure 3).
The amino group was included in the targets for two reasons.
First, its presence would facilitate the preparation of ad-
ditional analogues through, for example, reductive amination.
Second, this group would be protonated at physiological pH
and thus would be able to form strong ionic interactions with
the anionic (carboxylate) groups that are typically present
in glycosyltransferase active sites.13 This charge would also
mimic the oxacarbenium ion that develops in the glycosy-
lation transition state.13
Compounds 5 and 6 are sterochemically related in that 6
can be obtained from the enantiomer of 5 by oxidative
cleavage of the acyclic diol moiety (Figure 4). In this paper,
Figure 2. Proposed conformations of UDP-R-D-galactofuranose
(3) and decaprenyl â-D-arabinofuranosyl phosphate (4).
studies on the synthesis of potential inhibitors of mycobac-
terial arabinofuranosyl- and galactofuranosyltransferases,3b-e
we wanted to prepare mimetics of 1 and 2 in which the five-
membered ring was locked into these conformations. This
conformational restriction could be expected to “pre-orga-
nize” the molecules for enzyme recognition and thus lead
to enhanced affinity. A similar approach has found wide-
spread application in the development of inhibitors of nucleo-
tide-processing enzymes,11 as well as in the identification
of oligonucleotides that bind to their complementary nucle-
otide sequence with high affinity (e.g., locked nucleic
acids12).
Figure 4. Stereochemical relationship between 5 and 6.
we describe a synthetic approach to 5 and 6 that takes
advantage of this relationship and allows the preparation of
the targets in a highly convergent manner from a common
intermediate.
The synthesis of the targets started with the known14 allylic
alcohol 7 (Scheme 1). Reaction of 7 with oxalic acid in
aqueous acetone led to ketal hydrolysis in 92% yield, thus
affording ketone 8. The hydroxyl group was next protected
as a MOM ether under acidic conditions; the product of this
reaction, 9, was obtained in 72% yield. Epoxidation of the
alkene with m-CPBA afforded a 70% yield of 10, which was
(8) Bela´nˇova´, M.; Dianisˇkova´, P.; Brennan, P. J.; Completo, G. C.; Rose,
N. L. Lowary, T. L.; Mikusˇova´, K. J. Bacteriol. 2008, 190, 1141.
(9) Wolucka, B. A.; McNeil, M. R.; de Hoffmann, E.; Chojnacki, T.;
Brennan, P. J. J. Biol. Chem. 1994, 269, 23328.
(10) Gordon, M. T.; Lowary, T. L.; Hadad, C. M. J. Org. Chem. 2000,
65, 4954.
(11) Selected examples: (a) Comin, M. J.; Agbaria, R.; Ben-Kasus, T.;
Huleihel, M.; Liao, C.; Sun, G. Y.; Nicklaus, M. C.; Deschamps, J. R.;
Parrish, D. A.; Marquez, V. E. J. Am. Chem. Soc. 2007, 129, 6216. (b)
Smee, D. F.; Hurst, B. L.; Wong, M.-H.; Glazer, R. I.; Rahman, A.; Sidwell,
R. W. AntiViral Res. 2007, 76, 124. (c) Prichard, M. N.; Keith, K. A.;
Quenelle, D. C.; Kern, E. R. Antimicrob. Agents Chemother. 2006, 50, 1336.
(d) Marquez, V. E.; Hughes, S. H.; Sei, S.; Agbaria, R. AntiViral Res. 2006,
71, 268. (e) Tchilibon, S.; Joshi, B. V.; Kim, S. K.; Duong, H. T.; Gao, Z.
G.; Jacobson, K. A. J. Med. Chem. 2005, 48, 1745. (f) Kim, H. S.; Ohno,
M.; Xu, B.; Kim, H. O.; Choi, Y. S.; Ji, X. D.; Maddileti, S.; Marquez, V.
E.; Harden, T. K.; Jacobson, K. A. J. Med. Chem. 2003, 46, 4974.
(12) Jepsen, J. S.; Sorensen, M. D.; Wengel, J. Oligonucleotides 2004,
14, 130.
(13) Breton, C.; Snajdrova, L.; Jeanneau, C.; Koca, J.; Imberty, A.
Glycobiology 2006, 16, 29R.
(14) Srikrishna, A.; Kumar, P. P. Tetrahedron 2000, 56, 8189.
882
Org. Lett., Vol. 10, No. 5, 2008