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