6754
J . Org. Chem. 1996, 61, 6754-6755
Communications
Ta ble 1
A Ra d ica l Ap p r oa ch to Asym m etr ic Ald ol
Syn th esis†
reaction T
overall yield
(%)
F-ds
(4/d ia -4)
entry
substrate
(°C)
1
2
3
4
5
1a
1b
1c
1a
1b
-78
-78
77
74
47a
69
50
5/1
6/1
7/1
7/1
8/1
Philip Garner,* Raymond Leslie, and
J ames T. Anderson
-78
-100
-100
Department of Chemistry, Case Western Reserve University,
Cleveland, Ohio 44106-7078
a
16% of the decarboxylative rearrangement product i-PrCH(O-
Sugar)SPyr was isolated as well.
Received August 5, 1996
Sch em e 1
Asymmetric versions of the aldol addition reaction
continue to attract the attention of organic chemists.1 A
major impetus for synthetic developments in this area
comes from the variety of antibiotics that incorporate
aldol retrons directly into their structures. While most
practical asymmetric aldol reactions still rely on (sto-
ichiometric) chiral auxiliaries to control developing ster-
eochemistry, catalytic systems utilizing enzymes2 as well
as chiral Lewis acids3 have now been reported. The aldol
addition of enolates (or their equivalents) to aldehydes
and ketones generally proceeds by a polar addition type
of mechanism.4 This usually has certain implications
regarding functional group compatibility, aldol substitu-
tion pattern, etc., which must be taken into account. We
now report a conceptually novel approach to asymmetric
aldol synthesis based on the stereocontrolled addition of
a chiral hydroxyalkyl radical equivalent5 to a nitroalkene.
It is further shown that the free aldol can be released
(without dehydration) and the sugar-derived chiral aux-
iliary efficiently processed for reuse.
tocol,7 these carboxylic acids were converted to their
PTOC esters 2 and irradiated with a sunlamp in the
presence of 2-nitropropene at the indicated temperature
(see Table 1 and Scheme 1). The clean formation of
adducts corresponding to 3 was detected by TLC but it
was difficult to evaluate the F-diastereoselectivity at this
stage since thiopyridyl ether formation (R to the nitro
group) was stereorandom. Conversion of the geminal
nitro thioether functionality to a ketone was best ac-
complished by first filtering the crude reaction mixture
through silica gel (to remove DCU) and then exposing
the unresolved adducts to buffered reductive Nef condi-
tions.8 As shown in Table 1, the protected aldols 4 could
be obtained in excellent overall yields from 1 (better than
90% per step in optimized cases). The kinetic diastere-
omer ratios (4/d ia -4) were readily determined by com-
The sequence begins with the hydroxy acid glycosides
1, which are readily prepared by acid-catalyzed addition
of the corresponding R-hydroxy ester (stereochemistry
irrelevant)6 to tri-O-benzyl-D-glucal followed by saponi-
fication. Following a modified version of Barton’s pro-
1
paring the crude H NMR spectra with those of deliber-
ately prepared mixtures.9
Glycoside cleavage with concomitant production of the
free aldol represented a potential difficulty because of the
ease with which the aldol product can suffer dehydration.
Attempted use of our previously elucidated conditions for
auxiliary removal (PPTS/MeOH)5 failed to give any
detectable aldol product. However, exposure of 4 to
PhSH + BF3‚OEt2, according to Danishefsky et al.,10
resulted in clean conversion to the 2-deoxythioglycosides
† Dedicated to Professor Paul Dowd on the occasion of his 60th
birthday.
(1) Review: Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994,
1, 317-338.
(2) Cf. Gijsen, H. J . M.; Wong, C.-H. J . Am. Chem. Soc. 1995, 117,
7585-7591.
(3) (a) Mikami, K.; Matsukawa, S. J . Am. Chem. Soc. 1994, 116,
4077-4078. (b) Carreira, E. M.; Singer, R. A.; Lee, W. Ibid. 1994, 116,
8837-8838. (c) Keck, G. E.; Krishnamurthy, D. Ibid. 1995, 117, 2363-
2364.
(7) Barton, D. H. R.; Togo, H.; Zard, S. Z. Tetrahedron 1985, 41,
5507-5516.
(4) There is some evidence that a SET mechanism can intervene
with aromatic aldehydes: Ashby, E. C.; Argyropoulos, J . N. J . Org.
Chem. 1986, 51, 472-476.
(8) McMurry, J . E.; Melton, J . J . Org. Chem. 1973, 38, 4367-4373.
(9) Approximately equimolar mixtures of 4 and d ia -4 were obtained
by adding (()-RCH(OH)CH2COMe (from the hydroxide-catalyzed aldol
reaction of RCHO and MeCOMe: Dubois, J . E. Ann. Chim. 1951, 6,
406-486) to tri-O-benzyl-D-glucal.
(5) Garner, P. P.; Cox, P. B.; Klippenstein, S. J . J . Am. Chem. Soc.
1995, 117, 4183-4184.
(6) Racemic R-hydroxy esters 1b and 1c were conveniently prepared
from their cyanohydrins: Evans, D. A.; Truesdale, L. K.; Carroll, G.
L. J . Chem. Soc., Chem. Commun. 1973, 55-56.
(10) Halcomb, R. L.; Boyer, S. H.; Wittman, M. D.; Olson, S. H.;
Denhart, D. J .; Liu, K. K. C.; Danishefsky, S. J . J . Am. Chem. Soc.
1995, 117, 5720-5749.
S0022-3263(96)01499-5 CCC: $12.00 © 1996 American Chemical Society
Garner, Philip
