Hydride Reductions and 1,2-Additions of Nucleophiles to Carbonyl Compounds Using Carbohydrate-Based Reagents and Additives - Carbohydrates: Tools for Stereoselective Synthesis - page 124

6.2.1
Modified Aluminohydrides

Scheme 6.1 summarizes the carbohydrate additives, available in a few steps from
d-glucose and d-xylose, respectively, employed for the asymmetric reduction of
carbonyl compounds using the archetypal hydride source LiAlH 4 . The first exam-
ples for this transformation were reported by Landor and coworkers [13-15].
Initially, monosaccharide derivatives 1 - 3 were chosen as chiral ligands for the
stereoselective reduction of differently substituted ketones (e.g., aryl, alkyl, and
acetylenic). Despite the breadth of an initial survey, 3- O -benzyl-1,2- O -
cyclohexylidene- -d-glucofuranose complex 2d, which proved to be one of the best

asymmetric inducers, created stereoselectivity of only 40% ee.

α

O OH

LiAlH 4
1 − 5

R 1 R 2 R 1 R 2

up to 98% yield
up to 40% ee

R 1 =R 2 =Aryl, Alkyl, Acetylenic

OH

HO HO

O H

O

Ph

O O

O

O
HO

HO OR HO OR

O O

HO HO

HO

OMe

4 5

1

O O O O

2a R=H
2b R=Me
2c R=Et
2d R=Bn
2e R=CH 2 Cy

3a R=H
3b R=Me
3c R=Bn

Scheme 6.1 Carbohydrate ligands employed in the stereoselective reduction of carbonyl
compounds using LiAlH 4 .

In a subsequent study, the selectivity was substantially improved (up to 70% for
the opposite enantiomer) by the addition of one equivalent of EtOH. To rationalize
the observed enantioselectivity the authors proposed the following model (Figure
6.1) [16, 17]. The hydrides available in complex 6b (X H 2 ) are diastereotopic

and therefore non-equivalent. H 1 is shielded by the 3- O -benzyl group and it is
therefore H 2 that is preferentially transferred to ketones to give secondary
(S) -alcohols.
Accordingly, when ethanol is added to the complex, the most reactive hydride
H 2 is removed and the reduction is accomplished by H 1 , yielding the correspond-
ing alcohol with opposite configuration [ (R) -enantiomer]. Moreover, another
important factor in this reaction is the presence of an aromatic group at C3 of the
additive, which probably interacts with the aromatic moiety of some aromatic
substrates and would explain the low asymmetric induction observed with certain
aryl ketones [18].
In addition to more common ketone substrates, the same authors also investi-
gated the reduction of isoelectronic ketoximes, ketoxime- O -alkyl ethers, and phe-
nylazomethines ( N -phenyl imines) with hydride-monosaccharide complex 6b,

=