DEDICATED TO PROFESSOR HC BROWN ON HIS ... - Sigma-Aldrich

3.3. α-Keto Acetals and α-Keto
Thioketals
Chiral hydride 2 efficiently reduced
aliphatic and aromatic α-keto acetals to the
corresponding α-hydroxy acetals in 87−99%
ee (eq 10). 43 The CBS reduction provided
excellent ee’s for aromatic analogs but
moderate ee’s for aliphatic ones. 20b Similarly,
the CBS reduction of both acyclic and cyclic
α-keto thioketals was highly enantioselective
(eq 11). 44
3.4. Keto Acids, Esters, and
Amides
Treatment of α- and β-keto acids with 4
and triethylamine led to the corresponding
Figure 5. Applications of Optically Active Halohydrins to the Synthesis of Chiral Drugs.
8 VOL. 35, NO. 1 • 2002
Epoxides
Reduction Conditions Yield (%) % ee
11b (0.1 equiv), BACH-EI (1.0 equiv), 25 °C 94-96 94-99, S
4 (1.1 equiv), -25 °C 72-92 92-97, R
α- and β-hydroxy acids in excellent ee’s. 45
Similarly, 3 successfully reduced α-, β-, and
γ-keto acids to the corresponding hydroxy
acids with very high ee’s (eq 12). 46 In the
case of α-keto esters, both 1 6 and 5 32
produced high ee’s (eq 13). However, these
reagents failed to reduce β-keto esters. 9 In
contrast, the reduction was successfully
achieved by mixed borohydrides, “(R)-Mix
A” [(R)-7] and “Mix B” (8), obtained from
the reaction of NaBH4 with (R,R’)-N,N’dibenzoylcystine
and (2R,3R)-tartaric acid,
respectively. (R)-7 11 produced the desired
aromatic β-hydroxy esters in 84−92% ee,
while 8 12 provided the aliphatic analogs in
68−84% ee (eq 14). “Mix C” (9), modified
with (S)-tert-leucine, was effectively used to
prepare the optically active α-hydroxy amide
29 as a key intermediate in the synthesis of
chiral diltiazem (30), a potent calcium
channel blocker (eq 15). 47
3.5. α,β-Enones and Ynones
eq 8
The oxazaborolidine-catalyzed reduction
of α,β-enones, using 11 35a,48 or 12 49 as the
catalyst, has been extensively studied. The
reduction is effective for all cases having
acyclic, endocyclic, or exocyclic double
bonds. To minimize the hydroboration of the
C=C bond by borane, these reductions were
carried out at low temperature. Interestingly,
the olefinic portion in acyclic enones
generally behaves as the large group for the
reduction. The stoichiometric reagents, 1, 4,