Chemistry Reference
In-Depth Information
*
NR
3
MeOH
O
26 or 27
Ph
OMe
Me
ZHN
*
34
R
3
N---H-O
O
Ph
O
OMe
Ph
O
-
ZN
O
ZN
*
HNR
3
O
O
33a
Scheme 2B.6.
only restricted by the acidity of the hydrogen. The successful activation of an alcohol
(pKa = 29 in DMSO [28]) in the highly enantioselective reaction by catalysts
26
and
27
suggested that the asymmetric base catalysis by a tertiary amine could, in principle, be
extended to a broad range of nucleophiles bearing C- H, O - H, N - H, S -H, and P- H
bonds. However, the true generality had to be gauged experimentally.
Experimental results implicating a considerable scope for the highly enantioselective
base catalysis by cinchona alkaloids soon appeared in the literature. In 2002, Deng,
McDaid, and others reported a highly enantioselective conjugate addition of aryl thiols
to cyclic enones (Scheme 2B.7) [29]. In contrast to the moderate enantioselectivity
reported earlier with natural cinchona alkaloids [30], Deng and McDaid showed that
(DHQD)
2
PYR (
39
), another modifi ed cinchona alkaloid bearing an aryl ether at the
C9-position, afforded excellent enantioselectivity for the conjugate additions of aryl
thiols
40
to six- to nine-membered cyclic enones. Interestingly, the sense of asymmetric
induction by
39
was found to be opposite to that by quinidine [30]. However, as neither
natural cinchona alkaloids nor
O
-acetyl quinidine was able to promote a Morita-Baylis-
Hillman reaction with methyl vinyl ketone (MVK) as a nucleophilic catalyst under
ambient conditions [31], it is almost certain that catalyst
39
mediated this highly enan-
tioselective conjugate addition via the activation of the aryl thiol as a base catalyst. This
extension of the highly enantioselective base catalysis by cinchona alkaloids to a reaction
that is mechanistically distinct from the enantioselective alcoholysis provided the fi rst
indications of the tremendous potential of cinchona alkaloids as chiral base catalysts for
asymmetric synthesis [32] .
In 2004, Bella and Jorgensen reported another effi cient enantioselective asymmetric
conjugate addition catalyzed by a cinchona alkaloid (Scheme 2B.8). In this reaction,
cinchona alkaloid
43
activated β - ketoesters
45
, a carbon nucleophile, for a highly enan-
tioselective reaction with alkynones
44
[33] .
In parallel to the aforementioned studies, chiral base catalysis also evolved with
another family of small organic molecules. In 2000, Miller, Guerin, and others reported
an enantioselective conjugate addition with HN
3
, generated
in situ
from TMSN
3
and
t
-
BuCO
2
H, catalyzed by peptide
49
bearing an imidazole side chain. Up to 85% ee was
obtained with
49
(Scheme 2B.9) [34a]. The imidazole group, most likely, exercised its
