Chemistry Reference
In-Depth Information
2B.2.2. The Emergence of Highly Enantioselective Base Catalysis
A chiral acid or a chiral base can, in principle, promote an enantioselective nucleophile-
electrophile reaction. However, the development of a broadly useful platform, with
either metal complexes or organic molecules, for the activation of nucleophiles with base
catalysis represented a major challenge in asymmetric catalysis [14]. Early attempts to
meet this challenge centered on the use of cinchona alkaloids as readily available tertiary
amine catalysts. The extensive pioneering investigations by Wynberg and coworkers in
the 1970s and early 1980s showed that cinchona alkaloids were able to promote a wide
range of reactions as either base or nucleophilic catalysts [15]. However, in the only
cinchona alkaloid-catalyzed highly enantioselective reaction, a formal [2 + 2] cycloaddi-
tion between ketenes and aldehydes, the cinchona alkaloid catalyst clearly acted as a
nucleophilic catalyst [15,16].
Another notable study of cinchona alkaloid-catalyzed reactions, carried out fi rst by
Oada and later by Aitken, is the investigation of the enantioselective alcoholytic ring-
opening reactions of
meso
-anhydrides in the 1980s. In a screening of natural cinchona
alkaloids and their C9-epimers, Oada and coworkers obtained optimal, but still modest,
enantioselectivity with cinchonine (Method A, Scheme 2B.5) [17]. Oada and others also
detected a kinetic isotope effect with MeOD, thereby providing experimental evidence
that implicated a general base catalysis mechanism for the reaction [17b]. Aitken et al.
made the important observation that the enantioselectivity became higher when the
catalyst loading increased [17c,d]. Eventually, Bolm and coworkers attained excellent
enantioselectivity by employing 1.1 equivalents of quinine or quinidine (Method B,
Scheme 2B.5) [18]. The continuing lack of success in achieving an effi cient enantioselec-
tive reaction with a chiral amine as a base catalyst stood in contrast to the increasingly
successful applications of cinchona alkaloids [19], chiral imidazoles [20], and DMAP
derivatives [21] as effi cient nucleophilic catalysts.
In 2000, Deng and coworkers reported a highly enantioselective alcoholysis of
meso
-
anhydrides
28
in toluene with a catalytic amount of modifi ed cinchona alkaloids bearing
a C9-aryl ether group such as DHQD-PHN
26
and (DHQD)
2
AQN
27
(Method C,
Scheme 2B.5) [22]. At the same time, Bolm and coworkers found that the same trans-
formation could be promoted in high enantioselectivity with 10 mol % quinidine in the
presence of a stoichiometric amount of another tertiary amine, pempidine (Method D,
Scheme 2B.5 ) [23] .
Following their initial discovery, Deng and coworkers extended the
27
- catalyzed
alcoholysis to the highly enantioselective kinetic resolution of several distinct classes of
racemic cyclic anhydrides (
30
,
33
, and
36
) [24-27]. In parallel to these synthetic studies,
they also carried out kinetic studies on the
27
-catalyzed methanolysis of the urethane-
protected
N
- carboxyanhydride (UNCA)
33
, and found that the reaction demonstrated
fi rst-order dependence on the anhydride, the alcohol, and the catalyst
26
. Moreover, a
kinetic isotope effect was also detected for the alcoholysis with MeOD [25]. As described
by Deng and coworkers in 2001, these results are only consistent with a general base
catalysis mechanism in which catalyst
26
or
27
activates the nucleophile (methanol) by
forming an amine alcohol hydrogen - bonding complex (Scheme 2B.6 ) [25,27] . These
synthetic and mechanistic studies of the cinchona alkaloid-catalyzed alcoholysis demon-
strated that, for the fi rst time, the general base catalysis by a small chiral molecule could
promote highly enantioselective reactions with a broad substrate scope. Importantly,
this form of nucleophile-activating asymmetric catalysis is mediated via a hydrogen-
bonding interaction between the chiral catalyst and an acidic hydrogen, and is therefore
