Complementary to enantioselective transformations of planar functionalities, catalytic desymmetrization of meso compounds is another fundamentally important strategy for asymmetric synthesis. However, experimentally established stereochemical models on how a chiral catalyst discriminates between two enantiotopic functional groups in the desymmetrization of a meso substrate are particularly lacking. This article describes our endeavor to elucidate the chemical mechanism and characterization of the active conformation of the cinchona alkaloid-derived catalyst for a desymmetrization of meso cyclic anhydrides via asymmetric alcoholysis. First, our kinetic studies indicate that the cinchona alkaloid-catalyzed alcoholysis proceeds by a general base catalysis mechanism. Furthermore, the active conformer of the cinchona alkaloid-derived catalyst DHQD-PHN was clarified by catalyst conformation studies with a designed, rigid cinchona alkaloid derivative as a probe. These key mechanistic insights enabled us to construct a stereochemical model to rationalize how DHQD-PHN differentiates the two enantiotopic carbonyl groups in the transition state of the asymmetric alcoholysis of meso cyclic anhydrides. This model not only is consistent with the sense of asymmetric induction of the asymmetric alcoholysis but also provides a rationale on how the catalyst tolerates a broad range of cyclic anhydrides. These mechanistic insights further guided us to develop a novel practical catalyst for the enantioselective alcoholysis of meso cyclic anhydrides.cinchona alkoloid | desymmetrization | organocatalysis | general base catalysis | hydrogen bonding C omplementary to enantioselective transformations of planar functionalities, catalytic desymmetrization of meso compounds is another fundamentally important strategy for asymmetric synthesis (1-5). However, our understanding of how a chiral catalyst discriminates between two enantiotopic functional groups in a meso substrate at the molecular level is particularly lacking. Our group reported a desymmetric alcoholysis of a wide range of meso cyclic anhydrides with modified cinchona alkaloids to generate highly enantiomerically enriched hemiesters (5-10). Thus, we have initiated mechanistic studies to investigate how the modified cinchona alkaloids are able to efficiently differentiate the two enantiotopic carbonyl groups while tolerating variations of the substituents of the anhydrides. Herein we describe the experimental results that have enabled us to construct a transition state model to answer these mechanistic questions and to develop a practical catalyst guided by insights gained from our mechanistic studies.
Results and DiscussionIn order to shed light on the origin of the catalytic activity on the enantioselective alcoholysis of meso cyclic anhydrides, we carried out kinetic studies on the methanolysis of cis-2,3-dimethyl succinic anhydride (1a) (SI Appendix). Upon treatment with the mono cinchona alkaloid DHQD-PHN (3) and the bis cinchona alkaloid ðDHQDÞ 2 AQN (4) in diethyl ether at...