Enantioselective Total Syntheses of Several Bioactive Natural Products Based on the Development of Practical Asymmetric Catalysis

Abstract

I present herewith enantioselective total syntheses of several bioactive natural products, such as (−)-strychnine, (+)-decursin, (−)-cryptocaryolone diacetate, (−)-fluoxetine, and aeruginosin 298-A, based on practical asymmetric catalyses (Michael reaction, epoxidation, and phase-transfer reaction) that I developed with co-workers in Prof. Shibasaki's group over the past 5 years. In the first part of this review, I discuss the great improvement of catalyst efficiency in an ALB-catalyzed asymmetric Michael reaction of malonate and application to the pre-manufacturing scale (greater than kilogram scale) and enantioselective total synthesis of (−)-strychnine with the development of novel domino cyclization. To broaden the substrate generality of the Michael reaction, we developed a highly stable, storable, and reusable La–O-linked-BINOL complex. Further extension of the reaction using β-keto ester as a Michael donor was achieved with the development of a La–NR-linked-BINOL complex, thereby improving indole alkaloid syntheses. In the second section, I discuss enantioselective total synthesis of (+)-decursin using catalytic asymmetric epoxidation. To achieve the synthesis, we developed a new La–BINOL–Ph₃As=O (1 : 1 : 1) complex catalyst system, which has much higher reactivity and broader substrate generality than the previously developed catalyst systems. This allowed us to achieve catalytic asymmetric epoxidation of α,β-unsaturated carboxylic acid derivatives with high enantioselectivity and broad substrate generality for the first time by changing the lanthanide metal and reaction conditions. Among them, catalytic asymmetric epoxidation of α,β-unsaturated morpholinyl amides is quite useful in terms of synthetic utility of the corresponding α,β-epoxy morpholinyl amides. Highly catalyst-controlled enantio- or diastereoselective epoxidation of the α,β-unsaturated morpholinyl amides, coupled with diastereoselective reduction of β-hydroxy ketones, enabled the synthesis of all possible stereoisomers of 1,3-polyol arrays with successful enantioselective total synthesis of several 1,3-polyol natural products, such as (−)-cryptocaryolone diacetate. In addition, the development of a new regioselective epoxide-opening reaction of α,β-epoxy amides to the corresponding α- and β-hydroxy amides enhanced the usefulness of the present epoxidation and was applied to the enantioselective total synthesis of (−)-fluoxetine. In the final section, I report the development of a new asymmetric two-center organocatalyst (TaDiAS) and its application to the enantioselective synthesis of aeruginosin 298-A and its analogues. Because of the remarkable structural diversity of TaDiAS, a practical asymmetric phase-transfer reaction with broad substrate generality was achieved. As a result, we succeeded in developing a highly versatile synthetic method for aeruginosin 298-A and its analogues. Inhibitory activity studies of the compounds against the serine protease trypsin provided preliminary information about their structure–activity relations.