Enantioselective total syntheses of several bioactive natural products based on the development of practical asymmetric catalysis

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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 coworkers 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-Ph 3As=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.

Original languageEnglish
Pages (from-to)1031-1052
Number of pages22
JournalChemical and Pharmaceutical Bulletin
Issue number9
Publication statusPublished - Sept 1 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • Drug Discovery


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