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Synthetic Studies toward Indole Alkaloids and Catalytic Asymmetric Staudinger–Aza-Wittig Reaction via Desymmetrization

  • Author(s): Cai, Lingchao
  • Advisor(s): Kwon, Ohyun
  • et al.
Abstract

In Chapter 1, we developed a catalytic asymmetric total synthesis of (–)-actinophyllic acid, with the key step being a chiral phosphine-catalyzed [3 + 2] annulation between an imine and an allenoate to form a pyrroline intermediate in 99% yield and 94% ee. The synthesis also features a CuI-catalyzed coupling between a ketoester and a 2-iodoindole to shape the tetrahydroazocine ring; intramolecular alkylative lactonization; SmI2-mediated intramolecular pinacol coupling between ketone and lactone subunits to assemble the complex skeleton of (–)-actinophyllic acid; and an unprecedented regioselective dehydroxylation.

In Chapter 2, we applied our phosphine-catalyzed [4 + 2] annulation between an imine and an allenoate toward the synthetic studies on akuammiline indole alkaloids. We successfully constructed indole fused [3.3.1]azabicycles from [4 + 2] annulation precursor via Barbier reaction in high yields. We also developed a Lewis acid promoted dehydration to form the key indole–quinonemethide intermediate, which could generate a challenging quaternary carbon by trapping with a carbon nucleophile. By adopting this strategy, we proposed a pathway to finish formal total syntheses of aspidodasycarpine and lonicerine.

In Chapter 3, we have successfully developed the catalytic asymmetric Staudinger–aza-Wittig reaction. Historically, both Staudinger and Wittig reactions need stoichiometric amounts of phosphine, which impede the development of catalytic asymmetric versions of these reactions. In 2006, Marsden and co-workers reported the first asymmetric Staudinger–aza-Wittig reaction with stoichiometric chiral phosphine, which was undesirable considering economic efficiency and environmental concerns. Based on our previous study, we found that the bridged [2.2.1]bicyclic phosphine oxide had higher efficiency than the known phosphine oxides during the reduction cycle in the presence of silane. In this project, after screening various Brønsted acids, we could realize the catalytic asymmetric Staudinger–aza-Wittig reaction at room temperature.

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