Rapid Generation of Molecular Complexity by Chemical Synthesis: Highly Efficient Total Synthesis of Hexacyclic Alkaloid (−)‐Chaetominine and Its Biosynthetic Implications

Abstract

The efficiency becomes a key issue in today's natural product total synthesis. While biomimetic synthesis is one of the most elegant strategies to achieve synthetic efficiency and thus to approach the ideal synthesis, most biogenetic pathways are unknown or unconfirmed. In this account, we demonstrate, through the shortest and also the most efficient asymmetric total syntheses of the hexacyclic alkaloid (-)-chaetominine to date, that on the basis of biogenetic thinking, one can develop quite efficient bio-inspired total synthesis, which in turn serves to suggest and chemically validate plausible biosynthetic routes for the natural product. The synthetic strategy thus developed is also inspiring for the development of other synthetic methods and efficient total synthesis of other natural products.

Total Synthesis of the Proposed Structure of (−)-Novofumigatamide, Isomers Thereof, and Analogues. Part I

“…Such a process usually delivers the thermodynamic endo products for simpler analogous compounds with hexahydropyrrolo[2,3- b ]indole frameworks. 49 − 51 The failure to promote the direct diastereoselective bromocyclization of tryptophan derivative 53 prompted us to try this classical indirect methodology to obtain the endo -pyrrolidinoindoline 52 . This alternative required the preparation of enantiomer ( R )- 53 and its subsequent diastereoselective bromocyclization to obtain the exo product as the major compound.…”

“…Endo diastereomers of hexahydropyrrolo­[2,3- b ]­indoles have also been selectively prepared through an epimerization of the enolizable Cα-position of the corresponding exo isomers, a transformation that occurs through a base-promoted generation of an enolate and a subsequent kinetic protonation at low temperature. Such a process usually delivers the thermodynamic endo products for simpler analogous compounds with hexahydropyrrolo­[2,3- b ]­indole frameworks. − The failure to promote the direct diastereoselective bromocyclization of tryptophan derivative 53 prompted us to try this classical indirect methodology to obtain the endo -pyrrolidinoindoline 52 . This alternative required the preparation of enantiomer ( R )- 53 and its subsequent diastereoselective bromocyclization to obtain the exo product as the major compound.…”

Enantioselective total syntheses of (+)-stemofoline and three congeners based on a biogenetic hypothesis

“…It should be noted that many of these methods are biomimetic or bioinspired in that they rely on known biogenetic routes or hypotheses. But for those natural products whose biogenetic pathways are unknown or have not been investigated in detail, it is necessary to develop biogenetic hypotheses 13 , 14 .…”