Issue 20, 2018

Enantioselective isoquinuclidine synthesis via sequential Diels–Alder/visible-light photoredox C–C bond cleavage: a formal synthesis of the indole alkaloid catharanthine

Abstract

An enantioselective route to substituted chiral isoquinuclidines, present in alkaloids such as catharanthine, deserpidine, ibogamine and ibogaine, has been developed using a “ketene equivalent” approach. Organocatalyzed Diels–Alder reaction of an N-protected dihydropyridine with acrolein using a valine derived 1,2-aminoalcohol catalyst occurs with high er and dr. Subsequent Ru(Bipy)3Cl2·(H2O)6 catalyzed photoredox cleavage generates an N-protected isoquinuclidinone, providing rapid access to the core structures of a variety of important indole alkaloids. Optimized conditions for the enamine mediated photocleavage employed the use of silica gel, acetic acid (1.5 equiv.) and piperidine (3.0 equiv.), a blue LED light source, and pure oxygen rather than air. The two-step sequence utilizes acrolein as a ketene dienophile equivalent providing a new approach to asymmetric “ketene” Diels–Alder reactions. Further elaboration of the resultant isoquinuclidines permitted an enantioselective route to intermediates previously employed in total syntheses of catharanthine and deserpidine.

Graphical abstract: Enantioselective isoquinuclidine synthesis via sequential Diels–Alder/visible-light photoredox C–C bond cleavage: a formal synthesis of the indole alkaloid catharanthine

Supplementary files

Article information

Article type
Research Article
Submitted
09 aug 2018
Accepted
04 sep 2018
First published
05 sep 2018

Org. Chem. Front., 2018,5, 2934-2939

Enantioselective isoquinuclidine synthesis via sequential Diels–Alder/visible-light photoredox C–C bond cleavage: a formal synthesis of the indole alkaloid catharanthine

S. J. Kim and R. A. Batey, Org. Chem. Front., 2018, 5, 2934 DOI: 10.1039/C8QO00849C

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