Tropane and related alkaloid skeletons via a radical [3+3]-annulation process

Tropanes and related bicyclic alkaloids are highly attractive compounds possessing broad biological activity. The authors report a mild, simple protocol for synthesizing N-arylated 8-azabicyclo[3.2.1]octane (tropane) and 9-azabicyclo[3.3.1]nonane (homotropane) derivatives in good yields and with high diastereoselectivity from simple starting materials via visible-light photoredox catalysis. The bicyclic aniline derivatives produced are difficult to access via classical Robinson tropane synthesis and are valuable scaffolds for medicinal chemistry. The unprecedented [3+3] radical annulation exploits ethyl 2-(acetoxymethyl)acrylate as a 1,3-bis radical acceptor and cyclic N,N-dialkylanilines as 1,3-bis radical donors. Success relies on efficient electron transfer and highly selective deprotonation of aminium radical cations to generate α-amino radical intermediates.

Eloïse Colson, Julie Andrez, Ali Dabbous, Fabrice Dénès, Vincent Maurel, Jean-Marie Mouesca, Philippe Renaud