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

Colson, Eloïse; Andrez, Julie; Dabbous, Ali; Dénès, Fabrice; Maurel, Vincent; Mouesca, Jean-Marie; Renaud, Philippe (2022). Tropane and related alkaloid skeletons via a radical [3+3]-annulation process. Communications chemistry, 5(1), p. 57. Springer Nature 10.1038/s42004-022-00671-x

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Tropanes and related bicyclic alkaloids are highly attractive compounds possessing a broad biological activity. Here we report a mild and simple protocol for the synthesis of N-arylated 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane derivatives. It provides these valuable bicyclic alkaloid skeletons in good yields and high levels of diastereoselectivity from simple and readily available starting materials using visible-light photoredox catalysis. These bicyclic aniline derivatives are hardly accessible via the classical Robinson tropane synthesis and represent a particularly attractive scaffold for medicinal chemistry. This unprecedented annulation process takes advantage of the unique reactivity of ethyl 2-(acetoxymethyl)acrylate as a 1,3-bis radical acceptor and of cyclic N,N-dialkylanilines as radical 1,3-bis radical donors. The success of this process relies on efficient electron transfer processes and highly selective deprotonation of aminium radical cations leading to the key α-amino radical intermediates.

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