Diversity-Oriented Synthesis of Bioactive Azaspirocycles

A collection of novel azaspirocyclic beta-arylethylamines was prepared in good yield and excellent dia-stereoselectivity by an expedient strategy that features condensation of a cyclic ketone with an amino allylsilane and a tandem aza-Sakurai cyclization to generate several different spirocyclic N-heterocycles. Subsequent elaboration of the spirocyclic scaffold was achieved via Pictet-Spengler cyclizations, Suzuki cross-coupling reactions, N-functionalizations, and olefin refunctionalization reactions to create a diverse library of compounds, several of which have nanomolar affinity for the sigma 1 receptor and trans membrane protein 97 (TMEM97). (C) 2019 Elsevier Ltd. All rights reserved.