Hydrogen Bond Controlled Anti‐Aza‐Michael Addition: Diastereoselective Synthesis of Cyclobutene‐Containing Amino Acid Derivatives

Abstract

AbstractThe chemical reactivity encoded in a highly substituted cyclobutane platform, which contains the (E,E)‐dimethyl 2,2′‐(cyclobutane‐1,2‐diylidene)diacetate structural motif, has been explored. The cyclobutane platform features a C2 axis of symmetry as well as a dense and interconnected ring functionalization pattern that is defined by two allylic/benzylic stereogenic oxygen‐containing quaternary centers with a 1,2‐trans configuration and two exocyclic acrylate chains. The reactivity profile of the cyclobutane platform is defined by two important kinetic barriers (steric strain and antiaromaticity) and two structure‐biased chemical processes: (1) the thermally‐driven [3,3] sigmatropic rearrangement between one of the two equivalent aryloates and the corresponding allylic acrylate chain and (2) the allylic nucleophilic substitution (SN2′ reaction) that involves a tertiary aryloate and its exocyclic double bond (anti‐Michael addition). The reaction of platform 3a with secondary amines delivered the corresponding cyclobutene amino acid derivatives 15a–15f in excellent yields (up to ≥95 %) and high diastereoselectivities (up to 99:1). Computational studies are described to rationalize the observed diastereoselectivity.