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

• Published in: European journal of organic chemistry 2015-06, Vol.2015 (16), p.3462-3469
• Main Authors: Tejedor, David, Méndez-Abt, Gabriela, González-Platas, Javier, Fernández, Israel, García-Tellado, Fernando
• Format: Article
• Language: English
• Subjects: Amino acids; Diastereoselectivity; Hydrogen bonds; Michael addition; Sigmatropic rearrangement
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201500269

The 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. The H‐bond makes the difference. The stereochemical outcome of the nucleophilic addition of secondary amines to a fully substituted cyclobutane platform is governed by an NH···O=C interaction between the incoming amine and benzoate leaving group. This interaction directs the addition to the same face as that of the leaving group to form the most kinetically accessible amino acid derivative.