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

By David Tejedor, Gabriela Méndez-Abt, Javier González-Platas, Israel Fernández and Fernando García-Tellado


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.This research was supported by the Spanish Ministerio de Economía y Competitividad (MINECO), the European FEDER and Regional Development Fund (grant numbers CTQ2011-28417-C01-02, CTQ-2013-44303-P), and the Red de Excelencia Consolider (grant number CTQ2014-51912-REDC). G. M.-A. thanks the Spanish Ministerio de Educación y Ciencia (MEC) for an FPU grant. The ORFEO-CINQA network is also acknowledged.Peer Reviewe

Topics: Hydrogen bonds, Diastereoselectivity, Sigmatropic rearrangement, Michael addition, Amino acids
Publisher: 'Wiley'
Year: 2016
DOI identifier: 10.1002/ejoc.201500269
OAI identifier:
Provided by: Digital.CSIC
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