Amino Acid Schiff Base Bearing Benzophenone Imine As a Platform for Highly Congested Unnatural α-Amino Acid Synthesis

Abstract

Unnatural α-amino acids are invaluable building blocks in synthetic organic chemistry and could upgrade the function of peptides. We developed a new mode for catalytic activation of amino acid Schiff bases, serving as a platform for highly congested unnatural α-amino acid synthesis. The redox active copper catalyst enabled efficient cross-coupling to construct contiguous tetrasubstituted carbon centers. The broad functional group compatibility highlights the mildness of the present catalysis. Notably, we achieved successive β-functionalization and oxidation of amino acid Schiff bases to afford dehydroalanine derivatives bearing tetrasubstituted carbon. A three-component cross-coupling reaction of an amino acid Schiff base, alkyl bromides, and styrene derivatives demonstrated the high utility of the present method. The diastereoselective reaction was also achieved using menthol derivatives as a chiral auxiliary, delivering enantiomerically enriched α-amino acid bearing α,β-continuous tetrasubstituted carbon. The synthesized highly congested unnatural α-amino acid could be derivatized and incorporated into peptide synthesis.

Advances in Asymmetric Amino Acid Synthesis Enabled by Radical Chemistry

“…Asymmetric synthesis of the quaternary α,α-AA derivatives 152 by radical coupling of a glycinate 151 bearing chiral auxiliary with bromides catalyzed by copper(II) acetate (Nishikata, Yazaki and Ohshima, 2020). [185] Scheme 62. Synthesis of a chiral difluoromethylene-linked serine analogue 155 by conjugate addition of radical generated from a chiral alanine derivative 153 to the carbohydrate 154 (Motherwell, 1997).…”

“…[183] 6. Radicals Generated from AA Derivatives in Conjugate Additions Another promising approach for the synthesis of nonproteinogenic AAs are based on generating the αcarbon radicals from glycine equivalents [184,185] and a side-chain modification of AAs, [63,65,66] for example, Laspartic and glutamic acid derivatives via radical decarboxylation, [186] leucine and valine derivatives via radical CÀ H activation [187,188] or vinyl-and allylglycine derivatives via radical conjugate additions. [189,190] In this paragraph, we will discuss the fascinating works having a deal with these topics.…”

“…[193] Quite recently, Matsumoto et al described a new mode for the catalytic asymmetric synthesis of highly congested challenging non-proteinogenic α-aryl α-AAs by copper-catalyzed radical-radical coupling reaction. [185] The cooperative Brønsted base/copper(II) acetate catalysed radical addition of alkyl bromides to a chiral benzophenone imine substrate 151 bearing menthol auxiliary furnished the valuable quaternary α, α-disubstituted α-AA derivatives 152 with high diastereoselective control (up to 96:4 dr) in a range of 23-72% yields (Scheme 61). The removal of chiral auxiliary and benzophenone by acidic hydrolysis led to the target highly congested challenging α-aryl α-AAs.…”

“…The removal of chiral auxiliary and benzophenone by acidic hydrolysis led to the target highly congested challenging α-aryl α-AAs. [185] Based on control experiments, the authors proposed a catalytic cycle as depicted in Scheme 61. The deprotonation of the initial substrate 151 by a Brønsted base followed by the subsequent oxidation of enolate intermediate to resonance persistent azaallyl radical (I) via a SET mechanism and the concomitantly generated Cu(I) acetate activated alkyl bromide, providing tertiary alkyl radical species and, finally, the cross-coupling of two different tertiary radicals delivered the desired products 152 (Scheme 61).…”

“…However, as was mentioned by the authors, the alternative mechanism involved Cu(III)/Cu(I) pathway cannot be ruled out. [185] Scheme 67. Synthesis of the enantiopure α-AA derivatives (S)-173-175 by a side-chain modification of the unsaturated AA derivatives (S)-172 (Jackson, 2019).…”