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.
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