Abstract
A copper-catalysed regio- and stereoselective hydroamination of acrylates with hydrosilanes and hydroxylamines has been developed to afford the corresponding α-amino acids in good yields. The key to regioselectivity control is the use of hydroxylamine as an umpolung, electrophilic amination reagent. Additionally, a judicious choice of conditions involving the CsOPiv base and DTBM-dppbz ligand of remote steric hindrance enables the otherwise challenging C–N bond formation at the α position to the carbonyl. The point chirality at the β-position is successfully controlled by the Xyl-BINAP or DTBM-SEGPHOS chiral ligand with similarly remote steric bulkiness. The combination with the chiral auxiliary, (−)-8-phenylmenthol, also induces stereoselectivity at the α-position to form the optically active unnatural α-amino acids with two adjacent stereocentres.
Highlights
Introduction aAmino acids are prevalent structural motifs in many biologically active compounds and pharmaceutical agents, especially peptide drugs
There is a considerable challenge associated with the aforementioned reaction design; Guo and Buchwald recently reported the related attempt of the copper-catalysed regioselective hydroamination of cinnamates with 1,2-benzisoxazole as the electrophilic amino source (Scheme 4).26a While the (S,S)-Ph–BPE ligand successfully gave the corresponding b-amino acid derivative, the a-amino acid was not obtained at all, and instead
We have developed an umpolung-enabled copper-catalysed regioselective hydroamination of a,b-unsaturated esters with hydrosilanes and hydroxylamines to deliver the corresponding a-amino acid derivatives
Summary
Introduction aAmino acids are prevalent structural motifs in many biologically active compounds and pharmaceutical agents, especially peptide drugs. A copper-catalysed regio- and stereoselective hydroamination of acrylates with hydrosilanes and hydroxylamines has been developed to afford the corresponding a-amino acids in good yields.
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