Hydrogen-Mediated Reductive Coupling of Conjugated Alkynes with Ethyl (N-Sulfinyl)iminoacetates: Synthesis of Unnatural α-Amino Acids via Rhodium-Catalyzed C−C Bond Forming Hydrogenation

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Abstract
Rhodium-catalyzed hydrogenation of 1,3-enynes 1a − 8a and 1,3-diynes 9a − 13a at ambient temperature and pressure in the presence of ethyl (N-tert-butanesulfinyl)iminoacetate and ethyl (N-2,4,6-triisopropylbenzenesulfinyl)iminoacetates, respectively, results in reductive coupling to afford unsaturated α-amino acid esters 1b − 13b in good to excellent yields with exceptional levels of regio- and stereocontrol. Further hydrogenation of the diene containing α-amino acid esters 1b − 8b using Wilkinson's catalyst at ambient temperature and pressure results in regioselective reduction to afford the β,γ-unsaturated α-amino acid esters 1c − 8c in good to excellent yields. Exhaustive hydrogenation of the unsaturated side chains of the Boc- and Fmoc-protected derivatives of enyne and diyne coupling products 14b − 16b occurs in excellent yield using Crabtree's catalyst at ambient temperature and pressure providing the α-amino acid esters 14d − 16d, which possess saturated side chains. Finally, cross-metathesis of the Boc-protected reductive coupling product 14b with cis-1,4-diacetoxy-2-butene proceeds readily to afford the allylic acetate 14e. Isotopic labeling studies that involve reductive coupling of enyne 1a and diyne 9a under an atmosphere of elemental deuterium corroborate a catalytic mechanism in which oxidative coupling of the alkyne and imine residues is followed by hydrogenolytic cleavage of the resulting metallacycle. A stereochemical model accounting for the observed sense of asymmetric induction is provided. These studies represent the first use of imines as electrophilic partners in hydrogen-mediated reductive carbon−carbon bond formation.

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