Asymmetric Synthesis of Protected Unnatural α-Amino Acids via Enantioconvergent Nickel-Catalyzed Cross-Coupling

Abstract

Interest in unnatural α-amino acids has increased rapidly in recent years in areas ranging from protein design to medicinal chemistry to materials science. Consequently, the development of efficient, versatile, and straightforward methods for their enantioselective synthesis is an important objective in reaction development. In this report, we establish that a chiral catalyst based on nickel, an earth-abundant metal, can achieve the enantioconvergent coupling of readily available racemic alkyl electrophiles with a wide variety of alkylzinc reagents (1:1.1 ratio) to afford protected unnatural α-amino acids in good yield and ee. This cross-coupling, which proceeds under mild conditions and is tolerant of air, moisture, and a broad array of functional groups, complements earlier approaches to the catalytic asymmetric synthesis of this valuable family of molecules. We have applied our new method to the generation of several enantioenriched unnatural α-amino acids that have previously been shown to serve as useful intermediates in the synthesis of bioactive compounds.

Visible Light Induced Cu-Catalyzed Asymmetric C(sp3)–H Alkylation

“…With the rapid development of radical chemistry, the alkyl radicals involved coupling reactions have become reliable strategies to build C­(sp 3 )–C­(sp 3 ) bonds, especially for the asymmetric alkyl–alkyl couplings . Recently, Ni-catalyzed asymmetric cross couplings of alkyl electrophiles, such as alkyl halides, for synthesis of chiral C­(sp 3 )–C­(sp 3 ) bonds have achieved significant progress . Compared with prefunctionalized alkyl electrophiles, the C­(sp 3 )–H bond is considered a more convenient asymmetric alkylation substrate that has received much attention in the organic synthetic community during recent decades.…”

Generation of Organozinc Nucleophiles Based on the Biomass-Derived Platform Molecule 5-(Chloromethyl)furfural

“…Although the remaining mass balance was mainly starting material, entries 5 and 6 indicate that longer reaction time and higher temperature is either ineffective or even deleterious to yield. Some investigators have described filtering the organozinc reagent before use . In our hands, use of the filtered nucleophile solution of 3 only led to incomplete reactions.…”

“…Some investigators have described filtering the organozinc reagent before use. 21 In our hands, use of the filtered nucleophile solution of 3 only led to incomplete reactions.…”

Nickel-Catalyzed Selective Decarbonylation of α-Amino Acid Thioester: Aminomethylation of Mercaptans

“…Based on the previous literature reports ,, and mechanistic experiments, the elementary steps involved in the present nickel-catalyzed α-amino acid thioester decarbonylation aminomethylation is postulated in Scheme . Initially, oxidative addition of [Ni 0 ] and compound A occurs to generate the acyl-nickel (II) intermediate B.…”