Enantioselective Synthesis of α-Aminoboronic Acid Derivatives via Copper-Catalyzed N-Alkylation

Abstract

Due to burgeoning interest in the pharmaceutical industry in exploiting optically active α-aminoboronic derivatives as bioisosteres of α-amino acid derivatives, the discovery of methods for their catalytic asymmetric synthesis is an important challenge. Herein, we establish that a chiral copper catalyst (generated in situ from commercially available components) can achieve the enantioselective synthesis of α-aminoboronic derivatives via the coupling of two readily available partners, a carbamate and a racemic α-chloroboronate ester. Furthermore, we describe mechanistic studies that played a key role in the development of this new method and that provide insight into the optimized process.

Copper-Catalyzed Enantioconvergent Radical C(sp3)–N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)aromatic Amines under Ambient Conditions

“…More importantly, product 78 underwent the deprotection smoothly to generate propargylamine 96 bearing a terminal alkyne (the absolute configuration was determined to be R by X-ray crystallographic analysis, and the propargyl products 78 – 90 were assigned by analogy accordingly), which could serve as precursors for alkenes, alkanes, etc . Noteworthy is that no obvious loss of enantiopurity was observed during all of these transformations, thus demonstrating the practicality of this method as a robust complementary approach to reported strategies. − , …”

“…This is based on the fact that (hetero)­aromatic amines are one of the largest groups of commercially available feedstock chemicals, natural products, and drug molecules . Various methods have been successfully developed, including Tsuji–Trost-type allylic aminations of secondary allylic electrophiles, propargylic aminations of secondary propargylic carbonates, (dynamic) kinetic resolution N -alkylation by secondary alkyl halides, catalytic asymmetric amination reactions of racemic 3-bromooxindoles, and others. On the other hand, great efforts have recently been dedicated to the development of chiral earth-abundant first-row transition-metal catalysts, which could provide a suitable mechanism for enantioconvergence by converting the racemic alkyl halides to prochiral radicals via a single-electron reduction process. , In this content, Fu, Peters, and their co-workers have pioneered the copper-catalyzed enantioconvergent radical C­(sp 3 )–N coupling of racemic alkyl halides with N -nucleophiles under visible light irradiation. , Particularly, they have utilized anilines as the nucleophiles in the enantioconvergent coupling of alkyl halides to access chiral N -tertiary-alkyl anilines under photochemical conditions at −78 °C (Scheme B). , Despite this advance, the development of more catalytic systems is still highly desirable to realize the coupling of diverse alkyl halides and aromatic amines to access more N -alkyl aromatic amines under ambient conditions.…”

Chirality Amplification Over the Morphology Control of the Rod-Coil Molecules with Lateral Methyl Groups

“…Based on the strong Cotton signal of molecule 4 , we hypothesized that nano-tubes could be good candidates as nanoreactors for asymmetric synthesis. Enantioselective synthesis and enantioseparation have aroused enormous interest in pharmaceutical analysis, food chemistry, and life science. − Nucleophilic substitution is a fundamental class of reactions with widespread applications in organic synthesis …”

Recent Advances in the Preparation and Asymmetric Transformation of α-Haloboron Compounds

“…Just recently, the Fu group realized an asymmetric coupling of primary amides with racemic -chloroboronic esters using a copper catalyst, and they synthesized a series of chiral secondary amides (Scheme 28). 29 The product can be hydrolyzed to chiral secondary amines in the presence of hydrochloric acid, providing the possibility of obtaining chiral amino alcohols subsequently.…”