Visible‐Light‐Enabled Enantioconvergent Synthesis of α‐Amino Acid Derivatives via Synergistic Brønsted Acid/Photoredox Catalysis

Abstract

An unprecedented radical cross‐coupling reaction was achieved between glycine esters and racemic α‐bromoketones catalyzed by synergistic Brønsted acid/photoredox catalysis, thus serving as an efficient platform for the synthesis of highly valuable enantioenriched unnatural α‐amino acid derivatives. This dual catalysis provides a powerful capability to control the reactive radical intermediate and iminium ion, thereby enabling enantioconvergent bond‐formation in a highly stereochemical manner. An array of valuable enantioenriched unnatural α‐amino acid derivatives bearing two contiguous stereogenic centers are readily accessible with high diastereoselectivity and excellent enantioselectivity, which include α‐amino acids with a unique β‐fluorinated quaternary stereocenter or its β‐all‐carbon counterpart. A strong chiral amplification effect was observed in this dual catalytic system.

Highly Enantioselective Synthesis of N‐Unprotected Unnatural α‐Amino Acid Derivatives by Ruthenium‐Catalyzed Direct Asymmetric Reductive Amination

“…Enantiopure β‐branched α‐amino acids are very important molecules for the synthesis of modified pharmaceutical peptides and proteins with enhanced biological properties [1] . However, their synthesis remains challenging and underdeveloped [11g, 22] . Encouraged by the good results obtained for aryl and alkyl α‐keto amides, we wondered whether this strategy could be extended to β‐branched α‐keto amides to afford enantioenriched β‐branched α‐amino amides via a DKR process [23] .…”

Advanced Synthesis Using Photocatalysis Involved Dual Catalytic System

“…[162] Wang et al have been committed to the regioselective and enantioselective synthesis of non-protein α-amino acid series. [163] Based on the guidance of previous work, [164] in 2021, they successfully reported that the enantiomeric radial coupling reaction between glycine ester and racemic α-bromoketone of the photo-redox dual catalytic system was used to synthesize enantiomer-rich α-amino acid derivatives (Scheme 44).…”

Asymmetric Photocatalysis Enabled by Chiral Organocatalysts

“…in 2021 (Scheme 84). [154] This radical cross‐coupling process generated two chiral centers and featured high enantioselectivity and good diastereoselectivity. A wide range of racemic α‐bromoketones and glycine esters were well tolerated and generated α ‐amino acid derivatives in 51–89 % and 68–99 % ee with 1.2 : 1 to >20 : 1 dr.…”

“…No reaction occurred when propiophenone and N ‐phenyl glycine imino ester were treated under standard conditions, which excluded the Mannich‐type two‐electron pathway. Accordingly, the authors proposed that photoexcited catalyst *Ir III (* E 1/2 *III/II =+1.21 V vs. SCE) [14] oxidizes the glycine ester ( 85.1 , E 1/2 ox =+0.95 V vs. SCE), [154] followed by deprotonation and 1,2‐H shift to afford α ‐amino radical 85.3 and Ir II ( E 1/2 III/II =−1.37 V vs. SCE) [14] as strong reducing species (Scheme 85). This species then reduces α‐bromoketones 85.2 to produce radical intermediate 85.4 and regenerate Ir III photocatalyst.…”