Deracemization through Sequential Photoredox‐Neutral and Chiral Brønsted Acid Catalysis

Abstract

Catalytic deracemization is an ideal synthetic strategy due to its formally perfect atom utilization. Asymmetric photocatalysis has been appreciated as a promising tool to accomplish this attractive reaction pattern in an economical fashion, but it remains underdeveloped. Here, we report a new platform based on photoredox-neutral catalysis, allowing efficient and modular optical enrichment of α-amino esters and other valuable analogues. Two single-electron transfer processes between the photocatalyst and the substrates serve to provide the key prochiral intermediates, and the chiral Brønsted acid catalyst mediates enantioselective protonation to reconstitute a stereogenic CÀ H bond. The efficiency of deracemization is determined by the enantiofacial differentiation effect during the stereocentre-forming step.

Catalytic Deracemization Reactions

“…Very recently, Jiang et al facilitated the deracemization of αamino esters 30 by merging organo-photocatalyst cat-8 and chiral phosphoric acid cat-2d (Scheme 22). 97 Amino esters bearing various α-alkyl, α-aryl, and cyclic skeletons were tolerated in the reaction system. Deuteration could be achieved in the presence of a large amount of D 2 O without loss of enantioselectivity.…”

Light-driven redox deracemization of indolines and tetrahydroquinolines using a photocatalyst coupled with chiral phosphoric acid

“…1 Among these enantioselective photochemical reactions, light-driven deracemization has attracted a great deal of attention because optically pure products can be directly achieved from their corresponding racemates. 2–4 Summarizing these deracemization reactions reveals that they mainly focus on selective energy transfer and excited-state electron transfer strategies, which are well known to solve the bottleneck problem of kinetically microscopic reversibility in driving reactions out-of-equilibrium when converting a pair of racemates into a single enantiomer (Fig. 1A).…”

“…7 a , b In the latter, an initial achiral catalyst-mediated oxidation followed by a chiral phosphoric acid-catalyzed reduction process has been used for the synthesis of chiral indolines, tetrahydropyrano-[3,4- b ]indoles, and dihydropyrimidines. 7 c – e Inspired by the prominent superiority of enantioselective photocatalysis, 2–4 the development of a light-driven redox deracemization to directly prepare these chiral indolines and tetrahydroquinolines is highly desirable.…”

“…1A (racemization via triplet energy transfer)). 2 a For the excited-state electron transfer strategy, 3 the representative work reported by Knowles and Miller and co-workers ( Fig. 1B 2 ) utilizes two distinct chiral catalysts to mediate the two independent enantioselective steps, where the two in situ generated radical cations can be differentiated using a single chiral catalyst because of the different energy differences (pathway II via the inhibition of unfavorable II′ in the second step in Fig.…”

Catalytic asymmetric deuterosilylation of exocyclic olefins with mannose-derived thiols and deuterium oxide

“…Deuterium is an isotope of hydrogen and has widespread applications in organic synthesis, 1 a – f materials science, 1 g and medicinal chemistry. 1 h While numerous methods have been developed to incorporate deuterium into organic molecules in a site-selective fashion, 1–3 asymmetric deuteration remains underdeveloped, 4–7 particularly with prochiral or racemic substrates, although it has been known that deuterium can slow down epimerization of labile stereocenters and thus stabilize chemically unstable stereoisomers of drug molecules. 1 h…”