Catalytic α-Deracemization of Ketones Enabled by Photoredox Deprotonation and Enantioselective Protonation

Abstract

This study reports the catalytic deracemization of ketones bearing stereocenters in the α-position in a single reaction via deprotonation, followed by enantioselective protonation. The principle of microscopic reversibility, which has previously rendered this strategy elusive, is overcome by a photoredox deprotonation through single electron transfer and subsequent hydrogen atom transfer (HAT). Specifically, the irradiation of racemic pyridylketones in the presence of a single photocatalyst and a tertiary amine provides nonracemic carbonyl compounds with up to 97% enantiomeric excess. The photocatalyst harvests the visible light, induces the redox process, and is responsible for the asymmetric induction, while the amine serves as a single electron donor, HAT reagent, and proton source. This conceptually simple light-driven strategy of coupling a photoredox deprotonation with a stereocontrolled protonation, in conjunction with an enrichment process, serves as a blueprint for other deracemizations of ubiquitous carbonyl compounds.

Catalytic asymmetric conjugate addition of indolizines to unsaturated ketones catalyzed by chiral-at-metal complexes

“…To our surprise, excellent catalysts Λ-Rh1 showing powerful catalytic ability were designed and prepared by Meggers’ group, affording 3a in 92% yield with 96% ee (Table 1, entry 1). 9 Chiral Rh( iii ) complexes Λ-Rh2 and Λ-Rh3 developed by our group were examined subsequently (entries 2 and 3). Λ-Rh2 and Λ-Rh3 were as good as Λ-Rh1 in terms of reactivity and enantioselectivity (entries 2 and 3).…”

Light empowers contra-thermodynamic stereochemical editing

“…Building on the well-established enantioselective enolate protonation-mediated deracemization, Meggers and Chen recently envisioned that a successful one-pot catalytic deracemization of carbonyl compounds might be achieved if enolate formation could be divided into two elementary steps to overcome microscopic reversibility (Fig. 7) 28 . Specifically, photoinduced SET-reduction allowed generation of ketyl intermediate and subsequent HAT (lose of hydrogen), thus leading to net deprotonation.…”

Photochemical Deracemization at sp3-Hybridized Carbon Centers via a Reversible Hydrogen Atom Transfer

“…12 Very recently, the groups of Meggers and Chen reported a deracemization of 2pyridylketones based on a photoredox process in the course of which a chiral-at-metal rhodium enolate is stereoselectively protonated. 13 In Scheme 1 (c = concentration), the interconversion between two enantiomers ent-I and I of a chiral α-amino acid derivative is depicted occurring by a reversible hydrogen atom transfer (HAT) via radical II. 14 We hypothesized that a photochemical deracemization might be possible in this scenario by a single catalyst which would discriminate between ent-I and I.…”

“…While it is thermodynamically impossible to achieve the conversion of a racemate into an enantiomer under equilibrium conditions, − photochemical deracemization reactions are viable with the light energy compensating the entropic penalty of the process . Although envisioned for over 50 years, highly selective photochemical deracemization reactions have only recently been realized. − …”

“…In a different approach, Knowles, Miller, and co-workers employed a three-component catalytic system composed of an achiral iridium complex, a chiral phosphoric acid, and a chiral cysteine-based tetrapeptide to deracemize ureas in a sequence of electron, proton, and hydrogen-atom transfer steps . Very recently, the groups of Meggers and Chen reported a deracemization of 2-pyridylketones based on a photoredox process in the course of which a chiral-at-metal rhodium enolate is stereoselectively protonated …”