Formal enantioconvergent substitution of alkyl halides via catalytic asymmetric photoredox radical coupling

Abstract

Classic nucleophilic substitution reactions (SN1 and SN2) are not generally amenable to the enantioselective variants that use simple and racemic alkyl halide electrophiles. The merging of transition metal catalysis and radical chemistry with organometallic nucleophiles is a versatile method for addressing this limitation. Here, we report that visible light-driven catalytic asymmetric photoredox radical coupling can act as a complementary and generic strategy for the enantioconvergent formal substitution of alkyl haldies with readily available and bench-stable organic molecules. Single-electron reductive debrominations of racemic α-bromoketones generate achiral alkyl radicals that can participate in asymmetric Csp3–Csp3 bonds forming cross-coupling reactions with α-amino radicals derived from N-aryl amino acids. A wide range of valuable enantiomerically pure β2- and β2,2-amino ketones were obtained in satisfactory yields with good-to-excellent enantioselectivities by using chiral phosphoric acid catalysts to control the stereochemistry and chemoselectivity. Fluoro-hetero-quaternary and full-carbon quaternary stereocenters that are challenging to prepare were successfully constructed.

The Persistent Radical Effect in Organic Synthesis

“…α‐Amido alkyl radicals can also be generated by SET oxidation and subsequent decarboxylation with a dicyanopyrazine‐derived chromophore (DZP) as the photocatalyst using α‐amino acids 79 as radical precursors (Figure ) . In combination with α‐bromo ketones as C‐radical precursors, selective cross‐coupling can be achieved.…”

“… Asymmetric cross‐coupling of bromoketones 78 with longer‐lived α‐amido alkyl radicals derived from carboxylic acids 79 …”

Recent developments in enantioselective photocatalysis

“…As in the previous examples, the azaarene nitrogen is proposed to be protonated by the CPA to form chiral ion pair 130, which is then reduced by DPZ •− to give ketyl radical 130 • . The radical 130 • is then reduced further to the carbanion 130 − , which is protonated enantioselectively to give alcohols 131 in excellent yields and enantioselectivities (38 examples, up Jiang et al also reported a series of radical coupling reactions using different CPAs 135a-g and DPZ, with the first examples using α-bromoketones 136 and α-amino acids 137 as radical precursors (Scheme 19a) [66]. The proposed mechanism proceeds through a reductive quenching cycle to generate α-amino radical 137 • and DPZ •− , which can reduce 136 to give α-carbonyl radical 136 • .…”

Der “Persistent Radical Effect” in der organischen Chemie

“…Die α‐Amidoalkyl‐Radikale können auch durch SET‐Oxidation und anschließende Decarboxylierung mit einem von Dicyanopyrazin abgeleiteten Chromophor (DZP) als Photokatalysator mit α‐Aminosäuren 79 als Radikalvorläufer erzeugt werden (Abbildung ) . In Kombination mit α‐Bromketonen als C‐Radikalvorläufer wurde eine selektive Kreuzkupplung durchgeführt.…”

“… Asymmetrische Kreuzkupplung von Bromketonen 78 mit langlebigen von Carbonsäuren 79 abgeleiteten α‐Amidoalkyl‐Radikalen …”