An enantioselective synthesis of 3-aryl-4-phosphonobutyric acid esters via Cu-catalyzed asymmetric conjugate reduction

The asymmetric conjugate reduction of 3-aryl-4-phosphonobutenoates has been demonstrated which provides an enantioselective synthesis of optically active 3-aryl-4-phosphonobutyric acid esters. A wide range of 3-aryl-4-phosphonobutenoate derivates are reduced with high enantioselectivities (up to 94% ee) using an (S)-Segphos/Cu(OAc)2·H2O catalyst system (1 or 5 mol %) in the presence of PMHS and t-BuOH. The reduction is influenced by the steric and electronic effects of the substrates.

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Methyl 4-(dimethoxyphosphoryl)-3-phenylbutanoateC13H17O5PEe: 94%[α]D20=-0.5 (c 1.58, CHCl3)Source of chirality: asymmetric synthesisConfiguration: n.d.

Methyl 4-(dimethoxyphosphoryl)-3-(2-methoxyphenyl)butanoateC14H21O6PEe: 68%[α]D20=-1.5 (c 1.21, CHCl3)Source of chirality: asymmetric synthesisConfiguration: n.d.

Methyl 4-(dimethoxyphosphoryl)-3-(3-methoxyphenyl)butanoateC14H21O6PEe: 93%[α]D20=-1.2 (c 1.61, CHCl3)Source of chirality: asymmetric synthesisConfiguration: n.d.

Methyl 4-(dimethoxyphosphoryl)-3-(4-methoxyphenyl)butanoateC14H21O6PEe: 83%[α]D20=-1.1 (c 1.35, CHCl3)Source of chirality: asymmetric synthesisConfiguration: n.d.

Methyl 3-(4-bromophenyl)-4-(dimethoxyphosphoryl)butanoateC13H18BrO5PEe: 92%[α]D20=-3.9 (c 1.23, CHCl3)Source of chirality: asymmetric synthesisConfiguration: n.d.

Methyl 3-(4-chlorophenyl)-4-(dimethoxyphosphoryl)butanoateC13H18ClO5PEe: 92%[α]D20=-3.6 (c 1.14, CHCl3)Source of chirality: asymmetric synthesisConfiguration: S

Methyl 4-(dimethoxyphosphoryl)-3-(4-fluorophenyl)butanoateC13H18FO5PEe: 91%[α]D20=-1.8 (c 1.10, CHCl3)Source of chirality: asymmetric synthesisConfiguration: n.d.

Methyl 4-(dimethoxyphosphoryl)-3-(4-nitro-phenyl)butanoateC13H18NO7PEe: 90%[α]D20=-3.4 (c 1.45, CHCl3)Source of chirality: asymmetric synthesisConfiguration: n.d.

Methyl 3-(3-chlorophenyl)-4-(dimethoxy-phosphoryl)butanoateC17H21O5PEe: 72%[α]D20=-2.4 (c 1.50, CHCl3)Source of chirality: asymmetric synthesisConfiguration: n.d.

Methyl 4-(dimethoxyphosphoryl)-3-(2-naphthyl)butanoateC17H21O5PEe: 90%[α]D20=-2.4 (c 1.02, CHCl3)Source of chirality: asymmetric synthesisConfiguration: n.d.

Methyl 4-(dimethoxyphosphoryl)-3-(2-thienyl)butanoateC11H17O5PSEe: 91%[α]D20=-3.8 (c 1.86, CHCl3)Source of chirality: asymmetric synthesisConfiguration: n.d.