Chemoenzymatic preparation of optically active secondary amines: a new efficient route to enantiomerically pure indolines

An efficient chemoenzymatic route for the synthesis of optically active substituted indolines has been developed. Different lipases have been tested in the alkoxycarbonylation of these secondary amines, Candida antarctica lipase A (CAL-A) was found to be the best biocatalyst for 2-substituted-indolines, and C. antarctica lipase B (CAL-B) for 3-methylindoline. The combination of lipases with a variety of allyl carbonates and tert-butyl methyl ether (TBME) as solvent has allowed the isolation of the carbamate and amine derivatives with a high level of enantiopurity.

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(S)-(−)-2-MethylindolineC9H11NEe = 99% (HPLC, Chiralcel OD)[α]D20=-16.3 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(R)-(−)-2-Methylindoline allyl carbamateC13H15NO2Ee = 99% (HPLC, Chiralcel OD)[α]D20=-47.4 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: R

(S)-(+)-2-PhenylindolineC14H13NEe = 97% (HPLC, Chiralcel OD)[α]D20=+65.4 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(R)-(−)-2-Phenylindoline allyl carbamateC18H17NO2Ee = 99% (HPLC, Chiralcel OB-H)[α]D20=-93.0 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: R

(S)-(−)-2-Methyl-5-methoxyindolineC10H13NOEe = 99% (HPLC, Chiralcel OD)[α]D20=-14.2 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(R)-(−)-2-Methyl-5-methoxyindoline allyl carbamateC14H17NO2Ee = 95%[α]D20=-54.6 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: R

(S)-(−)-5-Fluoro-2-methylindolineC19H10FNEe = 99% (HPLC, Chiralcel OD)[α]D20=-10.1 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S

(R)-(−)-5-Fluoro-2-methylindoline allyl carbamateC13H14FNO2Ee = 99% (HPLC, Chiralcel OB-H)[α]D20=-37.3 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: R

(R)-(−)-3-MethylindolineC9H11NEe = 99% (HPLC, Chiralcel OB-H)[α]D20=-30.2 (c 0.25, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: R

(S)-(−)-3-Methylindoline allyl carbamateC13H15NO2Ee = 97% (HPLC, Chiralcel OB-H)[α]D20=+21.2 (c 0.5, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: S