A stereoselective synthesis of (+)-L-733,060 from ethyl (R)-(+)-2,3-epoxypropanoate

An asymmetric synthesis of neurokinin substance P receptor antagonist (+)-L-733,060 starting from enantiomerically pure ethyl (R)-(+)-2,3-epoxypropanoate (ethyl glycidate) is described. The synthesis relies on a diastereoselective reductive amination, regioselective intramolecular epoxide opening, and in situ cyclization as the key steps.

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(R)-Oxiran-2-yl(phenyl)methanoneC9H8O2[α]D25=+53.7 (c 1.1, CH2Cl2)Source of chirality: ethyl (R)-(+)-2,3-epoxypropanoateAbsolute configuration: (2R)

(S)-N-Benzyl-1-((S)-oxiran-2-yl)-1-phenylmethanamineC16H17NO[α]D25=+57.8 (c 1.8, CH2Cl2)Source of chirality: ethyl (R)-(+)-2,3-epoxypropanoateAbsolute configuration: (1S,2S)

(4S,5R)-3-Benzyl-5-(hydroxymethyl)-4-phenyloxazolidin-2-oneC17H17NO3[α]D24=+21.1 (c 1.0, CH2Cl2)Source of chirality: ethyl (R)-(+)-2,3-epoxypropanoateAbsolute configuration: (4S,5S)

(1S,2R)-1-(Benzylamino)-3-(tert-butyldimethylsilyloxy)-1-phenylpropan-2-olC22H33NO2Si[α]D24=+32.2 (c 1.7, CH2Cl2)Source of chirality: ethyl (R)-(+)-2,3-epoxypropanoateAbsolute configuration: (1S,2R)

tert-Butyl (1S,2R)-3-(tert-butyldimethylsilyloxy)-2-hydroxy-1-phenylpropylcarbamateC20H35NO4Si[α]D25=+17.2 (c 1.1, CH2Cl2)Source of chirality: ethyl (R)-(+)-2,3-epoxypropanoateAbsolute configuration: (1S,2R)

(4S,5R)-tert-Butyl 5-(hydroxymethyl)-2,2-dimethyl-4-phenyloxazolidine-3-carboxylateC17H25NO4[α]D24=+31.8 (c 1.1, CH2Cl2)Source of chirality: ethyl (R)-(+)-2,3-epoxypropanoateAbsolute configuration: (4S,5R)

(4S,5S)-tert-Butyl 5-((E)-3-methoxy-3-oxoprop-1-enyl)-2,2-dimethyl-4-phenyloxazolidine-3-carboxylateC20H27NO5[α]D24=-36.8 (c 0.9, CH2Cl2)Source of chirality: ethyl (R)-(+)-2,3-epoxypropanoateAbsolute configuration: (4S,5S)

(5S,6S)-5-Hydroxy-6-phenylpiperidin-2-oneC11H13NO2[α]D25=+52.0 (c 1.1, CH2Cl2)Source of chirality: ethyl (R)-(+)-2,3-epoxypropanoateAbsolute configuration: (5S,6S)

(2S,3S)-tert-Butyl-3-hydroxy-2-phenylpiperidine-1-carboxylateC16H23NO3[α]D24=+42.6 (c 0.54, CHCl3)Source of chirality: ethyl (R)-(+)-2,3-epoxypropanoateAbsolute configuration: (2S,3S)

(2S,3S)-3-(3,5-Bis(trifluoromethyl)benzyloxy)-2-phenylpiperidineC20H19NOF6[α]D24=+34.8 (c 0.9, CHCl3)Source of chirality: ethyl (R)-(+)-2,3-epoxypropanoateAbsolute configuration: (2S,3S)