l-Proline derived arylmethanamine ligands and their application in the copper-catalyzed asymmetric Henry reaction: a rare example of a Cu-complex with a dicopper tetraacetate core

A series of novel epimeric arylmethanamine ligands were synthesized from l-proline. Both epimers were subsequently examined in the copper(II)-catalyzed asymmetric Henry reaction. Product yield and stereoselectivity up to 92% ee indicated that the (S,S)-epimer was superior to the diamine with an (S,R)-configuration. An enhancement of enantioselectivity driven by the formation of a Cu(II) complex with a dicopper tetraacetate core was discovered. Two types of crystalline Cu(II) complexes were isolated, and their structures were established by X-ray analyses.

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(S)-tert-Butyl 2-((S)-amino(phenyl)methyl)pyrrolidine-1-carboxylateC16H24N2O2[α]D23 = −78.0 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(1S,7aS)-1-Phenyltetrahydro-1H-pyrrolo[1,2-c]imidazol-3(2H)-oneC12H14N2O[α]D23 = −71.6 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (1S,7aS)

(S)-tert-Butyl 2-((R)-amino(phenyl)methyl)pyrrolidine-1-carboxylateC16H24N2O2[α]D23 = +8.4 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(1R,7aS)-1-Phenyltetrahydro-1H-pyrrolo[1,2-c]imidazol-3(2H)-oneC12H14N2O[α]D23 = −153.3 (c 0.5, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (1R,7aS)

(R)-N,N-Dimethyl-1-((S)-1-methylpyrrolidin-2-yl)-1-phenylmethanamineC14H22N2[α]D23 = −33.5 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(R)-N-Methyl-1-phenyl-1-((S)-pyrrolidin-2-yl)methanamineC12H18N2[α]D23 = −53.1 (c 0.7, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(R)-N,N-Dimethyl-1-phenyl-1-((S)-pyrrolidin-2-yl)methanamineC13H20N2[α]D23 = +0.6 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

1-((R)-Phenyl((S)-pyrrolidin-2-yl)methyl)piperidineC16H24N2[α]D23 = +2.1 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

1-((R)-Phenyl((S)-pyrrolidin-2-yl)methyl)pyrrolidineC15H22N2[α]D23 = −35.5 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-1-Methyl-2-((R)-phenyl(pyrrolidin-1-yl)methyl)pyrrolidineC16H24N2[α]D23 = −79.2 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-1-(2,3,4,5,6-Pentamethylbenzyl)-2-((R)-phenyl(pyrrolidin-1-yl)methyl)pyrrolidineC27H38N2[α]D23 = −55.4 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

1-((S)-Phenyl((S)-pyrrolidin-2-yl)methyl)pyrrolidineC15H22N2[α]D23 = −18.8 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(S)-N-Methyl-1-phenyl-1-((S)-pyrrolidin-2-yl)methanamineC12H18N2[α]D22 = +64.0 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(S)-N-Methyl-1-(1-(2,3,4,5,6-pentamethylbenzyl)pyrrolidin-2-yl)methanamineC18H30N2[α]D23 = −26.4 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (S)

(S)-Methyl 1-(2,3,4,5,6-pentamethylbenzyl)pyrrolidine-2-carboxylateC18H27NO2[α]D23 = −44.4 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (S)

(R)-((S)-1-(2,3,4,5,6-Pentamethylbenzyl)pyrrolidin-2-yl)(phenyl)methanolC23H31NO[α]D23 = −3.8 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-((S)-1-(2,3,4,5,6-Pentamethylbenzyl)pyrrolidin-2-yl)(phenyl)methanolC23H31NO[α]D23 = +120.1 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(R)-2-((S)-Azido(phenyl)methyl)-1-(2,3,4,5,6-pentamethylbenzyl)pyrrolidineC23H30N4[α]D23 = −58.9 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-2-((S)-Azido(phenyl)methyl)-1-(2,3,4,5,6-pentamethylbenzyl)pyrrolidineC23H30N4[α]D23 = −57.5 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(R)-((S)-1-(2,3,4,5,6-Pentamethylbenzyl)pyrrolidin-2-yl)(phenyl)methanamineC23H32N2[α]D23 = −2.7 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-((S)-1-(2,3,4,5,6-Pentamethylbenzyl)pyrrolidin-2-yl)(phenyl)methanamineC23H32N2[α]D23 = −15.1 (c 0.5, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(R)-N-Methyl-1-((S)-1-(2,3,4,5,6-pentamethylbenzyl)pyrrolidin-2-yl)-1-phenylmethanamineC23H34N2[α]D26 = −12.7 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-N-Methyl-1-((S)-1-(2,3,4,5,6-pentamethylbenzyl)pyrrolidin-2-yl)-1-phenylmethanamineC24H34N2[α]D25 = −16.5 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(S)-tert-Butyl 2-((S)-hydroxy(4-methoxyphenyl)methyl)pyrrolidine-1-carboxylateC17H25NO4[α]D23 = −17.9 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(S)-tert-Butyl 2-((S)-hydroxy(mesityl)methyl)pyrrolidine-1-carboxylateC19H29NO3[α]D23 = +13.1 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(S)-tert-Butyl 2-((S)-(3,5-di-tert-butylphenyl)(hydroxy)methyl)pyrrolidine-1-carboxylateC24H39NO3[α]D23 = −17.9 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(S)-tert-Butyl 2-((S)-hydroxy(4-methoxy-3,5-dimethylphenyl)methyl)pyrrolidine-1-carboxylateC19H29NO4[α]D23 = −13.2 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(S)-tert-Butyl 2-((S)-hydroxy(naphthalen-1-yl)methyl)pyrrolidine-1-carboxylateC20H25NO3[α]D23 = −32.4 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,S)

(S)-tert-Butyl 2-((R)-amino(4-methoxyphenyl)methyl)pyrrolidine-1-carboxylateC17H26N2O3[α]D23 = −7.2 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-tert-Butyl 2-((R)-amino(mesityl)methyl)pyrrolidine-1-carboxylateC19H30N2O2[α]D23 = +32.4 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-tert-Butyl 2-((R)-amino(3,5-di-tert-butylphenyl)methyl)pyrrolidine-1-carboxylateC24H40N2O2[α]D23 = −26.5 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-tert-Butyl 2-((R)-amino(4-methoxy-3,5-dimethylphenyl)methyl)pyrrolidine-1-carboxylateC19H30N2O3[α]D23 = +15.4 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-tert-Butyl 2-((R)-amino(naphthalen-1-yl)methyl)pyrrolidine-1-carboxylateC20H26N2O2[α]D23 = +95.3 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-tert-Butyl 2-((R)-(4-methoxyphenyl)(methylamino)methyl)pyrrolidine-1-carboxylateC13H20N2O[α]D23 = −63.7 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-tert-Butyl 2-((R)-mesityl(methylamino)methyl)pyrrolidine-1-carboxylateC15H24N2[α]D17 = −35.6 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-tert-Butyl 2-((R)-(3,5-di-tert-butylphenyl)(methylamino)methyl)pyrrolidine-1-carboxylateC20H34N2[α]D23 = −55.7 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-tert-Butyl 2-((R)-(4-methoxy-3,5-dimethylphenyl)(methylamino)methyl)pyrrolidine-1-carboxylateC15H24N2O[α]D22 = −60.5 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-tert-Butyl 2-((R)-(methylamino)(naphthalen-1-yl)methyl)pyrrolidine-1-carboxylateC16H20N2[α]D23 = −115.5 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

1-((R)-(4-Methoxyphenyl)((S)-pyrrolidin-2-yl)methyl)pyrrolidineC16H24N2O[α]D21 = −30.2 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

(S)-tert-Butyl 2-((R)-mesityl(methylamino)methyl)pyrrolidine-1-carboxylateC18H28N2[α]D22 = −45.5 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)

1-((R)-(3,5-Di-tert-butylphenyl)((S)-pyrrolidin-2-yl)methyl)pyrrolidineC23H38N2[α]D23 = −27.4 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesis from l-ProlineAbsolute configuration: (2S,R)