Asymmetric synthesis of 1,3-aminoketals

The asymmetric synthesis of α-chiral 1,3-aminoketals 1, useful chiral building blocks for piperidine preparation, was achieved in seven steps involving highly diastereoselective 1,4-addition of Davies’ lithium amide to an α,β-unsaturated ester. Problems of partial racemization observed during transformation of the ester moiety into a keto function, via a Weinreb amide, were solved using non-conventional experimental conditions. This procedure allowed the preparation of the title compounds in >90% enantiomeric excess.

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Methyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-3-phenyl-propanoateC25H27NO2De = 94%[α]D25=+5.6 (c 1.04, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

Methyl (3R,αR)-3-(N-benzyl-N-α-methylbenzylamino)butanoateC20H25NO2De = 95%[α]D25=-1.2 (c 1.15, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Methyl (3R,αR)-3-(N-benzyl-N-α-methylbenzylamino)hexanoateC22H29NO2De = 97%[α]D25=+14.9 (c 1.52, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Methyl (3S,αR)-3-(3,4-dimethoxyphenyl)-3-(N-benzyl-N-α-methylbenzylamino)propanoateC27H31NO4De = 92%[α]D25=+2.0 (c 1. 2, CH3OH)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

(3S,αR)-3-(N-Benzyl-N-α-methylbenzylamino)-3-phenyl-(N′-methoxy-N′-methyl)propanamideC26H30N2O2[α]D25=+12.7 (c 1.14, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

(3R,αR)-3-(N-Benzyl-N-α-methylbenzylamino)-(N′-methoxy-N′-methyl)butanamideC21H28N2O2[α]D25=+28.7(c 1.47, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

(3R,αR)-3-(N-Benzyl-N-α-methylbenzylamino)-(N′-methoxy-N′-methyl)hexanamideC23H32N2O2[α]D25=+55.3 (c 1.09, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

(3S,αR)-3-(3,4-Dimethoxyphenyl)-3-(N-benzyl-N-α-methylbenzylamino)-(N′-methoxy-N′-methyl)propanamideC28H34N2O4[α]D25=+54.5 (c 0.92, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

(3S)-3-Amino-3-phenyl-(N-methoxy-N-methyl)propanamideC11H16N2O2[α]D25=-23.8 (c 1.13, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S)

(3R)-3-Amino-(N-methoxy-N-methyl)hexanamideC8H18N2O2[α]D25=-23.3 (c 1.32, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R)

(3S)-3-Amino-3-(3,4-dimethoxyphenyl)-(N-methoxy-N-methyl)propanamideC13H20N2O4[α]D25=-13.3 (c 1.02, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S)

(3S)-3-(N-Benzyloxycarbonylamino)-3-phenyl-(N′-methoxy-N′-methyl)propanamideC19H22N2O4[α]D25=-6.9(c 1.62, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S)

(3R)-3-(N-Benzyloxycarbonylamino)-(N′-methoxy-N′-methyl)butanamideC14H20N2O4[α]D25=+8.3 (c 1.74, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R)

(3R)-3-(N-Benzyloxycarbonylamino)-(N′-methoxy-N′-methyl)hexanamideC16H24N2O4[α]D25=+15.1 (c 2.23, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R)

(3S)-3-(N-Benzyloxycarbonylamino)-3-(3,4-dimethoxyphenyl)-(N′-methoxy-N′-methyl)propanamideC21H26N2O6[α]D25=-16.2 (c 1.29, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S)

(2′S)-2-[2′-(N-Benzyloxycarbonylamino)-2′-phenyl]-ethyl-2-methyl-1,3-dioxolaneC20H23NO4[α]D25=-11.4 (c 1.32, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′S)

(2′S)-2-Benzyl-2-[2′-(N-benzyloxycarbonylamino)-2′-phenyl]-ethyl-1,3-dioxolaneC26H27NO4[α]D25=-2.5 (c 0.61, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′S)

(2′S)-2-Ethyl-2-[2′-(N-benzyloxycarbonylamino)-2′-phenyl]-ethyl-1,3-dioxolaneC21H25NO4[α]D25=-7.5 (c 1.32, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′S)

(2′R)-2-Butyl-2-(2′-N-benzyloxycarbonylamino)-propyl-1,3-dioxolaneC18H27NO4[α]D25=-3.6 (c 1.32, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′R)

(2′R)-2-Methyl-2-(2′-N-benzyloxycarbonylamino)-pentyl-1,3-dioxolaneC17H25NO4[α]D25=+2.2 (c 1.08, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′R)

(2′S)-2-[-2′-(N-Benzyloxycarbonylamino)-2′-(3,4-dimethoxyphenyl)]-ethyl-2-methyl-1,3-dioxolaneC22H27NO6[α]D25=+0.9 (c 1.03, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′S)

(2′S)-2-(2′-Amino-2′-phenyl)-ethyl-2-methyl-1,3-dioxolaneC12H17NO2Ee = 93%[α]D25=-13.5 (c 2.21, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′S)

(2′S)-2-Benzyl-2-(2′-amino-2′-phenyl)-ethyl-1,3-dioxolaneC18H21NO2Ee = 90%[α]D25=+1.9 (c 1.01, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′S)

(2′S)-2-Ethyl-2-(2′-amino-2′-phenyl)-ethyl-1,3-dioxolaneC13H19NO2Ee = 92%[α]D25=-18.0 (c 1.05, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′S)

(2′R)-2-Butyl-2-(2′-amino)-propyl-1,3-dioxolaneC10H21NO2Ee = 95%[α]D25=-8.6 (c 1.21, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′R)

(2′R)-2-Methyl-2-(2′-aminopentyl)-1,3-dioxolaneC9H19NO2Ee = 95%[α]D25=-1.7 (c 1.15, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′R)

(2′S)-2-[2′-Amino-2′-(3,4-dimethoxyphenyl)]ethyl-2-methyl-1,3-dioxolaneC14H21NO4Ee = 92%[α]D25=-24.5 (c 1.29, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2′S)