Chelation controlled reduction of N-protected β-amino ketones toward the synthesis of HPA-12 and analogues

Diastereoselective reduction of N-protected β-amino ketones does not proceed effectively under the conditions used for chelation controlled reductions of N-alkyl β-amino ketones. A thorough analysis of various conditions required for the stereoselective reduction of γ-aryl-γ-oxo-β-amino alcohols is reported. The products of the syn-selective reduction are used for the preparation of a ceramide trafficking inhibitor HPA-12 and analogues.

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(4R,5R)-3-(tert-Butyloxycarbonyl)-2,2,5-trimethyl-4-((2-phenyl-1,3-dithian-2-yl)methyl)oxazolidineC22H33NO3S2[α]D25 = +4.2 (c 0.700, CHCl3)Source of chirality: l-ThreonineAbsolute configuration: (4R,5R)

(4R,5R)-3-(tert-Butyloxycarbonyl)-2,2,5-trimethyl-4-((2-(4-methoxyphenyl)-1,3-dithian-2-yl)methyl)oxazolidineC23H35NO4S2[α]D25 = −12.9 (c 0.610, CHCl3)Source of chirality: l-ThreonineAbsolute configuration: (4R,5R)

(4R,5R)-3-(tert-Butyloxycarbonyl)-2,2,5-trimethyl-4-((2-(3,4-dimethoxyphenyl)-1,3-dithian-2-yl)methyl)oxazolidineC24H37NO5S2[α]D25 = −8.1 (c 0.610, CHCl3)Source of chirality: l-ThreonineAbsolute configuration: (4R,5R)

(2R,3R)-3-(tert-Butyloxycarbonylamino)-4-(2-phenyl-1,3-dithian-2-yl)butan-2-olC19H29NO3S2[α]D25 = +7.0 (c 0.283, CHCl3)Source of chirality: l-ThreonineAbsolute configuration: (2R,3R)

(2R,3R)-3-(tert-Butyloxycarbonylamino)-4-(2-(4-methoxyphenyl)-1,3-dithian-2-yl)butan-2-olC20H31NO4S2[α]D25 = +12.5 (c 0.400, CHCl3)Source of chirality: l-ThreonineAbsolute configuration: (2R,3R)

(2R,3R)-3-(tert-Butyloxycarbonylamino)-4-(2-(3,4-dimethoxyphenyl)-1,3-dithian-2-yl)butan-2-olC21H33NO5S2[α]D25 = +7.1 (c 0.700, CHCl3)Source of chirality: l-ThreonineAbsolute configuration: (2R,3R)

(3R,4R)-3-(tert-Butyloxycarbonylamino)-4-hydroxy-1-phenylpentan-1-oneC16H23NO4[α]D25 = −2.2 (c 0.900, CHCl3)Source of chirality: l-ThreonineAbsolute configuration: (3R,4R)

(3R,4R)-3-(tert-Butyloxycarbonylamino)-4-hydroxy-1-(4-methoxyphenyl)pentan-1-oneC17H25NO5[α]D25 = −6.4 (c 0.466, CHCl3)Source of chirality: l-ThreonineAbsolute configuration: (3R,4R)

(3R,4R)-3-(tert-Butyloxycarbonylamino)-1-(3,4-dimethoxyphenyl)-4-hydroxypentan-1-oneC18H27NO6[α]D25 = +1.9 (c 1.050, CHCl3)Source of chirality: l-ThreonineAbsolute configuration: (3R,4R)

(1S,3R)-3-(tert-Butyloxycarbonylamino)-1-phenylbutane-1,4-diolC15H23NO4[α]D25 = +32.5 (c 0.191, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1S,3R)

(1R,3R)-3-(tert-Butyloxycarbonylamino)-1-phenylbutane-1,4-diolC15H23NO4[α]D25 = −6.4 (c 0.333, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1R,3R)

(1S,3R)-3-(tert-Butyloxycarbonylamino)-1-p-tolylbutane-1,4-diolC16H25NO4[α]D25 = +21.2 (c 0.103, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1S,3R)

(1R,3R)-3-(tert-Butyloxycarbonylamino)-1-p-tolylbutane-1,4-diolC16H25NO4[α]D25 = +3.4 (c 0.910, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1R,3R)

(1S,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-isopropylphenyl)butane-1,4-diolC18H29NO4[α]D25 = −17.9 (c 0.111, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1S,3R)

(1R,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-isopropylphenyl)butane-1,4-diolC18H29NO4[α]D25 = +1.3 (c 0.716, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1R,3R)

(1S,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-methoxyphenyl)butane-1,4-diolC16H25NO5[α]D25 = +12.0 (c 0.083, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1S,3R)

(1R,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-methoxyphenyl)butane-1,4-diolC16H25NO5[α]D25 = +25.0 (c 0.950, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1R,3R)

(1S,3R)-3-(tert-Butyloxycarbonylamino)-1-(3,4-dimethoxyphenyl)butane-1,4-diolC17H27NO6[α]D25 = +4.2 (c 0.70, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1S,3R)

(1R,3R)-3-(tert-Butyloxycarbonylamino)-1-(3,4-dimethoxyphenyl)butane-1,4-diolC17H27NO6[α]D25 = −2.5 (c 0.400, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1R,3R)

(1S,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-fluorophenyl)butane-1,4-diolC15H22FNO4[α]D25 = −14.2 (c 0.266, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1S,3R)

(1R,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-fluorophenyl)butane-1,4-diolC15H22FNO4[α]D25 = +4.1 (c 1.216, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1R,3R)

(1S,3R)-3-(tert-Butyloxycarbonylamino)-1-(3-chlorophenyl)butane-1,4-diolC15H22ClNO4[α]D25 = −43.8 (c 0.086, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1S,3R)

(1R,3R)-3-(tert-Butyloxycarbonylamino)-1-(3-chlorophenyl)butane-1,4-diolC15H22ClNO4[α]D25 = +2.0 (c 0.500, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1R,3R)

(1S,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-phenylpentane-1,4-diolC16H25NO4[α]D25 = −19.4 (c 1.233, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1S,3R,4R)

(1R,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-phenylpentane-1,4-diolC16H25NO4[α]D25 = +5.6 (c 1.066, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1R,3R,4R)

(1S,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-(4-methoxyphenyl)pentane-1,4-diolC17H27NO5[α]D25 = −21.0 (c 0.616, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1S,3R,4R)

(1R,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-(4-methoxyphenyl)pentane-1,4-diolC17H27NO5[α]D25 = −4.2 (c 0.466, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1R,3R,4R)

(1S,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-(3,4-dimethoxyphenyl)pentane-1,4-diolC18H29NO6[α]D25 = −14.6 (c 0.883, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1S,3R,4R)

(1R,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-(3,4-dimethoxyphenyl)pentane-1,4-diolC18H29NO6[α]D25 = −5.5 (c 0.716, CHCl3)Source of chirality: Diastereoselective reductionAbsolute configuration: (1R,3R,4R)

N-((2R,4S)-1,4-Dihydroxy-4-phenylbutan-2-yl)dodecanamideC22H37NO3[α]D25 = −30.7 (c 0.533, CHCl3)Source of chirality: syn-Amino alcoholAbsolute configuration: (2R,4S)

N-((2R,4S)-1,4-Dihydroxy-4-p-tolylbutan-2-yl)dodecanamideC23H39NO3[α]D25 = −12.0 (c 0.250, CHCl3)Source of chirality: syn-Amino alcoholAbsolute configuration: (2R,4S)

N-((2R,4S)-1,4-Dihydroxy-4-(4-isopropylphenyl)butan-2-yl)dodecanamideC25H43NO3[α]D25 = −10.0 (c 0.300, CHCl3)Source of chirality: syn-Amino alcoholAbsolute configuration: (2R,4S)

N-((2R,4S)-4-(4-Fluorophenyl)-1,4-dihydroxybutan-2-yl)dodecanamideC22H36FNO3[α]D25 = −21.0 (c 0.666, CHCl3)Source of chirality: syn-Amino alcoholAbsolute configuration: (2R,4S)

N-((2R,4S)-4-(3-Chlorophenyl)-1,4-dihydroxybutan-2-yl)dodecanamideC22H36ClNO3[α]D25 = −13.8 (c 0.650, CHCl3)Source of chirality: syn-Amino alcoholAbsolute configuration: (2R,4S)