Homochiral lithium amides for the asymmetric synthesis of β-amino acids

Secondary homochiral lithium amides derived from α-methylbenzylamine undergo highly diastereoselective conjugate additions to a range of α,β-unsaturated esters. The corresponding β-amino acids are readily liberated by successive N-debenzylation and ester hydrolysis, furnishing (R)-β-amino butyric acid, (R)-β-amino pentanoic acid, (S)-β-leucine, (R)-β-amino octanoic acid, (S)-β-phenylalanine, (S)-β-tyrosine methyl ether, (S)-β-tyrosine hydrochloride and (S)-β-(2-methoxyphenyl)-β-amino propanoic acid in high yields and high ee. The application of this procedure to the synthesis of the natural products (R)-β-DOPA and (R)-β-lysine is demonstrated. The development of a simplified one-pot reaction protocol applicable to the multi-gram scale synthesis of homochiral β-amino esters is also delineated.

Secondary homochiral lithium amides derived from α-methylbenzylamine undergo highly diastereoselective conjugate additions to a range of α,β-unsaturated esters (>95% de), with the corresponding β-amino acids (>95% ee) readily prepared by successive N-debenzylation and ester hydrolysis.Figure optionsDownload as PowerPoint slide

Methyl (3R,αR)-3-(N-3,4-dimethoxybenzyl-N-α-methylbenzylamino)butanoateC22H29NO4[α]D20=-5.2 (c 1.1, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Benzyl (3R,αR)-3-(N-3,4-dimethoxybenzyl-N-α-methylbenzylamino)butanoateC28H33NO4[α]D20=+13.3 (c 1.3, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

tert-Butyl (3R,αR)-3-(N-3,4-dimethoxybenzyl-N-α-methylbenzylamino)butanoateC25H35NO4[α]D20=+2.3 (c 1.7, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Methyl (3R,αR)-3-(N-benzyl-N-α-methylbenzylamino)butanoateC20H25NO2[α]D20=-3.4 (c 1.2, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Benzyl (3R,αR)-3-(N-benzyl-N-α-methylbenzylamino)butanoateC26H29NO2[α]D20=+12.0 (c 1.2, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

tert-Butyl (3R,αR)-3-(N-benzyl-N-α-methylbenzylamino)butanoateC23H31NO2[α]D20=-3.7 (c 1.1, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Methyl (3R,αR,α′R)-3-(N,N-bis(α-methylbenzyl)amino)butanoateC21H27NO2[α]D20=-7.6 (c 1.1, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR,α′R)

Benzyl (3R,αR,α′R)-3-(N,N-bis(α-methylbenzyl)amino)butanoateC27H31NO2[α]D20=+9.6 (c 1.1, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR,α′R)

tert-Butyl (3R,αR,α′R)-3-(N,N-bis(α-methylbenzyl)amino)butanoateC24H33NO2[α]D20=+2.6 (c 1.2, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR,α′R)

Benzyl (3R,αR)-3-(N-benzyl-N-α-methylbenzylamino)pentanoateC27H31NO2[α]D20=+23.6 (c 1.1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

tert-Butyl (3R,αR)-3-(N-benzyl-N-α-methylbenzylamino)pentanoateC24H33NO2[α]D20=+22.4 (c 1.1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Benzyl (3R,αR)-3-(N-benzyl-N-α-methylbenzylamino)octanoateC30H37NO2[α]D20=+11.9 (c 1.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

tert-Butyl (3R,αR)-3-(N-benzyl-N-α-methylbenzylamino)octanoateC27H39NO2[α]D20=+7.6 (c 1.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

Methyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-3-phenylpropanoateC25H27NO2[α]D20=-4.2 (c 1.1, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

Benzyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-3-phenylpropanoateC31H31NO2[α]D20=+3.8 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-3-phenylpropanoateC28H33NO2[α]D20=+3.9 (c 0.7, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

Benzyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-3-(2-methoxyphenyl)propanoateC32H33NO3[α]D20=+8.6 (c 0.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-3-(2-methoxyphenyl)propanoateC29H35NO3[α]D20=+15.0 (c 0.9, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

Benzyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-3-(4-methoxyphenyl)propanoateC32H33NO3[α]D20=+7.1 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-3-(4-methoxyphenyl)propanoateC29H35NO3[α]D20=+2.2 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

Methyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-3-(4-benzyloxyphenyl)propanoateC32H33NO3[α]D20=-0.8 (c 2.0, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

Benzyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-3-(4-benzyloxyphenyl)propanoateC38H37NO3[α]D20=-3.5 (c 1.7, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3R,αS)-3-(3,4-methylenedioxyphenyl)-3-(N-benzyl-N-α-methylbenzylamino)propanoateC29H33NO4[α]D23=-0.3 (c 1.5, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αS)

tert-Butyl (3R,αS)-3-(3,4-dimethoxyphenyl)-3-(N-benzyl-N-α-methylbenzylamino)propanoateC30H37NO4[α]D22=-0.07 (c 0.95, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

Ethyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-4-methyl-pentanoateC23H31NO2[α]D20=-2.5 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

(3S,αR,αR′)-N-Benzyl-N-α-methylbenzyl 3-(N-benzyl-N-α-methylbenzylamino)-4-methyl pentamideC36H42N2O[α]D21=+89.3 (c 1.8, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR,αR′)

Benzyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-4-methyl-pentanoateC28H33NO2[α]D20=-4.8 (c 1.3, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-4-methyl-pentanoateC25H35NO2[α]D24=-1.9 (c 1.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

(S)-β-Tyrosine methyl ester hydrochlorideC10H14NO3Cl[α]D20=+10.6 (c 1.9, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-β-Tyrosine hydrochlorideC9H12NO3Cl[α]D25=+3.6 (c 1.4, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (3R,αS)-3-(3,4-dibenzyloxyphenyl)-3-(N-benzyl-N-α-methylbenzylamino)propanoateC42H44NO4[α]D22=-2.0 (c 1.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αS)

tert-Butyl (R)-3-(3,4-dihydroxyphenyl)-3-aminopropanoateC13H18NO4[α]D23=+1.0 (c 0.70, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(R)-β-DOPA hydrochlorideC9H12NO4Cl[α]D23=+1.0 (c 0.70, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert-Butyl (R)-3-aminopentanoateC9H19NO2[α]D20=-22.3 (c 1.5, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert-Butyl (R)-3-aminoctanoateC12H25NO2[α]D20=-14.3 (c 0.7, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

tert- Butyl (S)-3-phenyl-3-aminopropanoateC13H19NO2[α]D20=-21.0 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-(2-methoxyphenyl)-3-aminopropanoateC14H21NO3[α]D20=-20.0 (c 0.7, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-(4-methoxyphenyl)-3-aminopropanoateC14H21NO3[α]D20=-14.1 (c 0.8, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-4-methyl-3-aminopentanoateC10H21NO2[α]D20=-25.8 (c 3.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(R)-β-Aminopentanoic acidC5H11NO2[α]D20=-40.8 (c 0.8, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(R)-β-Aminooctanoic acidC8H17NO2[α]D24=-28.3 (c 0.5, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(S)-β-PhenylalanineC9H11NO2[α]D20=-7.0 (c 1.0, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-β-(2-Methoxyphenyl)-β-amino propionic acidC10H13NO3[α]D20=+15.5 (c 1.0, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-β-Tyrosine methyl etherC10H13NO3[α]D20=-1.4 (c 0.2, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-β-LeucineC6H13NO2[α]D24=-48.2 (c 1.1, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(R)-3-Aminopentanoic acid hydrochlorideC5H12NO2Cl[α]D20=-22.9 (c 0.8, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(R)-β-Aminoctanoic acid hydrochlorideC8H18NO2Cl[α]D20=-16.6 (c 1.1, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(S)-β-(2-Methoxyphenyl)-β-aminopropionic acid hydrochlorideC10H14NO3Cl[α]D20=+20.0 (c 0.5, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-β-(4-Methoxyphenyl)-β-aminopropionic acid hydrochlorideC10H14NO3Cl[α]D20=+2.7 (c 0.5, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (3R,αR)-3-(N-benzyl-N-[α-methylbenzyl]amino)-6-(N′,N′-di-tert-butoxycarbonylamino)hexanoateC35H52N2O6[α]D22=+6.4 (c 0.75, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,αR)

tert-Butyl (R)-3-amino-6-(N,N-di-tert-butoxycarbonylamino)hexanoateC20H38N2O6[α]D23=-5.7 (c 1.08, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(R)-β-LysineC16H30N2O6[α]D21=-19.3 (c 0.63, 1 M HCl)Source of chirality: asymmetric synthesisAbsolute configuration: (R)