Asymmetric synthesis of β-fluoroaryl-β-amino acids

The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to a range of β-fluoroaryl-α,β-unsaturated esters gave the corresponding β-amino esters with high diastereoselectivity and in good isolated yields. Sequential treatment of the resultant β-fluoroaryl-β-amino esters under optimised hydrogenolysis conditions, followed by ester hydrolysis with 2.0 M aq HCl, provided access to a range of β-fluoroaryl-β-amino acids in good yield.

A range of β-fluoroaryl-β-amino acids can be prepared in good yield via the diastereoselective conjugate addition of enantiopure lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to the corresponding β-fluoroaryl-α, β-unsaturated esters, followed by hydrogenolytic N-deprotection and ester hydrolysis.Figure optionsDownload as PowerPoint slide

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(2′-fluorophenyl)propanoateC28H32FNO2[α]D25 +7.6 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(3′-fluorophenyl)propanoateC28H32FNO2[α]D25 +3.4 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(4′-fluorophenyl)propanoateC28H32FNO2[α]D25 +4.7 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(2′,3′-difluorophenyl)propanoateC28H31F2NO2[α]D25 +16.0 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(2′,4′-difluorophenyl)propanoateC28H31F2NO2[α]D25 +18.0 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(2′,5′-difluorophenyl)propanoateC28H31F2NO2[α]D25 +17.5 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(2′,6′-difluorophenyl)propanoateC28H31F2NO2[α]D25 +16.0 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(3′,4′-difluorophenyl)propanoateC28H31F2NO2[α]D25 +19.5 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(3′,5′-difluorophenyl)propanoateC28H31F2NO2[α]D25 +22.0 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisabsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(2′,4′,5′-trifluorophenyl)propanoateC28H30F3NO2[α]D25 +22.0 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(pentafluorophenyl)propanoateC28H28F5NO2[α]D25 +35.0 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(2′-methyl-3′-fluorophenyl)propanoateC29H34FNO2[α]D25 +51.7 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(2′-fluoro-5′-methoxyphenyl)propanoateC29H34FNO3[α]D25 +11.4 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-(3′-phenoxy-4′-fluoro-phenyl)propanoateC34H36FNO3[α]D25 +5.0 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-[2′-fluoro-3′-(trifluoromethyl)phenyl]propanoateC29H31F4NO2[α]D25 +5.2 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,αR)

tert-Butyl (S)-3-amino-3-(2′-fluorophenyl)propanoateC13H18FNO2[α]D25 −9.3 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(4′-fluorophenyl)propanoateC13H18FNO2[α]D25 −7.9 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(2′-methyl-3′-fluorophenyl)propanoateC14H20FNO2[α]D25 −14.4 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(2′-fluoro-5′-methoxyphenyl)propanoateC14H20FNO3[α]D25 −5.7 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisabsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(3′-phenoxy-4′-fluorophenyl)propanoateC19H22FNO3[α]D25 −18.0 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-[2′-fluoro-3′-(trifluoromethyl)phenyl]propanoateC14H17F4NO2[α]D25 −8.1 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(2′,3′-difluorophenyl)propanoateC13H17F2NO2[α]D25 −22.0 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(2′,4′-difluorophenyl)propanoateC13H17F2NO2[α]D25-13.0 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(2′,5′-difluorophenyl)propanoateC13H17F2NO2[α]D25 −13.6 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(2′,6′-difluorophenyl)propanoateC13H17F2NO2[α]D25 −14.2 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(3′,4′-difluorophenyl)propanoateC13H17F2NO2[α]D25 −21.5 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(3′,5′-difluorophenyl)propanoateC13H17F2NO2[α]D25 −12.6 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(2′,4′,5′-trifluorophenyl)propanoateC13H16F3NO2[α]D25 −19.9 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

tert-Butyl (S)-3-amino-3-(pentafluorophenyl)propanoateC13H14F5NO2[α]D25 −26.2 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Amino-3-(2′,3′-difluorophenyl)propanoic acidC9H9F2NO2[α]D25 −2.5 (c 0.5 in H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Amino-3-(2′,4′-difluorophenyl)propanoic acidC9H9F2NO2[α]D25 −4.9 (c 0.5 in H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Amino-3-(2′,5′-difluorophenyl)propanoic acidC9H9F2NO2[α]D25 −3.2 (c 0.5 in H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Amino-3-(2′,6′-difluorophenyl)propanoic acidC9H9F2NO2[α]D25 −4.8 (c 0.5 in H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Amino-3-(3′,5′-difluorophenyl)propanoic acidC9H9F2NO2[α]D25 −4.5 (c 0.5 in H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Amino-3-(2′,4′,5′-trifluorophenyl)propanoic acidC9H8F3NO2[α]D25 −7.2 (c 0.5 in H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Amino-3-(2′-methyl-3′-fluorophenyl)propanoic acidC10H12FNO2[α]D25 −15.6 (c 0.5 in H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Amino-3-(2′-fluoro-5′-methoxyphenyl)propanoic acidC10H12FNO3[α]D25 −3.8 (c 0.3 in H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Amino-3-(3′-phenoxy-4′-fluorophenyl)propanoic acidC15H14FNO3[α]D25 −12.0 (c 0.5 in H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Amino-3-[2′-fluoro-3′-(trifluoromethyl)phenyl]propanoic acidC10H9F4NO2[α]D25 −2.2 (c 0.5 in H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)