Improved Schöllkopf construction of quaternary α-amino acids: efficient enantioselective synthesis of integrin LFA-1 antagonist BIRT-377

The Schöllkopf methodology for the asymmetric synthesis of α-amino acids which was previously not applicable to the construction of α,α-dialkylated (quaternary) α-amino acids, has been rendered practical for this purpose and applied in a highly efficient enantioselective synthesis of integrin LFA-1 antagonist BIRT-377.

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(3R,6S)-3-(4-Bromobenzyl)-6-isopropyl-5-methoxy-3-methyl-3,6-dihydro-2-pyrazinyl methyl etherC17H22BrN2O2Ee = 100%[α]D25=-70.0 (c 1, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,6S)

Methyl (2R)-2-amino-3-(4-bromophenyl)-2-methylpropanoateC11H14BrNO2Ee = >99%[α]D25=+16.7 (c 1, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: 2R

(5R)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-5-methyl-1H-imidazole-2,4(3H,5H)-dioneC17H13BrCl2N2O2Ee = >99%[α]D25=+121.4 (c 1, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: 5R

(5R)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-1,5-dimethyl-1H-imidazole-2,4(3H,5H)-dioneC18H15BrCl2N2O2Ee = >99%[α]D25=+127.1 (c 1, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: 5R