Application of asymmetric alkylation of malonic diester with phase-transfer catalysis: synthesis of LFA-1 antagonist BIRT-377

An efficient asymmetric synthesis of LFA-1 antagonist BIRT-377 using enantioselective phase-transfer catalytic alkylation has been developed. The alkylation of α-monosubstituted tert-butyl methyl malonate was catalyzed by a quaternary ammonium salt derived from a cinchona alkaloid to obtain the product with a quaternary stereogenic carbon in high yield and with high enantioselectivity. The chiral α,α-disubstituted product thus obtained was transformed into BIRT-377 through alternating chemoselective deprotection of the two ester groups followed by Curtius rearrangement.

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Methyl (R)-1-tert-butyl 3-methyl 2-(4-bromobenzyl)-2-malonateC16H21BrO4Ee = 89%[α]D20 = −2.5 (c 1.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R)

Methyl (R)-1-methyl 2-(4-bromobenzyl)-2-malonateC12H13BrO4Ee = 89%[α]D22 = +0.7 (c 3.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R)

(R)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-5-methylimidazolidine-2,4-dioneC17H13BrCl2N2O2Ee = 89%[α]D21 = +107.3 (c 2.7, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5R)

(R)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-1,5-dimethylimidazolidine-2,4-dioneC18H15BrCl2N2O2Ee = 89%[α]D21 = +115.6 (c 1.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5R)