A highly enantioselective α-benzoyloxylation of malonic diester has been achieved by phase-transfer catalysis. The reaction of α-monosubstituted tert-butyl methyl malonate with benzoyl peroxide in the presence of aqueous KOH and N-(9-anthracenylmethyl)cinchoninium chloride afforded the corresponding α,α-disubstituted products in generally excellent chemical yields (up to 99% yield) with high enantioselectivities (up to 96% ee). In addition, the utility of this methodology was exhibited by the synthesis of a mineralocorticoid receptor antagonist.

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.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)

Enantiomerically pure 3-methyl-β-proline was synthesized using an asymmetric phase-transfer-catalyzed alkylation of a cyanopropanoate to establish the all-carbon stereogenic center. The catalytic activity of 3-methyl-β-proline in the Mannich-type reaction between a glyoxylate imine and ketones/aldehydes was subsequently investigated. The catalyst was designed and found to be more soluble in nonpolar organic solvents relative to the unsubstituted β-proline catalyst, and as a result allowed for added flexibility during optimization efforts. This work culminated in the development of a highly anti-diastereo- and enantioselective process employing low catalyst loading.

An enantioselective phase-transfer catalytic alkylation of α-monosubstituted malonic diester has been developed. The alkylation of α-monosubstituted tert-butyl methyl malonate in the presence of N-(9-anthracenylmethyl)cinchoninium chloride afforded α,α-disubstituted products in high yields and with high enantioselectivities. Moreover, a successful gram-scale (10 mmol) experiment using the cinchona catalyst indicates the potential for practical applications of this methodology. To demonstrate the utility of this method, product with a quaternary chiral carbon was converted to both (R)- and (S)-α,α-dialkylated amino acids through alternative chemoselective transformation of the two ester groups.Keywords: asymmetric synthesis; malonic ester; organocatalysis; phase-transfer catalysis; quaternary stereocenter;