Synthesis of chiral non-racemic intermediates and Arg-Gly-Asp mimetics by CaLB-catalyzed resolution

The reactivity of both the ester and amine functions present in β-amino esters was tested in order to obtain the synthesis of enantiopure αvβ3 and α5β1 integrin ligands. CaLB successfully catalyzed both the enantioselective transesterification and the N-acylation of racemic β-amino esters, allowing the isolation of intermediates for the preparation of Arg-Gly-Asp (RGD) mimetic compounds. In particular, a CaLB-catalyzed amidation reaction with unprotected p-aminobenzylamine reduced the number of synthetic steps, thus avoiding protection and deprotection of the intermediate compounds. Following this procedure, RGD mimetics were isolated with high yields and enantiomeric purities.

Figure optionsDownload as PowerPoint slide

Benzyl 3-(benzyloxycarbonyl)aminobutanoateC19H21NO4Ee >98%[α]D24=-7.4 (c 2.7, CHCl3)Source of chirality: biocatalytic enantioselective transesterificationAbsolute configuration: (3R)

Isopropyl 3-(benzyloxycarbonyl)aminobutanoateC15H21NO4Ee 97%[α]D24=-20.2 (c 0.3, CHCl3)Source of chirality: biocatalytic enantioselective transesterificationAbsolute configuration: (3R)

Methyl 3-(2′-t-buthoxycarbonyl-acetyl)aminobutanoateC12H21NO5Ee 93%[α]D24=-13.4 (c 0.5, CHCl3)Source of chirality: biocatalytic enantioselelctive transesterificationAbsolute configuration: (3S)

Methyl 3-(2′-t-buthoxycarbonyl-acetyl)amino-4-methylpentanoateC14H25NO5Ee 80%[α]D24=-20.5 (c 1, CHCl3)Source of chirality: biocatalytic enantioselective acylationAbsolute configuration: (3R)

Benzyl 3-(2′-t-buthoxycarbonyl-acetyl)aminobutanoateC18H25NO5Ee >98%[α]D24=+10.4 (c 1, CHCl3)Source of chirality: biocatalytic enantioselective transesterificationAbsolute configuration: (3R)

Isopropyl 3-(2′-t-buthoxycarbonyl-acetyl)aminobutanoateC14H25NO5Ee 91%[α]D24=+16.0 (c 0.3, CHCl3)Source of chirality: biocatalytic enantioselective transesterificationAbsolute configuration: (3R)

Methyl 3-(2′-methoxycarbonyl-acetyl)aminobutanoateC9H15NO5Ee >98%[α]D24=+21.6 (c 1, CHCl3)Source of chirality: biocatalytic enantioselective acylationAbsolute configuration: (3R)

N-(2′-t-Butoxycarbonyl-acetyl)-3-amino-N′-(4′-aminobenzyl)butanamideC18H27N3O4Ee 93%[α]D24=+9.2 (c 1, CHCl3)Source of chirality: biocatalytic enantioselective acylationAbsolute configuration: (3R)

N-(2′-Hydroxycarbonyl-acetyl)-3-amino-N′-(4′-aminobenzyl)butanamideC14H19N3O4Ee 93%[α]D24=+13.4 (c 1, H2O)Source of chirality: biocatalytic enantioselective acylationAbsolute configuration: (3R)