Enantioselective desymmetrization of 2-substituted 1,2,3-propanetriols: its synthetic application to voglibose and triazole antifungal

Abstract

Installation of chiral quaternary carbons is considered to belong to one of the most difficult synthetic operations. Since oxygen- or nitrogen-containing q-uarternary stereogenic centers are ubiquitous in physiologically valuable natural products and pharmaceuticals, we have been particularly interested in those functionalities. Catalytic enantioselective desymmetrization of meso-2-substitu-ted glycerols has been developed to secure a novel synthetic route to chiral ter-tiary alcohols. The transformation has been realized by monobenzoylation using benzoyl chloride and triethylamine in the presence of the chiral catalysts in THF at ambient temperature. We developed the two kinds of catalysts. The first is the imine ligand (115)- $CuCl_2$ complex and the second is the known (S,S)-Ben-zylbisoxazoline ligand (44)- $CuCl_2$. The desymmetrization turned out to be gre-atly dependent on acylating reagent, base, solvent and needless to say, catalyst. In the part of imine ligand 115, extensive screening of chiral ligands led us to combine bromopyridinecarboxaldehyde 91 and phenyloxazoline amine 102 der-ived from tert-leucine, the bromo and phenyl substituents of which proved to be indispensable. All of the substrates have been desymmetrized to the corres-ponding monobenzoates with high enantioselectivity up to 96 % ee. In the part of (S,S)-Benzylbisoxazoline ligand (44)- $CuCl_2$, we have established a highly e-nantioselective monobenzoylation of prochiral 2-substituted 1,2,3-propantrio-ls to render various chiral tertiary alcohols up to 94% ee. The desymmetric fun-ctionalization has been elaborated using two complimentary asymmetric cataly-sts, the benzylbisoxazoline (44)- $CuCl_2$ and the imine oxazoline (90)- $CuCl_2$, relying on the substrate structures, of which the former is congruous with the 2-alkyl substituents and the latter is well-suited for the 2-vinyl, phenyl and be-nzyl substituents. The catalytic system allows broad structural diversity of subs-trates and...