Stereoselective synthesis of β-amino alcohols and glycosphingolipids: N-diphenylmethylene protection for tandem C-C/C-O bond formation.

Abstract

A new method for threo-selective synthesis of β-amino alcohols is described. This method employs N-diphenylmethylene-protected α-amino esters as starting materials. The α-amino ester is reduced to the oxidation state of an aldehyde with DIBAL or DIBAL:TRIBAL (1:1) followed by sequential addition of various Grignards and alkenyllithiums. The method is highly threo-selective (stereoselectivities ranged from 8:1 to > 20:1) and provides norpseudoephedrine and threo-sphingosine analogs in enantiomerically enriched form (> 97% ee). The mechanism of C-C bond formation was examined. A stable aluminoxy-acetal intermediate (generated by DIBAL reduction of the ester) was trapped with TMS-imidazole and isolated as the corresponding siloxy-acetal. The stereochemical outcome of the C-C bond forming step was shown to correlate with the steric bulk of the ester moiety. Bulky ester groups showed the greatest degree of threo-selectivity. These results suggest that the aluminoxy-acetal intermediate may be involved in determining stereoselectivity via either a tight-ion S(N)1-like or S(N)2-like reaction mechanism. A series of glycosyl acceptors was synthesized from N-diphenylmethylene-protected threo-sphingosine derivatives. These glycosyl acceptors undergo β-specific glycosylation using the method developed in this laboratory. This method capitalizes on a favorable hydrogen-bonding pattern imparted by the N-diphenylmethylene-protection. The favorable hydrogen-bonding enhances the nucleophilicity of the glycosyl acceptor relative to glycosyl acceptors with more conventional N-protection (i.e. Cbz, Boc, acyl etc.). This enhanced nucleophilicity allows the glycosylation to be carried out under mild conditions (AgOTfl, CH₂CI₂, RT overnight) and provides the corresponding β-glycosphingolipids in approximately 70% chemical yield.