Stereoselective synthesis of β-amino alcohols and glycosphingolipids: N-diphenylmethylene protection for tandem C-C/C-O bond formation.
AuthorPeterson, Matt Anders.
Committee ChairPolt, Robin L.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractA 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.