Glycosidase Inhibitors:  Synthesis of Enantiomerically Pure Aza-Sugars from Schiff Base Amino Esters via Tandem Reduction-Alkenylation and Osmylation

Nitrogen-in-the-ring “aza-sugars” have been synthesized in enantiomerically pure form from the amino acid l -alanine in excellent overall yield. The O'Donnell's Schiff base of l -alanine methyl ester 9a was converted to aza-sugar l -fuco-1-deoxy-nojirimycin, 18, and to the epimer l -gulo-1-deoxy-nojirimycin, 20, in eight steps. The overall yields were 20 and 29%, respectively. The methodology for the efficient generation of silyl- and benzyl-protected ( E )-3-lithio-2-propen-1-ols, and the use of these alkenyllithiums with iBu 5 Al 2 H as nucleophiles in the threo -selective tandem reduction−alkenylation of the Schiff base esters is described. Osmium-catalyzed cis -oxygenation of the resulting olefin products was selective for the galacto ( fuco ) amino polyols in all cases for the acyclic olefins, and was gulo -selective for the cyclic D-4,5-dihydropyridine pivalate, 17c . TEMPO-NaOCl was selective for oxidation of the primary position of the acyclic Schiff bases, and allowed for minimal protection/deprotection of the intermediates. The resulting N -benzhydryl heterocycles were easily deprotected with H 2 −Pd at atmospheric pressure.