Title

Studies on the Enantioselective Synthesis of Isofagomine

Authors

Mark Paulsen

Document Type

Article

Publication Date

2007

Abstract

Glycosidase inhibitors have recently demonstrated promise in the fight against diabetes and possibly AIDS. Isofagomine, a poly hydroxylated piperidine structure mimics sugars but is not digested by the body, inhibiting the enzymes functionality. As a result. I propose a novel enantioselective synthesis of Isofagomine that integrates enzymolysis and organometallic chemistry. First, crotonaldehyde is reacted with HCN in the presence of the enzyme oxynitrilase to form the cyanohydrin. The beauty of this step is that oxynitrilase, a cheap and robust enzyme isolated from almonds, induces the asymmetry in greater than 99% enantiomeric excess. A subsequent ethyl esterfication is then carried out on the cyanohydrin, maintaining enantiofidelity. The next step in the reaction sequence is a Grubb?s catalyzed cross-metathesis on the ethyl ester. Carbonate functionality is then added to prepare it for palladium-catalyzed nitromethylation which allows the addition of a nitromethyl group to a specific carbon while maintaining an enantiomeric excess of >95%. This mechanism is especially important because the addition of nitromethane introduces nitrogen and forms a carbon-carbon bond. After the palladium chiral transfer, a Sharpless dihydroxylation, followed by a catalytic hydrogenation and then finally a reduction of the carbonyl will afford the target compound Isofagomine.

Advisor

Donald Deardorff

Department

chem

Support

American Chemical Society-Petroleum Research Fund Grant

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