Title

Studies on the Enantioselective Synthesis of Isofagomine

Authors

Mark Paulsen

Document Type

Article

Publication Date

2008

Abstract

Glycosidase inhibitors have recently shown promise as potential medicines in the treatment of AIDS and diabetes. We propose a novel enantioselective synthesis of glycosidase inhibitor isofagomine that features both enzyme and organometallic catalysis. Crotonaldehyde, the starting material is first reacted with HCN in the presence of the enzyme oxynitrilase to form the (R)-cyanohydrin in greater than 99% enantiomeric excess. Treatment of the (R)-cyanohydrin with trimethyl silyl choride and ethanol converts the cyano moiety to an ethyl ester. Allyl benzyl ether is then cross-metathesized with the unsaturated hydroxy ester upon addition of Grubbs 2nd generation Hoveyda catalyst. Ethoxy carbonylation of the alcohol moiety preconditions the substrate for a novel palladium catalyzed 1,3, chiral nitromethylation reaction. This is the key step in the synthetic scheme because it converts a carbon-oxygen bond into a carbon-carbon bond while simultaneously undergoing a 1,3 chiral shift. A Sharpless dihydroxylation is then carried out on the α,β-unsaturated ester to form the hydroxylated product with stereoselective precision. A subsequent catalytic hydrogenation reduces the nitro group to the corresponding amine. It is expected that the corresponding amino ester will spontaneously undergo an intramolecular ring closing. In final, the carbonyl of the resulting lactam is then reduced with diborane to afford the target compound isofagomine.

Advisor

Don Deardorff

Department

chem

Support

Howard Hughes Medical Institute Undergraduate Science Education Grant

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