Stereoselective synthesis of constrained oxacyclic hydroxyethylene isosteres of aspartic protease inhibitors: aldol and Mukaiyama aldol methodologies for branched tetrahydrofuran 2-carboxylic acids.
The synthesis of diastereomeric 3-substituted-tetrahydrofuran 2-carboxylic acids in enantiopure form was achieved relying on aldol condensations of N-substituted alpha-amino aldehydes with enolates and enol silyl ethers of gamma-butyrolactone. Catalytic YbFOD leads to a high yield of a syn/syn-alpha-amino alcohol isomer. This was used as a constrained THF subunit in the synthesis of a peptidomimetic intended as an inhibitor of the enzyme BACE1, which is implicated in the cascade of events leading to plaque formation in Alzheimer's disease.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, C. P. 6128, Succ. Centre-Ville, Montréal, P. Q., Canada H3C 3J7. stephen.hanessian@umontreal.ca
Hou
Yihua
Y
Bayrakdarian
Malken
M
Tintelnot-Blomley
Marina
M
D000447:Aldehydes / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002264:Carboxylic Acids / Q000138:chemical synthesis*; D005030:Ethylenes / Q000138:chemical synthesis*; D005663:Furans / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D013055:Spectrophotometry, Infrared
D000447:Aldehydes; D002264:Carboxylic Acids; D005030:Ethylenes; D005663:Furans; D011480:Protease Inhibitors; C018674:tetrahydrofuran; C116609:3-hydroxybutanal; C036216:ethylene; D016282:Aspartic Acid Endopeptidases