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Stereoselective Synthesis of Constrained Azacyclic Hydroxyethylene Isosteres as Aspartic Protease Inhibitors: Dipolar Cycloaddition and Related Methodologies toward Branched Pyrrolidine and Pyrrolidinone Carboxylic Acids

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journal contribution
posted on 2005-08-19, 00:00 authored by Stephen Hanessian, Hongying Yun, Yihua Hou, Marina Tintelnot-Blomley
The synthesis of three vicinally substituted azacyclic carboxylic acids in enantiopure form was achieved from a common α-amino aldehyde originating from l-leucine. Pyrrolidines and pyrrolidinones were elaborated from α,β-unsaturated γ-hydroxy-δ-amino acids via azomethine ylide 1,3-dipolar addition and conjugate addition/cyclization strategies, respectively. The azacyclic amino acids were incorporated in a pseudopeptide now encompassing a hydroxyethylene isostere. Low nanomolar inhibition of BACE1, an enzyme implicated in the cascade of events leading to plaque formation in Alzheimer's disease, was found with a pyrrolidinone analogue.

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