Total Synthesis of Ezetimibe, a Cholesterol Absorption Inhibitor

Ezetimibe
(1), a strong β-lactamic cholesterol
absorption inhibitor, was synthesized from (R)-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one 7. Independent pathways were
analyzed in order to select the optimal one, which involved 1,3-dipolar
cycloaddition with C-(4-benzyloxyphenyl)-N-(4-fluorophenyl)-nitrone (8), intramolecular
nucleophilic displacement at the benzylic position of the lactone,
cleavage of the N–O bond, elimination of a water molecule,
hydrogenation of the double bond, rearrangement of the six-membered
lactone ring into a β-lactam moiety, and final deprotection
of the phenolic hydroxyl group. Highly stereoselective Sc­(OTf)3-catalyzed 1,3-dipolar cycloaddition was the most crucial
step of the synthesis. Owing to the rigid transition state of the
cycloaddition, the absolute configuration of the starting lactone
controlled the formation of other stereogenic centers of the final
molecule 1.