Synthesis of ACAT inhibitors through substitution using allylic picolinate and copper reagent

Abstract

Amide of an octanoic acid possessing an aryl group at C3 position is a highly potent ACAT inhibitor. In this paper, we describe a synthetic access to this class of compounds as optically active forms. The key reaction is substitution of the allylic picolinate of ( S, Z)-8-(benzyloxy)oct-5-en-4-ol with a copper reagent derived from (benzo[ d][1,3]dioxol-4-yl)MgBr and CuBr·Me 2S to produce anti S N2′ product regio- and stereo-selectively. The product was hydrogenated to afford ( S)-3-benzo[ d][1,3]dioxol-4-yloctan-1-ol, which upon oxidation furnished the octanoic acid. Finally, the acid was converted with 2,6-( i-Pr) 2C 6H 3NH 2 to the target amide via acid chloride. In a similar way, the one-carbon long homolog was synthesized.