Total Synthesis of (+) -Pyripyropene A. A Potent, Orally Bioavailable Inhibitor of Acyl-CoA:Cholesterol Acyltransferase

摘要

A promising, fundamentally new approach to the prevention and treatment of atherosclerosis is based upon inhibition of acyl-CoA:cholesterol acyltransferase (ACAT), the enzyme that catalyzes intracellular esterification of cholesterol. This strategy may permit suppresion of three distinct, ACAT- dependent steps in the pathology of atherosclerosis: absorption of dietary cholesterol in the gut, hepatic synthesis of lipoproteins, and deposition of oily cholesleryl esters within the developing arterial lesions. In 1993, we reported the isolation, planar structures, and initial biological evaluation of the py-ripyrapenes A-D (1-4), potent ACAT inhibitors isolated from Aspergillus fumigates FO-1289. These novel, polyoxygenated mixed polyketide-terpenoid (meroter-penoid) metabolites contain a fused pyridyl alpha-pyrone moiety and eight contiguous stereocenters; subsequently, we determined the relative and absolute stereochemistries of 1 as well, employing NOE-difference and Mosher eater NMR studies in conjunction with X-ray crystallography.