Total Synthesis of an Atropdiastereomer of RP-66453 and Determination of Its Absolute Configuration

摘要

RP-66453 (1), a secondary metabolite, was isolated from an Actinomycetes strain by Helynck and co-workers at Rhone-Poulenc Rorer. This new bicyclic compound binds very selectivity to the neurotenisn receptor from guinea pigs (IC_(50) = 30 μg mL~(-1)). Subsequent structural modification has led to the discovery of potent neurotensin antagonists claimed to be useful for treating psychosis and Alzheimer's and Parkinson's diseases. Structurally, RP-66453 belongs to a growing family of macrocycles that include the vancomycin class of antibiotics, chlorpeptin, and kistamine, The presence of strained macrocycles with both endo aryl-aryl and aryl-aryl ether bonds is the common structural feature of these complex and medicinally relevant natural products.