An Approach to Amphimedine and Related Marine Alkaloids Utilizing an Intramolecular Kondrat'eva Pyridine Synthesis

A strategy for the synthesis of the marine alkaloid amphimedine (1) and its congeners 2–5 has been investigated. The approach involves an intramolecular Diels-Alder reaction of a 4,5-disubstituted oxazole (Kondrat’eva reaction) to produce the ABC ring system of these natural products, followed by a photoenolization/electrocyclization to construct the D ring. The key oxazole olefin 30 was prepared in several steps starting from pyridine ester 10 and o-aminostyrene (19). The route to 30 utilized a Kozikowski modification of the Schollkopf oxazole synthesis as a key step. Thermolysis of oxazole 30 provided fused pyridine 31 via the desired [4 + 2] cycloaddition. Attempts to cyclize derived aldehyde 32 photochemically failed, affording primarily decarbonylation products.