Studies towards the biomimetic synthesis of the stephacidin family of natural products and the concise and versatile synthesis of d,l-brevianamide B, C-12A-epi-malbrancheamide and structurally related analogs

2006 Fall.Includes bibliographical references.The total synthesis of stephacidin A, avrainvillamide and stephacidin B was envisioned to proceed through a biomimetic intramolecular Diels-Alder cylcoaddition. The Diels-Alder precursor was thought to come from the coupling of (L)-prolinamide with a α-ketoacid indole, which would subsequently form the requisite azadiene. While the desired α-ketoacid indole was not stable enough to be synthetically formed, a pseudo- α-ketoacid was successfully designed. The coupling of this vinyl ether carboxylic acid indole moiety with (L)-prolinamide provides an interesting intramolecular Diels-Alder (IMDA) precursor, which might prove to be a useful synthetic prototype for the IMDA. A similar coupling between a pseudo-α-ketoacid and (L)-prolinamide was applied to a different system of compounds, which led to a biomimetically-inspired intramolecular Diels-Alder reaction that diastereoselectively formed the characteristic bicyclo[2.2.2]diazaoctane core of the brevianamides. A concise synthesis of d,l-brevianamide B was successfully designed through a Fischer indole reaction of the key tricyclic IMDA cycloadduct and phenyl hydrazine. This IMDA / Fischer indole route to form the indolic bicyclo[2.2.2]diazaoctane core has proven to be a versatile method to access C-12a-epi-malbrancheamide and structurally related analogs for biological activity studies