Preparation of para-disubstituted benzenes, formation of optically pure cyclic amines by intramolecular conjugate displacement and total synthesis of marinopyrrole B

Abstract

The first chapter of this thesis describes a method for making para-disubstituted benzenes. The process involves reaction of acetylides with aldehydes to give 1,4-diols, triple bond reduction and oxidation of the resulting 1,4-diols to 1,4-diketones. Treatment of the 1,4-diketones with vinylmagnesium bromide, followed by ring-closing metathesis and dehydration, affords para-disubstituted benzenes. The method was applied to the synthesis of C5-aryl carbohydrates. The second chapter describes an intramolecular conjugate displacement (ICD) between a nitrogen nucleophile and a Morita-Baylis-Hillman acetate with a chiral auxiliary for making optically pure cyclic amines. Removal of the chiral auxiliary from the ICD products with DIBAL-H provides optically pure six- or seven-membered cyclic amines having a stereogenic center α to nitrogen. The last chapter of this thesis describes the first total synthesis of the marine antibiotic alkaloid, marinopyrrole B, which shows very strong activity against methicillin-resistant Staphylococcus aureus. It is known that marinopyrrole B can not be made directly by bromination of marinopyrrole A, and so bromination of one pyrrole unit at an early stage was the basis of my successful route. The nitrogen of the brominated pyrrole was alkylated with a Michael acceptor having an allylic leaving group, and the product was then modified to construct the second pyrrole via a Paal-Knorr reaction. The nitrogen of the resulting 1,3'-bipyrrole was then protected, followed by addition of an appropriate Grignard reagent, oxidation and deprotection reactions, to obtain a 1,3'-bipyrrole with two aromatic carbonyl groups. Finally, dichlorination and demethylation generated racemic marinopyrrole B.