A formal synthesis of loracarbef and total synthesis of polypyrrolidinoindoline alkaloids

Chapter 1 details a new formal total synthesis of the carbacephem antibiotic loracarbef (2b). The synthesis employed an alkylation reaction (11 → 40) to build the carbon framework, and a reductive desulfonylation (40 → 41) to set the requisite cis stereochemistry of the β-lactam ring. The key step of the synthesis is a halide-terminated N-acyliminium alkyne cyclization (43 → 45), which achieved a novel preparation of the carbacephem nucleus.; Chapter 2 provides a comprehensive introduction to the polypyrrolidinoindoline class of alkaloids. A detailed account of the existing data on the quadrigemines is presented, including the data not yet published in the general chemical literature. Previous synthetic efforts towards these alkaloids, as well as general methods for the synthesis of contiguous quaternary carbon centers, are detailed.; Chapter 3 details the first total synthesis of (–)-chimonanthine. A novel double Heck cascade established the critical quaternary carbon centers (3a and 3a′) in a single step in high yield, and with complete control over stereochemistry. The methodology was employed to complete the first enantioselective total synthesis of (–)-chimonanthine ( 45) and (+)-calycanthine (46), and resulted in the reassignment of the absolute configuration of the chiral chimonanthines.; Chapter 4 discloses an additional method for the synthesis of bispyrrolidinoindoline alkaloids that utilized a double alkylation between a chiral, enantiomerically pure dielectrophile and a dihydroisoindigo dienolate. The reaction between dihydroisoindigo 4 and ditriflate 15 forges contiguous quaternary carbon centers in high yield in a single step and with excellent control over relative stereochemistry. The strategy was employed to complete total syntheses of (+)-chimonanthine (26) and (–)-calycanthine (27).; Chapter 5 presents the first total synthesis of a quadrigemine stereoisomer utilizing an “inside-out” approach. The dialkylation approach was employed with oxygenated isoindigo 12 to synthesize diallyloxy meso-chimonanthine 23. The highlight of the approach is a double Heck reaction (30 → 31) that was used to build the external quaternary carbon centers. The double Heck cyclization was found to occur with near perfect substrate control. Enoxysilane 31 was elaborated to complete the first total synthesis of a quadrigemine stereoisomer 37.