PART 1: APPLICATION OF MICROBIAL REDUCTION: SYNTHETIC STUDIES OF PSEUDOGUIANOLIDES. PART 2: SYNTHETIC STUDIES OF POLYENE MACROLIDES (ASYMMETRIC SYNTHESIS, ENZYMATIC, SOLID STATE NMR, PIMARICIN)
Abstract
The pseudoguaianolides are a group of sesquiterpenes which exhibit cytotoxic and antitumor activity. Their principle structural feature is a 5,7-fused ring; Chapter 1 presents a review of successful racemic approaches to this hydroazulene system. The goal of the research presented in Part 1 is to demonstrate the utility of microbially reduced 2,2'disubstituted cyclopentadiones in making use of previously examined synthetic approaches, with the added premise of asymmetry, hitherto not demonstrated in any pseudoguaianolide synthesis. The formal chiral syntheses of 6 pseudoguaianolides was projected. Part 2 details the approach to an efficient enantiospecific synthesis of pimaricin aglycone. A flexible synthesis of this polyene macrolide could provide access to a host of natural and synthetic tricothecenes, not only for medicinal evaluation, but also for structural determination. Chapter 3 examines some of the spectroscopic studies, and the synthetic chemistry of polyene macrolides published to date. Our approach to pimaricin aglycone involves three stages: (1) the synthesis of optically active fragments; (2) their fusion to form the macrocycle; (3) final decoration of the skeleton. Microbial reduction and known enzymatic methods provided the chiral starting materials. After elaboration, they were fused to form the carbon skeleton of pimaricin aglycone save one carbon atom. The mild conditions developed should prove useful in future syntheses of other members of the family of polycene macrolides. The first ('13)C NMR solid-state spectrum was obtained for any member of the polyene macrolides. The existence of a 6-membered hemiketal in solid amphotericin was unambiguously proven. The method shown demonstrates a new, efficient analysis method for these highly insoluble substances.
Degree
Ph.D.
Subject Area
Organic chemistry
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