UC San Diego

(+)-Zwittermicin A (1) is a water-soluble natural antibiotic isolated from the fermentation of the soil-born bacterium Bacillus cereus. This dissertation research describes the elucidation of the configuration of 1 and total synthesis of its enantiomer. Chapter two describes determination of absolute configuration at C4, relative configuration for C8-C14 in Zwittermicin A and proposes an absolute configuration for 1. Determination of carbon 4 absolute configuration was accomplished using Marfey' s method. Construction of model compunds and evaluated by pair-wise ¹³C NMR chemical shift difference analysis gave relative configuration for the C10-C14 stereocenters. A configuration for 1 was proposed based on this data in conjunction with previously published biosynthesis data and relative configuration for C8-C10. Chapter three describes the synthesis of the proposed structure for (+)- 1, revision of the structure and synthesis of ( - )-1. The proposed structure for 1 was synthesized and evaluation of this compound with authentic natural (+)-1 revealed difference that resulted in a revision of the proposed structure of 1. A 22-step synthesis of ( - )-1 revealed this compound to be identical to (+)-1 by NMR while having an equal but opposite [alpha]D thereby verifying the revised structure. Chapter four describes a short enantioselective synthesis of the C9-C15 portion of zwittermicin A. Taking advantage of the symmetry in the C9 -C15 portion of 1allowed for rapid synthesis of this portion to give an enantiomer of an advanced intermediate in the synthesis of ( - )-1. Chapter five describes the synthesis of analogs and diastereomers of 1 and bioassay of them and previously synthesized compounds. Two diastereomeric analogs representing the C1-C10 portion of 1 were synthesized. In addition two diastereomers of 1 were synthesized. These compounds along with previously synthesized compounds representing C9-C15 in 1 were tested for biological activity. Chapter six describes work on sulfone chemistry related to synthesis of 1. Sulfone anion and dianion additions to various aldehydes were evaluated. Techniques for removal of the sulfone moiety from addition products were also investigated. Sulfone chemistry was used to synthesize two standards for use in a HPLC sphingolipid analysis method