California Sea Grant College Program

Bengazole A is a highly potent antifungal agent from a marine sponge of the genus Jaspis sp. The structure of bengazole A contains a bis-(oxazolyl)methanol moiety which is an unprecedented motif among natural products. In addition, bengazole A is the only known marine natural product that contains a C5 monosubstituted oxazole. This dissertation research describes work towards the total synthesis of bengazole A and the development of new synthetic methodology.

Chapter 2 details the initial work on the synthesis of bengazole A including the attempted synthesis of the undescribed 2-formyloxazoline. While efforts to prepare a 2- formyloxazoline were unsuccessful, a novel oxidative rearrangement of 2-methyloxazoline to a dihydrooxazinone was discovered.

Chapter 3 develops the methodology of the oxazoline-dihydrooxazinone oxidative rearrangement, describes the chemistry of 3-unsubstituted dihydrooxazinones, and utilizes the oxidative rearrangement for the synthesis of optically pure (S)-tert-leucine. The mechanism of the oxidative rearrangement was investigated by kinetic studies, isolation of an intermediate, and 13C labeling studies. These studies led to refinement of the proposed mechanism of reaction.

Chapter 4 describes the preparation of an advanced intermediate incorporating C1-­C9 of bengazole A by taking advantage of the ambident nucleophilicity of 2-lithiooxazole with preferential C4 addition to aldehydes. The aldehyde used in the synthesis, a precursor to the bengazole side chain, C1-C6, was prepared from the inexpensive sugar D-galactose.

Chapter 5 outlines a synthetically useful preparation of C5 monosubstituted oxazoles for incorporation in the last stage of bengazole A synthesis. The methodology allows selective deprotonation-electrophilic addition at C5 of 2-methylthiooxazole for the construction of 5-substituted oxazoles. The methylthio group is then conveniently removed by reductive desulfurization with Raney nickel.