UC San Diego

ABSTRACT

Steps Away from (–)-Azaspirene: Synthesis of the Core Spirocycle

Chemical Studies in Copper(I) Iodide Dimethyl Sulfide Catalyzed Asymmetric Conjugate Addition

Wittig Chemistry in the Teaching Laboratory: A Novel Water-Organic Interface Reaction

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Michael John Barker Kelly

Doctor of Philosophy in Chemistry

University of California San Diego 2019

San Diego State University 2019

Doctor Bernt Mikael Bergdahl, Chair

Azaspirene is a fungal metabolite isolated by the Osada1 group in 2002 from the soil fungus Neosartorya sp. that has been shown to have promising inhibition of angiogenesis1,2 in vitro and in vivo, and which may be the key to the synthesis and elucidation of the structurally-similar pseurotin family of compounds. The pseurotin family of compounds is interesting because its members have been shown to have a wide range of interesting therapeutic effects, which will be discussed in detail. Unfortunately, it is impractical to isolate sufficient quantities of azaspirene from its natural source (85 mg were obtained from a 15 liter culture1). In addition, the previous synthetic routes to azaspirene are notoriously difficult and low-yielding. Because of these issues, sufficient material has been difficult to obtain to satisfy the twin goals of thorough biological testing to confirm the anti-angiogenic effects of azaspirene and the synthesis and elucidation of its derivatives. The overarching goal in part I has been to find a simpler, more accessible route to azaspirene, and through it the pseurotin family.

Silyl groups have been used extensively in organic synthesis as valuable protecting groups, bulky directing groups, and masked hydroxyl groups6. In 2002, the Bergdahl lab published new methodology for asymmetric silyl conjugate addition reactions with monosilylcuprates and oxazolidinones7. This methodology was expanded further in 2005 with the introduction of a novel stoichiometric copper iodide-dimethyl sulfide complex8. Combining the two approaches, and with further development that allows the catalytic use of the copper complex, we have probed the scope of the technique and shown its utility in Part II.

The Wittig reaction is a fundamental synthetic organic reaction which has been extensively used for more than fifty years to build organic frameworks through its robust creation of carbon-carbon double bonds3. However, for most of its history relatively harsh conditions have been employed to push the reaction forward. In 2007, the Bergdahl lab was able to conceive an alternative4 which used aqueous sodium bicarbonate and stabilized ylides to effect the same change in high yields. In Part III, this important methodology has been expanded. An efficient lab protocol was developed for use in teaching the reaction to undergraduates in a lab setting5.