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Description
(–)-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. This 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, discussed within, 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 groups.3 In 2002, the Bergdahl lab published new methodology for asymmetric silyl conjugate addition reactions with monosilylcopper reagents and oxazolidinones.4 This methodology was expanded further in 2005 with the introduction of a novel stoichiometric copper iodide-dimethyl sulfide complex.5 Combining the two approaches, and with further development that allows the catalytic use of the copper complex, it was possible to probe the scope of the technique and show 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 bonds.6 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 alternative7 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 setting.8
