A Convergent Total Synthesis of (+)-Wortmannin

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DESCRIPTION (provided by applicant): Wortmannin, an anti-fungal and anti-inflammatory antibiotic known for almost fifty years, has only succumbed to one racemic total synthesis and one partial synthesis from hydrocortisone. In addition to its antibiotic properties, wortmannin was found to be a potent phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor in the early 1990s. PI 3-kinase has been suggested as an anti-cancer target and as such, interest in the use of wortmannin for preventing the proliferation of cancer cells has been suggested. However, because of wortmannin's high general toxicity, analogs that preserve wortmannin's high PI 3-kinase inhibition properties but omit its toxicity have been deemed necessary for any potential drug applications. With this in mind, our specific aim is to develop an asymmetric total synthesis of wortmannin that is convergent, flexible, and of sufficient brevity to eventually facilitate the synthesis of numerous derivatives for further biological testing. Our proposed route involves separately forming two halves of the molecule and later joining them via a Diels-Alder reaction to form one of the quaternary centers of wortmannin as well as the B ring. As this key Diels-AIde reaction is sterically cumbersome, investigations into properly matching the electronics of the diene and dienophile are likely necessary for success in this endeavor. If successful, an enantioselective and considerably shorter route then the, past synthesis would be achieved, allowing access to a greater variety of wortmannin analogs then has been previously possible.