Enantiodivergent Synthesis of (+) and (-) Pancratistatin

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DESCRIPTION (provided by applicant): This project is aimed at the ultimate goal of providing new therapeutic agents for the treatment of cancer. The alkaloid (+)-pancratistatin, extracted from Pancratium littorale bulbs, displays promising antineoplastic and antiviral activity and is currently undergoing preclinical evaluation by the US National Cancer Institute. However, the studies have been put on hold due to the limited quantity of material available from isolation. The alkaloid's limited availability has also plagued efforts towards the elucidation of its mechanism of action as well as structure - activity studies, which could be crucial for the identification of more potent and/or less toxic analogs. Therefore, the development of an efficient chemical route enabling gram-quantity preparation of (+)-pancratistatin will tremendously facilitate further biological and medicinal evaluation of this compound and its analogs, hence it has been a long-sought objective of the scientific community. The work proposed in this application focuses on a practical enantiodivergent synthesis of (+)-pancratistatin and enantiomeric (-)-pancratistatin from D-xylose. The latter compound has not been synthesized in enantiomerically pure form, in spite of recent data revealing the possibility of similar activity in the enantiomeric pancratistatin series. With the exception of three steps, the proposed syntheses of the two pancratistatin enantiomers are based on the same pathway. The key transformation is a ring-closing metathesis process, which represents a novel strategy for assembling the multi-functionalized ring C of the pancratistatin skeleton. The flexibility of the proposed synthetic scheme will allow for thorough optimization of the synthesis in search for high efficiency and practicality.