cataly&c(asymmetric(synthesis(of((...
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Cataly&c Asymmetric Synthesis of Either Enan&omer of the Calabar Alkaloids
Physos&gmine and Physovenine
Takaharu Matsuura, Larry E. Overman,* and Daniel J. Poon J. Am. Chem. Soc. 1998, 120, 6500-‐6503.
Presented by Derek Ahneman
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Larry E. Overman, Ph.D. • Born in Chicago, 1943 • B.A., Earlham College, 1965 • Ph.D., University of Wisconsin, 1969 • NIH Postdoctoral Fellow, Columbia University, 1969-‐1971 • Joined University of California, Irvine faculty, 1971 • DisTnguished Professor of Chemistry • Member of the NaTonal Academy of Sciences • Published over 350 scienTfic papers • Research focuses on reacTon development and the synthesis of pharmalogically acTve natural products • Perhaps best known for developing the Overman Rearrangement (shown below)
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Hexahydropyrroloindoles • Diverse class of natural products that exists with a carbon subsTtuent on the quaternary center (shown in red) • Examples include the Calabar alkaloids PhysosTgmine and Physovenine, whose synthesis is reported • Similar alkaloids include flustramine B, isolated from a marine bryozoan (on right)
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History of Physos&gmine
• Occurs naturally in the Calabar bean (on right) • First isolated in pure form in 1864 by Jobst and Hesse • First total synthesis completed in racemic form by Julian and Pikl in 1935 • Absolute configuraTon determined by Sir Robert Robinson 34 years a`er discovery • Brossi, Greig, and co-‐workers have recently improved synthesis of physosTgmine
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Medicinal Applica&ons of Physos&gmine
• Powerful inhibitor of acetyl cholinesterase (on right) • Various clinical uses include:
• To reduce intraocular pressure in glaucoma • To treat postoperaTve intesTnal atony (loss of muscle strength) and myasthenia gravis (autoimmune neuromuscular disease) • To relieve symptoms of Alzheimer’s disease
• PharmaceuTcal limitaTons of physosTgmine include:
• Short duraTon of acTon • Narrow therapeuTc window • Low selecTvity between different cholinesterase enzymes
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Topology of Physos&gmine and Physovenine
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General Synthe&c Strategy
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Physos&gmine/Physovenine Synthesis: Part 1/3
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Physos&gmine/Physovenine Synthesis: Part 2/3
• ReducTon of (S)-‐9 to (S)-‐10 was performed to determine the enanTopurity by chiral HPLC • (S)-‐9 was carried forward in >99% ee
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Physos&gmine/Physovenine Synthesis: Part 3/3
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Conclusion • PhysosTgmine was synthesized in 5.4% yield over 9 steps (15-‐20% on larger scale) • Physovenine was synthesized in 16.3% yield over 9 steps • Developed a versaTle route to hexahydropyrroloindoles • Either enanTomer of the natural products can be prepared • Asymmetric intramolecular Heck strategy useful due to the ability to append various groups to the quaternary carbon