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Efficient Entry to the Hasubanan Alkaloids: Enantioselective Total Synthesis

This article presents the first enantioselective total synthesis of (-)-Hasubanonine, (-)-Runanine, (-)-Delavayine, and (+)-Periglaucine, important alkaloids in Chinese medicine. The synthesis utilizes a TMS-cyclopentadiene Diels-Alder/retro Diels-Alder directing/protection strategy, resulting in a highly efficient route with minimal protections.

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Efficient Entry to the Hasubanan Alkaloids: Enantioselective Total Synthesis

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  1. Efficient Entry to the Hasubanan Alkaloids: First Enantioselective Total Synthesis of (-)-Hasubanonine, (-)-Runanine, (-)-Delavayine, and (+)-Periglaucine B.Herzon, Calandra, and King, ACIE, 2011, 50, 8863-8866 Presented By: Kirk W Shimkin Total Synthesis Spring 2012

  2. Seth B. Herzon • Born: Philadelphia, PA 1979 • B.S.: Temple University, 2002 • Ph.D.: Harvard University, 2006 • Advisor: Dr. Andrew Myers • Post-Doc: University of Illinois, 2006-2008 • Advisor: Dr. John F. Hartwig • 2008-present: Assistant professor, Yale University • Recent recipient of NSF career award and Alfred P. Sloan fellowship Nicholas Calandra • B.S.: St. Lawrence University, 2008 • Advisor: Dr. Larry French

  3. Journal covers from the Herzon group

  4. Hasubanan Alkaloids • Family of over 40 botanical natural products • Traditionally used in Chinese medicine • All share aza[4.4.3]-propellane skeleton • Structurally related to opium alkaloids (although opposite enantiomers), and is thought to possess analgesic properties for this reason. • Synthesis of other hasubanan alkaloids published by the Reisman group (CalTech) in the same volume of ACIE.

  5. Retrosynthesis

  6. Total Synthesis

  7. Diels-Alder protection strategy • Azaquinones are unstable to isomerization to 5-hydroxyindoles • Enantioselective Diels Alder with 5-TMS-cyclopentadiene serves as a directing group for absolute stereochemistry and prevents isomerization to 5-hydroxyindole

  8. Synthesis of (-)-hasubanonine

  9. Synthesis of (-)-runanine

  10. Synthesis of (-)-delavayine and (+)-periglaucine B

  11. Retro Diels-Alder • TMS group greatly increases reactivity towards retro diels-alder, because of stereoelctronic effects of the C-Si bond.

  12. Conclusion • (-)-hasubanonine: 13 steps, 5% (from aryl azide) • (-)-runanine: 12 steps, 11% (from aryl azide) • (-)-delavayine: 12 steps, 12% (from aryl azide) • (+)-periglaucine: 12 steps, 9% (from aryl azide) • Very efficient route with minimal protections • TMS-cyclopentadiene Diels-Alder/ retro Diels-Alder directing/protection strategy was developed and is proposed to be general.

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