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

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

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Journal covers from the Herzon group

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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.

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Retrosynthesis

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Total Synthesis

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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

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Synthesis of (-)-hasubanonine

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Synthesis of (-)-runanine

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

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Retro Diels-Alder

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

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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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