Efficient Entry to the Hasubanan Alkaloids: First Enantioselective Total Synthesis of (-)- Hasubanonine, (-)-Runanine, (-)-Delavayine, and (+)-Periglaucine B. Herzon, Calandra, and King, ACIE, 2011, 50, 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, –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 1

Journal covers from the Herzon group 2

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. 3

Retrosynthesis 4

Total Synthesis 5

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 6

Synthesis of (-)-hasubanonine 7

Synthesis of (-)-runanine 8

Synthesis of (-)-delavayine and (+)-periglaucine B 9

Retro Diels-Alder TMS group greatly increases reactivity towards retro diels-alder, because of stereoelctronic effects of the C-Si bond. 10

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. 11