Total Syntheses of (-)-Acutumine and (-)-Dechloroacutumine

King, S. M.; Calandra, N. A.; Herzon, S. B. Angew. Chem. Int. Ed. 2013, 52, 3642-3645.

Corey BaschSynthesis Presentation

4/30/13

Seth Herzon

2002- B.S. Chemistry, Temple University.

2006- PhD Chemistry, Harvard University.

2008-2012- Assistant Professor of Chemistry, Yale University.

2012-Present- Associate Professor, Yale.

19 Publications (independent career)-Total synthesis of natural products-MOA and target identification of anticancer natural products-Methodology-Reagent development

Awards: -Packard Fellowship-Sloan Fellowship-Cottrell Scholar Award-NSF Career Award-Eli Lilly New Faculty Award

(-)-Acutumine/Dechloroacutumine

(-)-Acutumine:

- Isolated from Sinomenium acutum.- Tetracyclic, spirocycle, 5 stereocenters.- Inhibits human T-cell proliferation.- Improves object/social recognition, memory in rat model.- Only one other total synthesis reported (Castle, 2009).

(-)-Dechloroacutumine:

- Isolated from Menispermum dauricum (Asian moonseed).- Direct metabolite of (-)-Acutumine.- No previously reported total synthesis.

Menispermum dauricum

Retrosynthesis

Formation of the Arylacetylide from D-Ribose

Addition of the Arylacetylide to the Bicyclic Core

Hydrostannylation and Hosomi-Sakurai Allylation

Setting the Oxidation State of the Spirocyclopentenone Ring and a Final Reduction

• Longest linear sequence: 23 steps

• (-)-Acutumine: 0.43 %

• (-)-Dechloroacutumine: 1.5 %

• First reported total synthesis of (-)-Dechloroacutumine

• Second reported total synthesis of (-)-Acutumine

Overview

Thank you!