Studies Directed Toward Synthesis of Hyperforin and Related Phloroglucins Literature Meeting Jad Tannous January 16, 2006

2 Outline 1.Introduction on the molecules 2.Hyperforin I.Biosynthesis of Hyperforin II.Kraus Synthesis of the Bicylic Core III.Young Synthesis of the Bicylic Core IV.My Research at Merck 3.Garsubellin A I.Takagi Development of the Bicyclo[3.3.1]nonenone Core II.Miesch New Cascade Reactions Starting from Acetylenic  - ketoesters III.Stoltz Progress Toward the Synthesis of Garsubellin A IV.Nicolaou Synthesis of a Fully Fonctionalized Bicyclic Core V.Shibasaki Synthesis of (±)-Garsubellin A

3 The Molecules: Phloroglucins

4 The Molecules: More Phloroglucins

5 Biosynthesis of Hyperforin: Biosynthesis of the hyperforin skeleton in Hypericum calycinum cell cultures

6 Biosynthesis of Hyperforin: First prenylation step

7 Biosynthesis of Hyperforin: Hypothetical mechanism of hyperforin biosynthesis

8 Authors Who Have Worked on Synthesis of Phloroglucins Hyperforin: Kraus, Nicolaou, Young, Metha (enantioselective), … Garsubellin A: Stoltz, Nicolaou, Shibasaki, Grossman, …

9 Studies toward Hyperforin What are the strategies? Kraus: Allylation followed by Mn-mediated oxidative cyclization Nicolaou: annulation of the gem-dimethyl-containing ring onto an existing cyclohexanone Young: Intramolecular allene-nitrile oxide cycloaddition

10 Kraus Synthesis of the Bicylic Core

11 Young Synthesis of the bicylic core

12 Young Synthesis of the bicylic core

13 My Research at Merck

14 My Research at Merck

15 Synthesis and Studies toward Garsubellin A What are the strategies? Shibasaki: C-C bond forming addition-elimination and aldol reactions Nicolaou: « Biomimetic » selenocyclization of a cyclic B-keto ester onto a pendant prenyl group Stoltz: Tandem Claisen-Dieckmann reaction of malonyl dichloride

16 Takagi Development of the Bicyclo[3.3.1]nonenone Core

17 Takagi Development of the Bicyclo[3.3.1]nonenone Core

18 Miesch New Cascade Reactions Starting from Acetylenic  -ketoesters

19 Miesch New Cascade Reactions Starting from Acetylenic  -ketoesters

20 Stoltz Progress Toward the Synthesis of Garsubellin A

21 Stoltz Progress Toward the Synthesis of Garsubellin A

22 Nicolaou Synthesis of a Fully Fonctionalized Bicyclic Core

23 Nicolaou Synthesis of a Fully Fonctionalized Bicyclic Core

24 Nicolaou Synthesis of a Fully Fonctionalized Bicyclic Core

25 Nicolaou Highly Functionalized Medium-Sized Rings

26 Shibasaki Retrosynthetic Analysis

27 Shibasaki Synthesis of (±)-Garsubellin A

28 Shibasaki Synthesis of (±)-Garsubellin A

29 Shibasaki Synthesis of (±)-Garsubellin A

30 Mechanism of the Wacker Oxidation:

31 Shibasaki Synthesis of (±)-Garsubellin A