1. 1 Applications of a Novel Nickel-Catalyzed Reductive Coupling Reaction Towards the Total Synthesis of Amphidinolide T1 Julie Farand April 1 st, 2004 Jamison et al, J. Am. Chem. Soc., 2004, 126, 998 Jamison, T.F. et al, Org. Lett., 2000, 26, 4221

2. 2 Introduction Methods of generating allylic alcohols Nickel-catalyzed coupling between alkynes and aldehydes alkynes and epoxides alkynes and imines Jamison’s methodology applied towards the total synthesis of amphidinolide T1

3. 3 Preparation of Allylic Alcohols Reductions, organomagnesium and organolithium reagents Reactive allylic sulfoxides via a [2,3]-sigmatropic rearrangement

4. 4 Preparation of Allylic and Homoallylic Alcohols Allylic oxidation with selenium dioxide Homoallylic alcohols via chiral or achiral crotyl and allyl metals

5. 5 Preparation of Allylic Alcohols : The Nozaki-Hiyama-Kishi Reaction Nozaki et al, J. Am. Chem. Soc., 1986, 108, 6048

6. 6 Nozaki-Hiyama-Kishi Mechanism In 1983, anhydrous CrCl 2 from ROC/RIC Corp (New Jersey) proved to contain ca. 0.5 mol% of Ni on the basis of Cr Aldrich Co. (90% purity) and Rare Metallic Co. (99.99% purity) offers anhydrous CrCl 2 free from Ni salts The success of this reaction heavily depended on the nature of the CrCl 2 ! Hiyama, T.; Nozaki, H. et al, Tetrahedron Letters, 1983, 24, 5281 Kishi Y. et al, J. Am. Chem. Soc, 1986, 108, 5644 Nozaki, H. et al, J. Am. Chem. Soc, 1986, 108, 6048

7. 7 Synthesis of Enantioselective (E)-Allylic Alcohols Oppolzer, W.; Radinov, N. J. Am. Chem. Soc., 1993, 115, 1593

8. 8 Oppolzer et al, J. Org. Chem., 2001, 66, 4766 Synthesis of Macrocyclic (E)-Allylic Alcohols

9. 9 Addition to RCHO by Zirconocene-Zinc Transmetallation Wipf, P.; Ribe, S. J. Org. Chem., 1998, 63, 6454

10. 10 Intramolecular Ni-Catalyzed Alkylative Cyclizations Montgomery, J.; Oblinger, E. J. Am. Chem. Soc., 1997, 119, 9065

11. 11 Montgomery, J.; Oblinger, E.; J. Am. Chem. Soc, 1997, 119, 9065 Nickel-Catalyzed Alkylative and Reductive Coupling

12. 12 Choice of Ligand Phosphine Ligands with EDG Soft neutral 2e - donor ligand σ-donor ability : (t-Bu) 3 P > Cy 3 P > (n-Bu) 3 P > Et 3 P > Ph 3 P Tolman, C. Chem. Rev. 1977, 77, 313

13. 13 π-acidic ligands (aldehyde) accelerate reductive elimination In the absence of (n-Bu) 3 P, unreacted RCHO can coordinate to Ni Direct reductive elimination is accompanied by a 2e - reduction of Ni Process disfavored by the coordination of good σ-donor (n-Bu) 3 P Reductive vs β-Hydride Elimination : Additive Effect?

14. 14 Catalytic Intermolecular Reductive Coupling of Alkynes and Aldehydes Jamison, T.F. et al, Org. Lett., 2000, 26, 4221

15. 15 Proposed Mechanism via an Oxametallacyle

16. 16 Choosing the Reducing Agent Montgomery, J.; Tang, X-Q. J. Am. Chem. Soc., 1999, 121, 6098 Jamison, T.F. et al, Org. Lett., 2000, 26, 4221

17. 17 Catalytic Intermolecular Reductive Coupling of Alkynes and Aldehydes

18. 18 Asymmetric Reductive Coupling with NMDPP Jamison, T.F. J. Am. Chem. Soc., 2003, 125, 3442

19. 19 Proposed Steric and Electronic Control

20. 20 Proposed Mechanism for Asymetric Reductive Coupling

21. 21 Catalytic Three-Component Coupling Reaction: Allylic Amines

22. 22 Boronic Acids in Catalytic Three-Component Couplings

23. 23 Enantioselectivities for Alkylative and Reductive Coupling Using (S)-(+)-NMDPP

24. 24 Proposed Mechanism for the Ni-catalyzed Coupling Reaction Between Alkynes and Imines Enantioselectivity and regioselectivity are determined in the same step and before the azametallacyclopentene Highly selective for alkylative coupling in MeOH

25. 25 Intermolecular Reductive Coupling of Alkynes and Epoxides Jamison, T.F.; Molinaro, C. J. Am. Chem. Soc, 2003, 125, 8076

26. 26 Reductive Cyclization via a Proposed Nickella(II)oxetane

27. 27 Summary of Nickel-Catalyzed Reaction Racemic and enantioselective allylic alcohols Allylic amines via three-component coupling Homoallylic alcohols

28. 28 Synthesis of Amphidinolide T1 The amphidinolides are a family of macrolides produced by marine dinoflagellates of the genus Amphidinium The marine algae live in symbiosis with the Okinawan flatworm Amphidinolide T1, a 19-membered macrolide, is cytotoxic against human epidermoid carcinoma KB and murine lymphoma L1210 cell lines Amphidinium carterae Amphidinium lactum Total Synthesis of Amphidinolide T1 Ghosh (2003) Fürstner (2003) Jamison (2004) Kobayashi, J. et al, J. Org. Chem., 2001, 66, 134

29. 29 Ghosh’s Enantioselective Synthesis of Amphidinolide T1 via Macrolactonization Ghosh, A.K.; Liu, C. J. Am. Chem. Soc., 2003, 125, 2374

30. 30 Fürstner’s Synthesis of Amphidinolide T1 via RCM Macrocyclization Fürstner, A. et al, J. Am. Chem. Soc., 2003, 125, 15512

31. 31 Jamison’s Approach : Ni-catalyzed reductive rxn alkyne-epoxide alkyne-aldehyde Jamison’s Approach to Amphidinolide T1 Jamison et al, J. Am. Chem. Soc., 2004, 126, 998

32. 32 Synthesis of Amphidinolide T1

33. 33 Mechanism Revisited

34. 34 Brown, H.C.; Bhat, K. J. Am. Chem. Soc.,1986, 108, 5919 Enantioselective Brown (Z)-Crotyl Addition

35. 35 Synthesis of Amphidinolide T1

36. 36 Synthesis of Amphidinolide T1

37. 37 Synthesis of Amphidinolide T1

38. 38 Synthesis of Amphidinolide T1

39. 39 Conclusion Two nickel-catalyzed carbon-carbon bond forming reactions were utilized during the synthesis of Amphidinolide T1: catalytic intermolecular alkyne-epoxide reductive coupling catalytic intramolecular alkyne-aldehyde reductive coupling This is the most direct synthesis of Amphidinolide T1 with 20 synthetic operations.

40. 40 Aknowledgements Prof Louis Barriault Irina Denissova Steve Arns Effie Sauer Jeff Warrington Roxanne Clément Patrick Ang Louis Morency Rachel Beingessner Gerardo Ulibarri Danny Gauvreau* Ross MacLean* Jermaine Thomas* Roch Lavigne Nathalie Goulet Christiane Grisé Financial Support University of Ottawa NSERC OGS Canada Foundation for Innovation Ontario Innovation Trust Premier’s Research Excellence Award Merck Frosst Canada Astra Zeneca Bristol Myers Squibb Boerhinger Ingelheim