New Progress of Gold in Organic Chemistry Recent Contribution of F. Dean Toste

1. Department of Chemistry University of Montreal March 17th , 2009 New Progress of Gold in Organic ChemistryRecent Contribution of F. Dean Toste William S. Bechara Charette Group Literature Meeting

2. Outline • General Properties of Gold • Particularities and advantages of Gold in Homogeneous Catalysis • Relativistic effects of Gold (Quantum Chemistry studies) • Examples of the Relativistic Effect • Initial Tryouts with Gold in Organic Chemistry • Contribution of F. Dean Toste in Homogeneous Gold(I) Catalysis • Mechanistic Studies • Applications in Total Synthesis

3. General Properties of Gold Au : [Xe] 6s1 4f14 5d10 • Oxidation States : Au-I to AuIII and AuV but AuI and AuIII dominate. • Electronegativity : Au  2.54 (~highest electronegativity of all metals) • Industrial use : medicine, dentistry, electronics, jewelry, food, etc  good resistance to oxidative corrosion, good conductor of heat and electricity, ductile, malleable…. • Organic Chemistry : heterogeneous and homogeneous catalysis • (Au0) (AuI and AuIII) J. Phys. Chem. A, 2006, 110 , 11332

4. Advantages of Gold in Organic Chemistry • Most reactions catalyzed by Au can be done without precautions to exclude air and humidity (sometimes done in water or MeOH). • Gold catalysts can be used for heterogeneous and homogeneous catalysis. • Relatively fast reactions. • Good potential to stabilize cationic reaction intermediates. • Versatile Lewis Acid  Gold species can activate various substrates, specially unsaturated molecules. e. g. alkynes, alkenes, allenes, diynes, allenynes, enynes... • A wide array of nucleophiles can be added to the activated substrates in an intramolecular or intermolecular fashion. e.g. O, N, C, F, S. F. Dean Toste Nature, 2007, 446, 395 F. Dean Toste J. Am. Chem. Soc., 2008, 130, 4517 Hashmi Angew. Chem. Int. Ed. 2005, 44, 6990

5. Particularities of Gold in Homogeneous Catalysts • Gold catalysts are considered as soft and mostly carbophilic Lewis acid. • Au(I) complexes areknown to activate C-C p-bonds towards nucleophilic addition. • Au(III) can also complex carbonyls and other heteroatoms (e.g. N, O, S) • Au(I) species are not nucleophilic (relative to the copper complexes). • Gold catalysts have a low propensity for β-H elimination and reductive elimination. • Au(I) and Au(III) complexes do not readily cycle between oxidation states in the catalysis. Difficult for cross-coupling. • Au(I) can pass through a cationic intermediate and a carbenoidspeciesin the reaction mechanism. • Strong relativist effect. Relativistic effects are crucial to understanding the electronic structure of heavy elements. F. Dean Toste Nature, 2007, 446, 395 P. Pyykko Angew. Chem. Int. Ed.2004, 43, 4412 F. Dean Toste Chem. Rev., 2008, 108 , 3351

6. Relativistic Effect of Gold • Relativistic Quantum chemistry describes the electron dynamics, chemical bonding and particularly the behaviour of the heavier elements of the periodic table (specially the elements in which the 4f and 5d orbitals are filled), aurophilicity (strong Au-Au interaction), etc. • It describes that Gold has a relativistic contraction of the 6s and 6p orbitals and an expansion of the 5d orbitals. This correspond to a lowering of the lowest unoccupied molecular orbital (LUMO) and therefore a strong Lewis acid. • It also results in greatly strengthened Au–L bonds (which can induce high chirality). • Different oxidation state influences the activity of the catalyst. Contraction of 6s and expansion of 5d orbitals 76Os 82Pb 73Ta 81Ti 77Ir 80Hg 78Pt 79Au F. Dean Toste Nature, 2007, 446, 395 , P. Pyykko Angew. Chem. Int. Ed.2004, 43, 4412

7. Influence of Oxidation States • Gold(I) and (III) can furnish different regioisomers : • Gold(III) catalyses the reaction by activating the ketone. • Gold(I) catalyses the reaction by activating the allene. V. Gevorgyan J. Am. Chem. Soc., 2005, 127, 10500 F. Dean Toste Nature, 2007, 446, 395

8. Initial tryouts with Gold in Organic Chemistry • First attempts using gold catalysis was mainly for oxidations : • Au(III) species J. Org. Chem., 1976, 41, 2742 Tetrahedron 1983, 39, 3181

9. Contribution in Homogeneous Gold Catalysis Prof. F. Dean Toste • Dean was born in 1971 in Azores, Portugal and soon moved to Canada. He majored in Chemistry and obtained a M.Sc. in Organic Chemistry at the University of Toronto with Prof. Ian W. J. Still. He then pursued his Ph.D. with Barry Trost at Stanford and a post-doctoral appointment with Robert Grubbs at Caltech. Dean is currently an Associate Professor of Chemistry at UC Berkeley. • His main research interest is the Gold(I)-Catalyzed C-C Bond Formation. • Published around 30 publications (~25 JACS) just on Gold chemistry in the past 5 years.  Around 10 reviews on gold chemistry in the past few years (2 by Toste).

10. Conia-Ene Reaction of b-Ketoesters with Alkynes F. Dean Toste J. Am. Chem. Soc., 2004, 126 , 4526

11. Proposed Mechanism F. Dean Toste J. Am. Chem. Soc., 2004, 126 , 4526

12. Allenyne Cycleisomerisation – Activated Ene Reaction F. Dean Toste J. Am. Chem. Soc., 2008, 130 , 4517

13. Mechanistic Studies – Ene Type Reaction  Intramolecular proton transfer F. Dean Toste J. Am. Chem. Soc., 2008, 130 , 4517

14. Mechanistic Studies Ene Reaction Metallacycles Vinylidenes p-Coordinations Mono Gold Phosphine Dual Gold Phosphine F. Dean Toste J. Am. Chem. Soc., 2008, 130 , 4517

15. Mechanistic Studies F. Dean Toste J. Am. Chem. Soc., 2008, 130 , 4517

16. Mechanistic Studies Metallacycles : • Experimentally : • Computationally :  Similar computational results for dual phosphine gold intermediate F. Dean Toste J. Am. Chem. Soc., 2008, 130 , 4517

17. Mechanistic Studies Vinylidenes : • Very unstable by computational energy • minimization, hight DG+ F. Dean Toste J. Am. Chem. Soc., 2008, 130 , 4517

18. Mechanistic Studies p-Coordinations : • Formation of unstabilized vinyl cation • Need of concerted C-C bond formation and asynchronous hydrogen transfer to avoid • unstable intermediate. • Very hight activation energy (computational • calculus) F. Dean Toste J. Am. Chem. Soc., 2008, 130 , 4517

19. Mechanistic Studies • Intermediate I also approved • by computational analysis F. Dean Toste J. Am. Chem. Soc., 2008, 130 , 4517

20. Catalytic Cycle F. Dean Toste J. Am. Chem. Soc., 2008, 130 , 4517

21. Synthesis of Benzopyrans F. Dean Toste J. Am. Chem. Soc., 2009, 131 , 3463

22. Proposed Mechanism Rearrangement of allylic oxonium intermediate F. Dean Toste J. Am. Chem. Soc., 2009, 131 , 3463

23. Mechanistic Studies 2,3-rearrangement 3,3-rearrangement 1,4-sigmatropic rearrangement Inversion of allyl moiety Impossible inversion F. Dean Toste J. Am. Chem. Soc., 2009, 131 , 3463

24. 1,3-Dipolar Cycloaddition of Munchnones F. Dean Toste J. Am. Chem. Soc., 2007, 129 , 12638

25. Proposed Mechanism F. Dean Toste J. Am. Chem. Soc., 2007, 129 , 12638

26. Intramolecular Cyclopropanation F. Dean Toste J. Am. Chem. Soc., 2009, 131 , 2056

27. Proposed Mechanism • Carbenoid • Intermediates F. Dean Toste J. Am. Chem. Soc., 2009, 131 , 2056

28. Stereoselective Olefin Cyclopropanation • Cis cyclopropanes – major product F. Dean Toste J. Am. Chem. Soc., 2005, 127 , 18002

29. Reaction Mechanism • Complete loss of ee, consistent with the formation of a vinyl gold(I) species F. Dean Toste J. Am. Chem. Soc., 2005, 127 , 18002

30. Pyrrole Synthesis – Acetylenic Schmidt Reaction F. Dean Toste J. Am. Chem. Soc., 2005, 127 , 11260

31. Reaction Mechanism F. Dean Toste J. Am. Chem. Soc., 2005, 127 , 11260

32. Intramolecular Hydroamination of Allenes F. Dean Toste J. Am. Chem. Soc., 2007, 129 , 2452

33. Cyclization of Silyl Enol Ethers F. Dean Toste Angew. Chem. Int. Ed.2006, 45, 5991

34. Ring Expanding Cycloisomerisation F. Dean Toste Org. Lett..2008, 10, 4315

35. Proposed Mechanism Nazarov-type electrocyclisation Backbonding F. Dean Toste Org. Lett..2008, 10, 4315

36. Applications in Total Synthesis • Ventricosene : Ring Expanding Cycloisomerization • (+)-Lycopladine A : Cyclisation os Silyl Enol Ether F. Dean Toste Org. Lett..2008, 10, 4315 F. Dean Toste Angew. Chem. Int. Ed.2006, 45, 5991

37. Conclusion • Properties and Avantages of Gold in Homogeneous Catalysis • Relativistic Effects of Gold and Examples • Applicationd of Gold in Organic Chemistry • Very Versatile and Useful Catalyst (Hight Yields and ee) • Large Contribution of F. Dean Toste • Mechanistic Studies • Applications in Total Synthesis •  Future Work : Further the understanding of Enantioselective and Seteroselective Mechanisms. (Transition States with ChiralLigands)

38. Are Gold Chemicals Expensive??? $/g Au Ag Cu Ti Rh Pt Pd TiCl2Cp2 2$ PtCl2 135$ AuCl140$ AgCl3$ CuCl5$ RhCl(PPh3)98$ PdCl2 42$ TiCl4 0.13$ AuCl3 94$ AgF6Sb12$ CuBr2 0.5$ PtCl4 114$ RhCl3 438$ Pd(OAc)2 59$ TiCl3 0.5$ AgOTf 6$ Cu(OTf)47$ PPh3AuCl 108$ Rh2(OAc)4 371$ Pd(PPh3)4 66$ PtCl2(PEt3) 2 149$ $$$

39. Myths – Does the Chemistry Comes from Gold???? • A very long time ago, the main goal of the alchemists was to produce gold from other substances, such as lead — presumably by the interaction with a mythical powerful substance called the philosopher’s stone. Although they never succeeded in this attempt, the alchemists promoted an interest in what can be done by reacting different substances and this apparently laid a foundation for today‘s chemistry.