1. Olefin Metathesis and Use in Tandem Reactions - The Work of Marc L. Snapper James Mousseau Literature Meeting 6 May 2008 1

2. Outline 2 Introduction to Metathesis Historical background Different types/catalysts Applications in tandem reactions Marc L. Snapper Snapper Research Tandem Cope Tandem Olefin Isomerization Tandem Kharasch Addition Tandem Cyclopropanation Tandem Allylic Alcohol Isomerization Tandem Oxidation Tandem Wittig

3. 3 Metathesis - Introduction As applied to alkenes, refers to the transposition of the alkene carbon atoms so that two new alkenes are formed Dates back to 1955 Very popular means of making C=C bonds A. W. Anderson and N. G. Merckling, U. S. U.S. Patent 2,721,189 (October 18, 1955)U.S. Patent 2,721,189

4. 4 Metathesis - Introduction Olefin metathesis has wide ranging applicability as evidenced by number of publications and citations Results from Web of Science search on olefin metathesis Accessed 2 May 2008

5. 5 Metathesis - 2005 Nobel Prize in Chemistry To Pierre Chauvin, Robert Grubbs and Richard Schrock for “the development of the metathesis method in organic synthesis”

6. 6 Ring Opening Metathesis Polymerizations (ROMP) Thermodynamically favoured for smaller rings Especially favoured for bridged systems

7. 7 Acyclic Diene Metathesis (ADMET) Used to polmerize certain terminal dienes to polyenes Double bond formed can be E or Z Grubbs, R. H., et al. J. Am. Chem. Soc. 2006, 128, 15358-15359

8. 8 Ring Closing Metathesis (RCM) Reaction is driven by the loss of ethylene Permits access of ring sizes that otherwise may be typically hard to make However if thermodynamically unfavourable polymerization may occur Nicolaou, K. C.., et al. Chem. Comm. 2006, 600-602

9. 9 Enyne (EM) and Alkyne (AM) Metathesis Furstner, A., et al. J. Am. Chem. Soc. 1999, 121, 9453-9454 Katz, T. J., et al. J. Am. Chem. Soc. 1985, 107, 737-738

10. 10 Cross Metathesis (CM) Chris Kendall, Literature Meeting March 20 2006 CM works particularly well when one of the components is slows to dimerize Blechert, S., et al. Angew. Chem. Int. Ed. 2003, 42, 1900-1923

11. The key reference Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360 Type I terminal olefins 1° allylic alcohols, amines (protected), esters allyl halides, silanes allyl boronate esters, phosphonates, phosphine oxides, sulfides styrenes (no large ortho groups) Type II 2° allylic alcohols, unptrotected 3° allylic alcohols acrylates, acrylamides, acrylic acid, acrolein, vinyl ketones vinyl epoxides perfluorinated alkane olefins styrenes (large ortho substituents) Type III 1,1-disubstituted olefins trisubstituted olefins (non-bulky) 4° allylic carbon 3° allylic alcohol (protected) vinyl phosphonates Type IV vinyl nitro olefins trisubstituted allylic alcohols (protected) For Grubbs II: Cross Metathesis (CM) Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360 Chris Kendall, Literature Meeting March 20 2006

12. 12 Metathesis - Catalytic Cycle Associative goes through 18e - cycle (ligand does not dissociate) Two potential pathways were proposed Grubbs, R. H., et al. J. Am. Chem. Soc. 1997, 119, 3887-3897

13. 13 Metathesis - Catalytic Cycle Dissociative 16e - pathway found to be dominant (~95%) Grubbs, R. H., et al. J. Am. Chem. Soc. 1997, 119, 3887-3897

14. 14 Metathesis - Catalysts Chris Kendall, Literature Meeting March 20 2006

15. 15 Metathesis - Tandem Reactions Grubbs, R. H., et al. J. Am. Chem. Soc. 2003, 125, 11360 Grubbs, R. H., et al. Angew. Chem. Int. Ed. 2002, 41, 807 Cossy, J., et al.Org. Lett. 2003, 5, 459

16. 16 Marc L. Snapper EDUCATION AND EXPERIENCE UNION COLLEGE, Schenectady, New York 1976-1980 B.S., Chemistry/Biology STERLING ORGANICS, Division of Sterling Drug, Rensselaer, New York 1980-1984 Research Chemist STANFORD UNIVERSITY, Stanford, California 1984-1990 Ph.D., Organic Chemistry, Advisor: Professor Paul A. Wender HARVARD UNIVERSITY, Cambridge, Massachusetts 1990-1993 NIH Postdoctoral Fellow, Advisor: Professor Stuart L. Schreiber BOSTON COLLEGE, Chestnut Hill, Massachusetts 1993-1999 Assistant Professor of Chemistry 1999- Professor of Chemistry HONORS AND AWARDS 1999-2001 Glaxo Wellcome Chemistry Scholar Award 1999-2000 Boston College Distinguished Research Award 1998-2001 Camille Dreyfus Teacher-Scholar Award 1998-2000 Alfred P. Sloan Research Fellowship 1998-1999 DuPont Young Professor Award 1997-1999 Lilly Grantee Award 1997-2000 National Science Foundation CAREER Development Award 1997-1998 Boston College Teaching Development Award 1996-1997 Boston College Faculty Fellowship 1995-1997 Massachusetts Breast Cancer Research Fellowship 1995-1996 Boston College Distinguished Junior Faculty Award 1990-1993 National Institutes of Health, NCI Postdoctoral Fellowship 1990-1991 Merck Postdoctoral Fellowship

17. 17 Snapper Research And obviously Tandem Metathesis!!!!!

18. 18 Metathesis - Cope Rearrangement Applied to the synthesis of +/- Asteriscanolide 9 step synthesis with the key step involving a tandem metathesis/Cope Rearrangement Had previously done a similar transformation, but not in tandem Snapper, M. L., et al. J. Am. Chem. Soc. 2000, 122, 8071-8072 Snapper, M. L., et al. J. Am. Chem. Soc. 1997, 119, 1478-1479

19. 19 Metathesis - Cope Rearrangement Snapper, M. L., et al. J. Am. Chem. Soc. 2000, 122, 8071-8072

20. 20 Metathesis - Cope Rearrangement Snapper, M. L., et al. J. Am. Chem. Soc. 2000, 122, 8071-8072 Key is a tandem reaction Cope occurs under relatively mild conditions Reason this occurs due to the absence of an alkyl group

21. 21 RCM Metathesis - Olefin Isomerization Snapper, M. L., et al. J. Am. Chem. Soc. 2002, 124, 13390-13391 Grubbs’ catalyst, in addition to metathesis, has been known to undergo hydrogenation Occassionally noted that isomerization could interfere with metathesis Explored the possibility of combining the two reactions

22. 22 RCM Metathesis - Olefin Isomerization Snapper, M. L., et al. J. Am. Chem. Soc. 2002, 124, 13390-13391 Found that 95/5 N 2 /H 2 was optimal hydride source Unsure the the hydride - Ru species 22

23. 23 RCM Metathesis - Olefin Isomerization Snapper, M. L., et al. J. Am. Chem. Soc. 2002, 124, 13390-13391

24. 24 RCM - Kharasch Addition Snapper, M. L., et al. J. Am. Chem. Soc. 2005, 127, 16329-16332 Kharasch reaction is a radical atom transfer reaction Earlier Snapper demonstrated that Grubbs I can promote the transformation Kharasch, M.S., et al. Science 1945, 102, 128 Snapper, M. L., et al. Tetrahedron 2004, 60, 7391-7396

25. 25 RCM - Kharasch Addition Snapper, M. L., et al. J. Am. Chem. Soc. 2005, 127, 16329-16332 Reaction was performed on cyclic substrates

26. 26 RCM - Kharasch Addition Snapper, M. L., et al. J. Am. Chem. Soc. 2005, 127, 16329-16332

27. 27 RCM - Kharasch Addition Snapper, M. L., et al. J. Am. Chem. Soc. 2005, 127, 16329-16332 Double Kharasch could be performed generating bicyclic products with 3 adjoining double bonds

28. 28 Enyne Metathesis - Cyclopropanation Snapper, M. L., et al. J. Am. Chem. Soc. 2006, 128, 52-53

29. 29 Enyne Metathesis - Cyclopropanation Snapper, M. L., et al. J. Am. Chem. Soc. 2006, 128, 52-53 29

30. 30 Enyne Metathesis - Cyclopropanation Reaction complimentary to that reported by Dixneuf Snapper, M. L., et al. J. Am. Chem. Soc. 2006, 128, 52-53 Dixneuf, P. H., et al. Org. Lett. 2005, 7, 3741-3743

31. 31 CM - Allylic Alcohol Isomerization Snapper, M. L., et al. Org. Lett. 2006, 8, 2603-2606 Quayle, P., et al. Synlett 2005, 572-576 Werner, H., et al. Organometallics 2003, 22, 1558-1560

32. 32 CM - Allylic Alcohol Isomerization Snapper, M. L., et al. Org. Lett. 2006, 8, 2603-2606 Ketones prevent over reduction 32

33. 33 CM - Allylic Alcohol Isomerization Snapper, M. L., et al. Org. Lett. 2006, 8, 2603-2606

34. 34 Metathesis - Oxidation Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762 Plietker, B., J. Org. Chem. 2003, 68, 7123-7125

35. 35 Metathesis - Oxidation Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762 Plietker, B., et al. J. Org. Chem. 2005, 70, 2402-2405

36. 36 Metathesis - Oxidation Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762

37. 37 Metathesis - Oxidation Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762

38. 38 Metathesis - Oxidation Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762

39. 39 Metathesis - Oxidation Snapper, M. L., et al. Org. Lett. 2006, 8, 4759-4762

40. 40 CM - Wittig Olefination Snapper, M. L., et al. Org. Lett. 2007, 9, 1749-1752 Lebel, H., et al. J. Am. Chem. Soc. 2004, 126, 320-328 Fujimura, O., et al. Tetrahedron 1998, 39, 625

41. 41 CM - Wittig Olefination Snapper, M. L., et al. Org. Lett. 2007, 9, 1749-1752

42. 42 Conclusions Advantages of tandem reactions are obvious Economics Environment Time Though individual reactions may not be interesting, finding methodology of combining them is Still much work to be done on the development on tandem chemistry............. Nature’s still way ahead of us