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

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

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

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,

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,

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

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

The key reference Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 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, Chris Kendall, Literature Meeting March

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,

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

14 Metathesis - Catalysts Chris Kendall, Literature Meeting March

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

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

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

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, Snapper, M. L., et al. J. Am. Chem. Soc. 1997, 119,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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