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Gregory C. Fu

“From Planarity to Chirality ” The research work of Gregory C. Fu by Maude Poirier October 2 nd , 2007. Gregory C. Fu. 1963 Born in Galion, Ohio 1984-1985 Researcher with Professor K. Barry Sharpless    MIT 1985-1991 Graduate student with Professor David A. Evans    Harvard University

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Gregory C. Fu

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  1. “From Planarity to Chirality”The research work of Gregory C. FubyMaude PoirierOctober 2nd, 2007

  2. Gregory C. Fu • 1963 Born in Galion, Ohio • 1984-1985 Researcher with Professor K. Barry Sharpless   MIT • 1985-1991Graduate student with Professor David A. Evans   Harvard University • 1991-1993 Postdoctoral fellow with Professor Robert H. Grubbs   CALTECH • 1993-1996 Assistant Professor of Chemistry   MIT • 1996-1998 Firmenich Assistant Professor of Chemistry   MIT • 1998-1999 Firmenich Associate Professor of Chemistry   MIT • 1999-present Professor of Chemistry   MIT

  3. Gregory C. Fu • 1963 Born in Galion, Ohio • 1984-1985 Researcher with Professor K. Barry Sharpless   MIT • 1985-1991Graduate student with Professor David A. Evans   Harvard University • 1991-1993 Postdoctoral fellow with Professor Robert H. Grubbs   CALTECH • 1993-1996 Assistant Professor of Chemistry   MIT • 1996-1998 Firmenich Assistant Professor of Chemistry   MIT • 1998-1999 Firmenich Associate Professor of Chemistry   MIT • 1999-present Professor of Chemistry   MIT

  4. Gregory C. Fu • 2007 Fellow, American Academy of Arts and Sciences • 2007 Catalysis Science Award, Mitsui Chemicals   • 2006 Mukaiyama Award, Society of Synthetic Organic Chemistry of Japan   • 2005 Fellow, Royal Society of Chemistry • 2004 Corey Award, American Chemical Society   • 2001 Springer Award in Organometallic Chemistry • 2000 School of Science Undergraduate Teaching Prize, Massachusetts Institute of Technology  • 2000 Chan Memorial Award in Organic Chemistry • 1999 Innovation Recognition Award, Union Carbide  • 1998 Bristol-Myers Squibb Award • 1998 Cope Scholar Award, American Chemical Society  • 1998 Synthetic Organic Chemistry Award, Pfizer  • 1997 Camille Dreyfus Teacher-Scholar Award • 1997 Alfred P. Sloan Research Fellow • 1997 Chemistry Scholar Award, Glaxo Wellcome  • 1996 Lilly Grantee Award, Eli Lilly  • 1996 Cottrell Scholar Award, Research Corporation  • 1995 American Cancer SocietyJunior Faculty Research Award • 1994 National Science FoundationYoung Investigator Award • 1993 Camille and Henry Dreyfus FoundationNew Faculty Award

  5. What is planar chirality ? • Chirality in molecules devoid of chiral centers 1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem.2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed.2006, 45, 968-973. 2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol.2007, 20, 1046-1052.

  6. What is planar chirality ? • Chirality in molecules devoid of chiral centers 1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem.2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed.2006, 45, 968-973. 2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol.2007, 20, 1046-1052.

  7. What is planar chirality ? • Chirality in molecules devoid of chiral centers 1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem.2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed.2006, 45, 968-973. 2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol.2007, 20, 1046-1052.

  8. What is planar chirality ? • Chirality in molecules devoid of chiral centers 1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem.2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed.2006, 45, 968-973. 2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol.2007, 20, 1046-1052.

  9. Nucleophilic catalyst development G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420.

  10. Nucleophilic catalyst development • Should be electron rich, enhancing the nucleophilicity of the catalyst • It’s steric environment should be tunable • Should lead to robust planar-chiral complexes for maximum versatility and for ease of handling G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420.

  11. Planar-Chiral nucleophilic catalyst synthesis G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420. J. C. Ruble, G. C. Fu, J. Org. Chem. 1996, 61, 7230-7231.

  12. Kinetic resolution, basic principles • Enantiomers react at different rates with other chiral compounds • The more theses rates are fart appart the better is • Selectivity factor s : k( fast-reacting enantiomer ) k( slow-reacting enantiomer ) ^ S = 10 For a review on kinetic resolution, see: H. B. Kagan, J. C. Flaud, Top. Stereochemi. 1988, 18, 249-330.

  13. Kinetic resolution, basic principles DG Rxn coordinates

  14. Kinetic Resolution of Secondary Alcohols • J. C. Ruble, H. A. Latham, G. C. Fu, J. Am. Chem. Soc.1997, 119, 1492-1493. • J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem.1998, 63, 2794-2795. • B. Tao, J. C. Ruble, D. A. Holc, G. C. Fu, J. Am. Chem. Soc,1999, 121, 5091-5092.

  15. Kinetic Resolution of Secondary Alcohols G. C. Fu, Acc. Chem. Res. 2000, 33, 412-420.

  16. Synthesis of Kagan’s ether analogue 1) M. Harmata, M. Kahraman, J. Org. Chem. 1999, 64, 4949-4952.

  17. Kinetic Resolution of Allylic Alcohols • J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem. 1998, 63, 2794-2795. • S. Bellemen-Laponnaz, J. Tweddell, J. C. Ruble, F. M. Breitling, G. C. Fu, Chem. Commun. 2000, 1009-1010.

  18. Epothilone A synthesis 1) S. Bellemen-Laponnaz, J. Tweddell, J. C. Ruble, F. M. Breitling, G. C. Fu, Chem. Commun. 2000, 1009-1010. 2) For the synthesis of Epothilone A, see: S. C. Sinha, C. F. Barbas, III and R. A. Lerner, Proc. Natl. Acad. Sci. USA,1998, 95, 14603.

  19. Epothilone A synthesis 1) S. Bellemen-Laponnaz, J. Tweddell, J. C. Ruble, F. M. Breitling, G. C. Fu, Chem. Commun. 2000, 1009-1010. 2) For the synthesis of Epothilone A, see: S. C. Sinha, C. F. Barbas, III and R. A. Lerner, Proc. Natl. Acad. Sci. USA,1998, 95, 14603.

  20. Kinetic Resolution of Secondary Amines 1) S. Arai, S. Bellemin-Laponnaz, G. C. Fu, Angew. Chem. Int. Ed. 2001, 40, 234-236.

  21. Asymmetric nucleophilic catalysist: Planar-chiral heterocycles B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc.1999, 121, 2637-2638.

  22. Asymmetric nucleophilic catalysist: Planar-chiral heterocycles B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc.1999, 121, 2637-2638.

  23. Asymmetric nucleophilic catalysist: Planar-chiral heterocycles B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc.1999, 121, 2637-2638.

  24. Asymmetric nucleophilic catalysist: Planar-chiral heterocycles B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc.1999, 121, 2637-2638.

  25. Asymmetric Staudinger synthesis of b-lactams 1) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc.2002, 124, 1578-1579. 2) E. C. Lee, B. L. Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586-11587.

  26. Asymmetric Staudinger synthesis of b-lactams 1) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc.2002, 124, 1578-1579. 2) E. C. Lee, B. L. Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586-11587.

  27. Asymmetric Staudinger synthesis of b-lactams 1) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc.2002, 124, 1578-1579. 2) E. C. Lee, B. L. Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586-11587.

  28. Building quaternary centers Steglich rearrangement 1) W. Steglich, G. Hofle, Tetrahedron Lett. 1970, 4727-4730. 2) For a review of asymmetric synthesis of quaternary stereocenter, see: E. J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed. 1998, 37, 388-401. 3) For an overview on the synthesis and significance of a-alkylated a-amino acids, see: T. Wirth, Angew. Chem. Int. Ed. 1997, 36, 225-227.

  29. Rearrangement of O-Acylation azlactone 1) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 11532-11533. 2) J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem, 1998, 63, 3154-3155.

  30. Rearrangement of O-Acylation azlactone 1) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 11532-11533. 2) J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem, 1998, 63, 3154-3155.

  31. Building quaternary centers: synthesis of oxindoles and benzofuranones I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.

  32. Building quaternary centers: synthesis of oxindoles and benzofuranones I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.

  33. Building quaternary centers: synthesis of oxindoles and benzofuranones I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.

  34. Building quaternary centers: synthesis of b-ketoesters A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc.2005, 127, 5604-5607.

  35. Building quaternary centers: synthesis of b-ketoesters A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc.2005, 127, 5604-5607.

  36. Building quaternary centers: synthesis of b-ketoesters Mechanistic studies A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc.2005, 127, 5604-5607.

  37. Building quaternary centers: synthesis of b-ketoesters Mechanistic studies A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc.2005, 127, 5604-5607.

  38. Building quaternary centers: synthesis of b-ketoesters Mechanistic studies A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc.2005, 127, 5604-5607.

  39. Building quaternary centers: synthesis of b-ketoesters Mechanistic studies A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc.2005, 127, 5604-5607.

  40. Planar-chiral Brønsted Acid catalyst B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.

  41. Planar-chiral Brønsted Acid catalyst B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.

  42. Planar-chiral Brønsted Acid catalyst B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.

  43. Planar-chiral Brønsted Acid catalyst • Support for a Brønsted-acid mechanism: • Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair. • The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes. • The ee of the product is inversely proportional to the concentration of the reaction. • Stereochemical outcome of the reaction can be explained by this pathway. G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.

  44. Planar-chiral Brønsted Acid catalyst • Support for a Brønsted-acid mechanism: • Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair. • The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes. • The ee of the product is inversely proportional to the concentration of the reaction. • Stereochemical outcome of the reaction can be explained by this pathway. G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.

  45. Planar-chiral Brønsted Acid catalyst • Support for a Brønsted-acid mechanism: • Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair. • The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes. • The ee of the product is inversely proportional to the concentration of the reaction. • Stereochemical outcome of the reaction can be explained by this pathway. G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.

  46. Planar-chiral Brønsted Acid catalyst • Support for a Brønsted-acid mechanism: • Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair. • The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes. • The ee of the product is inversely proportional to the concentration of the reaction. • Stereochemical outcome of the reaction can be explained by this pathway. G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.

  47. Planar-chiral Brønsted Acid catalyst S. L. Wiskur, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 6176-6177.

  48. Planar-chiral Brønsted Acid catalyst K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.

  49. Planar-chiral Brønsted Acid catalyst K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.

  50. Planar-chiral Brønsted Acid catalyst K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.

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