ASYMMETRIC EPOXIDATION OF OLEFINS BY SHI’S CATALYST AND SYNTHESIS OF CRYPTOPHYCIN 52

1. ASYMMETRIC EPOXIDATION OF OLEFINS BY SHI’S CATALYST AND SYNTHESIS OF CRYPTOPHYCIN 52 1st seminar Patrick Beaulieu October 30, 2003

2. OUTLINE

3. REAGENTS FOR EPOXIDATION PERACIDS Prilezhaev reaction Stereospecific syn addition

4. EPOXIDATION CATALYZED BY METAL 1- Peroxide metal complex Metal most frequently used : V, Ti High enantioselectivity with allylic alcohols Sharpless, K. B.J. Am. Chem. Soc. 1987, 109, 5765

5. 2- Oxo-based catalysts (M=O) Jacobsen-Katsuki catalyst Excellent for cis and trisubstituted olefins Poor ee obtained with trans substrates Jacobsen, E. N.J. Org. Chem. 1994, 59, 4378

6. DIOXIRANES byproduct Stereospecific syn addition Oxone : KHSO5.KHSO4.K2SO4 Yang, D.J. Am. Chem. Soc. 1996, 118, 11311

7. Generation of Dioxiranes → Isolated species 0.1M solution for DMDO 0.8M solution for TFDO → In situ generation Excess of oxone, NaHCO3 buffer at pH 7-8, in biphasic (CH2Cl2/H2O) or monophasic (CH3CN/H2O) conditions Organic syntheses, CV 9, 288

8. MECHANISM OF GENERATION AND REACTION WITH OLEFINS Edwards, J. O.Photochem. Photobiol. 1979, 30, 63 Shi, Y.J. Org. Chem.1998, 63, 6425-6426

9. NOVEL METHODOLOGIE Hydroden peroxide as primary oxidant → The solvent must be a nitrile → Big advantages for process chemistry * Less solvent required * Less salts introduced Bach, R. D.J. Org. Chem. 1983, 48, 888 Shi, Y.Tetrahedron 2001, 57, 5213

10. MECHANISTIC BACKGROUND FMO

11. TRANSITION STATE Planar Spiro Evidence for spiro mode 1- Experimental observation Epoxidation of cis alkene is 8.3 times faster Peracids have the same reactivity for both alkenes Baumstark, A. L.J. Org. Chem. 1988, 53, 3437

12. 2- Steric hindrence Cis alkene Trans alkene

13. 3- Computer calculation Stabilization with the oxygene electron lone pairs and the LUMO 7.4 Kcal/mol more stable Houk. K. N.J. Am. Chem. Soc. 1997, 119, 10147

14. ASYMMETRIC EPOXIDATION WITH DIOXIRANES First examples Low conversion Days to 1 week reaction 9-12.5% ee High conversion 24h-48h reaction 13-20% ee Curci, R.J. Chem. Soc; Chem. Commun. 1984, 155 Curci, R.Tet. Lett. 1995, 36, 5831

15. MAJOR BREAKTROUGH THE SHI’S CATALYST Epoxidation of olefins mediated by a fructose-derived ketone → Preparation of the D-enantiomer Commercially available : 106$ / 5g The enantiomer is prepared from a 5 steps procedure from L-sorbose Sugai, S.Tetrahedron, 1991, 47, 2133

16. → Preparation of the L-enantiomer Whistler, R. L.Carbohydr. Res. 1988, 175, 265-271

17. PRELIMINARY RESULTS Shi, Y.J. Am. Chem. Soc.1996, 118, 9806

18. OPTIMIZATION TOWARDS A ROBUST CATALYTIC CYCLE

19. KETONE CONFIGURATION Hydrate form ? Added steric hindrence?

20. pH EFFECT → Autodecompositon of oxone → Catalyst stability

21. pH EFFECT Shi, Y.J. Am. Chem. Soc. 1997, 46, 11224

22. KETONE REACTIVITY → Background reaction with oxone → Catalyst decomposition with oxone

23. THE BAYER-VILLIGER

24. THE BAYER-VILLIGER Shi, Y.J. Org. Chem. 2001, 66, 521

25. OPTIMIZED RESULTS Shi, Y.J. Am. Chem. Soc.1997, 119, 11224

26. OPTIMIZED RESULTS 82%, 95% ee 94%, 98% ee 94%, 89% ee Shi, Y.J. Am. Chem. Soc.1997, 119, 11224

27. CONJUGAISON EFFECT ON ENANTIOSELECTIVTY FMO

28. ORIGINE OF THE ENANTIOSELECTIVITY Major

29. ORIGINE OF THE ENANTIOSELECTIVITY Minor

30. ENERGY OF THE SPIRO TRANSITION STATE 0oC 78%, 98% ee 0oC

31. DRAWBACK → Low enantioselectivity with cis and terminal olefins 95%, 20% ee 90%, 24% ee 43%, 61% ee → Competition between spiro and planar transition state Shi, Y.J. Am. Chem. Soc.1997, 119, 11224

32. A LOOK AT THE TRANSITION STATE → The poor differentiation in the TS results in lower ee → A different approach or catalyst was then required

33. SOLUTION #1 Access to disubstituted geminal alkenes via 2,2-disubstituted vinylsilanes Murai, S.J. Org. Chem.1995, 60, 1834 Shi, Y.J. Org. Chem.1999, 64, 7675

34. SOLUTION #2 Improvement through catalyst design Effect of the spiro Five membered ring ketal Electronic attraction between Ph and NBOC group Shi, Y. J. Org. Chem.2002, 67, 2435

35. AN INTRIGUING REVERSE IN STEREOSELECTIVITY!

36. FURTHER RESULTS Effect the substituent Shi, Y.Org. Lett.2003, 5, 293

37. SYNTHESIS OF 2ND GENERATION SHI’S CATALYST Shi, Y.J. Org. Chem. 2003, 68, 4963

39. SUMMARY

40. TOTAL SYSTHESIS OF CRYPTOPHYCIN 52 • Natural product isolated from blue-green algae • Cryptophycin 1 exhibits a broad spectrum of antitumor activity in mice • First synthezised by Kitigawa in 1994 and than by Moore and Tius in 1995 • Cryptophycin 52 is in advanced clinical evaluation for the treatment of solid tumors • An improve synthesis done by the Eli Lilly research group in 2002

42. RETROSYNTHESIS

43. BLUE FRAGMENT SYNTHESIS

44. COUPLING OF BLUE AND RED FRAGMENTS

45. SHI EPOXIDATION

46. TRANSITION STATE OF EPOXIDATION

47. BLACK FRAGMENT SYNTHESIS

49. ACKNOWLEDGEMENTS Bill Ogilvie Livia Aumond Myra Bertrand Val Charbonneau Ami Jun-Yee Chin Josée Cloutier Heather Foucault Joseph Jebreen Marc Lafrance Alison Lemay Mathieu Lemay Joseph Moran