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,

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,

17. PRELIMINARY RESULTS Substrate Yield (%) ee (%) 81 90 84 87
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 Substrate Catalyst 3 eq Oxone 5 eq, pH 7-8
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
Catalyst 0.3 eq
oxone 1.4 eq, pH 10-11
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. Access to disubstituted geminal alkenes via
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. Improvement through catalyst design
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. Effect the substituent -OMe -Me -SO2Me p-NO2 o-NO2 ee (%) 83 84 90 78
FURTHER RESULTS
Effect the substituent
-OMe
-Me
-SO2Me
p-NO2
o-NO2
ee (%) 83 84 90 78
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