1. Recent Developments and Applications in Enantioselective Desymmetrisation Xin Linghu Department of Chemistry University of North Carolina, Chapel Hill

2. Outline Introduction Enantioselective Desymmetrisation of Different Functional Groups Cyclic anhydrides Epoxides Aldehydes and Ketones Alkenes Diols Summary Acknowledgement

3. Introduction to Enantioselective Desymmetrisation

4. Enantioselective Desymmetrisation in Total Synthesis 1987, Schreiber: 1992, Harada:

5. Enantioselective Desymmetrisation of Cyclic Anhydride: Previous Work 1985, Oda: 1999, Bolm: 1995, Seebach: RC-8C-9 HRScinchonine HSRcinchonidine OMeSRquinine OMeRSquinidine configuration

6. Formation of C-X Bond via Anhydrides Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542-9543.

7. Formation of C-C Bond via Anhydrides Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 174-175.

8. Formation of C-C Bond via Anhydrides entryligand% eeyield (%) 1(+)-1176 2(+)-21276 3(+)-33266 4(-)-43977 5(-)-58863 Shintani, R.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 1057-1059.

9. Formation of C-C Bond via Anhydrides Shintani, R.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 1057-1059. entryArMgX% eeyield (%) 1PhMgCl9291 2p-MeOC 6 H 4 MgBr8988 3p-FC 6 H 4 MgBr7882 4o-TolMgCl3766

10. Enantioselective Desymmetrisation of Epoxides: Previous Work

11. Cat. (10 mol), 4A MS

12. Enantioselective Ring Opening Catalyzed by Planar-Chiral Pyridine N-Oxides Tao, B.; Lo, M. M. C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 353-354. catalysttemp% ee Art11 Brt25 B -78°C60 Crt68 C-78°C92 entryRyield (%)% ee 1Ph8894 24-FC 6 H 4 9791 34-CH 3 C 6 H 4 9493 44-CF 3 C 6 H 4 9398 52-naphthyl8494 6CH 2 OBn9150

13. Enantioselective Ring Opening Catalyzed by Chiral Bipyridine N,N’-Dioxide Derivatives entryRyield (%)% ee (confgn) 1Ph9590 2CH 2 OCH 2 Ph9874 3CH 2 O(CH 2 ) 3 Ph9570 4-(CH 2 ) 4 -830 Nakajima, M.; Saito, M.; Uemura, M.; Hashimoto, S. Tetrahedron Lett. 2002, 43, 8827-8829.

14. Asymmetric Ring Opening with TMSCN Catalyzed by (pybox)Yb Complexes entrysubstrateligandtemp (°C)time (d)yield (%) % ee (confgn) 1(S,S)-b-45490 91 (1S, 2R) 2(S,S)-a-10783 92 (1R, 2S) 3(S,S)-b-40780 90 (2S, 3R) 4(S,S)-a0786 83 (1R, 3S, 4R) 5(S,S)-a-10772 87 (3R, 4R) Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001-1004.

15. Enantioselective Alkylation of Vinyloxiranes 121211 yield (%)928680687890 % ee663785767197 S N 2’/S N 2>99/198/287/1375/2593/798/2 Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.; Feringa, B. L. Org. Lett. 2000, 2, 933-936.

16. Desymmetrisation by Enantioselective Deprotonation Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361-14384.

17. Enantioselective  -Deprotonation of Epoxides: Previous Work 1996, Hodgson:

18. Enantioselective  -Deprotonation of Epoxides: Previous Work 1980, Whitesell and Felman: 1993, Milne and Murphy: 1998, Andersson:

19. Enantioselective Alkylative Double Ring Opening of Epoxides Hodgson, D. M.; Maxwell, C. R.; Miles, T. J.; Paruch, E.; Stent, M. A. H.; Matthews, I. R.; Wilson, F. X.; Witherington, J. Angew. Chem. Int. Ed. 2002, 41, 4313-4316.

20. Enantioselective Alkylative Double Ring Opening of Epoxides Hodgson, D. M.; Maxwell, C. R.; Miles, T. J.; Paruch, E.; Stent, M. A. H.; Matthews, I. R.; Wilson, F. X.; Witherington, J. Angew. Chem. Int. Ed. 2002, 41, 4313-4316.

21.  -Deprotonated Epoxides as Nucleophiles entryEyield (%)% ee 1TMS7274 2SnBu 3 6079 3PhCH(OH)8076 4PhCO6877 5Et 2 C(OH)7577 6EtCH(OH)7476 7EtCO6778 8EtOCO5881 Hodgson, D. M.; Gras, E. Angew. Chem. Int. Ed. 2002, 41, 2376-2378.

22. First Desymmetrisation of Centrosymmetric Diepoxide in Natural Product Synthesis Holland, J. M.; Lewis, M.; Nelson, A. Angew. Chem. Int. Ed. 2001, 40, 4082-4084.

23. First Desymmetrisation of Centrosymmetric Diepoxide in Natural Product Synthesis

24. Enantioselective Desymmetrisation of Ketones and Aldehydes: Previous Work 1990, Roush: 1998, Takemoto: 1998, Arai and Shioiri: 1984, Hanessian:

25. Enantioselective Desymmetrisation of Ketones and Aldehydes: Previous Work 1997, Bolm: 1995, Aubé : 1998, Ward:

26. Enantioselective Baeyer-Villiger Oxidations by Transition Metal Catalysis Uchida, T.; Katsuki, T.; Ito, K.; Akashi, S.; Ishii, A.; Kuroda, T. Helv. Chim. Acta 2002, 85, 3078-3089. Watanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43, 4481-4485.

27. Enantioselective Baeyer-Villiger Oxidations by Organocatalysis entryRyield (%)% ee 14-MeOC 6 H 4 6761(+) 24-MeC 6 H 4 5362(+) 3Ph6763(S) 44-BrC 6 H 4 2868(+) 54-ClC 6 H 4 3466(S) 64-FC 6 H 4 5565(+) Murahashi, S.-I.; Ono, S.; Imada, Y. Angew. Chem. Int. Ed. 2002, 41, 2366-2368.

28. Rhodium-Catalyzed Desymmetrisation of 4-Alkynals entryRyield (%)% ee 1n-C 5 H 11 9592 2Cy9495 3(CH 2 ) 3 Cl91 4CH 2 OMe9382 Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10296-10297.

29. Enantioselective Reduction of 2-Alkyl-1,3-diketones Ohtsuka, Y.; Koyasu, K.; Ikeno, T.; Yamada, T. Org. Lett. 2001, 3, 2543-2546.

30. Synthesis of a Potential Intermediate for Pseudomonic Acid B Honda, T.; Kimura, N. Org. Lett. 2002, 4, 4567-4570.

31. 1987, Schreiber: 1996, Landais: 1990, Ito: Enantioselective Desymmetrisation of Alkenes: Previous Work

32. 1985, Whitesell: 1994, Martin: 1992, Mikami: Enantioselective Desymmetrisation of Alkenes: Previous Work

33. 1998, Schrock and Hoveyda:

34. Preparation of Cyclic Amines Through Mo- Catalyzed Asymmetric RCM entryArcat.yield (%)% ee 1Pha7898 2p-OMePha8197 3p-BrPha8198 4o-OMePhb7784 5o-BrPhb9082 Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991-6997.

35. Enantioselective Ru-Catalyzed RCM Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225-3228.

36. Enantioselective Ru-Catalyzed RCM

37. Weatherhead, G. S.; Ford, J. G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 1828-1829. Tandem Catalytic Asymmetric ROM/RCM

38. Weatherhead, G. S.; Ford, J. G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 1828-1829. Tandem Catalytic Asymmetric ROM/RCM

39. Desymmetrisation of Meso Bicyclic Hydrazines by Enantioselective Hydroboration entryRyield (%)% ee 1CO 2 Et4983 2CO 2 Bn9084 3CO 2 Bu5880 4-CONPhCO-7860 Luna, A. P.; Ceschi, M. A.; Bonin, M.; Micouin, L.; Husson, H. P.; Gougeon, S.; Estenne-Bouhtou, G.; Marabout, B.; Sevrin, M.; George, P. J. Org. Chem. 2002, 67, 3522-3524.

40. Luna, A. P.; Ceschi, M. A.; Bonin, M.; Micouin, L.; Husson, H. P.; Gougeon, S.; Estenne-Bouhtou, G.; Marabout, B.; Sevrin, M.; George, P. J. Org. Chem. 2002, 67, 3522-3524. Desymmetrisation of Meso Bicyclic Hydrazines by Enantioselective Hydroboration

41. Asymmetric Synthesis of Polyhydroxylated Celastraceae Sesquiterpene Cores Spivey, A. C.; Woodhead, S. J.; Weston, M.; Andrews, B. I. Angew. Chem. Int. Ed. 2001, 40, 769-771.

42. Enantioselective Desymmetrisation of Meso- Decalin Diallylic Alcohols by Zr-Based SAE Spivey, A. C.; Woodhead, S. J.; Weston, M.; Andrews, B. I. Angew. Chem. Int. Ed. 2001, 40, 769-771.

43. 1998, Oriyama: 1998, Fu: 1996, Trost: Enantioselective Desymmetrisation of Diols: Previous Work

44. 1997, Fujioka: 1997, Harada: Enantioselective Desymmetrisation of Diols: Previous Work

45. Pd-Catalyzed Enantioselective Oxidation Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475-7476.

46. Asymmetric Oxidation of Meso-Diols under Photo-Irradiation entrysubstrateyield (%)% eeconfign 1a49591R, 4S 2b57651R, 5S 3c6463- 4d66 1R, 6S Shimizu, H.; Nakata, K.; Katsuki, T. Chem. Lett. 2002, 1080-1081.

47. Enantioselective Desymmetrisation of Meso Cyclic Allylic Bisdiethylphosphate entryR1R1 R2R2 R3R3 a/ba/byield (%) 1iBuCHPh 2 3-Ph94:654 2iBuCHPh 2 3,5-Cl 2 94:647 3iBuCHPh 2 3,5-tBu 2 87:1342 4MeCHPh 2 3,5-Cl 2 86:1462 5iBuCHPh 2 H84:1654 6iBuCHPh 2 5,6-(CH) 4 -83:1749 7MeCHPh 2 H31:6913 8iPrCHPh 2 H30:7012 9tBu(R)-CH(Me)CyH24:7626 Piarulli, U.; Daubos, P.; Claverie, C; Roux, M; Gennari, C. Angew. Chem. Int. Ed. 2003, 42, 234-236.

48. Pd-Catalyzed Enantioselective Ring Opening with Dialkylzinc entryRR1R1 R2R2 yield (%) % ee 1MeHF8790 2Me Br6790 3Me H7689 4MeHO(CH 2 )O8591 5EtHF8992 6EtHO(CH 2 )O9192 Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000, 122, 1804-1805.

49. Rh-Catalyzed Enantioselective Ring Opening with Organoboronic Acids entryXyield (%)% ee 14-Me8895 2None9195 32-Men.r.- 44-Cl95 53-Cl7399 62-Cln.r.- 73-I8595 84-Ac7194 94-OMe8796 103-OMe9195 Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311-1314.

50. Desymmetrisation of Diols with a Dinuclear Zinc Asymmetric Catalyst Trost, B. M.; Mino, T. J. Am. Chem. Soc. ASAP

51. Summary Previous works on the enantioselective desymmetrisation have been introduced briefly according to different functional groups Recent developments in the enantioselective desymmetrisation have been surveyed based on different functional groups Recent applications of enantioselective desymmetrisation in natural products synthesis have been shown

52. Acknowledgement Dr. Jeffrey Johnson Johnson group