1. 中国科学院大连化学物理研究所 万伯顺 新型手性 SAA 配体的设计合成 与应用研究 第五届全国有机化学学术讨论会报告，郑州大学

2. (S)-(+)-thalidomide (R)-(+)-thalidomide （镇静剂和止吐剂） 致畸剂 手性与人类健康 :“ 反应停 ” 悲剧 http://www.chirality.ouvaton.org/homepage.htm

3. Examples of privileged chiral ligands Diels-Alder Mukaiyama aldol aldehyde allylation hydrogenation alkene isomerization Heck reaction hydrogenation hydrophosphination hydroacylation hydrosilylation Bayer-Villager oxidation Diels-Alder aldehyde allylation ester alcoholysis iodolactonization alkene reduction imine reduction Ziegler-Natta polymerization Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691

4. epoxidation epoxide ring-opening Diels-Alder imine cyanation conjugate addition Diels-Alder Mukaiyama aldol conjugate addition cyclopropanation aziridination dihydroxylation acylation heterogeneous hydrogenation phase transfer catalysis Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691 Examples of privileged chiral ligands

5. Thinking……  Catalysts: chiral ligands a.Cost b.Availability “Readily available catalysts for simplifying asymmetric reactions” Our consideration

6. Idea for development of chiral ligands Development of easily available and readily tunable ligands using multicenter and grafting strategy Derived from readily and commercially available chiral starting chemicals

7. Novel Sulfamide-Amine Alcohol Ligands (SAA) Application of Grafting Strategy Boshun Wan*, J. Org. Chem. 2004, 69, 9123

8. Synthetic route of Ts-Based SAA Ligand

9. Ts-Based SAA ligands

10. 1. The size of the fluxional group R is a primary determinant of enantioselectivies ? 2. What is the difference effect of R 1, and X …? New Ms,Tf-Based SAA ligands

11. New Tf-Based SAA ligands

12. New Ms-Based SAA ligands

13. 1 Asymmetric addition of diethylzinc to aldhydes Application of Reactions 2 Asymmetric addition of phenylacetylene to aldehydes 4 Asymmetric hydrogenation transfer reaction 3 Asymmetric addition of phenylacetylene to ketones

14. How about SAA ligands? 1. Asymmetric addition of diethylzinc to aldhydes Figure: Chiral sulfonamide-type ligands using Ti(O i Pr) 4 for dialkylzinc addition to aldehyde.

15. Pu, L.; Yu, H,-B. Chem. Rev. 2001, 101, 757. Our idea 1. Asymmetric addition of diethylzinc to aldhydes

16. (S)(S) (R)(R)

17. Comparisons 1. Asymmetric addition of diethylzinc to aldhydes

18. entryligandR % isolated yield % ee 17bPh86>99 (R) 24o-Cl-Ph74>99 (S) 341-naphthyl70>99 (S) 47bo-Cl-Ph92>99 (R) 57b1-naphthyl70>99 (R) 64c-C 6 H 11 51>99 (S) 77bi-C 4 H 9 36>99 (R) 1. Asymmetric addition of diethylzinc to aldhydes

19. Summary-1 Boshun Wan*, J. Org. Chem. 2004, 69, 9123

20. Zn + Ligand Ti + Zn + Ligand Characteristics: 2. Asymmetric addition of phenylacetylene to aldehydes Reviews see: (a) Tetrahedron 2003, 59, 9873 (b) Eur. J. Org. Chem. 2004, 4095

21. (a) T. Mukaiyama* et al, Chem. Lett. 1979, 447; (b) E. J. Corey* et al, J. Am. Chem. Soc.1994, 116,3151; (c) E.M. Carreira* et al, J. Am. Chem. Soc. 2000, 122, 1806; (d) E.M. Carreira* et al, Org. Lett. 2000, 2, 4233. (e) B. Jiang* et al, Chem. Commun. 2002, 1524; (f) B. Jiang* et al, Tetrahedron Lett. 2002, 43, 8323. Amine alcohols species 2. Asymmetric addition of phenylacetylene to aldehydes

22. (a) S. Dahmen, Org. Lett. 2004, 6, 2113; (b) R. Wang* et al, Tetrahedron: Asymmetry 2004, 15, 3155; (c) R. Wang* Tetrahedron Lett. 2005, 46, 863; (d) C. Wolf*, J. Am. Chem. Soc. 2006, 128, 10996; (e) B. M. Trost* et al, J. Am. Chem. Soc. 2006, 128, 8; (f) B. G. Davis* et al, Org. Lett. 2006, 8, 207 Amine alcohols species 2. Asymmetric addition of phenylacetylene to aldehydes

23. Sulfonamides and Amides ligands (a) (b) R. Wang* et al, Adv. Synth. Catal. 2006, 348, 506; (b) R. Wang* et al, Adv. Synth. Catal. 2005, 347, 1659-1665; (c) R. Wang* et al,Org.Lett 2004, 6, 1193; (d) R. Wang* et al, Angew. Chem. Int. Ed. 2003, 42, 5747; (e) X. P. Hui* et al, J. Mol. Catal. A-Chemical 2007, 269, 179. (f) J. X. Xu* et al, Org. Lett., 2005, 7, 2081; 2. Asymmetric addition of phenylacetylene to aldehydes

24. Binaphthol-based ligands (a) L. Pu* et al, Org. Lett. 2002, 4, 4143; (b) L. Pu* et al, Org. Lett. 2002, 4, 1855; (c) A. S. C. Chan* et al, J. Am. Chem. Soc. 2002, 124, 12636; (d) A. S. C. Chan* et al, Chem. Commun., 2002, 172 (e) M. Shibasaki* et al, J. Am. Chem. Soc. 2005, 127, 13760; 2. Asymmetric addition of phenylacetylene to aldehydes

25. Binaphthol-based ligands (a) L. Pu* et al, Angew. Chem. Int. Ed. 2006, 45, 122; (b) L. Pu* et al, J. Org. Chem. 2007, 72, 4340 ; (c) L. Pu Tetrahedron 2006, 62, 9335; (d) L. Pu* et al, P. N. A. S. 2004, 101, 5417; (e) A. S. C. Chan* et al, Tetrahedron: Asymmetry 2003, 14, 449 2. Asymmetric addition of phenylacetylene to aldehydes

26. High e.e. Zn(OTf) 2 Ti(O i Pr) 4 High e.e. How about SAA ligands? $ =10 times of ZnEt 2 Moisture sensitive Origins 2. Asymmetric addition of phenylacetylene to aldehydes

28. EntryLigandRIsolated yield (%)ee (%) b 14Ph9961 21Ph7915 34p-F-Ph7250 44p-Br-Ph7650 54p-MeO-Ph8660 64p-Me-Ph9656 74p-NO 2 -Ph7084 84o-Me-Ph9982 941-naphthyl8581 104cyclohexyl9839 114isovaleric9924 124pelargonic3926 131cyclohexyl9926 Boshun Wan*, Chirality, 2005, 17, 245 2. Asymmetric addition of phenylacetylene to aldehydes

29. (a) Cozzi, P. G. Angew. Chem. Int. Ed. 2003, 42, 2895 (b) Saito, B.; Katsuki, T. Synlett 2004, 9, 1557 Lewis acid center Lewis base center Zn (salen) as a bifunctional complex 3. Asymmetric addition of phenylacetylene to ketones

30. a.Lu, G.; Li, X. S.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew.Chem., Int. Ed. 2003, 42, 5057 b.Zhou, Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org. Lett. 2004, 6, 4147 c.Liu, L.; Wang, R.; et al, J. Org. Chem. 2005, 70, 1084-1086.. Chiral ligands for aromatic ketones 3. Asymmetric addition of phenylacetylene to ketones

31. a. Cozzi, P. G.; Alesi, S. Chem. Commun. 2004, 2448. b. Wang, R.*; et al, Tetrahedron: Asymmetry 2004, 15, 3757. Without using zinc reagent or Lewis acid 3. Asymmetric addition of phenylacetylene to ketones

32. ? No additional Lewis acid Poor catalysts Expectation 3. Asymmetric addition of phenylacetylene to ketones

33. The valuated ligands in the reaction 3. Asymmetric addition of phenylacetylene to ketones

34. EntrySubstrateYield (%)ee (%) 1acetophenone6678 22′-chloroacetophenone8365 32′-fluororoacetophenone4053 42′-methylacetophenone3367 53′-chloroacetophenone7570 61′-naphthacetophenone5055 72′-naphthacetophenone6583 Boshun Wan*, J. Mol. Catal. A: Chemical 2005, 237, 126. 3. Asymmetric addition of phenylacetylene to ketones

35. [RuCl 2 (p-cymene)] 2 / ligand i PrOH/ KOH HCOOH/ (C 2 H 5 ) 3 N H 2 O / HCOONa 4. Asymmetric hydrogenation transfer reaction

36. TsDPEN Known chiral ligands (H 2 O/HCOONa) 4. Asymmetric hydrogenation transfer reaction

37. The evaluated ligands 4. Asymmetric hydrogenation transfer reaction

38. cheaper storable Successful conversion 4. Asymmetric hydrogenation transfer reaction

39. entryketone% conversion% ee 11699.375 (R) 217>9943 (R) 318>9950 (R) 41998.248 (R) 52097.478 (R) 62197.883 (R) 72295.081 (R) 82398.583 (R) 92498.677 (R) 102597.174 (R) 112656.965 (R) 122797.250 (R) 132896.562 (R) 4. Asymmetric hydrogenation transfer reaction

40.  Firstly introducing a new type of chiral N,O-ligand hydrochloride into the reaction performed in water and air.  The catalyst is stable, commercially available and low-cost.  The destined products were easily departed from the catalytic system by adding some ether in the reaction mixture. Boshun Wan*, Tetrahedron Lett. 2005, 46, 7341 Advantage: 4. Asymmetric hydrogenation transfer reaction

41. (S)-Chiral Ligand (S)- or (R)- Products (R)-Chiral Ligand (S)-Chiral Ligand (S)-Chiral Ligand* (S)-Chiral Ligand+Additive (R)-Chiral Ligand × Reversal of enantioselectivity

42. Boshun Wan*, J. Mol. Catal. A: Chemical 2005, 225, 33 Reversal of enantioselectivity by adding Ti(O i Pr) 4 Reaction 1 Reversal of enantioselectivity

43. Reversal of enantioselectivity by adding Ti(O i Pr) 4 Boshun Wan*, J. Mol. Catal. A: Chemical 2005, 232, 9. Reaction 2 Reversal of enantioselectivity

44. Boshun Wan*, J. Mol. Catal. A: Chemical 2005, 232, 9. Relationship between Ti/L and ee Reversal of enantioselectivity

45. Conclusions Design and synthesized the novel chiral sulfamide- amine alcohols ligands (SAA) using multicenter and grafting strategy Applied them into asymmetric addition reactions  Applied the strategy and novel ligands into other asymmetric reactions

46. Acknowledgements 毛金成 博士 金 薇 博士生 黎红旺 硕士生

47. Thank You for Your Attention! Welcome to My Group! http://www.chs.dicp.ac.cn