中国科学院大连化学物理研究所

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

2. 手性与人类健康:“反应停”悲剧 (S)-(+)-thalidomide 致畸剂 (R)-(+)-thalidomide （镇静剂和止吐剂） 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. Science2003, 299, 1691

4. Examples of privileged chiral ligands 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. Science2003, 299, 1691

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

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

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

8. Synthetic route of Ts-Based SAA Ligand

9. Ts-Based SAA ligands

10. New Ms,Tf-Based SAA ligands 1. The size of the fluxional group R is a primary determinant of enantioselectivies ? 2. What is the difference effect of R1, and X …?

11. New Tf-Based SAA ligands

12. New Ms-Based SAA ligands

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

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

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

16. 1.Asymmetric addition of diethylzinc to aldhydes (S) (R)

17. 1.Asymmetric addition of diethylzinc to aldhydes Comparisons

18. 1.Asymmetric addition of diethylzinc to aldhydes

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

20. 2. Asymmetric addition of phenylacetylene to aldehydes Zn + Ligand Characteristics: Ti + Zn + Ligand Reviews see: (a) Tetrahedron2003, 59, 9873 (b) Eur. J. Org. Chem. 2004, 4095

21. 2. Asymmetric addition of phenylacetylene to aldehydes Amine alcohols species (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.

22. 2. Asymmetric addition of phenylacetylene to aldehydes Amine alcohols species (a) S. Dahmen, Org. Lett. 2004, 6, 2113; (b) R. Wang* et al,Tetrahedron: Asymmetry2004, 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

23. 2. Asymmetric addition of phenylacetylene to aldehydes 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.Lett2004, 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;

24. 2. Asymmetric addition of phenylacetylene to aldehydes 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;

25. 2. Asymmetric addition of phenylacetylene to aldehydes 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 Tetrahedron2006, 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

26. 2. Asymmetric addition of phenylacetylene to aldehydes Origins How about SAA ligands? Zn(OTf)2 High e.e. $ =10 times of ZnEt2 Ti(OiPr)4 High e.e. Moisture sensitive

27. 2. Asymmetric addition of phenylacetylene to aldehydes

28. 2. Asymmetric addition of phenylacetylene to aldehydes Boshun Wan*,Chirality, 2005, 17, 245

29. 3. Asymmetric addition of phenylacetylene to ketones Lewis acid center Lewis base center Zn (salen) as a bifunctional complex (a) Cozzi, P. G. Angew. Chem. Int. Ed. 2003, 42, 2895 (b) Saito, B.; Katsuki, T. Synlett2004, 9, 1557

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

31. 3. Asymmetric addition of phenylacetylene to ketones Without using zinc reagent or Lewis acid a. Cozzi, P. G.; Alesi, S. Chem. Commun.2004, 2448. b. Wang, R.*; et al,Tetrahedron: Asymmetry2004, 15, 3757.

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

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

34. 3. Asymmetric addition of phenylacetylene to ketones Boshun Wan*,J. Mol. Catal. A: Chemical2005, 237, 126.

35. 4. Asymmetric hydrogenation transfer reaction iPrOH/ KOH HCOOH/ (C2H5)3N [RuCl2(p-cymene)]2 / ligand H2O / HCOONa

36. 4. Asymmetric hydrogenation transfer reaction Known chiral ligands (H2O/HCOONa) TsDPEN

37. 4. Asymmetric hydrogenation transfer reaction The evaluated ligands

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

39. 4. Asymmetric hydrogenation transfer reaction

40. 4. Asymmetric hydrogenation transfer reaction Advantage: • 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

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

42. Reversal of enantioselectivity Reversal of enantioselectivity by adding Ti(OiPr)4 Reaction 1 Boshun Wan*,J. Mol. Catal. A: Chemical2005, 225, 33

43. Reversal of enantioselectivity Reversal of enantioselectivity by adding Ti(OiPr)4 Reaction 2 Boshun Wan* ,J. Mol. Catal. A: Chemical2005, 232, 9.

44. Reversal of enantioselectivity Relationship between Ti/L and ee Boshun Wan* ,J. Mol. Catal. A: Chemical2005, 232, 9.

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