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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.

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Presentation on theme: "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."— Presentation transcript:

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

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, (e) B. Jiang* et al, Chem. Commun. 2002, 1524; (f) B. Jiang* et al, Tetrahedron Lett. 2002, 43, 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, ; (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, 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

27

28 EntryLigandRIsolated yield (%)ee (%) b 14Ph Ph p-F-Ph p-Br-Ph p-MeO-Ph p-Me-Ph p-NO 2 -Ph o-Me-Ph naphthyl cyclohexyl isovaleric pelargonic cyclohexyl9926 Boshun Wan*, Chirality, 2005, 17, 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, Chiral ligands for aromatic ketones 3. Asymmetric addition of phenylacetylene to ketones

31 a. Cozzi, P. G.; Alesi, S. Chem. Commun. 2004, b. Wang, R.*; et al, Tetrahedron: Asymmetry 2004, 15, 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 (%) 1acetophenone ′-chloroacetophenone ′-fluororoacetophenone ′-methylacetophenone ′-chloroacetophenone ′-naphthacetophenone ′-naphthacetophenone6583 Boshun Wan*, J. Mol. Catal. A: Chemical 2005, 237, 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 (R) 217>9943 (R) 318>9950 (R) (R) (R) (R) (R) (R) (R) (R) (R) (R) (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!


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