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

(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

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

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

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

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

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

Synthetic route of Ts-Based SAA Ligand

Ts-Based SAA ligands

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

New Tf-Based SAA ligands

New Ms-Based SAA ligands

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

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.

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

(S)(S) (R)(R)

Comparisons 1. Asymmetric addition of diethylzinc to aldhydes

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

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

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

(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

(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

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

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

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

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

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

(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

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

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

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

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

EntrySubstrateYield (%)ee (%) 1acetophenone ′-chloroacetophenone ′-fluororoacetophenone ′-methylacetophenone ′-chloroacetophenone ′-naphthacetophenone ′-naphthacetophenone6583 Boshun Wan*, J. Mol. Catal. A: Chemical 2005, 237, Asymmetric addition of phenylacetylene to ketones

[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

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

The evaluated ligands 4. Asymmetric hydrogenation transfer reaction

cheaper storable Successful conversion 4. Asymmetric hydrogenation transfer reaction

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

 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

(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

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

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

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

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

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

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