A Self-Supporting Strategy for Chiral Catalyst Immobilization

Transcription

1 ISCHIA ADVACED SCHL F RGAIC CHEMISTRY Ischia (aples), September 27 - ctober 2, 2008 (50+10 min) A Self-Supporting Strategy for Chiral Catalyst Immobilization Kuiling Ding Shanghai Institute of rganic Chemistry, Chinese Academy of Sciences, China

2 Some Challenges in Asymmetric Catalysis Asy Catalysis Selectivity: There is no given catalyst that is universal for all substrates. Catalyst diversity Reactivity and Efficiency : 1-10 mol% catalyst loading is not practical % or less. rocess chemistry: speed up the rate for catalyst discovery in customer synthesis. Catalyst recovery and reuse. Cost, energy, solvent, safety, and others.

3 Combinatorial Approach to Asymmetric Catalysis Chiral Ligand Library A with m Members + + M n+ Ligand Library B with n Members (chiral, achiral or racemic) Kagan guni, oyori Related Concepts Brown (1986) asymmetric amplification Yamamoto(1989) chiral poisoning Faller (1993) asymmetric activation Mikami (1997) Related Concepts molecular recognition and assembly dynamic combinatorial chemistry Lehn (1999) ACIE 2001, 40, 544. ACIE 2003, 42, JACS 2002, 124, 10. JACS 2002, 124, JACS 2005, 127, JACS 2006, 128, JACS 2008,130, in press. CEJ 2002, 8, CEJ 2003, 9, CEJ 2008, 14, in press ASC 2005, 347, ASC 2006, 348, L 2002, 4, L 2003, 5, JC 2004, 69, 146. EJC 2006, EJC 2008, Modular Chiral Catalyst Library with m x n Members! High Throughput Screening (HTS) on Target Reactions Highly Efficient and Enantioselective Catalysts Chemspeed Synthesizer HLC-CD Concept Article Chem. Eur. J. 2004, 10, Feature Article Chem. Commun. 2008,

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5 Exceptionally Efficient Catalysts for Enantioselective Hetero-Diels-Alder Reaction RCH + Si Me (1) (2) mol% L5/L5/Ti or L5/L6/Ti CF 3 CH R up to >99% yield 99.8% ee H H H H L5 L6 Highly efficient: 0.1% % of cat. loading! Very high yield and enantioselectivity Room temperature and solvent free J. Long, K. Ding, et al., J. Am. Chem. Soc. 2002, 124,

6 Asymmetric HDA Reaction: A Facile Approach to Lactone Sub-unit of Chiral Drugs F R H H H lactone sub-unit H lactone sub-unit R = H, compactin R = Me, Mevacor Lipitor, $13.6 billion (2006) Me RCH + Si (1) (2) Catalyst CF 3 CH R R H

7 Exceptionally Efficient Catalysts for Quasi Solvent-Free Enantioselective Carbonyl-Ene Reaction % Cat H L1/L1/Ti orl1/l2/ti + Et Et H Ar Me solvent-free Ar * 76-99% yield a: Ar = C 6 H 5 1b: Ar = 4-ClC 6 H 4 1c: Ar = 4-FC 6 H 4 1d: Ar = 4-CH 3 C 6 H 4 3a: Ar = C 6 H 5 (98.2% ee) 3b: Ar = 4-ClC 6 H 4 (99.4% ee) 3c: Ar = 4-FC 6 H 4 (98.4% ee) 3d: Ar = 4-CH 3 C 6 H 4 (97.1% ee) I F 3 C H H H H I F 3 C L1 L2 Y. Yuan & K. Ding, Angew. Chem. Int. Ed. 2003, 42, 5478.

8 Exceptionally Efficient Catalysts for Quasi Solvent-Free Enantioselective Carbonyl-Ene Reaction H n n = 0, 1 + H Et L1/L1/Ti orl1/l2/ti ( mol %) solvent-free 94-99% yield n H * Et n = 0 (91% ee) n = 1 (92% ee) I F 3 C n = 0 I L1 H H F 3 C L2 H H HH Trocade Y. Yuan & K. Ding, Angew. Chem. Int. Ed. 2003, 42, 5478.

9 General Strategy for Chiral Catalyst Immobilization Bonding atterns Covalent bonding Supports or Media hysisorption Electrostatic interactions Entrapment rganic olymers and Dendrimers; Inorganic Supports; on-conventional Media (such as water, fluorous inated liquids, ionic liquids, and Sc C 2 ) Fan, Q.; Li, Y.-M.; Chan, A. S. C. Chem. Rev. 2002, 102, D. E. De Vos, I. F. J. Van Kelecom,. A. Jacobs, Eds. Chiral Catalyst Immobilization and Recycling, Wiley-VCH, Weinheim, 2000.

10 Microporous Metal-rganic Frameworks. M. Yahgi, et al. ature, 2003, 423, 705; Science, 2003, 300, 1127.

11 Coordination etwork Material as A Zeolite-Like Heterogeneous Catalyst Cd Cd (4,4'-bpy) Cd( 3 ) 2 Cd Cd 5 (Counter ions are omitted for clarity) R H Me 3 SiC R = 2-MeC 6 H 4, 3-MeC 6 H 4, 1-naphthyl, 2-naphthyl. 5 (0.2 equiv.) CH 2 Cl 2, 40 0 C 24 h SiMe 3 R C 19-84% yields M. Fujita & K. gura, et al., J. Am. Chem. Soc. 1994, 116,

12 Microporous Homochiral Metal-rganic Frameworks Zn( 3 ) 2 H H H 2 /MeH H Ac D-2 Ac 2 + * + H h 2 h 3 4 5, 8% ee 6 K. Kim et al., ature, 2000, 404, 982.

13 Self-Supported Chiral Catalysts for Heterogeneous Enantioselective Catalysis + substrates chiral ligand metallic ion product A bottom-up strategy chiral metal-organic framworks or chiral metal-organic coordination polymer K. Ding et al. Chem. Eur. J. 2006, 12,

14 Self-Supported BIL-Ti Catalysts for Carbonyl-Ene Reaction H H linker Ti( i r) 4 i r H Ti H i r H H catalysts for carbonyl-ene reaction: 1 mol% of catalyst loading up to >99% yield and 96.5% ee linker n h Me + H Et Catalyst 1 mol% H. Sasai et al., Angew. Chem. Int. Ed. 2003, 42, H. Guo, X. Wang et al, Tetrahedron Lett. 2004, 45, X. Wang, H. Guo et al. Chem. Eur. J. 2005, 11, H Et h up to 99% yield 96.5% ee

15 Highly Stable and Enantioselective Heterogeneous Titanium Catalysts for Asymmetric xidation of Sulfides Kagan, Modena, H H Linker Uemura, Bolm 1) 1 eq. Ti( i r) 4, rt,12 h 2) 40 eq. H 2, rt,12 h H 1a-c H linker: a Ti b (H 2 ) m m = 5 or 6 Linker n c single bond 2a-c X. Wang, H. Guo, et al., Chem. Eur. J. 2005, 11,

16 Highly Stable and Enantioselective Heterogeneous Titanium Catalysts for Asymmetric xidation of Sulfides R 3a-g S R' Reused for 8 times, Life time > 1 month 98.2->99.9% ee 2a-c, 5 mol% xidant ( 2 eq.) CCl days R 4a-g S R' up to >99.9% ee 35-45% yield 3a: R = H, R' = Me 3b: R = 4-Me, R' = Me 3c: R = 4-Br, R' = Me 3d: R = 4-F, R' = Me 3e: R = 3-Br, R' = Me 3f: R = 2, R' = Me 3g: R = H, R' = Et Run Y (%) Ee (%) > X. Wang, H. Guo et al., Chem. Eur. J. 2005, 11,

17 Heterogeneous Titanium Catalysts for Asymmetric Ring pening of Expoide linker polymeric BIL/Ti (1 mol%) + BnH 2 BnH H recycled 12 times >90% yield 94-97% ee Ti polymeric BIL/Ti linker = 1,4-phenylene linker = -CH 2 CH 2 CH 2 CH 2 - * n H elfinavir H Sh H C4 unit H H H Cf. Sagawa, S.; Inaba, T. J. rg. Chem. 1999, 64, H. Bao, Z. Wang & K. Ding et al., J. Am. Chem. Soc. 2008, in the press.

18 The Impact of Bridging Spacers on the Self-Supported Catalysts + + chiral unit metallic ion

19 The Impact of Bridging Spacers on the Self-Supported Catalysts + chiral unit metallic ion

20 Multitopic Ligands Containing BIL Units with Various Bridging Spacers spacer 1a-g = H H a b spacer single bond f c d g e 1h 1i

21 Self-Supported BIL-La Catalysts with Various Bridging Spacers Self-supported BIL/La catalyst (S)-BIL La(III) Cf. M. Bougauchi, S. Watanabe, T. Arai, H. Sasai, M. Shibasaki, J. Am. Chem. Soc. 1997, 119, K. Daikai, M. Kamaura, J. Inanaga, Tetrahedron Lett. 1998, 39,

22 Self-Supported BIL-La Catalysts for Epoxidation of Enones h 3a h + CHM 2a-i (5.0 mol%) MS 4A, THF, RT h 3 (15 mol%) h β α 4a h a b c single bond 97.6 (R,S) 83.7 (R,S) 82.9 (R,S) 91.5 (R,S) d 95.5 (R,S) 1h e f 93.3 (R,S) 95.1 (R,S) g 84.2 (R,S) 95.0 (R,S) 1i

23 Self-Supported BIL-La Catalysts for Epoxidation of Enones R R' 4a: R = h, R' = h 4b: R = 4-F-h, R' = h 4c: R = 4-Cl-h, R' = h 4d: R = 4-Br-h, R' = h 4e: R = 4-2 -h, R' = h 4f: R = 4-C-h, R' = h 4g: R = h, R' = 4-Me-h 4h: R = i-r, R' = h 2a (5 mol%) h 3 = (15 mol%) MS 4A, THF, RT R 3 1 R' 2 CMH (1.5 equiv.) h 91-99% yield 97.6% ee (R,S) 96.2% ee (R,S) 96.0% ee (R,S) 95.6% ee (R,S) 95.7% ee (R,S) 94.3% ee (R,S) 95.0% ee (R,S) 84.9% ee (R,S) X. Wang, L. Shi, et al. Angew. Chem. Int. Ed. 2005, 44,

24 Recovery and Reuse of Self-Supported BIL- La Catalysts h h + oxidant 2a (5.0 mol%) MS 4A, THF, RT h β α h 3a 4a Run h 3 [mol%] Time [h] Yield [%] [b] Ee [c] [%] (Config.) [d] > (R,S) > (R,S) > (R,S) La leaching: <0.4 ppm > (R,S) (R,S) (R,S) X. Wang, L. Shi, et al. Angew. Chem. Int. Ed. 2005, 44,

25 Modular Monodentate hosphorous Ligands for Rh(I)-Catalyzed Asymmetric Hydrogenation R X X R' R' R 1a X = R 1b X = alkyl or aryl 1c X = R 2, Monohos M. Reetz (2000) B. L. Feringa (2000). ringle (2000) 2a X = R 2b X = R 2, Spirohos Q. Zhou (2002) 3, Dpenhos K. Ding (2005)

26 Monohos/Rh Catalyst: from Homogeneous to Heterogeneous + Rh + + linker Rh + Excellent catalyst for asymmetric hydrogenation [Rh] linker n Linker = a: b: c: single bond B. L. Feringa, et al, J. Am. Chem. Soc. 2000, 122, Y. Liu & K. Ding, J. Am. Chem. Soc. 2005, 127,

27 Self-Supported Catalysts for Heterogeneous Enantioselective Hydrogenation R R' 1 mol% of catalyst R HAc H 2 R = H, h, Me; R' = CMe, H R' HAc 94-97% ee [Rh] linker self-supported catalyst n X. Wang et al. J. Am. Chem. Soc. 2004, 126,

28 Catalyst Recycling CH 3 HAc 2c 1mol%, 40 atm H 2 C 2 CH 3 toluene, rt, 10h HAc 3a 4a Run Conv.(%) b >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 E.e. (%) c

29 Use of Hydrogen Bonds as the Bridging Linker: From Dimeric Supramolecules to olymeric Chiral Catalyst chiral ligand unit solvent hydrogen-bonding unit dimeric supramolecules metallic ions polymeric chiral catalyst n L. Shi & K. Ding, Angew. Chem. Int. Ed. 2006, 45,

30 Self-Supported Monohos/Rh(I) Catalyst H H H SupraMonohos (1a) 2 H H H H H H [Rh] n [Rh] = Rh(cod)BF 4 CH 2 Cl 2 or Toluene [Rh(cod) 2 ]BF 4 L. Shi & K. Ding, Angew. Chem. Int. Ed. 2006, 45,

31 Self-Supported Monohos/Rh(I) Catalyst for Enantioselective Hydrogenation >99% conv % ee >99% conv. 91% ee

32 High Enantioselectivity and Facile Recovery H 3 C CH 3 HAc 2, 1 mol% H 2, 40 atm, toluene H 3 C C 2 CH 3 HAc Rh leaching < 1 ppm Table 2. Recycling and reuse of the self-supported catalysts 2b in enantioselective hydrogenation of 3b. a Run conv. >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 96 [%] b Ee [%] c L. Shi & K. Ding, Angew. Chem. Int. Ed. 2006, 45,

33 Schematic Representation of Continuous Flow Reaction System for Chiral Catalysis H 2 flow control check valve peek tube H 2 Cylinder Stainless Steel Cross A B C UM reaction column product GC analysis >100 hr with >99% yield 96-97% ee self-supported catalyst

34 Schematic Representation of the Strategy + n homo-ligand polymer + + n Multitopic Ligands Metallic Ion hetero-ligand polymer rogrammed Assembly Ar Ar Cl Ru Ar Ar Cl H 2 H 2 h h Cf. R. oyori, et al. J. Am. Chem. Soc. 1995, 117, 2675.

35 Self-Supported oyori-type Catalyst Me Ar 2 Ar 2 H 2 H 2 Ar 2 H 2 Ar 2 1a Ar = C 6 H 5 H 1b Ar = 3,5-(CH 3 ) 2 C 6 H Me [(C 6 H 6 )RuCl 2 ] 2 DMF Ar 2 Ar 2 Cl Ru Cl H 2 H 2 Me n 3a Ar = C 6 H 5 3b Ar = 3,5-(CH 3 ) 2 C 6 H 3 Liang, Y. et al. J. Am. Chem. Soc. 2005, 127,

36 Self-Supported oyori-type Catalyst for Asymmetric Hydrogenation of Ketones Ar 4a-h + H 2 H 0.1 mol% of Catalyst 3b K t Bu, i-rh Ar 5a-h 97.4% ee 97.5% ee 96.2% ee Cl 96.9% ee Br 97.2% ee F 96.2% ee 98.1% ee 94.5% ee 94.2% ee (0.01 mol % of cat) Run Y (%) >99 >99 >99 >99 >99 >99 97 Ee (%)

37 Zr Zr Zr Zr h hcl Ru h hcl L L Zr Zr Zr Zr h hcl Ru h h Cl L L 8a L-L = (R,R)-DE 9a L = DMF Ar 8b L-L = (R,R)-DE 9b L = DMF mol% H 8a or 8b + H 2 R K t Bu, i-rh Ar R up to >99% yield; 99% ee, 8 recycles R 1 1 mol% H 9a or 9b + H R2 2 MeH R up to >99% yield, 95% ee, 5 recycles R2 Lin, W. et al. J. Am. Chem. Soc. 2003, 125, 11490; Lin, W. et al. Anew. Chem. Int. Ed. 2003, 42, 6000.

38 Carbonyl-ene reaction Epoxidation Sulfoxidation Ring pening of Epoxide Hydrogenation Summary and utlook A Concept Article, see: K. Ding, et al. Chem. Eur. J. 2006, 12,

39 Acknowledgements Coworkers Dr. Wang Zheng Dr. Christian A. Sandoval Dr. Long Jiang Dr. Yuan Yu Dr. Yuxue Liang Dr. Xisheng Wang Dr. Xingwang Wang Dr. Qing Jing Dr. Yan Liu Mr. Lei Shi Dr. Baoguo Zhao Foundations ational atural Science Foundation of China Major Basic Research Development rogram of China (973 roject) Chinese Academy of Sciences Science & Technology Commission of Shanghai Municipality