Bo Yang Nov. 18 th, 2009

Transcription

1 Bo Yang ov. 18 th,

2 utline Introduction Traditional Stepwise Synthesis Approach ne-pot Synthesis Approach Conclusions 2

3 Importance of Fused Ring Structures Kubo, K. et al. Chem. Phram. Bull. 1979, 23, 2372 Ar Tu, S-J. et al. J. Comb. Chem. 2009, 11, 428 H H CH 3 Fused indole derivative Anti-inflammatory Muscle relaxation Anticancer and antioxidant Leukemialine inhibitor Zeng, C.-C. et al. J. rg Chem. 2009, 74, 6383 Me H H Hernandez, F. et al. Synlett. 2001, 1387 H 3 C H 3 C Indenoisoquinolinecamptothecin analogue Topoisomerase I inhibitor Brian, M. F. et al. J. Med. Chem. 2003, 46, 3275 H H Fiscalin A H H Antiobiotics Michael, J. P. et al. at. Proc. Rep. 2004, 21, 650 H Bn Me Benzomalvin A eurokinin K1 receptor inhibitor Sun, H. H. et al. J. Antibiot. 1994, 47, 515 H H Asperlicin E H H Antiobiotics Goetz, M. A. et al. J. Antibiot. 1988, 41, 875 3

4 Traditional Stepwise rganic Synthesis 4

5 Stepwise Synthesis of Fused Ring Structures 6 Isoquinolinones verall Yield: 8% Brookings, D. et al Bioorg. Med. Chem. Lett. 2007, 17, 562 Yazmin, M. et al Tetrahedron Lett. 2004, 45,

6 Stepwise Synthesis of Fused Ring Structures 12 R 2 R 1 H Quinazolinones verall Yield: 37% Ganesan, A. et al. J. rg. Chem. 1998, 63, 2432 Gronnow, M. J. et al. rg. Process Res. Dev. 2005, 9, 516 6

7 Traditional Stepwise rganic Synthesis energy solvent silica gel 7

8 Waste Generated in Research 8

9 Chemical Waste Produced in U.S. Toxics Total Disposl or ther Releases, billion pounds 9

10 ur Goal Solution Efficient and Green Synthesis 10

11 Synthetic Efficiency Low cost Energy Solvent Silica gel Short reaction time High reaction yields 11

12 Green Chemistry Also called Benign Chemistry or Clean Chemistry Refers to the field of chemistry dealing with: - synthesis (the path to making chemicals) -processing (the actual making of chemicals) -use of chemicals that reduce risks to humans and impact on the environment. Adapted from P. T. Antastas & J. J. Breen, J. Cleaner Production,

13 ne-pot Synthesis Commercially available starting materials 13

14 Requirements for ne-pot Synthesis A Side products generated in each step should not interfere with other reactions. B D F G The yield for each reaction has to be high. 14

15 Requirements for ne-pot Synthesis Side products generated in each step should not interfere with other reactions. The yield for each reaction has to be high. 15

16 ne-pot Approaches for Fused Ring Synthesis Transition Metal Catalyzed Synthesis Microwave Assisted Synthesis Microwave Assisted Aqueous Synthesis Electrochemical Aqueous Synthesis H H 50 CH 3 16

17 Strategy for Synthesis of Ring-fused Isoquinolinones EtC CH C I Chouhan, G.; Alper, H. rg. Lett. 2008, 10,

18 ptimizing Reaction Conditions 4 H verall Yield: 8% Chouhan, G.; Alper, H. rg. Lett. 2008, 10, 4987 Brookings, D. et al Bioorg. Med. Chem. Lett. 2007, 17, 562 Yazmin, M. et al Tetrahedron Lett. 2004, 45,

19 Exploring the Scope of the Reaction H H H H H H I I I CEt C S 2 Ph Me Me Me Me I I I I C C CEt CEt Chouhan, G.; Alper, H. rg. Lett. 2008, 10, 4987 Dijkstra, G.; Kruizinga, W. H.; Kellog, R. M.; J. rg. Chem. 1987, 52,

20 Proposed Reaction Mechanism base R 1 X R 2 n R 3 Chouhan, G.; Alper, H. rg. Lett. 2008, 10,

21 From Isoquinolinonesto xazoloisoquinolinones C Chouhan, G.; Alper, H. rg. Lett. 2008, 10, 4987 Chouhan, G.; Alper, H. J. rg. Chem. 2009, 74,

22 Possible DecarboxylationMechanism R 1 CEt R 2 I base R 1 R 2 CEt PdLnI 22

23 Synthesis of xazoloisoquinolinonelibrary EtC 65% EtC 48% Chouhan, G.; Alper, H. J. rg. Chem. 2009, 74,

24 Possible Effect of Substituentson the Ring H C R 3 R 3 Et C H 24

25 Synthesis of PyrazoloisoquinolinoneLibrary Chouhan, G.; Alper, H. J. rg. Chem. 2009, 74,

26 2-Bromo-Substituted MethyleneCompounds PPh 2 PPh 2 Xantphos Chouhan, G.; Alper, H. J. rg. Chem. 2009, 74,

27 Proposed Reaction Mechanism base R 1 X R 2 n R 3 Chouhan, G.; Alper, H. rg. Lett. 2008, 10,

28 Effect of Electron Rich Ligand 28

29 Summary Pros: Efficient Synthesis without intermediate purification Cons: ne final purification needed, use of transition metal as catalyst 29

30 Microwave-assisted ne-pot Synthesis 30

31 Microwave Assisted rganic Synthesis (MAS) Dipolar molecules which try to align themselves with an oscillating electric field. Charged particles in a solution will follow applied electric field. Kappe, C..; Dallinger, D. at. Rev.. Drug Discovery 2006, 5, 51 Gronnow, M. J.; White, R. J.; Clark. J. H.; Macquarrie, D. J. rg. Process Res. Dev. 2005, 9,

32 Microwave Assisted rganic Synthesis (MAS) Kappe, C..; Dallinger, D. at. Rev.. Drug Discovery 2006, 5, 51 Gronnow, M. J.; White, R. J.; Clark. J. H.; Macquarrie, D. J. rg. Process Res. Dev. 2005, 9,

33 Time Savings Associated with MAS Sarko, C. R. in Microwave-assisted rganic Synthesis (eds Tierney, J. P. & Lidstrőm, P.) (Blackwell, xford, 2005). 33

34 Time Savings Associated with MAS 34

35 Synthesis of DisubstitutedQuinazolinones X BnH 2 H H 41 80% Bn Liu, J.; Lee, J. Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.; McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46,

36 DistinguishingReaction Intermediates -(2-carboxyphenyl)- '-arylacylamidine IR Data 3448 cm cm cm cm cm cm -1 MR Data δ: 1.84, (Acetylamino)-phenylbenzamide MR Data δ: 2.45 (3H, s), (5H, m), 7.61 (1H, t, J = 4.6 Hz),7.90 (2H, J= 8.0 Hz), 8.3 (1H, t, J = 8.0 Hz). Errede, L. A. J. rg. Chem. 1976, 41, 1763 Kuroda,.; Hird,.; Cork, D. G. J. Comb. Chem. 2006, 8,

37 Synthesis of Core Structure Liu, J.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C. M. J. rg. Chem. 2005, 70,

38 ne-pot Synthesis of Core Structure 7 H 2 H H 2 C H Boc P(Ph) 3,pyridine MW,150 o C,10min HCl H 2 C 2 Me MW,220 o C,1.5min 36 H 56% R H H 2 R 1 H 2 C H Boc R2 2 HCl H 2 C 2 Me R R 1 R 2 Yield H Me H 62% R R 2 R 1 H H Cl H H Me i-pr 64% 79% Liu, J.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C. M. J. rg. Chem. 2005, 70,

39 Application in Total Synthesis of atural Products H Sclerotigenin Me H 2 60% H 2 C HBoc H 2 H H H Me Fumiquinazoline F Liu, J.; Kaselj, M.; Isome, Y.; Chapnick, J.; Zhang, B.; Bi, G.; Yohannes, D.; Yu, L.; Baldino, C. M. J. rg. Chem. 2005, 70, Liu, J.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C. M. J. rg. Chem. 2005, 70, 6339

40 Green Microwave-assisted ne-pot Synthesis Reaction Media: rganic Solvent Reaction Media: Water? 40

41 Water as Reaction Medium H2 Lidstrőm, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron. 2001, 57,

42 Synthesis of Isoxazolopyridine PhCH H Tu, S-J.; Zhang, X-H.; Han, Z-G.; Cao, X. D.; Wu, S-S.; Yan, S.; Hao, W. J.; Zhang, G.; Ma,. J. Comb. Chem. 2009, 11,

43 Synthesis of IsoxazolopyridineLibrary Ar C 6 H 5 4-FC 6 H 4 4-BrC 6 H 4 4-ClC 6 H 4 2-FC 6 H C 6 H C 6 H 4 2-ClC 6 H 4 2,4-Cl 2 C 6 H 3 4-CH 3 C 6 H 4 4-CH3C6H4 3,4-CH2C6H3 3,4-(CH3)2C6H3 3,4,5-(CH3)3C6H2 4-H-3-2C6H3 Tu, S-J.; Zhang, X-H.; Han, Z-G.; Cao, X. D.; Wu, S-S.; Yan, S.; Hao, W. J.; Zhang, G.; Ma,. J. Comb. Chem. 2009, 11,

44 Possible Reaction Mechanism X Ar Tu, S-J.; Zhang, X-H.; Han, Z-G.; Cao, X. D.; Wu, S-S.; Yan, S.; Hao, W. J.; Zhang, G.; Ma,. J. Comb. Chem. 2009, 11,

45 Possible Reaction Mechanism 45

46 Summary Pros: Shortened reaction time, aqueous media Cons: ne final purification needed, highly pressurized system, limited reaction scale 46

47 Electrochemical ne-pot Synthesis 47

48 Electrochemical Reaction 48

49 Electrochemical Reaction Battery xidation or reduction? Potential Salt bridge Solubility 49

50 RetrosyntheticAnalysis 50 H H CH 3 50

51 o-benzoquinone Electrochemical Chemical (EC) Reaction Zeng, C-C.; Liu, F-J.; Ping, D-W.; Hu, L-M.; Cai, Y-L.; Zhong, R-G. Tetrahedron. 2009, 65,

52 EC Mechanism Zeng, C-C.; Liu, F-J.; Ping, D-W.; Hu, L-M.; Cai, Y-L.; Zhong, R-G. Tetrahedron. 2009, 65,

53 ne-pot Synthesis of Fused IndoleDerivative Electrochemical Chemical Electrochemical Chemical (ECEC) Reaction Zeng, C-C.; Liu, F-J.; Ping, D-W.; Hu, L-M.; Cai, Y-L.; Zhong, R-G. J. rg. Chem. 2009, 74,

54 ECEC Mechanism Michael addition t-bu H CH 3 Zeng, C-C.; Liu, F-J.; Ping, D-W.; Hu, L-M.; Cai, Y-L.; Zhong, R-G. J. rg. Chem. 2009, 74,

55 Regioselectivity Zeng, C-C.; Liu, F-J.; Ping, D-W.; Hu, L-M.; Cai, Y-L.; Zhong, R-G. J. rg. Chem. 2009, 74,

56 Synthesis of Analogs 56

57 Summary Pros: ormal pressure, aqueous media Cons: nly work for redox, one final purification needed 57

58 Conclusions Are we efficient and green in synthesizing fused ring structures? 58

59 Acknowledgements Prof. Xuefei Huang Dino, Gilbert, Gopi, Hovig, Medha, Moe, Phil, Steve, Vivian All of you 59