Bo YangBo Yang

Nov. 18th, 2009

1

Outline

� Introduction

� Traditional Stepwise Synthesis Approach

� One-pot Synthesis Approach� One-pot Synthesis Approach

� Conclusions

2

Kubo, K. et al.

Chem. Phram. Bull. 1979, 23, 2372 Hernandez, F. et al.

Synlett. 2001, 1387

Importance of Fused Ring Structures

NO

O

OCH3

OH

OH

Fused indole derivative

Zeng, C.-C. et al.

J. Org Chem. 2009, 74, 6383Tu, S-J. et al.

J. Comb. Chem. 2009, 11, 428

Anti-inflammatory Muscle relaxation Anticancer and antioxidantLeukemialine inhibitor

N

O

ON O

NO

ArO

N

N

O

NH

Me

O

HN

N

N

N

O

H BnMe

Benzomalvin A

Sun, H. H. et al.

J. Antibiot. 1994, 47, 515

N

N

N

O

H

O

NH

HO

H

Asperlicin E

Goetz, M. A. et al.

J. Antibiot. 1988, 41, 875

Brian, M. F. et al.

J. Med. Chem. 2003, 46, 3275

N

NNH

O

O

HO

N

NH

O

H

Fiscalin A

Michael, J. P. et al.

Nat. Proc. Rep. 2004, 21, 650

3

N

O

NH3CO

H3CO

Indenoisoquinoline-camptothecin analogue

Topoisomerase I inhibitor

AntiobioticsAntiobiotics

Neurokinin NK1

receptor inhibitor

N

N

N

O

H

O

NH

HO

H

Traditional Stepwise Organic Synthesis

4

Stepwise Synthesis of Fused Ring Structures

Isoquinolinones

N

O6

5Brookings, D. et al Bioorg. Med. Chem. Lett. 2007, 17, 562

Yazmin, M. et al Tetrahedron Lett. 2004, 45, 2855

Overall Yield: 8%

O

N

N

R2

NH

R1

O

12

Quinazolinones

Stepwise Synthesis of Fused Ring Structures

6Ganesan, A. et al. J. Org. Chem. 1998, 63, 2432

Gronnow, M. J. et al. Org. Process Res. Dev. 2005, 9, 516

Overall Yield: 37%

Traditional Stepwise Organic Synthesis

7

energy

solvent

silica gel

Waste Generated in Research

8

Chemical Waste Produced in U.S.

Toxics Total Disposl or Other Releases, 20054.34 billion pounds

9http://www.epa.gov/tri/tridata/

Our Goal

10

Solution

Efficient and Green Synthesis

Synthetic Efficiency

Low cost Energy Solvent Silica gel

11

Short reaction time High reaction yields

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) - processing (the actual making of chemicals)

- use

of chemicals that reduce risks to humans and impact on the environment.

12Adapted from P. T. Antastas & J. J. Breen, J. Cleaner Production, 1997

One-pot Synthesis

13

Commercially availablestarting materials

Requirements for One-pot Synthesis

Side products generated in each step should not interfere with other reactions.

The yield for each reactionhas to be high.

D

G

FA

B

14

Requirements for One-pot Synthesis

Side products generated in each step should not interfere with other reactions.

The yield for each reactionhas to be high.

15

One-pot Approaches for Fused Ring Synthesis

� Transition Metal Catalyzed Synthesis

� Microwave Assisted Synthesis

� Microwave Assisted Aqueous Synthesis

� Electrochemical Aqueous Synthesis

16

NO

O

OCH3

OH

OH

50

Strategy for Synthesis of Ring-fused

Isoquinolinones

N

EtOOC

O

17

COI

COOH

Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 4987

Optimizing Reaction Conditions

18

Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 4987

Brookings, D. et al Bioorg. Med. Chem. Lett. 2007, 17, 562

Yazmin, M. et al Tetrahedron Lett. 2004, 45, 2855

NH

O4

Overall Yield: 8%

Exploring the Scope of the Reaction

COOEtH

H I

CNH

H I

SO2PhH

H I

19Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 4987

Dijkstra, G.; Kruizinga, W. H.; Kellog, R. M.; J. Org. Chem. 1987, 52, 4230

H I

COOEtMeO

MeO I

CNO

O I

CNMeO

MeO I

COOEtO

O I

base

R1

R2

X

N

R

O

n

Proposed Reaction Mechanism

O R3

Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 498720

From Isoquinolinones to Oxazoloisoquinolinones

CO

21Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 4987

Chouhan, G.; Alper, H. J. Org. Chem. 2009, 74, 6181

R1

R2 I

COOEt

R1

R2 PdLnI

COOEt

base

Possible Decarboxylation Mechanism

22

Synthesis of Oxazoloisoquinolinone Library

N

O

EtOOC

O

65%

EtOOC

23

N

O

EtOOC

O

48%

Chouhan, G.; Alper, H. J. Org. Chem. 2009, 74, 6181

Possible Effect of Substituents on the Ring

HC

24

CH

R3

O

O

EtO

R3

OO

Synthesis of Pyrazoloisoquinolinone Library

25Chouhan, G.; Alper, H. J. Org. Chem. 2009, 74, 6181

2-Bromo-Substituted Methylene Compounds

O

PPh2 PPh2

Xantphos

26Chouhan, G.; Alper, H. J. Org. Chem. 2009, 74, 6181

base

R1

R2

X

N

R

O

n

Proposed Reaction Mechanism

O R3

Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 498727

Effect of Electron Rich Ligand

28

Summary

� Pros:

Efficient Synthesis without intermediate purificationEfficient Synthesis without intermediate purification

� Cons:

One final purification needed, use of transition metal

as catalyst

29

Microwave-assisted One-pot Synthesis

30

Microwave Assisted Organic Synthesis (MAOS)

Dipolar molecules which try to align themselves with an oscillating electric field. Charged particles in a solution will

follow applied electric field.

31Kappe, C. O.; Dallinger, D. Nat. Rev.. Drug Discovery 2006, 5, 51

Gronnow, M. J.; White, R. J.; Clark. J. H.; Macquarrie, D. J. Org. Process Res. Dev. 2005, 9, 516

Microwave Assisted Organic Synthesis (MAOS)

32Kappe, C. O.; Dallinger, D. Nat. Rev.. Drug Discovery 2006, 5, 51

Gronnow, M. J.; White, R. J.; Clark. J. H.; Macquarrie, D. J. Org. Process Res. Dev. 2005, 9, 516

Time Savings Associated with MAOS

33Sarko, C. R. in Microwave-assisted Organic Synthesis (eds Tierney, J. P. & Lidstrőm, P.) 222-236 (Blackwell, Oxford, 2005).

Time Savings Associated with MAOS

34

Synthesis of Disubstituted Quinazolinones

X

35

BnNH2

NH

NH

O

O

Bn

80%

41

Liu, J.; Lee, J. Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.; McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241

N-(2-carboxyphenyl)-N'-arylacylamidine

3448 cm-1

2500-3300 cm-1

1639 cm-1

775 cm-1

694 cm-1

IR Data NMR Data

δ: 1.84, 6.8-8.4

Distinguishing Reaction Intermediates

1587 cm-1

2-(Acetylamino)-N-

phenylbenzamide

36Errede, L. A. J. Org. Chem. 1976, 41, 1763

Kuroda, N.; Hird, N.; Cork, D. G. J. Comb. Chem. 2006, 8, 505

NMR Data

δ: 2.45 (3H, s), 7.21-7.36 (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).

Synthesis of Core Structure

37Liu, J.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70, 6339

One-pot Synthesis of Core Structure

O

OHR1 R2

O

N

NNH

O

NH2

O

OH

P(OPh)3, pyridine

MW, 150 oC, 10 min

HO2C NH

Boc

H2N CO2MeHCl

56%

MW, 220 oC, 1.5 min

736

38Liu, J.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70, 6339

R R1 R2 Yield

H

H

Cl

Me

H

H

H

Me

i-Pr

62%

64%

79%O

N

NNH

O

NH2

OH

HO2C NH

BocH2N CO2MeHCl

R

2

R2

R1R

Application in Total Synthesis of Natural Products

O

N

N

NH

O

O

Sclerotigenin

HO2C NHBoc

NH2

O

OMe

60%

39

O

OH

NH2

N

N

O

NH

Me

O

HN

Fumiquinazoline F

Liu, J.; Kaselj, M.; Isome, Y.; Chapnick, J.; Zhang, B.; Bi, G.; Yohannes, D.; Yu, L.; Baldino, C. M. J. Org. Chem. 2005, 70, 10488

Liu, J.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70, 6339

Green Microwave-assisted One-pot Synthesis

40

Reaction Media: Organic SolventReaction Media: Water?

Water as Reaction Medium

41

H2O

Lidstrőm, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron. 2001, 57, 9225

Synthesis of Isoxazolopyridine

O

O

42

O

O

PhCHO +ON

H2N

+

47 48 49

Tu, S-J.; Zhang, X-H.; Han, Z-G.; Cao, X. D.; Wu, S-S.; Yan, S.; Hao, W. J.; Zhang, G.; Ma, N. J. Comb. Chem. 2009, 11, 428

Synthesis of Isoxazolopyridine Library

C6H54-FC6H44-BrC6H44-ClC6H42-FC6H44 NO C H

Ar

43

4-OCH3C6H43,4-OCH2OC6H33,4-(CH3O)2C6H33,4,5-(CH3O)3C6H24-OH-3-NO2C6H3

4-NO2C6H43-NO2C6H42-ClC6H42,4-Cl2C6H34-CH3C6H4

Tu, S-J.; Zhang, X-H.; Han, Z-G.; Cao, X. D.; Wu, S-S.; Yan, S.; Hao, W. J.; Zhang, G.; Ma, N. J. Comb. Chem. 2009, 11, 428

Possible Reaction Mechanism

44Tu, S-J.; Zhang, X-H.; Han, Z-G.; Cao, X. D.; Wu, S-S.; Yan, S.; Hao, W. J.; Zhang, G.; Ma, N. J. Comb. Chem. 2009, 11, 428

N ON

O Ar

X

Possible Reaction Mechanism

45

Summary

� Pros:� Pros:

Shortened reaction time, aqueous media

� Cons:

One final purification needed, highly pressurized

system, limited reaction scale

46

Electrochemical One-pot Synthesis

47

Electrochemical Reaction

48

Electrochemical Reaction

Oxidation or reduction?

Potential

Battery

49

SolubilitySalt bridge

Retrosynthetic Analysis

NO

O

OCH3

OH

OH

50

50

o-Benzoquinone

51Zeng, C-C.; Liu, F-J.; Ping, D-W.; Hu, L-M.; Cai, Y-L.; Zhong, R-G. Tetrahedron. 2009, 65, 4505

Electrochemical Chemical (EC) Reaction

EC Mechanism

52Zeng, C-C.; Liu, F-J.; Ping, D-W.; Hu, L-M.; Cai, Y-L.; Zhong, R-G. Tetrahedron. 2009, 65, 4505

One-pot Synthesis of Fused Indole Derivative

53Zeng, C-C.; Liu, F-J.; Ping, D-W.; Hu, L-M.; Cai, Y-L.; Zhong, R-G. J. Org. Chem. 2009, 74, 6383

Electrochemical Chemical Electrochemical Chemical (ECEC) Reaction

ECEC Mechanism

54Zeng, C-C.; Liu, F-J.; Ping, D-W.; Hu, L-M.; Cai, Y-L.; Zhong, R-G. J. Org. Chem. 2009, 74, 6383

Michaeladdition

NO

O

OCH3

t-Bu

O

OH

Regioselectivity

55Zeng, C-C.; Liu, F-J.; Ping, D-W.; Hu, L-M.; Cai, Y-L.; Zhong, R-G. J. Org. Chem. 2009, 74, 6383

Synthesis of Analogs

56

Summary

� Pros:

Normal pressure, aqueous mediaNormal pressure, aqueous media

� Cons:

Only work for redox, one final purification needed

57

Conclusions

58

Are we efficient and green in synthesizing fused ring structures?

Acknowledgements

� Prof. Xuefei Huang

� Dino, Gilbert, Gopi, Hovig, Medha, Moe, Phil, Steve, VivianVivian

� All of you

59