1 First Directed ortho Metalation (DoM) of 1,8-Naphthalene Diamides. Towards Nerve Growth Factor Inhibitors Christopher Jones†, Victor Snieckus†, Greg.

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Presentation transcript:

1 First Directed ortho Metalation (DoM) of 1,8-Naphthalene Diamides. Towards Nerve Growth Factor Inhibitors Christopher Jones†, Victor Snieckus†, Greg Ross ‡ † Department of Chemistry, Queen’s University, Kingston, ON, CANADA K7L 3N6 ‡ Department of Physiology, Queen’s University, Kingston, ON, CANADA K7L 3N6

2 Nerve Growth Factor (NGF) Involved in the neuronal development in the Central Nervous System and Peripheral Nervous System. Nerve Growth Factor is implicated in Alzheimer’s, epilepsy, stroke and pain. Production is stimulated in patients suffering from Arthritis pain. Inhibition of NGF causes reduction in pain levels. Ross, G. et al. J. Amer. Chem. Soc, , 1997

3 Previously Identified NGF Inhibitors Target Molecules Ross, G. et al. J. Amer. Chem. Soc, , 1997

4 Directed ortho Metalation (DoM) Reactions in Organic Synthesis E+E+ Hartung, C, Snieckus, V. Modern Arene Chemistry, Wiley-VCH, Weinheim. 2002, 330

5 Advantages of Directed ortho Metalation Recent Work 1. Kalinin,A.; Snieckus, V. et al. J Org Chem, 2003, 68, Chauder, B.; Snieckus, V. et al. Org Lett, 2002, 4, 815

6 Previous Work Involving 2,7-Disubstituted 1,8-Naphthalene Systems Wuest, J et al Organometallics, 1996,15, 1296

7 DoM Chemistry of Naphthalene- bis-Diethylamides. First Results Amide steric interactions provides high rotational barriers Amides are positioned parallel to each other and perpendicular to the aromatic ring. Jones, C; Snieckus, V.; Ross, G. unpublished results %

8 DoM Chemistry of Naphthalene 1,8-bis-Diethylamide Generalization Br 2 derivative achieved by Ipsodesilaytion reaction on the bis TMS derivative.

9 Mono or Di Deprotonation of Naphthalene bis-Diethylamide.What pathway does the deprotonation follow?? Mono or Di Deprotonation of Naphthalene bis-Diethylamide. What pathway does the deprotonation follow?? Determined by CD 3 OD Quench Experiments

10 Mono vs Bis Incorporation of Deuterium Monitored by EI + MS over Time M+ Peak at 326 M+ Peak increases to 328 after addition of SecBuLi and quench with CD 3 OD Time does not increase or decrease the 328 peak Time 010 Min 20 Min30 Min 1 Hr6 Hr M+ Peak at 328

11 What Role Does the Equivalents of Base Have on formation of Mono or Bis? Starting Material M+ Peak at 326 M+ Peak at Eqv 2.2 Eqv 3.3 Eqv 4.4 Eqv Number equivalents of s-BuLi do not have an effect on the formation of Mono vs Bis Deuterated product.

12 Bromo Ipsodesilaytion of Naphthalene- 1,8-dicarboxylic acid bis-diethylamide Colvin, E.W. Silicon in Organic Synthesis. Butterworth: London, 1988 General Ipso-substitution Reaction Synthesize unconventional substitution patterns. Alternative short route with improved yield. Regioselective,clean reaction with mild conditions. 78%

13 RLi Pd 0 DoM-Cross Coupling Connections

14 Suzuki - Miyaura Cross Coupling of 2,7 – diBr Naphthalene 1,8-Bis-Diethylamide

15 Acknowledgements Dr. Victor Snieckus Dr. Greg Ross Dr. Christian Hartung Dr. Bert Nolte Dr. Bernd Keller The Snieckus Group