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Christopher Jones † , Victor Snieckus † , Greg Ross ‡

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

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Christopher Jones † , Victor Snieckus † , Greg Ross ‡

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  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 chrisj@chem.queensu.ca

  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, 99 121, 1997

  3. Previously Identified NGF Inhibitors Target Molecules Ross, G. et al. J. Amer. Chem. Soc, 99 121, 1997

  4. Directed ortho Metalation (DoM) Reactions in Organic Synthesis 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, 5992 2. 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 50% • 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 Jones, C; Snieckus, V.; Ross, G. unpublished results 2003

  8. DoM Chemistry of Naphthalene 1,8-bis-Diethylamide Generalization • Br2 derivative achieved by Ipsodesilaytion reaction on the bis TMS derivative.

  9. Mono or Di Deprotonation of Naphthalenebis-Diethylamide.What pathway does the deprotonation follow?? • Determined by CD3OD Quench Experiments

  10. Mono vs Bis Incorporation of Deuterium Monitored by EI+ MS over Time M+ Peak at 326 M+ Peak at 328 Time 0 10 Min 20 Min 30 Min • M+ Peak increases to 328 after addition of SecBuLi and quench with CD3OD • Time does not increase or decrease the 328 peak 1 Hr 6 Hr

  11. What Role Does the Equivalents of Base Have on formation of Mono or Bis? M+ Peak at 328 M+ Peak at 326 2.2 Eqv 1.1 Eqv 3.3 Eqv 4.4 Eqv Starting Material • 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 General Ipso-substitution Reaction • Synthesize unconventional substitution patterns. • Alternative short route with improved yield. • Regioselective,clean reaction with mild conditions. 78% Colvin, E.W. Silicon in Organic Synthesis. Butterworth: London, 1988

  13. DoM-Cross Coupling Connections RLi Pd0

  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

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