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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. Double DoM of Naphthalene1,8-bis-Diethylamide 199 TL 6671

  8. 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

  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+-NEt2] Peak at 254 [M+2-NEt2] Peak at 256 Time 0 10 Min • • [M+-NEt2] Peak (254) diappears after addition of SecBuLi and quench with CD3OD • • Time does not increase or decrease the 256 peak • • Equivalents of base = 4.4 20 Min 30 Min 6 Hr 1 Hr

  11. What Role Does the Equivalents of Base Have on formation of Mono or Bis? [M+-NEt2] Peak at 254 2.2 Eqv 1.1 Eqv 3.3 Eqv 4.4 Eqv Starting Material • Equilibrium can be seen for 1.1 equivalents

  12. VT NMR Study Naphthalene-1,8-bis-Diethylamide Alkyl = Me, CH2Me, CH2Et, CH2Pri, CHME2, CH2Ph R =Me, COOH, COOMe, H AB System for CH2 of Amides (CH3 decoubled) Coalescence of AB System at 368°K

  13. Suzuki - Miyaura Cross Coupling of 2,7 – diHalo Naphthalene 1,8-Bis-Diethylamide

  14. Discovery of New Reactions Remote Metalation: Close Induced Proximity Effect (CIPE)

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