1 / 13

Directed Ortho Metalation of Naphthalene 1,8-bis(diethylamide) for Nerve Growth Factor Inhibitors

This research explores the directed ortho metalation (DoM) of naphthalene 1,8-bis(diethylamide) focusing on inhibitors for nerve growth factor (NGF), which plays a significant role in neuronal development and is implicated in conditions like Alzheimer’s, epilepsy, and chronic pain. By investigating the synthesis of NGF inhibitors through DoM, our work aims to contribute to pain management therapies. The study includes examples of metalation reactions and highlights the potential of these compounds in alleviating pain by effectively inhibiting NGF.

keely
Télécharger la présentation

Directed Ortho Metalation of Naphthalene 1,8-bis(diethylamide) for Nerve Growth Factor Inhibitors

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Directed ortho Metalation of Naphthalene 1,8-bis(diethylamide):Research Towards Nerve Growth Factor Inhibitors John Stephenson†, Christopher Jones††, Victor Snieckus†† † Department of Chemical Engineering, Queen’s University †† Department of Chemistry, Queen’s University Kingston, ON, Canada. K7L 3N6 8js5@qlink.queensu.ca

  2. Nerve Growth Factor (NGF) • Involved with 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 of protein is stimulated in patients suffering from Arthritis pain. • Inhibition of NGF causes reduction in pain levels. Shamovsky,et al. J Am Chem Soc, 1999, 121, 9797-9806

  3. Previously Identified NGF Inhibitors Target Molecules Marone, S. and Ross, G. 2000, World Patent No. WO0069829

  4. Directed ortho Metalation • Original Work • Gilman et al. J. Am. Chem. Soc.1939, 61, 106-109. • Wittig et al. Chem. Ber.1940, 73, 1197. 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

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

  6. Examples of double DoM Chemistry of Naphthalene 1,8-bis(diethylamide) E+ E Equiv % Yield CF3CH2I I 4.4 86% TMSCl TMS 4.4 50% DMF CHO 2.2 40% (MeS)2 SMe 2.2 74%

  7. Deprotonation of Naphthalenebis-diethylamide • Determined by CD3OD Quench Experiments

  8. 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

  9. Examples of mono DoM Chemistry of Naphthalene 1,8-bis(diethylamide) E+ E Equiv Mono% Bis% SM% TMSCl TMS 1.1 15% 25% 38% (SMe)2 SMe 1.1 ?% ?% ?% CF3CH2I I 1.1 ?% ?% ?% DMF CHO 1.1 14% 35% 47% Snieckus, V.; Jones, C.; Stephenson, J., 2003, unpublished results.

  10. Suzuki-Miyaura Cross Coupling • Used to form sp2 carbon-carbon bonds • Coupling of an aryl boronic acid with an aryl halide • Pd(PPh3)4 or Pd(dppf)Cl2 are common catalysts • Catalytic cycle of Suzuki cross coupling:

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

  12. Future Work Cross Coupling of Mono Product Cyclization of Mono Product

  13. Acknowledgements • Dr. Victor Snieckus • Chris Jones • Snieckus Group

More Related