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Title: Synthesis and evaluation of α-fluoro analogues of capsaicin and 2-(aminomethyl)piperidine derivatives
Author: Moraux, Thomas
ISNI:       0000 0004 2721 1692
Awarding Body: University of St Andrews
Current Institution: University of St Andrews
Date of Award: 2011
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Chapter 1 gives an overview of the fluorine chemistry field, from its early developments to recent applications in medicinal chemistry. The development of asymmetric electrophilic or nucleophilic installation of fluorine in organic molecules is highlighten. Chapter 2 of this thesis discusses the enantioselective synthesis of α-fluoroamides. The study is applied to the synthesis of fluoroenantiomers of the bioactive molecule capsaicin and short-chain analogues. The biological activity of these compounds is assayed with the TRPV1 receptor. Results show that enantioselective α-fluoroamides (R)-97, (R)-99 and (S)-99 can generate differentiated biological responses, from TRPV1 agonists to TRPV1 antagonists. Chapter 3 focuses on the optimisation and development of 2-(aminomethyl)piperidine (R)-251 dihydrochloride. The development of 2-(aminomethyl)piperidine (R)-251 as its ditetrafluoroborate salt proved to offer excellent reactivity and solubility for the preparation of derivatives. This tetrafluoroborate salt was used to improve the syntheses of organocatalysts 2,2,2-trifluoro-N-(piperidin-2-ylmethyl)acetamide 363 and 4-methyl-N-(piperidin-2-ylmethyl)benzenesulfonamide 364.The catalytic properties of these latter two molecules for asymmetric Mannich reaction is demonstrated. Both (R)-363 and (R)-364 show up to 86% ee, in a typical 20 mol% loading, but loading of (R)-363 as low as 5 mol% still induces the catalysis.
Supervisor: O'Hagan, David Sponsor: EPSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Asymmetric fluooroorganic chemistry ; Medicinal chemistry ; a-fluoroamides ; Capsaicin ; TRPV1 receptor ; 2-(aminomethyl)piperidine ditetrafluoroborate ; QD412.F1M7 ; Organofluorine compounds ; Organofluorine compounds--Synthesis ; Capsaicin--Derivatives ; Piperidine--Derivatives ; Pharmaceutical chemistry ; Asymmetry (Chemistry)