An Efficient and Facile Synthesis of Capsaicin‐Like Compounds as Agonists of the TRPV1 Receptor

Abstract

AbstractA new versatile synthetic route is described for the preparation of capsaicin‐like molecules which contain an α‐hydroxy ketone functional group mimicking the amide functional group in the capsaicin structure. The key reaction in this synthesis was the formation of α‐(dimethylamino)alkanenitriles as intermediates. These nitriles were successfully prepared from both aliphatic and aromatic aldehydes by reaction with dimethylamine and aqueous sodium cyanide. Treatment of the nitriles with lithium diisopropylamide (LDA) followed by reaction with various aldehydes led to the formation of α‐hydroxy ketone compounds, examples of which include 2‐hydroxy‐1‐(4‐hydroxy‐3‐methoxyphenyl)dodecan‐3‐one,(5R)‐ and (5S)‐2‐hydroxy‐1‐(4‐hydroxy‐3‐methoxyphenyl)‐5,9‐dimethyldec‐8‐en‐3‐one, representing novel capsaicin‐like molecules. Formation of (4‐benzyloxy‐3‐methoxyphenyl)acetaldehyde was also described from the Wittig reaction of 4‐benzyloxy‐3‐methoxybenzadehyde with an ylide reagent (methoxymethyl)triphenylphosphonium bromide followed by acid hydrolysis to form the title compound. This aldehyde represents a useful precursor for the synthesis of capsaicin‐like structures.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)