Isolation and Synthesis of Capsaicin

Even in its simplified form, the Nelson protocol will deter the most enthusiast natural-product chemist. Unsurprisingly, alternative protocols have been described in the proprietary literature, and their sheer number testify to the ingenuity and commitment of chemists to solve what is still today a daunting task. Some modern modifications to the Nelson method from the proprietary literature include the use of supercritical carbon dioxide to reduce the extraction of pigments in the preparation of the oleoresin [54], and the recourse to macroporous adsorption resins [55] or to repeated extraction with aqueous silver nitrate to trap capsaicinoids and reduce the number of partition steps [56]. 

Orito also developed a variation of this synthesis, based on the Wittig reaction of the phosphonium salt from isobutylbromide with a series of lactols. After alcohol-to-acid oxidation, a mixture of MNA isomers is obtained, then isomerized with nitrous acid [61,62]. 

In all these protocols, chemoselective amidation of vanillamine with NMA was achieved in satisfactory yield (about 80 %) by activation of the add to its corresponding chloride, followed by condensation with free vanillamine. Free vanillamine is much less stable than its corresponding chloride, and, owing to its polarity, it is difficult to extrad quantitatively from water solution, with loss of about 20 % of the product routinely observed in the desalification step [59]. Furthermore, the preparation of chlorides from polyunsaturated fatty acids is not trivial, and therefore alternative coupling protocols were investigated in a series of systematic studies dedicated to the structure-adivity relationships of capsaicinoids. 

Enzymatic syntheses of CPS have also been reported, using various lipase-catalyzed transacylations [69]. Interestingly, a biotechnological process to obtain natural vanillin from CPS has been developed, capitalizing on the enzymatic hydrolysis of CPS and the oxidation of vanillamine with a flavoprotein vanillyl alcohol oxidase [70]. 

TRV1 as the Biological Target of Capsaicin and the Ecological Raison d e of Capsaicinoids A Molecular View 

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