A practical synthesis of three aliphatic metabolites of capsaicin: 16-Hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-dehydrocapsaicin

Abstract

The first straightforward synthesis of 16-hydroxycapsaicin, 17-hydroxycapsaicin and 16,17-dehydrocapsaicin, the major aliphatic metabolites of capsaicin, is reported. The amidation of hept-6-enoic acid with vanillylamine hydrochloride, followed by olefin metathesis using 2-methylbut-3-en-2-ol as partner furnished 16-hydroxycapsaicin in 56.1% overall yield with excellent E-selectivity. The E-selective olefin metathesis of methyl hept-6-enoate with but-3-en-2-one led to α,β-unsaturated ketone compound, which was subject to Wittig reaction with Ph₃P⁺MeBr^-, providing the corresponding 1,3-diene derivative. After removing methyl group by hydrolysis and introducing hydroxyl group by hydroboration-oxidation, such diene could be further converted to 16,17-dehydrocapsaicin and 17-hydroxycapsaicin with overall yields of 35.6 and 7.8%, respectively.

GRAPHICAL ABSTRACT

Keywords:

• Capsaicin metabolites
• hydroboration-oxidation
• olefin metathesis
• Wittig reaction

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

We gratefully acknowledge the financial support from the National Natural Science Foundation of China (Grant No. 32072344), and the Scientific and Technological Project of CNTC (Grant No. 110202102001), the scientific research program of innovation platform in State Tobacco Monopoly Administration, and Innovation projects of Zhengzhou Tobacco Research Institute (Grant No. 442020CR0320).