Synthesis Of Capsaicin Analogs And A Preliminary Study On Its Pungency-structure Relationship

Capsaicinoids are active ingredients that cause pungency sensation in chili,including many compounds such as capsaicin and dihydrocapsaicin,in which capsaicin and dihydrocapsaicin content are more than 90%.Natural capsaicinoids have analgesic,anti-cancer,blood lipid regulation,body weight maintenance,antibacterial,antiinflammatory,anti-fatigue and lachrymatory effect,so they are widely used in medical,cosmetic,food additives,biological control,marine antifouling coatings and tear-gas weapon fields.The sources of capsaicinoids include three ways:(1)extraction from chili;(2)biosynthesis;(3)chemical synthesis.Extraction of capsaicin is uneconomic;biosynthesis of capsaicinoids is currently staying in the laboratory stage;chemical synthesis is the current industrial method for producing capsaicinoids.However,the existing synthesis methods have some problems such as multiple synthesis steps and harsh reaction conditions.Therefore,it is necessary to improve the chemical synthesis of capsaicinoids to overcome the existing problems.In the application of capsaicinoids,it is necessary to develop high pungent capsaicinoids.To design the high-pungent capsaicin compounds rationally,further research on the pungent-structure of capsaicin compounds is required.In this paper,the synthetic process of capsaicin analogs was modified.The synthesis of capsaicinoids includes three steps:(1)the synthesis of vanillylamine derivatives;(2)the synthesis of ethyl 8-methylnonenoate;(3)the ammonolysis of ester to capsaicin.For the synthesis of ethyl 8-methylnonenoate,ethyl 6-bromohexanoate and isobutyl magnesium bromide were used as raw materials,lithium tetrachlorocuprate as the catalyst,and NMP(N-methyl Pyrrolidone)as a co-solvent.The product ethyl 8-methylnonenoate was obtained from Grignard cross-coupling reaction with a yield of 83%.It is worth noting that the Grignard cross-coupling reaction was conducted at temperature of 0 ?,which is milder than the reaction conditions of-78 ?,and the yield is higher than that of the literature.For the synthesis of vanillylamine derivatives,it was found that some vanillylamine derivatives can be obtained by reducing oxime with nickel-aluminum alloy powder,and this reduction operation is simple and the yield is high.Among capsaicin analogs,the synthetic method of dihydrocapsaicin was explored firstly: dihydrocapsaicin was obtained with a yield of 73% by the ammonolysis reaction between ethyl 8-methylnonenoate and vanillylamine catalyzed by TBD(1,5,7-triazabicyclo [4.4.0] dec-5-ene).Based on the results above,twelve more capsaicin analogs were synthesized.The synthesis process of capsaicin analogs in this paper has some advantages such as readily available of raw materials,less steps,simple operation,high yield and less pollution.To explore the pungency-structure relationship of capsaicin analogs,the affinity constants between the capsaicinoids and the TRPV1 protein were measured using an enzyme-linked immunoassay.Correlated the pungency of the five compounds and their affinity constants,it was found that the pungency(P)and the logarithm of the affinity constant(lgKa)approximated a linear relationship: P = 510 lgKa-1701.7(correlation coefficient R = 0.957),resulting a new method for evaluating the pungency of compounds obtained.Using this pungency evaluation method,the pungency of twelve capsaicin analogs synthesized in this paper was predicted.After analyzed the relationship between the structure and the pungency,it was found that:(1)with the alkoxy carbon chain on 3-position benzene ring of capsaicin increased,the pungency gradually decreased;(2)the substitutions on the 3-and 4-position of benzene with hydroxyl or alkoxy contribute to the pungency of capsaicin;more substitutions on the benzene ring may be unfavorable to pungency;(3)unsaturated double bond in the aliphatic acid side chain are beneficial to the pungency;in addition,when the unsaturated double bond in the aliphatic acid side chain changed from trans to cis,it may be unfavorable to pungency.