Steglich Esterification of Activated Cinnamyl Cinnamate Derivatives and Computational Studies of Intramolecular Diels-Alder for Lignan Synthesis

Abstract

A ryltetralin and arylnaphthalene lignans consisting of methylenedioxy or trimethoxy groups, such as podophyllotoxin and phyllanthusmin C, are known to have effective anticancer properties. The synthesis of these compounds can be achieved through intramolecular Diels-Alder reactions on cinnamyl cinnamate ester derivatives. Furthermore, this ester is commonly synthesized through an esterification reaction between cinnamoyl halide and cinnamyl alcohol. In this study, cinnamyl cinnamate only produced a 41% yield, while a nearly quantitative yield of 98% was obtained using the Steglich reaction with N,N’-dicyclohexylcarbodiimide and 4-dimethylaminopyridine. This reaction was used to synthesize eight cinnamyl cinnamate ester derivatives, which consisted of methylenedioxy and trimethoxy groups, following a combinatorial synthesis. 3,4-Methylenedioxy- and 3,4,5-trimethoxycinnamyl alcohols were obtained by reducing methyl 3,4-methylenedioxycinnamate and 3,4,5-trimethoxycinnamic acid, respectively. The results showed that the ester yields were excellent, except for the ester derivatives of 3,4,5-trimethoxycinnamyl alcohol. This alcohol was unstable during column chromatography, leading to the direct esterification of the crude reduction products. A side product with Rf adjacent to the ester was obtained, thereby reducing the ester yield. The identification of this by-product and the intramolecular Diels-Alder reaction on the products obtained were described in this study. Computational studies showed that transforming reactants into products led to the production of one intermediate compound and two transition states (TS). Each TS represented the intramolecular Diels-Alder cycloaddition reaction and migration of [1,3]-hydrogen. Thermodynamic studies consistently revealed that a solvent environment could effectively reduce the activation energy associated with a chemical process.