Synthesis of Cinnamyl Cinnamate Ester Derivatives as Precursor for The Formation of Aryltetralin and Arylnaphtalene Lignans Using The Steglich Esterification Method
Rizky Arif Fajar Husandy Ritonga, Budi Arifin, Purwantiningsih Sugita, Suminar Setiati Achmadi

Department of Chemistry, Faculty of Mathematics and Natural Sciences, IPB University, Bogor

Abstract

Aryltetralin and arylnaphthalene lignans have anticancer, antiviral, and antitumor properties. In particular, the presence of methylenedioxy or trimethoxy groups in these lignans, as in podophyllotoxin and philanthusmin C, indicates good cancer inhibition ability. However, most of these lignans are not commercially available and need to be isolated or synthesized. Several synthetic methods have been reported, including the intramolecular Diels-Alder reaction. This method involves the cyclization of cinnamyl cinnamate ester derivatives. This ester is commonly synthesized through an esterification reaction between cinnamoyl halide and cinnamyl alcohol. However, using this reaction in this research, cinnamyl cinnamate is only produced in 41% yield from commercial cinnamoyl chloride and cinnamyl alcohol. On the contrary, a nearly quantitative yield (98%) was obtained using the Steglich reaction with N,N^-dicyclohexylcarbodiimide as the linker and 4-dimethylaminopyridine as the base. This reaction was then used to synthesize eight cinnamyl cinnamate ester derivatives with methylenedioxy and trimethoxy groups. Methylenedioxy- and 3,4,5-trimethoxycinnamyl alcohols were obtained by reducing the commercial acids. The ester yields were generally excellent (73-88%). However, the yield of ester derivatives of 3,4,5-trimethoxycinnamyl alcohol was poor (16-33%). This alcohol was unstable during column chromatography, so the crude reduction products were directly esterified. A side product with Rf adjacent to the ester resulted, thereby reducing the ester yield. The identification of this by-product and the intramolecular Diels-Alder reaction on the ester products obtained are currently being carried out.

Keywords: anticancer, cinnamic acid, cinnamyl alcohol, Diels-Alder, podophyllotoxin

Topic: Organic Chemistry