Heck Cyclization of 6-Bromo-4-O-methylconiferyl Acrylate Ester: A Preliminary Study of Podophyllotoxin Synthesis from Eugenol
Budi Arifin (1*), Yana Maolana Syah (1), and Didin Mujahidin (1)

1) Chemistry Study Program, Bandung Institute of Technology

Abstract

Podophyllotoxin is an aryltetralin lactone lignan with antiviral and anticancer properties. The demand for podophyllotoxin as a starting material for semisynthesis of more active derivatives is increasing. One method for producing podophyllotoxin is through chemical synthesis. Lignan is comprised of two phenylpropanoid units, so it can be synthesized from other phenylpropanoid molecules, one of which is eugenol, a primary constituent of clove essential oil. The potential for eugenol as a starting material for lignan is enormous because Indonesia is the world^s leading clove producer. For podophyllotoxin synthesis from eugenol, we proposed a new method synthesizing a 6-bromoconiferyl ester from eugenol, followed by a Heck-tandem cyclization of the ester. This paper presents the results of a preliminary study of Heck-tandem cyclization of the 6-bromo-4-O-methylconiferyl acrylate ester to a simpler podophyllotoxin analogue. The acrylic ester was synthesized from eugenol with a yield of 42% in three steps: methylation, bromination, and dehydrobromination-nucleophilic substitution. Heck cyclization was performed in DMF solvent with or without the presence of PPh3 ligand, using different amounts and types of catalyst (PdCl2, Pd(OAc)2, Pd(PPh3)4, and PdCl2(PPh3)2) and base (K2CO3, Cs2CO3, DBU, Et3N, and NaOAc),. However, under the various reaction conditions examined, the expected cyclization reaction did not occur. The ester hydrolyzes to generate 6-bromo-4-O-methylconiferyl alcohol, which is subsequently oxidized to form 6-bromo-4-O-methylconiferaldehyde when the reaction is prolonged at a high temperature or with a stronger base. The stiffness of the (E)-double bond in the cinnamyl group appears to hinder the molecular structure from bending into the conformation required for coupling between the acrylate^s terminal double bond and the aryl bromide groups.

Keywords: Anticancer- Antiviral- Bromination- Clove- Methylation- Palladium- Phenylpropanoid-

Topic: Organic Chemistry