Application of benzyl protecting groups in the synthesis of prenylated aromatic compounds Sina I. Odejinmi and David F. Wiemer * Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA Received 6 February 2005; accepted 25 March 2005 Available online 13 April 2005 Abstract—Benzyl ethers have proven to be useful protecting groups for synthesis of phenols bearing isoprenoid chains because the benzyl groups can tolerate the conditions of halogen–metal exchange used to introduce the side chains yet are cleaved in good yields upon treatment with sodium s-butanol. Ó 2005 Elsevier Ltd. All rights reserved. Prenylated aromatic compounds often have been found as natural products, and they have displayed a wide range of biological activities. Various compounds have shown antiviral, anticancer, 1 antimicrobial, 2,3 and anti- fungal properties. 4 Others have been reported to func- tion as insect repellents, 5 immunosuppressive agents, 6 and opioid receptor modulators. 7 Representative exam- ples, illustrating isoprenoid chains of different lengths and varied oxidation patterns, include montadial (1), 8 pawhuskin C (2) 7 the ganomycins (3, 4), 3 piperoic acid (5) 9 and arieianal (6). 10 Recently we have become interested in the synthesis of prenylated aromatic compounds because of their inter- esting structures and novel bioactivities. 11 One feature common to both the compounds we have targeted and many others is the presence of at least one phenolic group on the aromatic ring ortho to the isoprenoid sub- stituent. In addition, functionality such as phenol or hydroxyl groups, aldehydes, and/or carboxylic acids commonly can be found on the aromatic ring and/or the isoprenoid chain. Thus while there are many strate- gies that can be employed to attach an isoprenoid chain to an aromatic ring, these generally require phenol pro- tection and the protection/deprotection strategy must be compatible with other functional groups found on the ring and on the side chain. Many different protecting groups might be employed for phenol protection, 12 but the abundance of functionality encountered in these systems and the demanding condi- tions often employed to attach the isoprenoid chain OH OH HO O OH O HO OH H O OH OH HO HO 2 5 CHO OH OH H O 1 R COOH OH HO 3 R = OH 4 R = H 6 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.03.187 Keywords: Benzyl ether; Protecting group; Montadial; Piperoic acid. * Corresponding author. Tel.: +1 319 335 1365; fax: +1 319 335 1270; e-mail: david-wiemer@uiowa.edu Tetrahedron Letters 46 (2005) 3871–3874 Tetrahedron Letters