FULL PAPER DOI: 10.1002/ejoc.201101193 A Multicomponent Carba-Betti Strategy to Alkylidene Heterodimers – Total Synthesis and Structure–Activity Relationships of Arzanol Alberto Minassi,* [a] Lavinia Cicione, [a] Andreas Koeberle, [b] Julia Bauer, [b] Stefan Laufer, [b] Oliver Werz, [c] and Giovanni Appendino* [a] Keywords: Natural products / Polyphenols / Medicinal chemistry / Drug discovery / Synthetic methods / Multicomponent reactions / Betti reaction Using the synthesis of the heterodimeric phloroglucinyl pyr- one arzanol as a benchmark reaction, a carba-version of the Betti multicomponent reaction has been developed. Capi- talizing on the fluorous activation of the phenolic component and the use of iminium ions as bivalent and “transmissive” Introduction Because of their high atom economy, multicomponent reactions (MCRs) represent a premium strategy compared to one-pot reactions. [1] Most MCRs are triggered by the nucleophilic attack of a carbon nucleophile on an iminium ion and involve the formation of at least one carbon–nitro- gen bond. Outside the realm of transition metals, nitrogen- free MCRs have not yet been given systematic attention de- spite their biological relevance [2] and potential to increase chemical diversity. As weak acids, phenols are, in principle, excellent substrates for MCRs, as exemplified by the vener- able Betti reaction. In this Mannich-type condensation, a Schiff base, generated in situ from an amine and a carbonyl compound, is trapped by a phenol to generate an α-aryl- amine (Scheme 1). [3] The tendency of phenols to form homodimeric adducts with carbonyl derivatives [4] has so far prevented the development of isosteric, nonnitrogenous ver- sions of the Betti reaction, and this area has so far remained a terra incognita for organic synthesis. [5] Our interest in carba-versions of the Betti reaction was piqued by the discovery of arzanol (4a), [6] which is a hetero- [a] Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy Fax: +39-0321-375821 E-mail: minassi@pharm.unipmn.it appendino@pharm.unipmn.it [b] Department for Pharmaceutical Analytics, Pharmaceutical In- stitute, University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany E-mail: stephan.laufer@uni-tuebingen.de [c] Department of Pharmaceutical/Medicinal Chemistry, University of Jena, Philosophenweg 14, 07743 Jena, Germany E-mail: oliver.werz@uni-jena.de Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201101193. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2012, 772–779 772 aldehyde equivalents, the reaction has been used to colonize a biologically privileged but previously inaccessible area of chemical space and investigate the structure–activity rela- tionships of arzanol towards a series of proinflammatory tar- gets (mPGES-1, 5-LO). Scheme 1. Multicomponent Betti reaction (X = ArN) and its carba version [X = C(COR) 2 ]. dimeric compound formally derived from Michael addition of the prenylated acylphloroglucinol 3 to a reactive methyl- ene-2,4-dioxopyrone (2, Scheme 2). Compound 4a is similar to the Betti base monophyllidin (5), which is a Zanthoxylum alkaloid, [7] and the two compounds are examples of how Scheme 2. Putative carba-Betti biogenesis of 4a and the structure of 5.