SYNTHESIS OF DIMERS OF THE NATURAL COMPOUNDS RHODODENDROL, RASPBERRY KETONE AND TYROSOL

Hydroxylated biphenyl unit is embedded in many structures of bioactive natural products and some of them are present in compounds of high biological relevance. It is previously reported by us that generally dimers manifested higher antioxidant efficiency than those of the corresponding monomers [1]. In our laboratory we are actively engaged in the synthesis and biological evaluation of hydroxylated natural-like biphenyls [2]. 4-(4-hydroxyphenyl)-2-butanol, 4-(4-hydroxyphenyl)-2-butanone, 2-(4-hydroxyphenyl)ethanol, commonly known respectively as rhododendrol 1, raspberry ketone 2 and tyrosol 3 are natural phenols which displayed remarkable variety of biological activities. Rhododendrol, mostly present in Acer nikoense and Betula platyphylla, was developed as a tyrosinase inhibitor for lightening/whitening cosmetics [3]. Raspberry ketone, occuring on a variety of fruits, including raspberries, cranberries, and blackberries, sometimes used in perfumery and cosmetics, was proved to restrain oxidative stress and the lipid peroxidation reaction, and to prevent damage in liver cells [4]. Tyrosol is a natural phenolic antioxidant present in a variety of natural sources. It is one of the main natural phenols found in olive oil. As antioxidant, tyrosol can protect cells against injury due to oxidation [5]. We herein report the synthesis, by oxidative coupling reaction mediated by methyltributyl ammonium permanganate (MTBAP), of novel C2-symmetry 2,2?-dihydroxy-5,5?-disubstitued-1,1?-biphenyls (4-6) related to natural phenols rhododendrol, raspberry ketone and tyrosol (1-3). All synthesized compounds were obtained as air stable solids or oils and easily purified by flash chromatography. References: [1] Kancheva V., Kazakova A.S., Fabbri D., Dettori M.A., Delogu G., Janiak M-J. and Amarowic R. Food Chem. 2014, 157, 263-274. Profumo E., Buttari B., D'Arcangelo D., Tinaburri L., Dettori M.A., Fabbri D., Delogu G. and Riganò R. Oxid. Med. Cell. Longev, 2016, Article ID 1246485; [2] Pisano M., Palomba A., Tanca A., Pagnozzi D., Uzzau S., Addis M.F., Dettori M.A., Fabbri D., Palmieri G. and Rozzo C. BMC Cancer 2016, 16:317. Ruzza P., Serra P.A., Fabbri D., Dettori M.A., Rocchitta G. and Delogu G. Eur. J. Med. Chem. 2017, 126, 1034. Maioli M., Basoli V., Carta P., Fabbri D., Dettori M.A., Cruciani S., Serra P.A. and Delogu G. PlosOne 2018, 13(2): e0192178. [3] Sasaki M., Kondo M., Sato K., Umeda M., Kawabata K., Takahashi Y., Suzuki T., Matsunaga K. And Inoue S. Pigm. Cell Melanoma Res. 2014, 27; 754. [4] Wang L., Meng X. and Zhang F. J Med. Food. 2012, 15, 495. [5] Rodríguez-Morató J., Boronat A., Kotronoulas A., Pujadas M., Pastor A., Olesti E., Pérez-Mañá C., Khymenets O., Fitó M., Farré M. and & De la Torre R. Drug Metab. Rev. 2016, 48, 218.