Dicarotenoid esters of bivalent acids Magdolna Ha ´da, Veronika Nagy, Aniko ´ Taka ´tsy, Jo ´ zsef Deli, Attila Ago ´cs * Department of Biochemistry and Medical Chemistry, University of Pe ´cs, Medical School, Szigeti u ´ t 12, H-7624 Pe ´cs, Hungary Received 11 February 2008; revised 6 March 2008; accepted 27 March 2008 Available online 29 March 2008 Abstract For the evaluation of the synthesis of dendritic esters from carotenoids the C 20 apocarotenoid retinol was chosen for model studies, being a commercially available hydroxy carotenoid. Dimers were synthesized from retinol with dicarboxyl cores and from retinol succinate with other hydroxy carotenoids. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Carotenoid; Retinol; Diester; Dimer Carotenoids, being naturally occurring antioxidants and having various biological effects including anti-cancer and cardioprotective, have been the focus of food biochemists recently. 1 Dimers and dendrimers of these compounds have not been synthesized until now, although they can have interesting properties especially when combined with the advantages of carotenoids. These compounds may have enchanced antioxidant activity and could be used for aggregation studies. 2 Carotenoid diesters are not unknown in the literature, and there are examples including enzy- matic reactions with carotenoid acids 3 and reactions between carotenoid acids and carotenols. 4 However, the chemistry described there cannot be directly applied for the synthesis of the esters described in this Letter. In our present Letter we describe the synthesis of some retinol dimers and their precursors which can serve as a starting point for further studies with other hydroxy carotenoids and later form a basis for the synthesis of carotenoid dendrimers. Retinol was chosen as a model compound for other carotenoids being not too expensive and easily accessible (Fig. 1). Other carotenoids were isolated from natural sources or purchased except for 4 0 -hydroxy-echinenone, which was produced by the partial reduction of canthaxan- thin with sodium borohydride. Our aim was to make dicarotenoid diesters of bivalent acids in which secondary interactions are possible between the two polyene chains. To achieve this, retinol and various other carotenoids were esterified with several cyclic acid anhydrides. The results of these experiments are summa- rized in Table 1. These anhydrides were chosen after sev- eral unsuccessful trials with the corresponding acyl dichlorides. In general, the reactions of carotenoids with acyl chlorides in pyridine or in dichloromethane/pyridine gave several by-products, whereas anhydrides gave cleaner reactions. 5,6 All of the hydroxyl groups of the carotenoids were ester- ified with succinic anhydride forming the corresponding mono- and disuccinates bearing free carboxyl groups. Unfortunately, maleic anhydride appeared to be too reac- tive, whereas phthalic anhydride did not give even the cor- responding monoesters. The retinol succinate monoester formed (1) can be cou- pled with other carotenoid alcohols via the Steglich- method using dicyclohexyl carbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP) in dichloromethane (Fig. 2). 7 The reaction gave homo- and heterodimers (2a– c) in good yields, and the conversion of the alcohols was about 70–80%. The dimers could be crystallized from 0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2008.03.137 * Corresponding author. Tel.: +36 72 536001x1864; fax: +36 72 536225. E-mail address: attila.agocs@aok.pte.hu (A. Ago ´ cs). Available online at www.sciencedirect.com Tetrahedron Letters 49 (2008) 3524–3526