Abstract
Facile syntheses of 3-O-carbamoyl, -sulfamoyl, or -pivaloyl derivatives of 13α-oestrone and its 17-deoxy counterpart have been carried out. Microwave-induced, Ni-catalysed Suzuki–Miyaura couplings of the newly synthesised phenol esters with phenylboronic acid afforded 3-deoxy-3-phenyl-13α-oestrone derivatives. The carbamate and pivalate esters proved to be suitable for regioselective arylations. 2-(4-Substituted) phenyl derivatives were synthesised via Pd-catalysed, microwave-assisted C–H activation reactions. An efficient, one-pot, tandem methodology was elaborated for the introduction of the carbamoyl or pivaloyl group followed by regioselective C-2-arylation and subsequent removal of the directing group. The antiproliferative properties of the novel 13α-oestrone derivatives were evaluated in vitro on five human adherent cancer cell lines of gynaecological origin. 3-Sulfamate derivatives displayed substantial cell growth inhibitory potential against certain cell lines. The newly identified antiproliferative compounds having hormonally inactive core might be promising candidates for the design of more active anticancer agents.
Highlights
At the beginning of the 2000s, transition metals and, in particular, palladium came into focus in regard to the development of carbon–carbon coupling reactions
Encouraged by our recent results, here we report the synthesis of 13a-oestrone carbamates, sulfamates, and pivalates suitable for C–H activation and cross-coupling reactions
Certain less common, but more robust phenol derivatives might be utilised as substrates in crosscoupling reactions
Summary
At the beginning of the 2000s, transition metals and, in particular, palladium came into focus in regard to the development of carbon–carbon coupling reactions. Ei-ichi Negishi, and Akira Suzuki received the Prize for “palladium-catalysed cross couplings in organic synthesis”[2] These cross-coupling reactions have found remarkable utility in the synthesis of natural products and biologically active compounds. A wide range of their applications in the pharmaceutical industry increased their value even more These coupling reactions are catalysed by zerovalent palladium, utilising organohalides as electrophilic and organometallic compounds as nucleophilic partners. Beside the synthetic advantages of aryl carbamates, sulfamates, or pivalates in directed C–H activations, these phenol derivatives are popular coupling partners in cross-coupling reactions (Scheme 1)[9,14]. Encouraged by our recent results, here we report the synthesis of 13a-oestrone carbamates, sulfamates, and pivalates suitable for C–H activation and cross-coupling reactions. Evaluation of in vitro antiproliferative action of the newly synthesised compounds against five human reproductive cancer cell lines was accomplished
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