A new facile synthesis of steroid dimers containing 17,17′-dicarboxamide spacers

Abstract

a b s t r a c tA set of new steroid dimers linked through ring D-ring D were synthesized via catalytic diaminocarbonylation of 17-iodo-5 a-androst-16-ene, in the presence of palladium-phosphine in situ catalysts and aliphatic or aromatic diamines as N-nucleophiles. The dimeric steroidal comp ounds containing 17,17 0 -dicarboxamide spacers were obtained through highly chemoselective reactions in good isolated yields and completely characterized by spectro scopic techniques.Ó 2013 Elsevier Ltd. All rights reserved.Steroids are widely found in both plant and animal kingdoms, and play crucial roles in biological systems.1,2 Among them, dimeric steroids constitute a class of compound s, which have recently attracted much attention due to their remarkable properties as potential cytotoxic, antimalarial, anticancer, and cholesterol lowering drugs as well as molecular umbrellas in drug delivery. [3][4][5][6][7][8][9] In addition to their pharmacologic al importance, several dimeric and oligomeric steroids display micellar activity, 10 they can also act as ligands for proteins and trigger cellular processes or may promote the affinity of ligands to their binding locations by providing extra anchoring points to the active site of certain domains. 11,12 Some of the dimers show liquid-crystal behaviour 13 and play key roles in rate enhancem ent from hydrophobic binding. 3 Thus, other environmentall y sustainab le alternativ es to promote steroid dimerizatio ns still constitute a great challenge. It is well established that transition-m etal-catalyzed reactions are versatile tools to introduce different functionalities into specific positions of the steroidal framework, which can render marked changes in their biologica l properties. 30 Recently, our groups have reported several examples on the aminocarbonylation of steroidal alkenyl-iodide s toward carboxamides . 31 Nevertheless, to the best of our knowledge, there is only one example on the synthesis of dimeric steroids involving Pd-catalyzed carbonylativ e dimerization of alkenyl-iodide intermediates , to form 17-carbox ylic anhydrides, in the presence of carbon monoxide and water. 32 It should be also noted that the application of diamines as N-nucleop hiles in palladium-cata lyzed aminocar bonylation toward dicarboxamide s is unprecedented. Therefore, the iodoalkene-based catalytic synthetic strategy described herein provides a complete ly new, facile, efficient, and atom economic methodology for the preparation of steroid dimers. A set of dimeric androst-16-en es with structurally different dicarboxamide spacers at C-17 was synthesized via one-pot, one-step palladium-cata lyzed aminocar bonylation of 17-iodo-5 a-androst-16-ene (1), which was obtained by the modified Barton's procedure from the correspond ing 17-ketone. The carbonylativ e dimeriza tion reaction leading to steroidal dicarboxami des (2a-2d) took place under relatively mild conditions (30 bar CO, 100 °C), with nearly full conversion of the initial iodo alkenyl steroid in 5 h. The symmetric androst-16-en e ...

One‐Step Synthesis of Dicarboxamides through Pd‐Catalysed Aminocarbonylation with Diamines as N‐Nucleophiles

“…[43] The steroid dicarboxamides 7c, 7d and 7e were synthesised by aminocarbonylation of 17-iodo-5α-androst-16-ene as previously reported. [30] …”

“…Selected dicarboxamide compounds from each family (2a, 2c, 2d, 4c and 4f), in addition to the previously developed steroid dimers 7c, 7d and 7e [30] (Figure 3), were evaluated as cytotoxic agents against A549 human lung carcinoma cells, which have frequently been chosen by our group [40] and others [41,42] as a suitable cell culture to perform toxicity tests. Therefore, concentration-response experiments were performed to establish the cytotoxic activity of each selected compound (Figure 4).…”

“…Dicarboxamide steroid dimers [30] also evaluated in this study as cytotoxic agents against A549 human lung carcinoma cells. We observed that N,NЈ-(butane-1,4-diyl)dibenzamide (4c) was the most efficient cytotoxic agent when a high agent concentration (50 μm) was used, resulting in the death of 65 % of the A549 cells.…”

“…Only a few studies relating to this subject have been reported to date; they include the synthesis of dicarboxamides through aminocarbonylation of diiodo substrates, [28] or through the application of diamines as N-nucleophiles. Among the latter, the synthesis of selenophene derivatives [29] and our recent work on the preparation of 5α-androst-16-ene dimers [30] are the only examples reported so far.…”

A novel Pd-catalysed sequential carbonylation/cyclization approach toward bis- N -heterocycles: rationalization by electronic structure calculations

“…Furthermore, their preparation is often accomplished through laborious experimental procedures involving numerous synthetic steps and difficult isolation/purification of intermediates, leading to expensive and low-yielding global synthesis [39][40][41]. Therefore, prompted by our previous investigation into the potential and synthetic applications of Pd-catalysed aminocarbonylation [34,[42][43][44], the seminal works of Yamamoto's group on the double carbonylation of aryl halides [45][46][47][48][49][50] and the review on the synthesis of 2-ketoamides in catalytic reactions [51], herein we report a novel one-pot synthetic route towards bis-N-heterocyclic derivatives (indole-based hydropyrazinones, benzodiazepinones and hydroquinoxalines), through a sequential Pd-catalysed amino double carbonylation/cyclization strategy, using carbon monoxide and structurally different aliphatic diamines as N-nucleophiles. Electronic structure calculations were carried out to rationalize the reaction selectivity for indole-based cyclic molecules with the different amines.…”