Heterogeneous asymmetric Michael additions using environmentally friendly catalysis : application of chiral inorganic-organic hybrid materials

In the last few decades, the development of environmentally benign, sustainable processes for the preparation of optically pure intermediates used in the pharmaceutical, food and agrochemical industries received increasing attention. Processes applying recyclable, chiral heterogeneous catalysts based on readily available, natural, optically pure compounds may be convenient alternatives of the classical asymmetric synthetic methods. During our studies, we have attempted the development of novel heterogeneous catalysts by adsorption of natural amino acids on the surface of inorganic oxides. These materials formed either in-situ during reactions or prepared ex-situ were tested in various asymmetric Michael additions. Amino acids adsorbed on laponite were found the most efficient in catalyzing the addition of aldehydes or ketones to nitrostyrene derivatives. In these reactions occurring via enamine catalysis, the material obtained by adsorption of proline was found to be a highly active and stereoselective catalyst, although proline afforded low enantioselectivities. In the Michael addition of nitroalkanes or β-keto esters to unsaturated ketones, both laponite and alumina were efficient in increasing the enantioselectivities. In these reactions, which take place through iminium catalysis, only moderate enantioselectivities could be reached. The chiral inorganic-organic hybrid materials were characterized by infrared spectroscopy and powder X-ray diffractometry, evidencing bonding of the amino acids on the surface of the oxides. Our results demonstrated that an inorganic surface on which a chiral organocatalyst is immobilized by simple adsorption may have beneficial effect on the asymmetric reaction catalyzed by the chiral material, due to surface improved asymmetric induction. In conclusion, these hybrid materials are promising candidates for future application in environmentally friendly processes

Design, synthesis and biological evaluation of novel estrone phosphonates as high affinity organic anion-transporting polypeptide 2B1 (OATP2B1) inhibitors

Organic anion-transporting polypeptide 2B1 (OATP2B1) is a multispecific membrane transporter mediating the cellular uptake of various exo- and endobiotics, including drugs and steroid hormones. Increased uptake of steroid hormones by OATP2B1 may increase tumor proliferation. Therefore, understanding OATP2B1′ s substrate/inhibitor recognition and inhibition of its function, e.g., in hormone-dependent tumors, would be highly desirable. To identify the crucial structural features that correlate with OATP2B1 inhibition, here we designed modifications at four positions of the estrane skeleton. 13α- or 13β-estrone phosphonates modified at ring A or ring D were synthesized. Hirao and Cu(I)-catalyzed azide–alkyne click reactions served in the syntheses as key steps. 13β-Derivatives displayed outstanding OATP2B1 inhibitory action with IC50 values in the nanomolar range (41–87 nM). A BODIPY-13α-estrone conjugate was additionally synthesized, modified at C-3-O of the steroid, containing a four-carbon linker between the triazole moiety and the BODIPY core. The fluorescent conjugate displayed efficient, submicromolar OATP2B1 inhibitory potency. The newly identified inhibitors and the structure–activity relationships specified here promote our understanding about drug recognition of OATP2B1