Selagibenzophenone A (1) and its isomer selagibenzophenone B (2) were recently described as natural products from Selaginella genus plants with PDE4 inhibitory activity. Herein, we report the first total syntheses of both compounds. By comparing spectroscopic data of the synthetic compounds with reported data for the isolated material, we demonstrate that the structure of one of the two natural products was incorrectly assigned, and that in fact isolated selagibenzophenone A and selagibenzophenone B are identical compounds. The synthetic strategy for both 1 and 2 is based on a cross-coupling reaction and on the addition of organometallic species to assemble the framework of the molecules. Identifying a suitable starting material with the correct substitution pattern is crucial because its pattern is reflected in that of the targeted compounds. These syntheses are finalized via global deprotection. Protecting the phenols as methoxy groups provides the possibility for partial control over the selectivity in the demethylation thanks to differences in the reactivity of the various methoxy groups. Our findings may help in future syntheses of derivatives of the biologically active natural product and in understanding the structure–activity relationship.

A new method of synthesis of an analogue of Bolm's 2,2'-bipyridine ligand based on the catalytic [2 + 2 + 2] cyclotrimerization of 1-halodiynes with nitriles was developed. Crucial step of the whole synthesis turned out to be homodimerization of a substituted 2-bromopyridine to the corresponding bipyridine, that was studied and optimized. The newly prepared bipyridine (S,S)-2 was then tested as a chiral ligand in metalcatalyzed enantioselective reactions. Out of the studied reactions the most promising results were obtained in epoxide ring opening (82% yield, 98% ee) and Mukaiyama aldol reaction (> 96% yield, 99/1 dr, 92% ee). In the case of Mukaiyama-aldol reaction as well as in the Michael addition, novel ligand 2 proved its robustness compared to Bolm's ligand as it was less sensitive to the purity of used reagents.

The ring-opening of epoxides is a synthetically significant process widely applied in all kinds of chemistry. Herein, we report the catalytic and highly enantioselective variant of this reaction exploiting our recent endeavors to design and synthesize chiral bipyridine type ligands. A Sc-complex with a newly developed bipyridine ligand exhibited high reactivity and stereocontrol in the desymmetrization of meso-epoxides with various alcohols. The respective enantiomerically enriched 1,2alkoxyalcohols were obtained with e.r. values of up to 99.5:0.5 for various alcohols regardless of their nature (benzyl, alkyl, cycloalkyl, allyl, propargyl, etc.). We attempted ring-opening of meso-epoxides with anilines as well; however, it proceeded with lower enantioselectivity and was strongly depended on the electronic effect of substituents attached to the aromatic ring.

We report a modular synthetic approach towards novel derivatives of the naturally occurring arylated benzophenone selagibenzophenone A. The initial strategy for the construction of the carbon framework of the derivatives relied on the Suzuki reaction of 2,4,6-tribromobenzonitrile, and the addition of the aryl lithium species to nitrile to generate imine. However, the formed imines showed remarkable stability toward hydrolysis. Therefore, Suzuki cross-coupling was carried out with 2,4,6-tribromobenzaldehyde and the subsequent addition of organometallic species to the aldehyde. Oxidation of the resulting alcohol ensured the access to desired ketones. The importance of the developed modular strategy is underlined by the discovery of several derivatives with selective cytotoxic effects and potential anti-inflammatory activity superior to the effect of the natural product.

One pathway for the preparation of enantiomerically pure compounds from prochiral substrates is the use of metal complex catalysis with chiral ligands. Compared to the other frequently used chiral ligands, chiral 2,2’-bipyridines have been underexploited, despite the data indicating that such ligands have considerable potential in synthetic chemistry. One of those is the so-called Bolm’s ligand, a compound possessing chiral alcohol moieties in the side chains attached to the 2,2’-bipyridine scaffold. Various metal salts have been used in combination with Bolm’s ligand as potent catalysts able to bring about enantioselective alkylations, allylations, conjugate additions, desymmetrization of meso-epoxides, aldol reactions, etc. This review aims to summarize Bolm’s ligand applications in the area of enantioselective synthesis over the last three decades since its preparation.