Rafał Kowalczyk

Copper-catalyzed direct sulfoximination of azoles and polyfluoroarenes under ambient conditions.

The direct dehydrogenative C-N coupling of azoles or polyfluoroarenes with N-H sulfoximines proceeds effectively in the presence of a copper catalyst at room temperature under air to afford the corresponding N-arylsulfoximines in good to high yields.

Enantioselective construction of cis-2,6-disubstituted dihydropyrans: total synthesis of (-)-centrolobine.

This paper presents a simple and efficient route to chiral cis-6-substituted 2-(2-hydroxyethyl)-5,6-dihydro-2H-pyrans, a versatile chiral building block. The strategy is based on three key transformations: enantioselective hetero-Diels-Alder (HDA) reaction of aldehyde with Danishefskys diene, selective reduction of carbonyl function, and Claisen or related rearrangement. The synthetic utility of the methodology is illustrated by total synthesis of antibiotic (-)-centolobine.

Synthesis of CF3-Substituted Sulfoximines from Sulfonimidoyl Fluorides

N-Protected trifluoromethyl-substituted sulfoximines have been prepared by treatment of sulfonimidoyl fluorides with a combination of the Ruppert-Prakash reagent (TMSCF(3)) and tetrabutyl ammonium fluoride (TBAF). The starting materials were accessed following two synthetic routes, and for each reaction sequence the substrate scope was evaluated. Accordingly, a wide variety of aryl-substituted products were obtained in moderate to good yield.

Site and stereoselectivity in sulfa-Michael addition to equivocally activated conjugated dienes

The regiochemical course of sulfa-Michael addition of thiols to terminally divergently activated dienes partially incorporated in a cyclic system, as in substituted 2-(3-oxocyclohexenyl)-vinyls, can be to some extent altered by the choice of activation method. The ratio of products of competing 1,4- and 1,6-addition reactions is dependent on the potency of the electron withdrawing group. The iminium ion catalysis favors 1,6-addition to the cyclic ketone group, changing the product preference for dienes terminated with ketone and aryl ester groups. Application of 9-epi-aminoquinine analogues and an acid allowed for both regioselective and enantioselective (up to 90% ee) addition at the distant δ position.

Potent covalent inhibitors of bacterial urease identified by activity-reactivity profiling

Covalent enzyme inhibitors constitute a highly important group of biologically active compounds, with numerous drugs available on the market. Although the discovery of inhibitors of urease, a urea hydrolyzing enzyme crucial for the survival of some human pathogens, is a field of medicinal chemistry that has grown in recent years, covalent urease inhibitors have been rarely investigated until now. Forty Michael acceptor-type compounds were screened for their inhibitory activities against bacterial urease, and several structures exhibited high potency in the nanomolar range. The correlation between chemical reactivity towards thiols and inhibitory potency indicated the most valuable compound - acetylenedicarboxylic acid, with Ki∗=42.5nM and logkGSH=-2.14. Molecular modelling studies revealed that acetylenedicarboxylic acid is the first example of highly effective mode of binding based on simultaneous bonding to a cysteine residue and interaction with nickel ions present in the active site. Activity-reactivity profiling of reversible covalent enzyme inhibitors is a general method for the identification of valuable drug candidates.

trans-1,2-Diaminocyclohexane-based sulfonamides as effective hydrogen-bonding organocatalysts for asymmetric Michael–hemiacetalization reaction

An easily attainable bifunctional monosulfonamide derivative of DACH was an effective catalyst for Michael addition–hemiacetalization reactions, providing products with ees exceeding 99% under optimized conditions. High enantioselectivities were achieved with just 0.2% mol catalyst loading. The sulfonamide outperformed analogous thiourea and squaramide-based organocatalysts.