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Diversity-oriented synthesis (DOS) is a rich source for novel lead structures in Medicinal Chemistry. In this study, we present a DOS-compatible method for synthesis of compounds bearing a free thiol moiety. The procedure relies on Rh(II)-catalyzed coupling of dithiols to diazo building blocks. The synthetized library was probed against metallo-β-lactamases (MBLs) NDM-1 and VIM-1. Biochemical and biological evaluation led to identification of novel potent MBL inhibitors with antibiotic adjuvant activity.

α-Diazo homophotalimides were reacted with various propiolic acids on Rh 2 (esp) 2 catalysis. The resulting propiolate esters were transformed into novel, heterocyclic Δ α,β -spirobutenolides in good to excellent product yields. The approach represents a fundamentally novel entry into natural-like Δ α,β -spirobutenolides present in many biologically active natural products as well as fully synthetic compounds endowed with diverse biological activities. The Δ α,β -spirobutenolides thus obtained were shown to inhibit thioredoxin reductase, a selenocysteine enzyme target for cancer. Moreover, for the best compound in the series (TrxR IC 50 1.49 ± 0.08 μM), it was shown, using MALDI-TOF mass-spectrometry, that it selectively binds selenocysteine in the presence of a 10-fold excess of cysteine. This validates the new compound as a promising lead for anticancer therapy development.

A novel 3-phenyl-4-thiaglutaric anhydride was employed as a highly reactive partner for the Castagnoli-Cushman reaction. This, in combination with the use of DMF as a reaction medium, resulted in a drastic lowering of the reaction temperature to ambient (compared to the 110–150 °C range typical for similar processes involving glutaric anhydride) and an extended reaction scope (with respect to substitution pattern in the imine component). Diastereomeric products were separated, in the form of respective methyl esters, and their comparative NMR characterization led to preliminary generalizations regarding the syn- and anti-series.

Sterically demanding indolenines were employed as cyclic imine substrates in the Joullie–Ugi reaction with diverse isocyanides and carboxylic acids resulting in a new type of conformationally constrained indoline-based peptidomimetic compounds.

Sterically demanding indolenines are employed as cyclic imine substrates in the title reaction with isocyanides and carboxylic acids, resulting in a new type of conformationally constrained indoline-based peptidomimetics.

The first solvent-free protocol for the atom-economical Castagnoli–Cushman reaction is reported. It substantially broadens the reaction scope with respect to achievable substitution patterns around the privileged lactam cores compared to the traditional reaction format employing aromatic hydrocarbon solvents. The convenient product isolation protocol involves the use of aqueous base and acid solutions.

Unlike its trans counterpart, the cis-configured scaffold derived from the Castagnoli–Cushman reaction (CCR) is scarce and has not been explored in bioactive compound design. We found that conducting this reaction in DMF (in contrast to conventional toluene or xylene) led to a significantly higher proportion of cis-configured lactams in the diastereomeric product mixture. This allowed us, for the first time, to obtain and thoroughly characterize both stereoisomers of a significant number of lead-like CCR lactams. Simple rules for 1H NMR-based stereochemical assignment have been devised and correlated with the single-crystal X-ray structures obtained for pure cis- and trans-configured lactams.

The diversity of dicarboxylic acid anhydrides employable in the Castagnoli–Cushman reaction (CCR) was traditionally thought to be limited to the classical succinic and glutaric anhydrides—as well as to its remarkably more reactive counterpart, homophthalic anhydride. The diversity of the lactam products resulting from this extremely powerful, three-component reaction could have been perceived as somewhat limited and the reaction itself may have often been associated with forcing temperatures (thereby limiting, in public mind, the functional group tolerance that this reaction is capable of displaying). In this Digest we aim to provide a glimpse of the remarkable advancements the diversity of the anhydride component for the CCR has taken, summarize the consequences these advancements may have for the scope and applicability of the reaction and pencil in some directions this exciting area of organic chemistry could be taking in the near future, particularly based on the current efforts in our group.

Cyclocondensation of ethyl (imidazolidine-2-ylidene)acetate with aromatic esters bearing labile halogen in ortho-position leads to fused heterocycles, which is formed by substitution of halogen atom with α-carbon atom of cyclic ketene aminal and binding of nitrogen atom with carbonyl carbon atom of aromatic ester.

Cyclocondensation of ethyl (imidazolidine-2-ylidene)acetate with aromatic esters bearing labile halogen in ortho-position leads to fused heterocycles, which is formed by substitution of halogen atom with α-carbon atom of cyclic ketene aminal and binding of nitrogen atom with carbonyl carbon atom of aromatic ester.

Reaction of α-carbonylacetamidines existing in the enediamine tautomeric form with the substituted ortho-fluoronitrobenzene afforded products of the replacement of the fluorine by the α-C atom of amidine. The latter underwent cyclization into cinnoline 1-oxides on treatment with sodium hydride.

vinylacetamidoximes, which are adducts of α-(amino-carbonyl)acetamidoximes with esters of propiolic and acetylenedicarboxylic acids. Various types of pyrroles are formed as a result of this rearrangement [17, 18]. The present work is devoted to investigation of the direction and synthetic potential of the rearrangement of

Reactions of diaminoacrylic acid derivatives (I) with (het)aromatic nitriles containing a labile halogen atom in the o-position provides access to fused diaminoazides via the intermediacy of the chlorine substitution products.

2-Arylquinazolines (III) are synthesized in good yields, whereas the use of 2-bromobenzaldehyde (IV) affords low yields due to a competing reaction leading to dihydrotriazine (V).

Baylis-Hillman adducts [1, 2] are polyfunctional compounds with high synthetic potential. They contain three electrophilic centers and so can react with different nucleophilic reagents including dinucleophiles to form cyclic systems. We have studied the reaction of the acetylated adduct 1 (prepared from 4-chlorobenzaldehyde and methylacrylate [3]) with the benzand acetamidines 2a,b and with S-methylisothiourea (2c).

The cyclocondensation of α-acylacetamidines with esters of 2-fluoro-5-nitrobenzoic and 4-chloro-2-methyl-5-pyrimidinecarboxylic acids leads to condensed azines. The reaction proceeds chemoselectively such that the α-carbon atom of the amidine replaces the halogen atom in the aromatic ring, while the amino group reacts with the ester group.

The cyclocondensation of aromatic o-halo ketones and o-halo nitriles with ethyl 3,3-diaminoacrylate proceeds as the replacement of the aromatic halogen by the α-carbon atom of the enediamine, while the amino group of the enediamine is bound by the α-carbon atom of the ketone or nitrile group.

The cyclocondensation of the N-oxide of the methyl ester of nicotinic acid with 3,3-diamino-1-phenylpropenone and the ethyl ester of 3,3-diaminoacrylic acid in the presence of benzenesulfonyl chloride gives the corresponding 2,7-naphthyridines. The cyclocondensation of 3,3-diamino-1-phenylpropene with the N-oxides of dimethyl 3,5-pyridinedicarboxylate and quinolines containing an electrophilic group at in position 3 yields products of the nucleophilic attack of the carbon nucleophilic site of the enediamine at the 2-pyridine ring position, while the amine group binds to the exocyclic electrophilic group.

Cyclocondensation of α-acylacetamidine with 2-methylsulfanyl-4,6-dichloropyrimidine-5-carbaldehyde proceeds chemo- and regioselectively involving replacement by the α-carbon of the amidine of the chlorine in the aromatic ring and a reaction of the amino group with the formyl group.