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Unsaturated spirocyclic lactams stemming from a variant of the three-component Castagnoli–Cushman reaction successfully underwent hydrogenation to enable access to fully saturated spirocyclic lactams. The subsequent lactam reduction gave rise to 2-spiro piperidine building blocks. The latter can be further elaborated in compound libraries and, on their own, show propensity to activate trace amine-associated­ receptor 1 (TAAR1), an important target for CNS disease.

An unusual type of highly reactive sultam-based dicarboxylic acids and correscponding anhydrides was employed in the Castagnoli-Cushman reaction delivering diastereomerically pure adducts at room temperature. Due to steric congestion, the initial adducts were prone to decarboxylation affording diastereomeric mixtures of bicyclic sultam lactams, separable by HPLC. The choice of a protecting group on the sultam nitrogen atom allows liberation of the

A diastereoselective three-component one-pot lactam synthesis involving the in situ generation of imines via the Staudinger/aza-Wittig tandem reaction combined with the Wolff rearrangement and ketene–imine cycloaddition was developed.

An attempted Regitz diazo transfer onto homophthalic anhydride led to the discovery of an unexpected ring contraction, which gave

A novel tandem approach to trisubstituted γ-sultams has been developed involving N-alkylation of methanesulfonanilides with EWG-substituted allyl bromides followed by intramolecular Michael addition. A series of various isothiazolidine 1,1-dioxides have been prepared under mild transition-metal-free conditions in high yields and trans-diastereoselectivity (confirmed by X-ray crystallography). The dependence of reactivity on electronic properties of substrates has been investigated.

A N-(2-methoxy-2-oxoethyl)-N-(phenylsulfonyl)glycine monomethyl ester of the respective dicarboxylic acid was involved in a reaction with imines promoted by acetic anhydride at an elevated temperature. Instead of the initially expected δ-lactam products of the Castagnoli–Cushman-type reaction, medicinally important 3-amino-2-azetidinones were obtained as the result of cyclization, involving a methylene group adjacent to an acid moiety. In contrast, replacing alcohol residue with hexafluoroisopropyl in the same substrate made another methylene group (adjacent to the ester moiety) more reactive to furnishing the desired δ-lactam in the Castagnoli–Cushman fashion.

New types of cyclic diazo compounds capable of Rh(II)-catalyzed spirocyclizations with tetrahydrofuran have been discovered. The formation of the spirocyclic framework is thought to proceed via the...

Metal-free, thermally promoted synthesis of 3-alkoxy-3-alkoxycarbonyl-2-azetidinones via the Wolff-Staudinger β-lactam synthesis using dialkyl diazomalonates is described. The reaction appears fairly general and delivers only one diastereomer.

A convenient one-pot approach to the preparation of α-diazo-β-ketosulfones from sulfonyl chlorides is described. It involves the conversion of the sulfonyl chloride to sodium sulfinate, alkylation of the latter with α-haloketones followed by diazo transfer using the ‘sulfonyl-azide-free’ (‘SAFE’) protocol in aqueous medium. The simple and expedient method relies on readily available starting materials and provides facile access to a wide variety of valuable diazo reagents for organic synthesis.

The earlier reported three-component Castagnoli-Cushman-type synthesis of 1,4,6-trisubstituted 1,6-dihydropyridin-2-(3H)-ones from 3-arylglutaconic acids, primary amines, and aromatic aldehydes has been further investigated. It was shown to proceed via 3-arylglutaconic anhydrides, which, in turn, were found to give superior results in the two-component reactions with imines. The initial formation of the Castagnoli-Cushman carboxylic acids was shown to be the case, and their decarboxylation was found to follow a complex, "forked" pathway, which was confirmed by deuterium incorporation experiments.

The earlier described reaction of homophthalic anhydrides with aromatic ketones and ammonium acetate was tested for cyclic ketones (yielding spirocyclic motifs) and aliphatic aldehydes. In contrast to previous findings, the reaction was found to require no catalyst at all and to be applicable, in the non-catalyzed format, to these new carbonyl substrates as well as aromatic ketones. The reaction typically proceeds with high diastereoselectivity; if not, the initial diastereomeric mixture can be quantitatively equilibrated into a single, trans-diastereomer on treatment with aqueous base.

Thermally promoted reaction of α-acyl-α-diazoacetates with imines has been investigated. The transformation, earlier reported predominantly under transition metal catalyzed conditions, delivers α-alkoxycarbonyl-substituted β-lactams with outstanding diastereoselectivity. DFT calculations performed in order to evaluate energetically feasible reaction pathways revealed the intermediacy of 1,3-oxazin-4-one intermediates hitherto never implicated in the Staudinger synthesis of β-lactams.

Rh(II)-catalyzed decomposition of certain cyclic α-diazocarbonyl compounds in the presence of cyclic ethers has been shown to give bicyclic ring expansion products. These are thought to arise from a [1,4]-alkyl shift toward the carbonyl oxygen atom and are in contrast with the recently observed spirocyclic products of a Stevens-type [1,2]-alkyl shift within the postulated oxonium ylide intermediate. Quantum chemical calculations performed at the B3LYP/6-31G* level of theory showed that the former reaction pathway (toward fused bicycles) is kinetically preferred.

For the preparation of compound libraries of Michael acceptors with tunable reactivity toward nuclophilic selenocysteine residue of thioredoxin reductase, a range of 3-arylglutaconic acids were required. The existing methods at the time had limited scope or involved several steps. A hitherto undescribed protocol for direct palladium(II) acetate-catalyzed arylation of glutaconic acid dimethyl ester at position 3 has been developed with a diverse set of arenediazonium tosylates followed by hydrolysis. This generally good-yielding two-step sequence displayed a propensity to deliver E-configured coupling products while compounds mostly featured in the literature were predominantly Z-configured. The possibility for preparing a library of 4-arylpyridine-2,6(1H,3H)-diones has been exemplified.

Attempted use of 3-arylglutaconic acids in the three-component version of the Castagnoli-Cushman reaction with amines and aromatic aldehydes resulted in an unexpected formation of 4,6-diaryl 1,6-dihydropyridine-2(3 H)-ones. These are of interest as representatives of a rare heterocyclic chemotype for de novo biological investigation. Alternatively, these compounds can be oxidized into their 2-pyridone counterparts, stereoselectively reduced to give cis-configured 4,6-diaryl 2-piperidones, or isomerized to 5,6-dihydropyridin-2(1 H)-ones. All the three scaffolds are well represented in the bioactive compound domain.

Human thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing enzyme which plays a crucial role in regulating numerous redox signalling pathways within the cell. While its functioning is important in all cells, levels of TrxR1 expression are higher in cancer cells, possibly as an adaptation to much higher levels of reactive oxygen species and the need for more extensive DNA synthesis. This makes TrxR1 an attractive target for cancer therapy development. Inspired by the structure of disulphide compounds which have advanced through various stages of clinical development, we designed a series of dithiodiglycolic acid derivatives. These were prepared from respective thiol synthons using an iodine- or benzotriazolyl chloride-promoted oxidative disulphide bond formation. Inhibition of TrxR present in cell lysates from human neuroblastoma cells (SH-SY5Y) and rat liver cells indicated several compounds with a potential for TrxR inhibition. Some of these compounds were also tested for growth inhibition against two human cancer cell lines and normal human keratinocytes., Graphical Abstract

A series of medicinally important dihydropyridin-2(1H)-ones have been prepared via a novel [4 + 2]-formal cycloaddition reaction of chalcone imines and homophthalic anhydrides, which is a rare example of lactam construction from an imine acting as a four-atom building block. In contrast to previous studies on the reactivity of homophthalic anhydrides towards similar substrates, N-tosyl chalcone imines, we found the possibility of switching chemoselectivity by changing substituents at the nitrogen atom, which leads to the formation of heterocycles instead of the expected carbocycles. This reaction is very similar in appearance to the classic 1,2-addition of cyclic anhydrides to imines, often referred to as the Castagnoli-Cushman reaction, but differs in mechanistic details (representing a 1,4-reaction of imine). The developed atom-economical, stereoselective and catalyst- and chromatography-free protocol provided facile access to 28 structurally diverse heterocyclic products (in up to 88% yield) including synthetically challenging annelated tricyclic and previously unreported pentaaryl-substituted dihydropyridin-2(1H)-ones.

Rare cis-configured 2,4-disubstituted 1-alkylpyridines were envisioned as ligands for trace amine associated receptor 1 (TAAR1). They were synthesized in diastereomerically pure form with the decarboxylative Castagnoli–Cushman reac-tion followed by two reduction events. Despite showing no affinity to TAAR1 as was anticipated, these novel, druglike and CNS-focused compounds will be of much utility in sub-sequent lead generation pursuits.

A wide range of α-diazo-β-ketosulfones have been applied to thermally promoted tandem Wolff rearrangement – Staudinger [2+2] cycloaddition with imines to give polysubstituted β-lactam sulfones. Dia­stereomerically pure syn-diastereomers were obtained in good yields and the relative stereochemistry was confirmed by single-crystal X-ray crystallography. These findings significantly expand the scope of this transformation, in contrast to substantial limitations reported previously. Moreover, this methodology enables flexible exploration of new substitution patterns around the privileged β-lactam core for drug design and optimization.

The earlier reported three-component Castagnoli-Cushman-type synthesis of 1,4,6-trisubstituted 1,6-dihydropyridin-2-(3

The (3+3) anellation of alkynones and cyclic amidines is a novel and unexpected approach to generate intensively blue luminescent tricyclic 2-aminopyridinium salts with quantum yields Φf up to 63 % in water. By implementation into a consecutive three-component reaction, these title compounds are obtained rapidly and efficiently in a diversity-oriented fashion. Most interestingly, these bi- and tricyclic 2-aminopyridinium salts emit in dichloromethane and water solutions, thus making them interesting novel luminophore probes for bioanalytics, as well as in the solid state, thus making them blue emitters with tunable efficiency.

Five lactam chemotypes amenable by the Castagnoli-Cushman reaction of imines and cyclic anhydrides have been investigated for their ability to activate p53 tumor suppressing transcription factor thus induce apoptosis in p53+ cancer cells. A virtual library of 1.07 million chemically diverse compounds based on these scaffolds was subjected to in silico screening first. The compounds displaying high docking score were visually prioritized to identify the best-fitting compounds, i. e. the ones which adequately mimic the interactions of clinical candidate inhibitor Nutlin-3a. These 38 compounds were synthesized and tested for apoptosis induction in p53+ H116 cancer cells to identify 9 potent apoptosis-inducers (two of them exceeding the activity of Nutlin-3a) which belonged to four different chemotypes. The activation of p53 involved in the proapoptotic activity observed was supported by effective induction of EGFP expression in human osteocarcinoma U2OS-pLV reporter cell line. Moreover, the two most potent apoptosis inducers displayed antiproliferative profile identical to several known advanced p53 activators: they inhibited the growth of p53+/+ HCT116 cells in much lower concentration range compared to p53-/- HCT116 cells.

The first example of employing a mixed carboxylic-sulfonic anhydride in reaction with imines is reported. Unlike its well-studied isostere homophthalic anhydride, benzo[c][1,2]oxathiin-3(4H)-one 1,1-dioxide gave no product of a formal [4 + 2] cycloaddition and only followed an alternative reaction pathway toward β-lactams, presumably, via a formal [2 + 2] cycloaddition (a Staudinger-type reaction). Optimized reaction conditions involve the use of triethylamine as a base promoter, which also allows isolating the product β-lactam benzene sulfonic acids as respective triethylammonium salts by conventional column chromatography. The reaction shows some preference to trans-isomer formation; pure diastereomers can be isolated in some cases.

The first example of the Buchner-Curtius-Schlotterbeck reaction of cyclic ketones with a stabilized cyclic diazo compound partner is described. The approach towards spirocyclic scaffolds has been exemplified with readily available ∝-diazo-γ-butyrolactone. The reaction proved to be viable with BF3∙OEt2 as the preferred catalyst and displayed substantial sensitivity to the size of the cyclic ketone.