Synlett

Synlett 2024; 35: A134-A147DOI: 10.1055/s-0043-1763994Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, GermanyArticle in Thieme eJournals:Table of contents

We report here the chemo- and regioselective demethylation of 2-bromo-3,5-dimethoxy-α-resorcylic acid esters by a thiolate nucleophilic displacement reaction. Optimized conditions facilitate yields up to 93% for o-bromo-selective demethylation of diverse ester derivatives of dimethoxy 2-bromo-α-resorcylic acid. Our results highlight a new, efficient, and reliable demethylation reagent, as well as a useful steric bias directing strategy.

A novel and efficient method has been established for synthesizing a variety of heterotriarylmethanes with good yields by employing a metal-free self-coupling reaction of benzofuran azadienes. The involvement of t-BuONa is essential in this process. Remarkably, this technique boasts mild reaction conditions and exceptional compatibility with various functional groups, rendering it a versatile and invaluable asset in the realm of organic synthesis.

Microwave-assisted conditions were adapted to our previously published synthesis of 8-aryl-7-deazaguanines via cyclocondensation of phenacyl bromides with 2,4-diamino-6-hydroxypyrimidine in refluxing 1,4-dioxane. Upon microwave irradiation at 150–225 °C, 8-aryl-7-deazaguanines were obtained in high yield above 90% and within 15–60 min, compared to the 24–72 h that are required under reflux conditions. Three new fluorescent 8-heteroaryl-7-deazaguanines were additionally produced and characterized confirming our hypothesis that compounds of this class typically exhibit fluorescence properties, regardless of the aryl substituent.

A simple redox-neutral method for the regioselective preparation of 1,3- and 1,5-disubstituted 1,2,4-triazoles from the corresponding unactivated acyl hydrazides and the inexpensive, non-toxic, and shelf-stable formamidinium acetate was developed. The addition of zinc salts proved to be pivotal to ensure full regioselectivity for the 1,3-disubstitution pattern, while 1,5-disubstituted 1,2,4-triazoles could be accessed without. A variety of sensitive functional groups were tolerated, and [1,2,4]triazolo[4,3-a]pyridines were obtained from the corresponding 2-hydrazopyridines without Dimroth rearrangement.

Ketocalix[n]arenes can be prepared via oxidation of the methylene groups of protected calix[n]arenes. The presence of carbonyl groups at the bridges alters the preferred conformation and reactivity of the macrocycle and provides an entry point (via nucleophilic additions reactions) to a wide array of methylene-substituted derivatives as well as calix[n]radialenes.1 Introduction2 Synthesis of Ketocalix[n]arenes2.1 Ketocalix[4]arene Derivatives2.2 Systems Possessing both Carbonyl and Bromomethane Bridges2.3 Pentaoxoketocalix[5]arene and Hexaoxoketocalix[6]arene Derivatives2.4 Monooxo- and Dioxoketocalix[6]arenes3 Conformation of Ketocalixarenes4 Reactions of Ketocalixarenes4.1 Alkylation of the OH Groups4.2 Intramolecular Aromatic Nucleophilic Substitution4.3 Reduction of the Carbonyl Groups4.4 Reaction of 5c with PhLi4.5 Reaction with tert-Butyllithium5 From Ketocalix[n]arenes to Calix[n]radialenes and Calix[n]rotanes6 Summary and Outlook

Pseudo-natural products (pseudo-NPs), the chemically reengineered molecular skeletons generated by the deconstruction of NPs into fragments and their subsequent recombination, have gained immense attention in recent times owing to their ability to occupy a significant portion of the medicinally relevant NP-based molecular space, their possession of novel bioactivities, and their ability to address chemical and biological challenges. In this study, the reassembly of fragments of combretastatin, steganacin, podophyllotoxin, colchicine, and other natural products and drug molecules by a cis-lock fusion-edge recombination led to the generation of diarylpyrrole pseudo-NP-functionalized skeletons, named combretapyrroles. These combretapyrroles were synthesized with excellent substrate scope in good yields by a new cyanide-mediated nitrile-to-nitrile cycloaddition reaction of a vic-dinitrile combined with 1,1,3,3-tetramethylguanidine-mediated desilylative cleavage of TMSCN and in situ generation of cyanide. The differential acidity of the benzylic C–H moieties of the vic-dinitrile intermediate was found to influence regioselectivity in the mechanistic pathway and to provide different products. A cheminformatic analysis showed that the combretapyrroles occupy a unique drug-relevant chemical space that is rarely covered by NPs. Combretapyrroles also were found to possess drug-like physicochemical properties.

Pseudo-natural products (pseudo-NPs), the chemically reengineered molecular skeletons generated by the deconstruction of NPs into fragments and their subsequent recombination, have gained immense attention in recent times owing to their ability to occupy a significant portion of the medicinally relevant NP-based molecular space, their possession of novel bioactivities, and their ability to address chemical and biological challenges. In this study, the reassembly of fragments of combretastatin, steganacin, podophyllotoxin, colchicine, and other natural products and drug molecules by a cis-lock fusion-edge recombination led to the generation of diarylpyrrole pseudo-NP-functionalized skeletons, named combretapyrroles. These combretapyrroles were synthesized with excellent substrate scope in good yields by a new cyanide-mediated nitrile-to-nitrile cycloaddition reaction of a vic-dinitrile combined with 1,1,3,3-tetramethylguanidine-mediated desilylative cleavage of TMSCN and in situ generation of cyanide. The differential acidity of the benzylic C–H moieties of the vic-dinitrile intermediate was found to influence regioselectivity in the mechanistic pathway and to provide different products. A cheminformatic analysis showed that the combretapyrroles occupy a unique drug-relevant chemical space that is rarely covered by NPs. Combretapyrroles also were found to possess drug-like physicochemical properties.

Mer proto-oncogene tyrosine-protein kinase (MerTK), a part of the TAM (TYRO3, AXL, and MerTK) family, is directly correlated with metastasis and various types of cancers. The inhibition of this receptor is a promising strategy for more-effective chemotherapy. Considering the pharmacophoric features of the active domain of MerTK and the structural characteristics of the investigational drug BMS794833, we designed five new N-{4-[(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide analogues. In cytotoxicity studies, one of the analogues displayed a significantly higher cytotoxicity than cisplatin. It showed IC50 values of 2.09, 1.96, and 3.08 μM against A549, MCF-7, and MDA-MB-231 cancer cell lines, respectively. In drug metabolism and pharmacokinetic studies, it was the most stable analogue and displayed a moderate MerTK inhibitory potential. Molecular-docking studies were performed to corroborate the MerTK inhibition, and the same analogue achieved the most significant docking score (–12.33 kcal/mol). Docking interactions demonstrated that the imine and amine group of the 3-chloropyridine moiety of BMS794833 formed hydrogen bonds with the main chain of the ATP pocket residue Met674, while the oxygen atoms of the 4-oxo-1,4-dihydropyridine-3-carboxamide moiety established hydrogen bonds with the Lys619 and Asp741 amino acid residues of the allosteric pocket of MerTK protein. These promising results provide evidence that the N-{4-[(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide pharmacophore can give potential insights into the development of new MerTK inhibitors.

A novel one-pot cascade process of oxidation-initiated, N-heterocyclic carbene catalyzed, reintegration of dibenzyl ethers has been developed for the first time. This protocol allows straightforward access to α-hydroxy ketones from dibenzyl ethers. It is noteworthy that the present method is the first attempt to synthesize benzoin from dibenzyl ether.