Juraj Galeta

Substituted Diazatetracyclo[4.4.0.13,10.15,8]dodecanes as Stable Caged Proton Sponges

Herein, we report a molecular framework design differing significantly from the traditional topology of proton sponges. We developed a synthetic approach to the preparation of caged secondary amines by acid-catalyzed rearrangement of fused tetracyclic heterocycles synthesized by intramolecular criss-cross cycloaddition. Alkylation of amines led to air nonsensitive diazatetracyclo[4.4.0.1(3,10).1(5,8)]dodecanes (DTDs) with rare alicyclic scaffolding in high overall yields. Their pK(BH)+ values were determined by transprotonation experiments as well as their sensitivity toward nucleophiles, acids and bases. Crystal structures of free base and monoprotonated form are discussed.

Substituted homoallenyl aldehydes and their derivatives. Part 2: Azines

This paper deals with the preparation of a variously substituted non-symmetrical azine set. The starting molecule for their preparation was a protected hydrazone. The protection was performed applying Zwierzak’s method. This procedure is based on the transfer of hydrazine to diethylhydrazidophosphate, which reacts with aldehydes to produce protected hydrazones. In the second step of the procedure, under the action of sodium hydride, the addition of another aldehyde affords non-symmetrical azines in the reaction with the protected hydrazine. The procedure was shown to be a useful and effective method. In this, the second part of our study, we present results devoted to the preparation and full identification of non-symmetrical azines.

Substituted homoallenyl aldehydes and their derivatives. Part 1: Homoallenyl aldehydes and protected hydrazones

The paper presents a simple synthesis of substituted propargyl vinyl ethers and their subsequent thermally-initiated Claisen rearrangement leading to various 3-substituted homoallenyl aldehydes. Several methods, including Sonogashira coupling, base-promoted substitution on the triple bond by sodium amide or butyllithium, and the preparation of substituted propargyl alcohols, were used in the initial step. Phosphate-protected homoallenyl aldehyde hydrazone derivatives were synthesised and fully characterised. The stereochemistry of 9-anthracene carbaldehyde hydrazone, which, surprisingly, afforded both cis and trans isomers, was established using X-ray analysis.

ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles

A series of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles (DPPs) was synthesized and evaluated for their ALK5 inhibition activity. The most potent compounds displayed submicromolar IC50 values for ALK5. Preliminary profiling of one of the most active compounds in a panel of 50 protein kinases revealed its selectivity for ALK5. In cells, the compounds caused dose-dependent dephosphorylation of SMAD2, a well-established substrate of ALK5. In addition, the compounds blocked translocation of SMAD2/3 to nuclei of cells stimulated with TGFβ and the protein remained predominantly in cytoplasm, further confirming their molecular target. Therefore, novel DPP derivatives proved to be active as ALK5 inhibitors.

Homoallenyl azines in criss-cross cycloaddition reactions

Thermally initiated combined intra-intermolecular criss-cross cycloadditions of substituted nonsymmetrical allenyl azines with isocyanate or isothiocyanate dipolarophiles were investigated. Substituted 1,3,10-triazatricyclo[5.2.1.04,10]dec-6-en-2-ones or -dec-6-ene-2-thiones were obtained as the main products in moderate to very good yields. The thermal stabilities of the tricyclic adducts in reactions with the competing reactive dipolarophile dimethyl acetylenedicarboxylate were studied and are discussed. In some cases, substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles were found as side products. This reaction showed high atom economy and in all cases we observed the presence of one diastereoisomer and regioisomer only, which was clearly revealed by crystallographic analysis.Graphical abstract