Emanuela Erba

Isothiazoles. Part VII. An efficient palladium-catalyzed functionalization of 3-amino-4-aryl-isothiazole 1,1-dioxides with organostannanes☆

Abstract The palladium-catalyzed reaction of 5-bromo-3-diethylamino-4-(4-methoxyphenyl)-isothiazole 1,1-dioxide (3) with a variety of vinyl-, aryl-, heteroaryl- and alkynylstannanes 4 provides a general and efficient method for the synthesis of 5-substituted isothiazole 1,1-dioxides 5. Different reaction conditions (catalyst, solvent, temperature) were tested for the coupling. The best results were obtained using toluene at reflux and benzylchlorobis(triphenylphosphine)palladium as catalyst. When organostannanes appeared to be less reactive, prolonged heating resulted in the formation of variable amounts of the reduction product 3-diethylamino-4-(4-methoxyphenyl)-isothiazole 1,1-dioxide (1).

Asymmetric modular synthesis of a semirigid dipeptide mimetic by cascade cycloaddition/ring rearrangement and borohydride reduction.

A new semirigid dipeptide mimetic was prepared on multigram scale, in good yield, and in a stereocontrolled way, starting from commercially available and unexpensive reagents, i.e., N-benzylpiperidone, tosyl azide, and proline methyl ester. The optimized multicomponent process consisted of a cascade click cycloaddition and a ring rearrangement reaction, followed by a reductive step. Theoretical calculations were performed to elucidate the reaction mechanism and support the stereochemical outcome of the reduction. Finally, the new scaffold was used for the preparation of model peptidomimetics, whose β turn conformation was confirmed by dynamic NMR experiments.

Click-chemistry approach to azacycloalkene monosulfonyl diamines: synthesis and computational analysis of the reaction mechanism

The cycloaddition reaction of the morpholino enamines of N-methylpiperidone and N-methyl tropinone with sulfonylazides was exploited, leading to a click-chemistry approach to uncommon azacycloalkene monosulfonyl diamines in good yields. A computational model for the key step decomposition of the triazoline intermediate was then realized by DFT calculations. The model explains the observed reaction outcome and leads to a new interpretation of the decomposition mechanism for 5-amino-1,2,3-triazolines.

3-Aryl-N-aminoylsulfonylphenyl-1H-pyrazole-5-carboxamides: a new class of selective Rac inhibitors

Through a computational approach, five new compounds with potent and selective Rac inhibitory activity were identified. In particular, compound 4 was shown to selectively inhibit Rac activity in a concentration-dependent manner by affecting the GEF-dependent GDP–GTP exchange. This compound was more potent than the original inhibitors previously identified.

2-Amidinylindole-3-carbaldehydes: Versatile Synthons for the Preparation of α-Carboline Derivatives

Abstract The 2-amidinylindole-3-carbaldehydes 1 are the key starting materials for the preparation of three classes of carbolines 2 , 6 and 7 in which the pyridine ring is characterised by a different substitution patterns. The carbolines 2 which are functionalized with an amino group in position 2, were obtained directly by heating 1 in presence of SiO 2 . The condensation of amidines 1 with arylmethylketones afforded unsaturated ketones 5 which on heating were transformed into 2,9-dialkyl-3-aroyl-9 H -pyrido[2,3- b ]indoles 7 . Instead, prolonged reaction of amidines 1 with arylmethylketones in t -BuOH/ t -BuOK gave 2-aryl-9 H -pyrido[2,3- b ]indoles 6 .

New esters of R-(+)-usnic acid

Abstract By reacting R -(+)-usnic acid ( 1 ) with propionic anhydride and chloroacetyl chloride and pyridine the corresponding diesters at the 8-OH and 9-OH groups ( 2b and c , respectively) were obtained. On reaction of compound 1 with aroyl chlorides and pyridine, the esterification occurred on OH-3 and on the enol form of the acetyl group at C-2 yielding the diesters 3a,c . A tetrabenzoate ( 4a ) and a diacetate-dibenzoate ( 4b ) of compound 1 were also produced.

Molecular insights into dimerization inhibition of c-Maf transcription factor

The Maf protein family belongs to the activator protein 1 (AP-1) superfamily of transcription factors that bind specific DNA target sequences through a basic region and exploit a leucine zipper (LZ) motif for protein-protein interactions leading to homo- or hetero-dimerization. Mafs unique DNA-binding domain contains a highly conserved extended homology region (EHR) that allows to recognize longer DNA sequences than other basic leucine zipper (bZIP) transcription factors. Inspired by the fact that overexpression of Mafs is observed in about 50% of cases of multiple myeloma, a hematological malignant disorder, we undertook a peptide inhibitor approach. The LZ domain of c-Maf, one of large Mafs, was produced by solid phase peptide synthesis. We characterized its secondary structure and dimerization properties, and found that dimerization and folding events are strictly coupled. Moreover, potential peptidic c-Maf dimerization inhibitors were computationally designed and synthesized. These compounds were demonstrated by circular dichroism (CD) spectroscopy and MALDI-TOF mass spectrometry to bind to c-Maf LZ monomers, to drive folding of their partially disordered structure and to efficiently compete with dimerization, suggesting a way for interfering with the function of c-Maf and, more generally, of intrinsically disordered proteins, till now considered undruggable targets.

4-Azidotetronic Acids: A New Class of Azido Derivatives

Abstract 4-Azidotetronic derivatives bearing different substituent groups on the carbon atom in position 3 were easily obtained by reaction of the corresponding 4-bromotetronic compounds with sodium azide in methanol at room temperature.

v-Triazolines. Part 37. Rearrangement reactions of 5-amino-1-(2-formyl-, -benzoyl-, -cyano-aryl)-ν-triazolines: new synthesis of 2-amino- and 2,4-diamino-quinolines and 2,4-diamino-1,7-naphthyridines

2-Aminoquinolines 4 were obtained in an one-pot reaction from arylacetaldehydes 1, secondary amines 2 and aryl azides 3 in refluxing benzene or xylene. 2,4-Diaminoquinolines and 2,4-diamino-l,7-naphthyridines 9 were prepared by heating arylacetaldehydes 1 with secondary amines 2 and aryl or pyridyl azides 8 and reaction with bases. Reaction intermediates were shown in certain cases to be 5-amino-ν-triazolines 5 and 10 undergoing thermal rearrangement to amidines 7 and 11 followed by intramolecular base-catalysed cyclocondensation.

2-Amidinylindole-3-carbaldehydes: synthesis of new tetracyclic compounds containing the pyrrolo[1,2-c]1,4-diazepine ring

2-Amidinylindol-3-carbaldehydes bearing an α-alkoxycarbonyl substituent on the cyclic-tertiary amine moiety were prepared. Pyrolysis of these amidines in diethylenglycol-monoethyl ether produced mainly a pyrrolo[1′,2′-1,2]-1,4-diazepino[5,6-b]indol-7,11-dione. A similar result was obtained starting from 2-amidinylbenzofuran-3-carbaldehyde.