Isocyanide as a key functional group for the synthesis of biologically active compounds

Abstract

The distinctive reactivity of isocyanides has been recognised as an advantageous characteristic for the formation of heterocyclic compounds. In the present manuscript new synthetic possibilities are explored involving the isocyanide group as the key point for the development of new reactions that allow the access to unpublished compounds. In particular, some of them show very promising pharmacological properties. According to the different final products accessed, the pharmacological studies and the resulting publications, this dissertation has been classified into six sections. Synthesis of DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). In all the synthesis of C2-endo-unsaturated PDBs published so far, the C2-endo double bond is installed either when the pre-PDB synthon is already synthesized or when the tricyclic core is already built. Both approaches involve several synthetic steps that, unfortunately, in the most part of the examples constitute a considerable drawback.

In order to avoid the cumbersome installation of the double bond after the formation of the tricyclic core, we investigate a new synthetic strategy that relies on the unprecedented use of enantiopure 3-acyl-5-alcoxycarbonyl-2-pyrrolines, synthesized by our group, as key starting materials. Interestingly, the methylketone appendage at the 3-position and the ester substituent at the 5 position are the most suitable to give access to the PBD compounds through known organic transformations.

In this section, objectives, discussion and experimental details to access enantiomerically pure PBDs will be commented.

First diastereoselective [3+2]cycloaddition reaction of diethyl isocyanomethylphosphonate and maleimides published in Org. Biomol. Chem. 2013, 11, 1640-1649.

Bicyclic α-iminophosphonates were prepared via the first diastereoselective silver catalyzed [3 + 2] cycloaddition reaction of diethyl isocyanomethylphosphonate and diversely N-substituted maleimides. The reduction of the resulting imine by catalytic hydrogenation led to cyclic α-aminophosphonates, which are α-aminoester surrogates. The relative stereochemistry of the adducts was confirmed by X-ray crystallographic analysis of one of the compounds. The diastereoselectivity of the cycloaddition reaction was rationalised by theoretical studies.

Easy Access to (2-imidazolin-4-yl)phosphonates by a microwave assisted multicomponent reaction, published in Tetrahedron, 2015, 71, 2872-2881. An efficient and user-friendly synthetic process involving the combination of multicomponent reaction methodology and microwave heating generates unprecedented (2-imidazolin-4-yl)phosphonates. This strategy presents a silver-catalysed, operationally simple and environmentally friendly transformation without the need of anhydrous atmosphere or additional solvents.

Neuroprotective effects of a structurally new family of high affinity imidazoline I2 receptor ligands published in ACS Chem. Neurosci. 2017, 8, 737-742.

The imidazoline I2 receptors (I2-IRs) are widely distributed in the brain, and I2-IR ligands may have therapeutic potential as neuroprotective agents. Since structural data for I2-IR remains unknown, the discovery of selective I2-IR ligands devoid of α2-adrenoceptor (α2-AR) affinity is likely to provide valuable tools in defining the pharmacological characterization of these receptors. We report the pharmacological characterization of a new family of (2-imidazolin-4-yl)phosphonates. Radioligand binding studies showed that they displayed a higher affinity for I2-IRs than idazoxan, and high I2/α2 selectivity. In vivo studies in mice showed that acute treatments with two of the compounds significantly increased p-FADD/FADD ratio (an index of cell survival) in the hippocampus when compared with vehicle-treated controls. Additionally, acute and repeated treatments with one compound markedly reduced hippocampal p35 cleavage into neurotoxic p25. The present results indicate a neuroprotective potential of (2-imidazolin-4-yl)phosphonates acting at I2-IRs.

Novel compounds as high affinity ligands under revision for protection as a patent and potent transference of technology.

La peculiar reactivitat dels isocianoacetats ha estat reconeguda com una avantatjosa característica en la formació de compostos heterocíclics. En aquest manuscrit es presenten noves possibilitat sintètiques utilitzant isocianoacetats com a punt clau per desenvolupar noves reaccions per accedir a nous compostos amb interès farmacològic. L’accés a aquests nous compostos s’ha realitzat a través de dues reaccions principals; les reaccions de cicloaddició i les reaccions multicomponent. En les reaccions de cicloaddició s’ha descrit la preparació de les pirrolbenzodiazepines (PBD), gràcies a la utilització d’un precursor obtingut a través d’una cicloaddició formal [3+2], sota catàlisis cooperativa d’alcaloides de cincona i sals de plata i amb posterior enriquiment de l’excés enantiomèric per self-disproportonation of enantiomers via sublimació. També s’ha descrit la cicloadició [3+2] entre el isocianometilfosfonat de dietil (PhosMic) i maleimides per donar lloc a α-aminofosfonats bicíclics de manera diastereoselectiva, amb la confirmació de la seva estructura relativa per anàlisi de raig X. Pel que fa a les reaccions multimponent s’ha estudiat la reacció entre PhosMic, amines i cetones per donar lloc a les (2-imidazolin-4-il)fosfonats en condicions respectuoses amb el medi ambient, ja que la reacció presenta una elevada economia del àtom, és eficient i transcorre en unes condicions suaus gracies al us del microones. Finalment, la caracterització farmacològica d’aquest compostos en front dels receptor d’imidazolina del tipus 2 (I2-IRs), receptors àmpliament distribuïts en el cervell i relacionats amb activitat neuroprotectora, ha proporcionat nomes eines per poder estudiar-los.