Camilla Matassini

A step forward towards sustainable aerobic alcohol oxidation: new and revised catalysts based on transition metals on solid supports

The oxidation of alcohols is a reaction under continuous investigation, due to the importance of oxidation products and the necessity to perform it in a more sustainable way with respect to traditional procedures. In particular, the combination of a metal catalyst with molecular oxygen or air represents one of the best alternatives in this field. New catalysts are continuously proposed in the literature, and it is not often easy to compare their performances owing to the great amount of examples reported. Heterogeneous catalysts represent the best solution to heavy metal contamination of the products, provided that leaching has not occurred. Moreover, they ideally should be recovered without deactivation and reused after reaction. The employment of air or oxygen in non-flammable solvents (ideally, water) is also highly appreciated, for safety reasons. We have tried in this review to focus on some very recent reports on solid supported transition metal catalysts that strive to follow these principles thus performing oxidation in a more sustainable way while guaranteeing an acceptable substrate scope for synthetic utility.

Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones with Hypervalent Iodine Reagents

Hypervalent iodine compounds are viable reagents for the oxidation of N,N-disubstituted hydroxylamines to the corresponding nitrones, with IBX performing best. The procedure is very simple and user-friendly and affords the target compounds with high efficiency and regioselectivity, highlighting IBX as the reagent of choice for preparation of aldonitrones from nonsymmetric hydroxylamines. Evidence for a mechanism involving nitrogen to iodine coordination has been collected.

Human Acid β‐Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease

A collection of carbohydrate‐derived iminosugars belonging to three structurally diversified sub‐classes (polyhydroxylated pyrrolidines, piperidines, and pyrrolizidines) was evaluated for inhibition of human acid β‐glucosidase (glucocerebrosidase, GCase), the deficient enzyme in Gaucher disease. The synthesis of several new pyrrolidine analogues substituted at the nitrogen or α‐carbon atom with alkyl chains of different lengths suggested an interpretation of the inhibition data and led to the discovery of two new GCase inhibitors at sub‐micromolar concentration. In the piperidine iminosugar series, two N‐alkylated derivatives were found to rescue the residual GCase activity in N370S/RecNcil mutated human fibroblasts (among which one up to 1.5‐fold). This study provides the starting point for the identification of new compounds in the treatment of Gaucher disease.

Gold nanoparticles are suitable cores for building tunable iminosugar multivalency

The first example of iminosugars multimerization based on gold nanoparticle cores was achieved by a straightforward synthetic strategy based on the use of simple glycosides of α-D-mannose or β-D-glucose to modulate the density of biologically active pyrrolizidine and piperidine iminosugars at the gold surface. Exceptionally small and water dispersible gold colloids were obtained by self assembly of thiol ending sugar and novel iminosugar conjugates on the surface of in situ forming gold nanoparticles. The resulting nanostructures were characterized by different techniques. Preliminary screenings demonstrated that the novel nanosized architectures retain their bioactivity and make possible its modulation.

Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar

Summary The synthesis of new multivalent architectures based on a trihydroxypiperidine α-fucosidase inhibitor is reported herein. Tetravalent and nonavalent dendrimers were obtained by means of the click chemistry approach involving the copper azide-alkyne-catalyzed cycloaddition (CuAAC) between suitable scaffolds bearing terminal alkyne moieties and an azido-functionalized piperidine as the bioactive moiety. A preliminary biological investigation is also reported towards commercially available and human glycosidases.

Mechanistic Insight into the Binding of Multivalent Pyrrolidines to α‐Mannosidases

Novel pyrrolidine-based multivalent iminosugars, synthesized by a CuAAC approach, have shown remarkable multivalent effects towards jack bean α-mannosidase and a Golgi α-mannosidase from Drosophila melanogaster, as well as a good selectivity with respect to a lysosomal α-mannosidase, which is important for anticancer applications. STD NMR and molecular modeling studies supported a multivalent mechanism with specific interactions of the bioactive iminosugars with Jack bean α-mannosidase. TEM studies suggested a binding mode that involves the formation of aggregates, which result from the intermolecular cross-linked network of interactions between the multivalent inhibitors and two or more dimers of JBMan heterodimeric subunits.

Evidence for a multivalent effect in inhibition of sulfatases involved in lysosomal storage disorders (LSDs)

Two newly synthesized nonavalent polyhydroxylated pyrrolidine iminosugars are the first examples of multivalent inhibitors of GALNS and IDS lysosomal enzymes, whose deficiency leads to Morquio A syndrome and Hunter disease, respectively, and pave the way to a pharmacological chaperone or stabilizing enzyme therapy for these LSDs.

Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors

This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective α-glucosylation of the key pyrrolizidine intermediate 13, was accomplished. The activity of compound 8 as trehalase inhibitor towards C. riparius trehalase was evaluated and the results showed that 8 was active in the μM range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 9–11 bearing a pyrrolidine nucleus instead of the pyrrolizidine core were synthesized. The biological data showed the key role of the linker chain’s length in inducing inhibitory properties, since only compounds 9 (α,β-mixture), bearing a two-carbon atom linker chain, maintained activity as trehalase inhibitors. A proper change in the glucosyl donor-protecting groups allowed the stereoselective synthesis of the β-glucoside 9β, which was active in the low micromolar range (IC50 = 0.78 μM) and 12-fold more potent (and more selective) than 9α towards the insect trehalase.

Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones: The Search for More Sustainable Selective and Practical Stoichiometric Oxidants

Nitrones are key intermediates for the total synthesis of nitrogen-containing natural products and analogues. The direct oxidation of the corresponding N,N-disubstituted hydroxylamines is one of the most straightforward methods to access such compounds. In this account, we describe the state of the art of this oxidative transformation using stoichiometric reagents. We will focus on the efforts made in the last 25 years to oxidize polyhydroxylated cyclic hydroxylamines, due to our long-standing interest in the total synthesis of alkaloids and other glycomimetics. Particular attention will be devoted to the discussion of the regioselectivity issue arising when unsymmetrical and highly functionalized substrates are involved.