Synthesis and reactions of donor cyclopropanes: efficient routes to cis- and trans-tetrahydrofurans

A detailed study on the synthesis and reactions of silylmethylcyclopropanes is reported. In their simplest form, these donor-only cyclopropanes undergo Lewis acid promoted reaction to give either cis- or trans-tetrahydrofurans, with the selectivity being reaction condition-dependant. The adducts themselves are demonstrated to be an important scaffold for structural diversification. The combination of a silyl-donor group in a donor-acceptor cyclopropane with novel acceptor groups is also discussed

Supporting‐electrolyte‐free electrochemical methoxymethylation of alcohols using a 3D‐printed electrosynthesis continuous flow cell system

We describe the development of a novel low‐cost small‐footprint 3D‐printed electrosynthesis continuous flow cell system that was designed and adapted to fit a commercially available Electrasyn 2.0. The utility and effectiveness of the combined flow/electrochemistry system over the batch process was demonstrated in the development of an improved and supporting‐electrolyte‐free version of our anodic methoxymethylation of alcohols

The asymmetric aza-silyl-prins reaction: Synthesis of enantiopure piperidines

The design and development of the first asymmetric aza-silyl-Prins reaction is reported, giving rise to valuable and diverse piperidines and pipecolic acid derivatives in both high yields and as single enantiomers. The creation of a novel chiral auxiliary-homoallylic amine for the aza-silyl-Prins reaction is essential to its success

Organic electrosynthesis: From academia to industry

The growing impetus to develop greener and more cost-efficient synthetic methods has prompted Chemists to look for new ways to activate small organic molecules. Among them, electrosynthesis is one of the greenest and cheapest since it is possible to perform redox reactions without the need for any chemical reagents. Even though electrosynthesis is on the verge of a resurgence, it is far from being a new discipline. In fact, organic electrosynthesis was popularised by Manual Baizer in the early 60s while working at Monsanto. In this article, we will review the major, as well as the most recent, achievements in industrial organic electrosynthesis

A palladium iodide-catalyzed oxidative aminocarbonylation–heterocyclization approach to functionalized benzimidazoimidazoles

A novel carbonylative approach to the synthesis of functionalized 1H-benzo[d]imidazo[1,2-a]imidazoles is presented. The method consists of the oxidative aminocarbonylation of N-substituted-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-amines, carried out in the presence of secondary nucleophilic amines, to give the corresponding alkynylamide intermediates, followed by in situ conjugated addition and double-bond isomerization, to give 2-(1-alkyl-1H-benzo[d]imidazo[1,2-a]imidazol-2-yl)acetamides. Products were obtained in good to excellent yields (64–96%) and high turnover numbers (192–288 mol of product per mol of catalyst) under relatively mild conditions (100 °C under 20 atm of a 4:1 mixture of CO–air), using a simple catalytic system, consisting of PdI2 (0.33 mol %) in conjunction with KI (0.33 equiv)

Anodic oxidation of dithiane carboxylic acids: a rapid and mild 2 way to access functionalized orthoesters

A new electrochemical methodology has been developed for the preparation of a wide variety of functionalized orthoesters under mild and green conditions from easily accessible dithiane derivatives. The new methodology also offers an unprecedented way to access tri(fluorinated) orthoesters, a class of compound that has never been studied before. This provides the community with a rapid and general method to prepare libraries of functionalized orthoesters from simple and readily available starting materials

C(sp3)-C(sp3) bond formation via electrochemical alkoxylation and subsequent Lewis acid promoted reactions

A two-step transition metal-free methodology for the C(sp3)−C(sp3) functionalisation of saturated N-heterocyclic systems is disclosed. First, aminal derivatives are generated through the anodic oxidation of readily accessible carboxylic acids. Then, in the presence of BF3 ⋅ OEt2, iminium ions are unmasked and rapidly alkylated by organozinc reagents under flow conditions. Secondary, tertiary and quaternary carbon centers have been successfully assembled using this methodology. Such an approach is especially relevant to drug discovery since it increases C(sp3)-functionalities rapidly within a molecular framework. As proof of concept, our methodology was applied to derivatization of peptides and an API

Glycosylation site prediction using ensembles of Support Vector Machine classifiers

Article discussing the performance of different computational methods for prediction of glycosylation sites from amino acid sequences

Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity