A detailed mechanistic understanding of the malonoyl peroxide mediated dihydroxylation of alkenes is presented. The reaction is first order in both alkene and peroxide with stoichiometric water playing a dual role. An ionic mechanism is proposed and supported by the use of 18O isotopically labelled peroxide, a radical clock probe and DFT calculations. Hammett analysis suggests the reaction proceeds via a discrete carbocation intermediate which is consistent with the stereochemical outcome of the transformation. A subsequent Woodward-type 1,3-dioxolan-2-yl cation has been trapped in situ and the mechanism of hydrolysis defined by isotopic labelling studies. Stable reaction intermediates have been isolated and characterised by X-ray crystallographic analysis and minor competing reaction pathways identified

Malonoyl peroxide 7, prepared in a single step from the commercially available diacid, is an effective reagent for the oxidation of aromatics. Reaction of an arene with peroxide 7 at room temperature leads to the corresponding protected phenol which can be unmasked by aminolysis. An ionic mechanism consistent with the experimental findings and supported by isotopic labeling, Hammett analysis, EPR investigations and reactivity profile studies is proposed.The oxidation and functionalization of hydrocarbons is a central facet of the chemical industry for the production of hightonnage commodities and the preparation of high-value pharmaceuticals, agrochemicals and fine chemicals. Therefore, methods for selective oxidation of C-H bonds are of great importance.1 Phenols represent a key class of oxidized hydrocarbon.2 While there are a small number of reports in which arenes are oxidized to the respective phenols using peroxides and strong acids as additives, 3 the oxidation of aromatic C-H bonds still presents a synthetic challenge specifically with respect to avoiding over oxidation. Scheme 1. C-H oxidation using phthaloyl peroxide. 2A recent report from the laboratories of Houk and Siegel described a metal-free oxidation of aromatic carbon-hydrogen bonds which was proposed to proceed through an intriguing reverse-rebound mechanism (Scheme 1). 4Reaction of mesitylene 2 with 1.3 equiv. of phthaloyl peroxide 1 in hexafluoroisopropanol (HFIP) followed by basic solvolysis gave the phenol 3 (97%). The method outlined in Scheme 1 represents a significant advance in arene oxidation. The proposed mechanistic pathway for the transformation suggested homolytic fission of the weak oxygen-oxygen bond leading to diradical 4. Addition of this radical to the arene gives 5 which though H-atom abstraction provides the observed product 6. Ester hydrolysis leads to the phenol 3 (97%, 2 steps). The procedure has wide functional group tolerance and arene over oxidation did not prove problematic. We believed two fundamental opportunities existed for development of this procedure: Firstly, phthaloyl peroxide 1 is known to be very shock sensitive and explodes violently when heated, representing a significant hazard. 5,6 Secondly, the proposed reverse-rebound mechanism leading to 6 was based upon theoretical studies. Provision of experimental evidence to support this pathway would be of great importance to the understanding and development of this procedure. In recent years we have been interested in the chemistry of cyclic diacylperoxides and have shown that malonoyl peroxide 7, 7 and related derivatives, 8 are effective for the syndihydroxylation of alkenes.9 This reagent provides significant advantages over phthaloyl peroxide 1 within the syndihydroxylation reaction in terms of yield, selectivity, reaction rate, substrate scope and operating temperature.10,11 Given our experience in understanding the mechanism of reactions involving the peroxide 7, 12 together with the specific advantages provided in alkene dihydroxylation we el...

Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life (t 1/2 ) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t 1/2 . UCB7362 is estimated to achieve 9 log 10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.

The reaction of glycine-N-methyl amide with paraformaldehyde in the presence of ytterbium triflate (1 mol%) leads to a novel cage structure 6 which is chiral at nitrogen. Single crystal X-ray analysis and DFT calculations suggest this cage structure is rigid and adopts a single low energy conformation. Use of single enantiomer α-amino amides results in two diastereomeric tertiary amines that differ in their absolute configuration at nitrogen. These diastereoisomers interconvert under acidic conditions but are configurationally stable under basic conditions and can be readily separated by either crystallisation or column chromatography. By reacting racemic chiral α-amino amides a third diastereomeric cage can also be isolated through this reaction protocol. Preparation of mixed cages by reacting two different α-amino amides is also possible allowing for greater structural diversity in the products to be attained. Preliminary mechanistic studies show that all three methylene units in the cage structure are labile and can be replaced under acidic reaction conditions.