Towards the synthesis of novel protein phosphatase inhibitors

Protein phosphatases (PPases) are important enzymes which mediate dephosphorylation of proteins in eukaryotic cells. These enzymes are involved in a variety of cellular processes, and disruption of their activity has been shown to be involved in the development of diseases such as cancers and Alzheimer’s. Protein phosphatase inhibitors (PPIs) have been used to regulate the activity of these enzymes, and hence, control the development of the cellular processes related to them. However, the lack of potent and selective readily accessible PPIs is a major obstacle to the understanding of these complex biological pathways, and the development of reliable synthetic routes towards new PPIs has therefore generated a significant amount of interest. Several naturally occurring PPIs possess the “ADDA” residue , which has been shown to be crucial for their inhibitory activity. We would like here to report the synthesis of “ADDA”-isoforms such as enantio-ADDA 1 and enantio-iso-ADDA 2 through a convergent approach taking advantage of cross-metathesis methodology, non-aldol aldol and aza-Claisen rearrangements, as well as β-lactam chemistry. We envisage using our synthetic approaches as a platform to generate a wide range of novel “ADDA”-containing analogues, which might lead to the discovery of potent and selective PPIs, which could be generated in multi-gram scale

Fluorinated musk fragrances : the CF2 group as a conformational bias influencing the odour of civetone and (R)-muscone

This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) and the European Research Council (ERC). The authors acknowledge the EPSRC National Mass Spectrometry Facility (Swansea). M.Y. thanks the China Scholarship Council for financial support. D.O'H. thanks the Royal Society for a Wolfson Research Merit Award.The difluoromethylene (CF2) group has a strong tendency to adopt corner over edge locations in aliphatic macrocycles. In this study, the CF2 group has been introduced into musk relevant macrocyclic ketones. Nine civetone and five muscone analogues have been prepared by synthesis for structure and odour comparisons. X-ray studies indeed show that the CF2 groups influence ring structure and they give some insight into the preferred ring conformations, triggering a musk odour as determined in a professional perfumery environment. The historical conformational model of Bersuker and co-workers for musk fragrance generally holds, and structures that become distorted from this consensus, by the particular placement of the CF2 groups, lose their musk fragrance and become less pleasant.PostprintPeer reviewe

Zusammenfassung

N-Heterocyclic carbenes (NHCs) have been shown to be useful ligands for the Suzuki-Miyaura cross-coupling at low catalyst loadings. We now report that the commercially available and air-stable [Pd(IPr)(cin)Cl] pre-catalyst permits the formation of various functionalized biaryls from aryl chlorides and boronic acids (37 examples) under very mild conditions using a mixture of ethanol/water as solvent and an inorganic base

N-Aryl-9,10-phenanthreneimines as scaffolds for exploring non-covalent interactions: a structural and computational study

A series of 10-[(4-halo-2,6-diisopropylphenyl)imino]phenanthren-9-ones and derivatives of the phenanthrene-9,10-dione ligand have been synthesised and structurally characterised to explore two types of noncovalent interactions, namely the influence of the steric bulk upon the resulting C–H···π and π-stacking interactions and halogen bonding. Selected noncovalent interactions have additionally been analysed by DFT and AIM techniques. No halogen bonding has been observed in these systems, but X lone pair···π, C–H···O=C and C–H···π interactions are the prevalent ones in the halogenated systems. Removal of the steric bulk in N-(2,4,6-trimethylphenyl)-9,10-iminophenanthrenequinone affords different noncovalent interactions, but the C–H···O=C hydrogen bonds are observed. Surprisingly, in N-(2,6-dimethylphenyl)-9,10-iminophenanthrenequinone and N-(phenyl)-9,10-iminophenanthrenequinone these C–H···O=C hydrogen bonds are not observed. However, they are observed in the related 2,6-di-tert-butylphenanthrene-9,10-dione. The π-interactions in dimers extracted from the crystal structures have been analysed by DFT and AIM. Spectroscopic investigations are also presented and these show only small perturbations to the O=C–C=N fragment

Insights into the catalytic activity of [Pd(NHC)(cin)Cl] (NHC = IPr, IPrCl, IPrBr) complexes in the Suzuki-Miyaura reaction

The authors gratefully acknowledge the European Commission (EC) for funding through the seventh framework program SYNFLOW, the European Research Council (ERC) (Advanced Investigator Award “FUNCAT” to S. P. N.), The Engineering and Physical Sciences Research Council (EPSRC) and AstraZeneca (Studentship to C. M. Z.).The influence of C4,5-halogenation on palladium N-heterocyclic carbene complexes and their activity in the Suzuki-Miyaura reaction have been investigated. Two [Pd(NHC)(cin)Cl] complexes bearing IPrCl and IPrBr ligands were synthesized. After determining electronic and steric properties of these ligands, their properties were compared to those of [Pd(IPr)(cin)Cl]. The three palladium complexes were studied using DFT calculations to delineate their behaviour in the activation step leading to the putative 12-electron active catalyst. Experimentally, their catalytic activity in the Suzuki-Miyaura reaction involving a wide range of coupling partners (30 entries) at low catalyst loading was studied.PostprintPeer reviewe

A new synthetic route to p-methoxy-2,6-disubstituted anilines and their conversion into N-heterocyclic carbene precursors

The development of new N-heterocyclic carbenes (NHC) is a key feature in this now mainstream research area to access novel chemical properties and reactivity that are essential for the discovery of original applications. Up to now, only a few reliable methods have proven suitable for the preparation of methoxylated anilines to ultimately access methoxylated NHC. We are pleased to report here a straightforward and scalable approach to address this matter.Publisher PDFPeer reviewe

Synthesis and characterisation of Au(I)-(ITent) complexes

The ERC (Advanced Investigator Award-FUNCAT), the EPSRC and Syngenta are gratefully acknowledged for support of this work. Umicore AG is acknowledged for their generous gift of auric acid. S.P.N. is a Royal Society Wolfson Research Merit Award holder.The synthesis of novel [AuCl(ITent)] and [Au(OH)(ITent)] complexes is reported. They have been fully characterised and their steric parameters were assessed by calculating percent buried volumes and producing steric maps from their crystal structures in the solid state.PostprintPeer reviewe

A new synthetic route to p-methoxy-2,6-disubstituted anilines and their conversion into N-heterocyclic carbene precursors

The development of new N-heterocyclic carbenes (NHC) is a key feature in this now mainstream research area to access novel chemical properties and reactivity that are essential for the discovery of original applications. Up to now, only a few reliable methods have proven suitable for the preparation of methoxylated anilines to ultimately access methoxylated NHC. We are pleased to report here a straightforward and scalable approach to address this matter

Convergent synthesis of (2R,3R,8R,9R)-N-Boc-ADDA

The convergent synthesis of N-Boc-(2R,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldec adenoic acid (enantio-N-Boc-ADDA) is reported. Our flexible approach takes advantage of highly efficient non-aldol aldol and cross-metathesis methodologies

Directed Studies Towards The Total Synthesis of (+)-13-Deoxytedanolide: Simple and Convenient Synthesis of C8-C16 Fragment

International audienceA straightforward synthesis of the enantioenriched C8-C16 south part of (+)-13-deoxytedanolide has been reported. The strength of this approach relies on the preparation of similar functionalized fragments via the transformation of a unique dihydrofuran building block through a 1,2-metallate rearrangement