Nucleosides functionalized at the 2 '-position play a crucial role in therapeutics, serving as both small-molecule drugs and modifications in therapeutic oligonucleotides. However, the synthesis of these molecules often presents substantial synthetic challenges. Here we present an approach to the synthesis of 2 '-functionalized nucleosides based on enzymes from the purine nucleoside salvage pathway. Initially, active-site variants of deoxyribose-5-phosphate aldolase were generated for the highly stereoselective synthesis of d-ribose-5-phosphate analogues with a broad range of functional groups at the 2-position. Thereafter, these 2-modified pentose phosphates were converted into 2 '-modified purine analogues by construction of one-pot multienzyme cascade reactions, leading to the synthesis of guanosine (2 '-OH) and adenosine (2 '-OH, 2 '-Me, 2 '-F) analogues. This cascade allows for the control of the 2 '-functional group alongside 2-stereochemistry. Our findings demonstrate the capability of these biocatalytic cascades to efficiently generate 2 '-functionalized nucleosides, starting from simple starting materials. The chemical synthesis of nucleoside analogues with modifications at the 2-position often requires multiple steps and the extensive use of protecting groups. Now, biocatalytic cascades are reported for the synthesis of 2-functionalized sugars and 2 '-functionalized nucleosides, using enzymes derived from those of the purine nucleoside salvage pathway.

Advancements in transition metal catalyzed C-H activation/functionalization cascades have allowed the synthetic chemist's toolbox to be significantly expanded. Despite this, protocols for the remote alkynylation of linear aliphatic amines still remain limited. Herein, a palladium-catalyzed directing-group approach to alkynylation of aliphatic amines is disclosed. The synthetic utility was demonstrated with a gram-scale reaction and a functional group compatibility test.

With the first generation medicinal chemistry synthesis as a starting point, we describe herein process development of AZD4573, an oncology drug candidate. In addition to improved yields and removal of chromatographic steps, we have addressed other factors such as availability of starting materials as well as safety of the chemistry involved. With several steps involving volatile, reactive, and non-UV active materials, reaction optimization was facilitated by implementing off-line 1H NMR analysis of crude mixtures. Key transformations targeted for process development included a Wolff–Kishner reduction, an iridium-catalyzed borylation, and enzymatic resolution of a racemic amino-ester.

Here we describe the development of biaryl 2,5-diphenylphospholanes as a new class of C-2-symmetric, monodentate ligands for asymmetric Suzuki-Miyaura (ASM) reactions. Screening of a series of exemplary phospholanes led to the identification of two ligands that were used to prepare a range of atropisomeric biaryl and heterobiaryl products with good to excellent levels of enantioselectivity (up to 97:3 e.r.) under mild conditions. DFT studies suggest that the formation of a constraining ligand pocket and coordination of one of the biaryl methoxy groups in the optimised ligands to the metal centre is crucial for restricting conformational freedom in the bond-forming step.

With the recent increase in research into ferroelectric, anti-ferroelectric and piezoelectric materials, studying the solid-state properties in situ under applied electric fields is vital in understanding the underlying processes. Where this behaviour is the result of atomic displacements, crystallographic insight has an important role. This work presents a sample environment designed to apply an electric field to single-crystal samples in situ on the small-molecule single-crystal diffraction beamline I19, Diamond Light Source (UK). The configuration and operation of the cell is described as well as its application to studies of a proton-transfer colour-change material.

The designation of starting materials (SMs) for pharmaceuticals has been a topic of great interest and debate since the first ICH quality guidance was published. The increase in the number and variety of commercialized oligonucleotides (antisense oligonucleotides-ASOs, small interfering RNAs-siRNAs, etc.) in recent years has reignited dialogue on this topic because of the unique complexity of the monomeric nucleotides and other contributory materials used to manufacture oligonucleotides. The SM working group in the European Pharma Oligonucleotide Consortium (EPOC) was formed to help establish simple, risk-based criteria to guide the justification of oligonucleotide SMs. This article provides a description of the common types of SMs, classes of SM impurities, and control strategies that will be helpful to maintain manufacturing consistency.

The palladium-catalysed sp(3)C-H arylation of a selection of saturated amine scaffolds was investigated using substituted picolinamide directing groups. On the bornylamine scaffold, highly selective monoarylation takes place using unsubstituted picolinamide or 3-methylpicolinamide, whereas a double C-H arylation occurs with other substituents present, becoming a significant product with 3-trifluoromethylpicolinamide. DFT calculations were used to help rationalise the effect of directing groups on the C-H palladation steps which were found experimentally to be irreversible. The substituted picolinamide directing groups were also examined on acyclic amine scaffolds and in many cases increased yields and selectivity could be obtained using methylpicolinamides. For a selection of other amine scaffolds, the yield of C-H arylation could be improved significantly using 3-methylpicolinamide as the directing group and/or 3-methylpentan-3-ol as the solvent

Catalytic direct amidation reactions have been the focus of considerable recent research effort, due to the widespread use of amide formation processes in pharmaceutical synthesis. However, the vast majority of catalytic amidations are performed in non-polar solvents (aromatic hydrocarbons, ethers) which are typically undesirable from a sustainability perspective, and are often poor at solubilising polar carboxylic acid and amine substrates. As a consequence, most catalytic amidation protocols are unsuccessful when applied to polar and/or functionalised substrates of the kind commonly used in medicinal chemistry. In this paper we report a practical and useful catalytic direct amidation reaction using tert-butyl acetate as the reaction solvent. The use of an ester solvent offers improvements in terms of safety and sustainability, but also leads to an improved reaction scope with regard to polar substrates and less nucleophilic anilines, both of which are important components of amides used in medicinal chemistry. An amidation reaction was scaled up to 100 mmol and proceeded with excellent yield and efficency, with a measured process mass intensity of 8.

Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.

Pd-catalyzed α-arylation of methyl-OBO-ketone (OBO = 4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl) gives rise to arylated OBO-protected pyruvates. By appropriate prefunctionalization of the aryl ring or by subsequent functionalization at the α-carbonyl position of the arylated OBO-ketones, useful diketo OBO-protected carboxylates can be generated. Cyclization, aromatization, and OBO deprotection of these intermediates, using two distinct routes, gives access to valuable α-acyl heteroaromatic compounds.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Synthesis of substituted β-carbolines was accomplished by utilizing the catalytic enolate arylation reaction of ketones in conjunction with several 3-bromoindole derivatives. Quenching of the arylation reaction in situ with an electrophile allowed ready incorporation of functionality at the carboline C-4 position in an efficient one-pot protocol.

Herein, we report a silver-free Pd(II)-catalyzed C(sp3)-H arylation of saturated bicyclic and tricyclic amine scaffolds. The reaction provides good yields using a range of aryl iodides and aryl bromides including functionalized examples bearing aldehydes, ketones, esters, free phenols, and heterocycles. The methodology has been applied to medicinally relevant scaffolds. Two of the intermediate palladium complexes in the catalytic cycle have been prepared and characterized, and a mechanism is proposed. Removal of the directing group proceeded with good yield under relatively mild conditions.

A protected pyruvate equivalent is described that allows arylation and arylation/alkylation reactions to be performed at the methyl group. Utilization of the OBO derivative of the pyruvate ester allowed the application of palladium catalyzed arylation reactions together with subsequent alkylation, under basic conditions. Moreover, the OBO protecting group could be easily removed in one step to provide access to a wide range of substituted pyruvate derivatives.

Background The average length of stay (LOS) following a hip fracture in hospitals around the UK has been approximately 20 days in recent years. This can vary between hospitals and there are numerous factors that can affect LOS. We had the impression that LOS varied by Clinical Commissioning Group (CCG) from which the patient originates. The aim of our study was to discover whether the concern was valid, and if so, what the reasons may be. Methods We analysed hip fracture data collected at our Trust between September 2008 and December 2014. LOS was compared for each of three CCGs in our Trust's catchment areas, and those patients admitted from outlying CCGs. Sub-analysis was performed by patient age, ASA grade, abbreviated mental test score, procedure type and discharge destination to determine which factors influence LOS. Results 1847 patients were identified. After excluding deaths, missing data and extreme outliers, 1603 patients were included in the analysis. The median LOS varied from 14.9 to 23.4 days across CCGs. The major reason for this variation was discharge destination. CCGs associated with longer LOS had a significantly higher rate of discharge to the patient's own home, rather than institutional care. This was independent of patient age, mental status, ASA grade and promptness of surgery. Conclusion We have shown that CCGs vary in their performance to aid discharge. This directly influences a Trust's performance on the National Hip Fracture Database. Compared with other hospitals, our results show a poor outcome in terms of length of stay, but much better performance regarding home discharge. We recommend that more emphasis in future be placed on discharge destination than LOS.

The importance of chirality in drug development has increased rapidly over the past four decades. In response to this need a multitude of asymmetric reactions have been developed which have in turn greatly expanded the three dimensional design space accessible to medicinal chemists. This chapter highlights the importance of enantioselective synthesis as a means of attaining chirally pure compounds, important to modern drug discovery programmes. Several key stereoselective synthesis methods, which have found widespread application in the pharmaceutical industry, are discussed within. The first part of the chapter is concerned with asymmetric hydrogenation. This type of reaction can be used to facilitate the reduction of a wide range of substrate classes including alkenes, ketones, imines and heterocycles and has been used extensively in the synthesis of pharmaceuticals in early stage drug discovery programmes, process development and manufacture. The second part of this chapter discusses the use of chiral reagents for hydride reduction of ketones, a class of reaction widely used in the pharmaceutical industry. DIP-Cl and the CBS reagent are the focus of this section due to their extensive utility in drug discovery programmes. The third section of the chapter discusses the catalytic enantioselective oxidation of olefins. Asymmetric epoxidation and dihydroxylation, in particular the catalytic systems developed by Sharpless, Jacobson and Shi, are explored. The reliability of these systems for the enantioselective oxidation of double bonds and the utility of the resultant molecules have made the reactions hugely impactful in pharmaceutical chemistry. The chapter concludes with a review of the use of chiral auxiliaries and organocatalysis in an industrial setting. Chiral auxiliaries have been used extensively, and are particularly relevant in the early stages of drug discovery where robustness and broad applicability are more important than atom efficiency and cost. In contrast there have, thus far, been relatively few examples of organocatalysis in the industrial setting due, largely, to the relative infancy of the field. It is obvious, however, that there is massive potential for the application of this technology in the drug discovery arena in the years ahead.

A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.