Match-Making Reactors to Chemistry: A Continuous Manufacturing-Enabled Sequence to a Key Benzoxazole Pharmaceutical Intermediate

The focus of this study was to develop a chemical reaction sequence toward a key benzoxazole building block, required for clinical manufacturing of a lead candidate in the respiratory disease area. The chemistry consisted of initial low-temperature reactions with an organometallic reagent to generate the benzoxazole core, and was followed by noncryogenic transformations toward a sulfonamide substituent. With particular interest in continuous-flow manufacturing we attempted to integrate the entire sequence on lab scale. Subsequent in-depth process research, supported by PAT and calorimetry studies, revealed the critical parameters of each step, leading to a more rational attribution of mode of operation: flow, batch, or semibatch. Two bench-scale cascades of continuously stirred tank reactors (CSTRs) were constructed to meet the challenge of high exothermicity and solids formation and were key to smoothly upscaling the chemistry to deliver 17 kg of benzoxazole in superior yield, quality, and robustness

A Resource for the Transcriptional Signature of Bona Fide Trophoblast Stem Cells and Analysis of Their Embryonic Persistence

Trophoblast stem cells (TSCs) represent the multipotent progenitors that give rise to the different cells of the embryonic portion of the placenta. Here, we analysed the expression of key TSC transcription factors Cdx2, Eomes, and Elf5 in the early developing placenta of mouse embryos and in cultured TSCs and reveal surprising heterogeneity in protein levels. We analysed persistence of TSCs in the early placenta and find that TSCs remain in the chorionic hinge until E9.5 and are lost shortly afterwards. To define the transcriptional signature of bona fide TSCs, we used inducible gain- and loss-of-function alleles of Eomes or Cdx2, and EomesGFP, to manipulate and monitor the core maintenance factors of TSCs, followed by genome-wide expression profiling. Combinatorial analysis of resulting expression profiles allowed for defining novel TSC marker genes that might functionally contribute to the maintenance of the TSC state. Analyses by qRT-PCR and in situ hybridisation validated novel TSC- and chorion-specific marker genes, such as Bok/Mtd, Cldn26, Duox2, Duoxa2, Nr0b1, and Sox21. Thus, these expression data provide a valuable resource for the transcriptional signature of bona fide and early differentiating TSCs and may contribute to an increased understanding of the transcriptional circuitries that maintain and/or establish stemness of TSCs

Challenging assumptions of the enlargement literature : the impact of the EU on human and minority rights in Macedonia

This article argues that from the very start of the transition process in Macedonia, a fusion of concerns about security and democratisation locked local nationalist elites and international organisations intoa political dynamic that prioritised security over democratisation. This dynamic resulted in little progress in the implementation of human and minority rights until 2009, despite heavy EU involvement in Macedonia after the internal warfare of 2001. The effects of this informally institutionalised relationship have been overlooked by scholarship on EU enlargement towards Eastern Europe, which has made generalisations based on assumptions relevant to the democratisation of countries in Eastern Europe, but not the Western Balkans

A Lewis Base Catalysis Approach for the Photoredox Activation of Boronic Acids and Esters

We report herein the use of a dual catalytic system comprising of a Lewis base catalyst such as quinuclidin-3-ol or 4- dimethylaminopyridine combined with a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react via radical addition with electron-deficient olefins to efficiently form C–C coupled products in a redox neutral fashion. The Lewis base catalyst was shown to form a redox-active complex with either boronic esters or the trimeric form of the boronic acids (boroxines) in solution.We are grateful to Novartis Pharma AG (F.L.), the Erasmus Scholarship Scheme (L.G. and S.J.), and the EPSRC (S.V.L., Grants EP/K009494/1, EP/K039520/1, and EP/M004120/1) for financial support. U.K.S. and D.S. are thankful to the University of Leuven for postdoctoral funding and the FWO for a visiting postdoctoral scholarship (U.K.S.) at the University of Cambridge. E.V.V.d.E. would like to thank the Ministry of Education and Science of the Russian Federation for financial support (agreement number 02.a03.0008). We thank Dr. Berthold Schenkel and Dr. Gottfried Sedelmeier for insightful discussions. We thank Merck Rahway USA for the generous gift of the PC(1) photoredox catalyst

Europeanization without substance? EU-Turkey relations and gender equality in employment

This paper focuses on EU-Turkey relations through gender-related employment policy practices. We argue that Turkey is undergoing a process of ‘Europeanization without substance’, in which vague commitments and policy initiatives to enhance female labour force participation coexist uneasily with a contravening political discourse. This is not merely the result of a stalemate in accession negotiations, nor does it stem from the diversity of employment practices across the Union. It rather results from the deliberative discourses used by Turkey’s political leadership to selectively appropriate certain aspects of Europeanization to further a politically motivated agenda that, in essence, negates gender equality altogether. This, we argue in turn, is reflected in a set of practices, policy initiatives, and public statements that make substantive progress in EU-Turkey relations harder. This process is facilitated by the diminishing emphasis placed by the EU on gender equality in employment as manifested by the evolution of gender equality practices at EU level and reinforced by austerity-led policies during the economic crisis

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2^2)-C(sp3^3) Cross-Couplings in Flow

We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high-throughput continuous flow process was developed to perform a dual iridium- and nickel-catalyzed C(sp$^2$)–C(sp$^3$) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine-derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp$^2$)–C(sp$^3$) coupling method using boronic esters and cyano heteroarenes under flow conditions.Novartis Pharma AG, Engineering and Physical Sciences Research Council (Grant IDs: EP/K0099494/1, EP/K039520/1