GlaxoSmithKline (Ireland)

Abstract Compounds containing quaternary stereocentres are a valuable motif in biologically active compounds. Herein we present our strategy to utilise the hydrogen borrowing manifold to access α‐quaternary ketones via a tandem acceptorless dehydrogenation‐cyclisation cascade. This new application of the methodology results in the formation of five‐ and six‐membered carbocycles with a high degree of diastereoselectivity. Interestingly, benzylic alcohol substrates behaved anomalously and eliminated sulfinate in situ to give a set of rearranged α‐quaternary ketone products.

Specific bifidobacterial strains can reduce aberrant inflammatory responses, but the strain-specific factors that promote regulatory immune responses are not well elucidated. The aims of this study were to assess the effects of Bifidobacterium longum 1714™ on innate inflammatory responses and to identify the strain-associated features that mediate its immunomodulatory effects. B. longum 1714 induced peripheral blood mononuclear cell (PBMC) and monocyte derived dendritic cell (MDDC) cytokine secretion and costimulatory molecule expression in a strain specific manner. B. longum 1714 consumption reduced excessive cytokine responses in LPS-induced, stress-induced and obesity-induced inflammation in murine models. B. longum 1714 produced a branched hexasaccharide repeating unit exopolysaccharide (EPS), which selectively induced PBMC secretion of IL-10. Furthermore, B. longum 1714 produced tryptophan and indole lactic acid (ILA) in vitro, and ILA directly reduced TLR-induced proinflammatory cytokine secretion and NF-κB activation. Finally, increased plasma levels of tryptophan and kynurenic acid were identified in humans following B. longum 1714 consumption. B. longum 1714 influences the immune system through intrinsic features associated with strain specific surface EPS and via secreted metabolic products, which demonstrates the potential for multiple mechanisms through which a specific probiotic may modulate immune responses and potential neuroprotective pathways.

The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser-Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C-H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.

A concise strategyfor the total synthesis of several Aspidosperma alkaloids is reported. A Suzuki–Miyauracross-coupling provides access to a 2-vinyl indole that undergoesa Diels–Alder cascade reaction with butyn-2-one to delivera pyrroloindoline intermediate. This undergoes cascade amidation,reduction, skeletal rearrangement, and intramolecular Michael additionto provide a common intermediate containing the full framework ofthe Aspidosperma alkaloids. The utilityof this intermediate is shown in the synthesis of four different naturalproducts.

Since the 1930s, fixed bed reactors (FBR) have been operated for continuous hydrogenation reactions in the petrochemical/fine chemical industries, with publications each year detailing engineering principles, scientific breakthroughs, equipment design and setup, from these industries. Only in the last two decades, FBR have started to be utilized in the pharmaceutical industry as a result of sustainability commitment and growing demand of complex and specialized drugs. Most of the engineering knowledge is transferable across industries; however, there are differentiators inherent to each industry, with the pharmaceutical industry having its own unique challenges. One of the main differentiators between industries is the reactor scale and, consequently, reactor catalyst requirements. Petrochemicals or fine chemicals operate on a large industrial scale, with up to 72 m high reactors, with an internal diameter on the order of 5 m (China Petroleum & Chemical Corporation), and require large volumes of catalysts because of the high product demand for thousands of tonnes per year, while for the pharmaceutical industry, a smaller scale reactor is required for product demand in the thousands of kilograms per year range. It is the reactor size that defines catalyst specifications, such as particle size and geometry. Many transformations have emerged from academic and medicinal chemistry groups utilizing the ThalesNano H-Cube; however, there are relatively few reported processes that have been scaled within the pharmaceutical industry. This Perspective outlines a review of continuous flow hydrogenation technologies; focusing on the trickle bed reactor (TBR) and the respective process operation and effect of process variables on reaction rate requirements for the pharmaceutical industry; it also reflects on transformation examples using TBR across the pharmaceutical industry.

We present a one-step Ugi reaction protocol for the expedient synthesis of photoaffinity probes for live-cell MS-based proteomics. The reaction couples an amine affinity function with commonly used photoreactive groups, and a variety of handle functionalities. Using this technology, a series of pan-BET (BET: bromodomain and extra-terminal domain) selective bromodomain photoaffinity probes were obtained by parallel synthesis. Studies on the effects of photoreactive group, linker length and irradiation wavelength on photocrosslinking efficiency provide valuable insights into photoaffinity probe design. Optimal probes were progressed to MS-based proteomics to capture the BET family of proteins from live cells and reveal their potential on- and off-target profiles.

A workflow for the development of organometallic processes in flow was applied to synthesize 1-(5-bromopyridin-2-yl)-2-methylpropan-2-ol, a pharmaceutical intermediate. Key factors and corresponding practical assessments required for the scale-up when transferring from batch to flow are highlighted. During the rapid process development, unexpected and expected issues concerned with the use of 1 M and 2 M lithium diisopropylamide in flow were encountered and overcome as they arose. Organolithium chemistry was operated in continuous flow mode; a reaction sequence of sp3 deprotonation and in-line acetone quench, followed by a semibatch workup was scaled up to multigram quantities in a rapid, fit-for-purpose manner for early-phase project delivery.

Metal-catalyzed C–N cross-coupling generally forms C–N bonds by reductive elimination from metal complexes bearing covalent C- and N-ligands. We have identified a Cu-mediated C–N cross-coupling that uses a dative N-ligand in the bond forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a Cu(II) complex bearing neutral N-ligands, such as nitriles or N-heterocycles. Subsequent generation of a putative Cu(III) complex enables the oxidative C–N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp<sup>2</sup>) precursors and can be applied to drug synthesis and late-stage N-arylation, and the limitations in the methodology are mechanistically evidenced.

Abstract A scalable metal‐, azide‐, and halogen‐free method for the synthesis of substituted 1,2,3‐triazoles has been developed. The reaction proceeds through a 3‐component coupling of α‐ketoacetals, tosyl hydrazide, and a primary amine. The reaction shows outstanding functional‐group tolerance with respect to both the α‐ketoacetal and amine coupling partners, providing access to 4‐, 1,4‐, 1,5‐, and 1,4,5‐substituted triazoles in excellent yield. This robust method results in densely functionalised 1,2,3‐triazoles that remain challenging to prepare by azide–alkyne cycloaddition (AAC, CuAAC, RuAAC) methods and can be scaled in either batch or flow reactors. Methods for the chemoselective reaction of either aliphatic amines or anilines are also described, revealing some of the potential of this novel and highly versatile transformation.

BackgroundThe adjuvanted recombinant zoster vaccine (RZV) is efficacious in preventing herpes zoster in adults ≥ 50 years. The current study investigates whether the vaccinees’ quality of life (QoL) and physical functioning (PF) are impacted by local and systemic reactions due to RZV. In a previous report of this phase III, open-label, multicenter study (NCT02979639), overall PF and QoL were not significantly affected by a first RZV dose. [1] Here we report the results from the same study after a second RZV dose and safety results from dose 1 up to study end.MethodsAdults aged ≥ 50 years were to receive 2 doses of RZV 2 months apart. Changes in mean Short Form health survey (SF-36) PF score between pre- and post-each RZV dose for 7 days, QoL, reactogenicity and safety were assessed.Results401 adults received dose 1 and 391 received dose 2 of RZV. Post-second RZV dose, the reported solicited local symptoms were pain (75.1%), erythema (22.4%) and swelling (13.9%), and the most frequent solicited systemic symptoms were fatigue (46.3%), headache (37.5%) and myalgia (32.9%). Grade 3 solicited symptoms were reported by 7.2% (local) and 11.1% (general) of participants, and 5 (1.2%) participants reported reactogenicity triggering medical attention post-second RZV dose. From first dose up to study end, 14 (3.5%) participants reported 21 serious adverse events, none related to RZV. In days 1–2, post-second RZV dose, a transient, clinically-important decrease in SF-36 PF score (table) was seen in those reporting grade 3 solicited symptoms, which impacted activities such as walking and climbing stairs. Overall, during the 7 days post-second RZV dose, a mean change of −0.4 points was observed from the mean baseline score, indicating the PF was not clinically meaningfully impacted. No overall quality-adjusted-life-year loss was recorded.ConclusionOverall, the QoL and PF of adults ≥ 50 years were not affected post-second RZV dose; a transient impact was observed in adults with grade 3 reactogenicity. These results and the observed reactogenicity and safety profile are consistent with first RZV dose results, as well as that of previous studies with the RZV vaccine in adults of similar age. Funding: GlaxoSmithKline Biologicals SA.1. Schmader et al., 2488, IDWeek 2018 DisclosuresAll authors: No reported disclosures.