Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients

he convenient, metal-free reduction of imines that contain an inexpensive and removable chiral auxiliary allowed for the synthesis of the immediate precursors of chiral active pharmaceutical ingredients (APIs). This protocol was carried out under batch and flow conditions to give the correspoding prod- ucts in high yields with almost complete stereocontrol. In the presence of trichlorosilane, an inexpensive and nontoxic reduc- ing agent, and an achiral Lewis base such as N,N-dimethyl- Introduction The pharmaceutical industry is gradually progressing towards enantiopure formulations. Most newly introduced drugs are chiral, and it is expected that approximately 95 % of pharma- ceutical drugs will be chiral by 2020. [1] In this context, chiral amines are considered a class of paramount importance, be- cause they are found in a plethora of compounds such as those of pharmaceutical interest as well as those developed for agro- chemicals, fragrances, and fine chemicals. [2] The reduction of the C=N group is one of the most widely used approaches to synthesize chiral amines, and over the last ten years, successful catalytic enantioselective methods based on both metal-pro- moted [3] and organocatalyzed [4] strategies have been devel- oped. When an industrial synthesis of a chiral pharmaceutical prod- uct must be planned, however, issues such as the chemical effi- ciency and robustness of the procedure, its general applicabil- ity, and economic considerations become crucially important. For these reasons, the applications of many chiral catalytic sys- tems are often not feasible, and the use of inexpensive and readily available chiral auxiliaries becomes an attractive and economic alternative. This also holds true for the synthesis of [a] Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy E-mail: [email protected] http://users2.unimi.it/Benagliagroup [b] Istituto di Scienze e Tecnologie Molecolari ISTM-CNR, Via Golgi 19, 20133 Milano, Italy [c] Department of Chemistry and Chemistry Center of Évora, University of Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under http://dx.doi.org/10.1002/ejoc.201601268. Eur. J. Org. Chem. 2017, 39–44 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim39 formamide, the formal syntheses of Rivastgmine, calcimimetic NPS R-568, and a Rho kinases inhibitor were successfully accom- plished. For the first time, both the diastereoselective imine re- duction and the auxiliary removal were efficiently performed in a micro- or mesoreactor under continuous-flow conditions, which paved the way towards the development of a practical process for the syntheses of industrially relevant, biologically active, enantiopure N-alkylamine

Flow synthesis of iodonium trifluoroacetates through direct oxidation of iodoarenes by Oxone®

Flow chemistry is considered to be a versatile and complementary methodology for the preparation of valuable organic compounds. We describe a straightforward approach for the synthesis of iodonium trifluoroacetates through the direct oxidation of iodoarenes in a simple flow reactor using an Oxone‐filled cartridge. Optimization has been carried out using the Nelder–Mead algorithm. The procedure allows a wide range of iodonium salts to be prepared from simple starting materials

Protein 4.1B Contributes to the Organization of Peripheral Myelinated Axons

Neurons are characterized by extremely long axons. This exceptional cell shape is likely to depend on multiple factors including interactions between the cytoskeleton and membrane proteins. In many cell types, members of the protein 4.1 family play an important role in tethering the cortical actin-spectrin cytoskeleton to the plasma membrane. Protein 4.1B is localized in myelinated axons, enriched in paranodal and juxtaparanodal regions, and also all along the internodes, but not at nodes of Ranvier where are localized the voltage-dependent sodium channels responsible for action potential propagation. To shed light on the role of protein 4.1B in the general organization of myelinated peripheral axons, we studied 4.1B knockout mice. These mice displayed a mildly impaired gait and motility. Whereas nodes were unaffected, the distribution of Caspr/paranodin, which anchors 4.1B to the membrane, was disorganized in paranodal regions and its levels were decreased. In juxtaparanodes, the enrichment of Caspr2, which also interacts with 4.1B, and of the associated TAG-1 and Kv1.1, was absent in mutant mice, whereas their levels were unaltered. Ultrastructural abnormalities were observed both at paranodes and juxtaparanodes. Axon calibers were slightly diminished in phrenic nerves and preterminal motor axons were dysmorphic in skeletal muscle. βII spectrin enrichment was decreased along the axolemma. Electrophysiological recordings at 3 post-natal weeks showed the occurrence of spontaneous and evoked repetitive activity indicating neuronal hyperexcitability, without change in conduction velocity. Thus, our results show that in myelinated axons 4.1B contributes to the stabilization of membrane proteins at paranodes, to the clustering of juxtaparanodal proteins, and to the regulation of the internodal axon caliber

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Anthropogenic intensification of short-duration rainfall extremes

Short- duration (1-3 h) rainfall extremes can cause serious damage to societies through rapidly developing (flash) flooding and are determined by complex, multifaceted processes that are altering as Earth's climate warms. In this Review, we examine evidence from observational, theoretical and modelling studies for the intensification of these rainfall extremes, the drivers and the impact on flash flooding. Both short- duration and long- duration (\textgreater1 day) rainfall extremes are intensifying with warming at a rate consistent with the increase in atmospheric moisture (~7% K-1), while in some regions, increases in short- duration extreme rainfall intensities are stronger than expected from moisture increases alone. These stronger local increases are related to feedbacks in convective clouds, but their exact role is uncertain because of the very small scales involved. Future extreme rainfall intensification is also modulated by changes to temperature stratification and large- scale atmospheric circulation. The latter remains a major source of uncertainty. Intensification of short- duration extremes has likely increased the incidence of flash flooding at local scales and this can further compound with an increase in storm spatial footprint to considerably increase total event rainfall. These findings call for urgent climate change adaptation measures to manage increasing flood risks

High-elevation precipitation patterns: Using snow measurements to assess daily gridded datasets across the Sierra Nevada, California

Gridded spatiotemporal maps of precipitation are essential for hydrometeorological and ecological analyses. In the United States, most of these datasets are developed using the Cooperative Observer (COOP) network of ground-based precipitation measurements, interpolation, and the Parameter-Elevation Regressions on Independent Slopes Model (PRISM) to map these measurements to places where data are not available. Here, we evaluate two daily datasets gridded at 1/16° resolution against independent daily observations from over 100 snow pillows in California's Sierra Nevada from 1990 to 2010. Over the entire period, the gridded datasets performed reasonably well, with median total water-year errors generally falling within ±10%. However, errors in individual storm events sometimes exceeded 50% for the median difference across all stations, and in many cases, the same underpredicted storms appear in both datasets. Synoptic analysis reveals that these underpredicted storms coincide with 700-hPa winds from the west or northwest, which are associated with post-cold-frontal flow and disproportionately small precipitation rates in low-elevation valley locations, where the COOP stations are primarily located. This atmospheric circulation leads to a stronger than normal valley-to-mountain precipitation gradient and underestimation of actual mountain precipitation. Because of the small average number of storms (<10) reaching California each year, these individual storm misses can lead to large biases (~20%) in total water-year precipitation and thereby significantly affect estimates of statewide water resources