Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

I. Catalytic asymmetric allylation of ketones: Development and synthetic applications. II. Catalytic asymmetric arylation of aldehydes: Practical approaches

In chapter 1, we described the development of a (BINOLate)Ti-based catalyst for the asymmetric allylation of ketones. The catalyst exhibits good to excellent levels of enantioselectivity across a broad range of substrates. The products, homoallylic alcohols, are versatile materials in organic synthesis and can be transformed into other useful chiral intermediates. It is noteworthy that high enantioselectivities were obtained with a variety of cyclic enone substrates, providing access to tertiary alcohols possessing both allylic and homoallylic double bonds. In chapter 2, we discussed the first catalyst for the asymmetric methallylation of ketones. The (H8-BINOLate)Ti complex showed better performance in methallyation than the (BINOLate)Ti catalyst, which is an excellent catalyst for the allylation of ketones. The larger dihedral angle of H8-BINOL may be responsible for the increased enantioselectivity over the BINOL-based catalyst. In addition, acetonitrile solvent was crucial for higher enantioselectivity in the methallylation. Acetonitrile may coordinate to the titanium catalyst and alter the structure of the catalyst. Under the optimized conditions, good to high levels of enantioselectivity were observed across a broad range of ketone substrates. These previously inaccessible tertiary homoallylic alcohols can be converted to various chiral building blocks as demonstrated by their conversion to tertiary β-hydroxy ketones. The synthetic utility of cyclic enone with our allylation was explored in chapter 3. The asymmetric allylation products of cyclic enones, cyclic 1,5-dien-3-ols, underwent the asymmetric allylation and diastereoselective epoxidation in one-pot using Ti-BINOLate. Beginning from achiral precursors, this one-pot sequence affects the generation of three contiguous stereocenters with excellent enantio- and diastereoselectivity and with high yields. We also demonstrated that the oxy-Cope rearrangement proceeded well on the cyclic 1,5-dien-3-ols. The resulting β-allyl cyclic ketones are the net result of an asymmetric conjugate addition of an allyl group to a cyclic enone, a reaction that remains challenging in asymmetric catalysis. In chapter 4, the catalytic arylation of aldehydes was developed beginning from readily available aryl halide. Key to the success of this methods is the introduction of a diamine, such as TEEDA. In the absence of TEEDA, the addition reaction is promoted by the LiCl byproduct, resulting in low enantioselectivity (2%). TEEDA inhibits the LiCl byproduct and allows the addition to proceed through the chiral zinc catalyst. Importantly, in the presence of the diamine it is not necessary to filter, centrifuge, or isolate the arylzinc reagents, minimizing decomposition of these pyrophoric and moisture sensitive materials. Also noteworthy is the fact that addition of functionalized aryl zinc reagents can be accomplished, enabling the synthesis of a variety of benzylic alcohols that were previously difficult to access in enantioenriched form

I. Catalytic asymmetric allylation of ketones: Development and synthetic applications. II. Catalytic asymmetric arylation of aldehydes: Practical approaches

In chapter 1, we described the development of a (BINOLate)Ti-based catalyst for the asymmetric allylation of ketones. The catalyst exhibits good to excellent levels of enantioselectivity across a broad range of substrates. The products, homoallylic alcohols, are versatile materials in organic synthesis and can be transformed into other useful chiral intermediates. It is noteworthy that high enantioselectivities were obtained with a variety of cyclic enone substrates, providing access to tertiary alcohols possessing both allylic and homoallylic double bonds. In chapter 2, we discussed the first catalyst for the asymmetric methallylation of ketones. The (H8-BINOLate)Ti complex showed better performance in methallyation than the (BINOLate)Ti catalyst, which is an excellent catalyst for the allylation of ketones. The larger dihedral angle of H8-BINOL may be responsible for the increased enantioselectivity over the BINOL-based catalyst. In addition, acetonitrile solvent was crucial for higher enantioselectivity in the methallylation. Acetonitrile may coordinate to the titanium catalyst and alter the structure of the catalyst. Under the optimized conditions, good to high levels of enantioselectivity were observed across a broad range of ketone substrates. These previously inaccessible tertiary homoallylic alcohols can be converted to various chiral building blocks as demonstrated by their conversion to tertiary β-hydroxy ketones. The synthetic utility of cyclic enone with our allylation was explored in chapter 3. The asymmetric allylation products of cyclic enones, cyclic 1,5-dien-3-ols, underwent the asymmetric allylation and diastereoselective epoxidation in one-pot using Ti-BINOLate. Beginning from achiral precursors, this one-pot sequence affects the generation of three contiguous stereocenters with excellent enantio- and diastereoselectivity and with high yields. We also demonstrated that the oxy-Cope rearrangement proceeded well on the cyclic 1,5-dien-3-ols. The resulting β-allyl cyclic ketones are the net result of an asymmetric conjugate addition of an allyl group to a cyclic enone, a reaction that remains challenging in asymmetric catalysis. In chapter 4, the catalytic arylation of aldehydes was developed beginning from readily available aryl halide. Key to the success of this methods is the introduction of a diamine, such as TEEDA. In the absence of TEEDA, the addition reaction is promoted by the LiCl byproduct, resulting in low enantioselectivity (2%). TEEDA inhibits the LiCl byproduct and allows the addition to proceed through the chiral zinc catalyst. Importantly, in the presence of the diamine it is not necessary to filter, centrifuge, or isolate the arylzinc reagents, minimizing decomposition of these pyrophoric and moisture sensitive materials. Also noteworthy is the fact that addition of functionalized aryl zinc reagents can be accomplished, enabling the synthesis of a variety of benzylic alcohols that were previously difficult to access in enantioenriched form

Mechanochemical synthesis of poly(trimethylene carbonate)s: an example of rate acceleration

Mechanochemical polymerization is a rapidly growing area and a number of polymeric materials can now be obtained through green mechanochemical synthesis. In addition to the general merits of mechanochemistry, such as being solvent-free and resulting in high conversions, we herein explore rate acceleration under ball-milling conditions while the conventional solution-state synthesis suffer from low reactivity. The solvent-free mechanochemical polymerization of trimethylene carbonate using the organocatalysts 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) are examined herein. The polymerizations under ball-milling conditions exhibited significant rate enhancements compared to polymerizations in solution. A number of milling parameters were evaluated for the ball-milling polymerization. Temperature increases due to ball collisions and exothermic energy output did not affect the polymerization rate significantly and the initial mixing speed was important for chain-length control. Liquid-assisted grinding was applied for the synthesis of high molecular weight polymers, but it failed to protect the polymer chain from mechanical degradation

Rh(III)- and Ir(III)-catalyzed direct C-H bond transformations to carbon-heteroatom bonds

The direct manipulation of C-H bonds is now a powerful tool in chemical synthesis. In achieving the current high standard of research progresses, Rh(III) and Ir(III) complexes played an important role to understand the nature of C-H bond activation. While numerous stoichiometric reactions of hydrocarbons with Rh (III) or Ir(III) complexes were scrutinized, their use in catalytic transformations has been relatively undeveloped until recently. Given their outstanding reactivity in C-H activation, they are highly promising candidates for inducing mild C-H functionalizations. In spite of a short development history, numerous contributions from leading research groups made big strides in highly efficient and selective C-H bond transformations for the C-C and C-heteroatom bond formation. In this report, we specifically focus on the Rh(III)- or Ir(III)-mediated direct C-H functionalizations for the C-heteroatom bond formation that is now a rapidly growing area. This report presents the current status of such catalytic systems including scope of substrates and coupling partners as well as brief mechanistic descriptions. © Springer International Publishing Switzerland 2015133411sciescopu

Mechanochemical Post-Polymerization Modification: Solvent-Free Solid-State Synthesis of Functional Polymers

Mechanochemical postpolymerization modification is reported herein. The fast and efficient synthesis of a library of macromolecules with functional diversity and structural uniformity was realized without a solvent by means of a high speed ball-milling technique. A series of polymers prepared from 4-vinylbenzaldehyde (4-VBA) underwent solid-state Schiff base formations with a series of amines and amine derivatives. The efficient mixing and energy delivery provided by the collisions between balls not only promoted rapid imine formation but also eliminated the need for a chemical solvent, which is highly desirable for green chemical synthesis

Metal-Free Hydrosilylation Polymerization by Borane Catalyst

The first example of metal-free hydrosilylation polymerization between dienes and disilanes is developed by using a borane catalyst, B(C6F5)3 to replace precious transitionmetal- based systems. Under the easy-to-handle and mild conditions, a step-growth polymerization of two readily available diene and disilane units was achieved with high degrees of polymerization. Various combinations of dienes and disilanes produced polycarbosilanes with a broad range of structures and properties. © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim113141sciescopu

Study of Sustainability and Scalability in the Cp∗Rh(III)-Catalyzed Direct C-H Amidation with 1,4,2-Dioxazol-5-ones

The practical aspects of Cp∗Rh(III)-catalyzed direct C-H amidation with 1,4,2-dioxazol-5-ones were investigated on the operational safety, use of green solvent, and scalability. Differential scanning calorimeter (DSC) measurement showed that 3-phenyl-1,4,2-dioxazol-5-one is thermally stable while benzoyl azide, a conventionally employed precursor of acyl nitrene, rapidly decomposes to isocyanate. It was confirmed that the replacement of acyl azide with 1,4,2-dioxazol-5-one brings not only high reactivity but also improvement in safety. In respect to a green process development, functional group tolerant Cp∗Rh(III) catalyst exhibited high reactivity in ethyl acetate, successfully replacing 1,2-dichloroethane solvent used in the original report. Upon the validation on safety and environmental concerns, scalability was also tested. Two different types of arenes bearing pyridyl and oxime directing groups showed excellent conversions on tens of gram scale reactions, and single recrystallization gave desired products with high yields and purity. © 2015 American Chemical Society148491sciescopu

Synthesis and Polymerization of Norbornenyl-Terminated Multiblock Poly(cyclohexene carbonate)s: A Consecutive Ring-Opening Polymerization Route to Multisegmented Graft Polycarbonates

We report a method for the synthesis of multisegmented polycarbonate graft copolymers. Using a β-diiminate zinc catalyst with a norbornene carboxylate initiator, we achieved living block copolymerizations of functionalized cyclohexene oxides and CO₂, yielding norbornenyl-terminated macromonomers with variable block sequences. Subsequent ring-opening metathesis polymerization of the norbornenyl-terminated macromonomers produced segmented graft copolymers. This method provides a facile route to core–shell structures with readily controllable molecular parameters

Synthesis of Polypropylene via Catalytic Deoxygenation of Poly(methyl acrylate)

We propose the defunctionalization of vinyl polymers as a strategy to access previously inaccessible polyolefin materials. By utilizing B(C6F5)(3)-catalyzed deoxygenation in the presence of silane, we demonstrate that eliminating the pendent ester in poly(methyl acrylate) effectively leaves a linear hydrocarbon polymer with methyl pendants, which is polypropylene. We further show that a polypropylene-b-polystyrene diblock copolymer and a polystyrene-b-polypropylene-b-polystyrene triblock copolymer can be successfully derived from the poly(methyl acrylate)-containing block polymer precursors and exhibit quite distinct materials properties due to their chemical transformation. This unique postpolymerization modification methodology, which goes beyond the typical functional group conversion, can offer access to a diverse range of unprecedented polyolefin block polymers with a variable degree of functional groups. © 2019 American Chemical Society11sciescopu