Second-Generation Atroposelective Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.

A chromatography-free asymmetric synthesis of GDC-6036 (1) was achieved via a highly atroposelective Negishi coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol % [Pd(cin)Cl]2 and 1 mol % (R,R)-Chiraphite to afford the key intermediate (Ra)-3. An alkoxylation of (Ra)-3 with (S)-N-methylprolinol (4) and a global deprotection generates the penultimate heterobiaryl intermediate 2. A controlled acrylamide installation by stepwise acylation/sulfone elimination and final adipate salt formation and crystallization delivered high-purity GDC-6036 (1).

A comprehensive methodology to study double emulsion stability.

HYPOTHESIS: The stability of emulsions requires the fast formation of viscoelastic interfaces between water and oil phases. In double emulsions, two surfactant types (hydrophilic and lipophilic) are present and two interfacial films are involved. Understanding cooperative adsorption of these surfactants and its implication on properties of water/oil/water interfacial films will enable replacing the empirical methodologies used in designing double emulsion systems with a knowledge-based approach. EXPERIMENTS AND MODEL: The distribution of surfactants between the water/oil interfaces was investigated using single droplet diffusion experiments and simulation of equilibrium surfactant density profiles. The stability of the interfaces against coalescence was characterized by dye transport in a leach cell and coalescence time of single droplets in a model experiment. The conformation of the surfactants at an interface was then examined via surface rheology, sum frequency generation spectroscopy, and dissipative particle dynamics simulation. FINDINGS: Two selected hydrophilic surfactants combined with a lipophilic surfactant induce very different properties at water/oil interfaces and different dye release behaviour from their corresponding double emulsions. Competitive adsorption of sodium dodecyl sulfate and lipophilic surfactant results in the improvement of encapsulation efficiency, elasticity of the interface, and resistance against coalescence due to the intercalation of surfactant alkyl chains into the oil chains.

Stereoselective Synthesis of the IDO Inhibitor Navoximod.

A highly efficient asymmetric synthesis of the IDO inhibitor navoximod, featuring the stereoselective installation of two relative and two absolute stereocenters from an advanced racemic intermediate, is described. The stereocenters were set via a crystallization-induced dynamic resolution along with two selective ketone reductions: one via a biocatalytic ketoreductase transformation and one via substrate-controlled hydride delivery from LiAlH(Ot-Bu)3. Following this strategy, navoximod was synthesized in 10 steps from 2-fluorobenzaldehyde and isolated in 23% overall yield with 99.7% ee and high purity.

Heterogeneous Metal-Organic Framework Catalysts for Suzuki-Miyaura Cross Coupling in the Pharma Industry.

The synthesis of drug substances (DS) requires the continuous effort of the pharma industry to ensure high sustainability standards. The Suzuki-Miyaura cross coupling is a fundamental C-C bond-forming reaction to produce complex DS intermediates. The present contribution points out the way in which the synthesis of DS intermediates by C-C cross coupling can be economically competitive, while minimizing waste by selecting the appropriate heterogeneous catalyst. By comparing homogeneous, immobilized heterogeneous catalysts on silica and metal-organic framework (MOF) catalysts, while considering the perspectives of academia and industry, the critical parameters for a successful industrial application of heterogeneous catalytic Suzuki-Miyaura cross coupling reactions were identified. Heterogeneous catalysts, such as MOFs, may provide a complementary platform for reducing waste and the costs of production related to such transformations.

Development of the Commercial Manufacturing Process for Ipatasertib.

Ipatasertib is a potent small molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple negative metastatic breast cancer. In this paper an overview of the development achievements towards the commercial manufacturing process is given. The convergent synthesis consists of ten steps with eight isolated intermediates and utilizes a wide range of chemical techniques and technologies to build-up this complex drug. All three stereocenters are introduced using enzyme or metal catalysis.

A State-of-the-Art Heterogeneous Catalyst for Efficient and General Nitrile Hydrogenation.

Cobalt-doped hybrid materials consisting of metal oxides and carbon derived from chitin were prepared, characterized and tested for industrially relevant nitrile hydrogenations. The optimal catalyst supported onto MgO showed, after pyrolysis at 700 °C, magnesium oxide nanocubes decorated with carbon-enveloped Co nanoparticles. This special structure allows for the selective hydrogenation of diverse and demanding nitriles to the corresponding primary amines under mild conditions (e.g. 70 °C, 20 bar H2 ). The advantage of this novel catalytic material is showcased for industrially important substrates, including adipodinitrile, picolinonitrile, and fatty acid nitriles. Notably, the developed system outperformed all other tested commercial catalysts, for example, Raney Nickel and even noble-metal-based systems in these transformations.

Asymmetric Hydrogenation of Unfunctionalized Tetrasubstituted Acyclic Olefins.

Asymmetric hydrogenation has evolved as one of the most powerful tools to construct stereocenters. However, the asymmetric hydrogenation of unfunctionalized tetrasubstituted acyclic olefins remains the pinnacle of asymmetric synthesis and an unsolved challenge. We report herein the discovery of an iridium catalyst for the first, generally applicable, highly enantio- and diastereoselective hydrogenation of such olefins and the mechanistic insights of the reaction. The power of this chemistry is demonstrated by the successful hydrogenation of a wide variety of electronically and sterically diverse olefins in excellent yield and high enantio- and diastereoselectivity.

A robust iron catalyst for the selective hydrogenation of substituted (iso)quinolones.

By applying N-doped carbon modified iron-based catalysts, the controlled hydrogenation of N-heteroarenes, especially (iso)quinolones, is achieved. Crucial for activity is the catalyst preparation by pyrolysis of a carbon-impregnated composite, obtained from iron(ii) acetate and N-aryliminopyridines. As demonstrated by TEM, XRD, XPS and Raman spectroscopy, the synthesized material is composed of Fe(0), Fe3C and FeN x in a N-doped carbon matrix. The decent catalytic activity of this robust and easily recyclable Fe-material allowed for the selective hydrogenation of various (iso)quinoline derivatives, even in the presence of reducible functional groups, such as nitriles, halogens, esters and amides. For a proof-of-concept, this nanostructured catalyst was implemented in the multistep synthesis of natural products and pharmaceutical lead compounds as well as modification of photoluminescent materials. As such this methodology constitutes the first heterogeneous iron-catalyzed hydrogenation of substituted (iso)quinolones with synthetic importance.

Correction: A robust iron catalyst for the selective hydrogenation of substituted (iso)quinolones.

[This corrects the article DOI: 10.1039/C8SC02744G.].

Highly Efficient Synthesis of a Staphylococcus aureus Targeting Payload to Enable the First Antibody-Antibiotic Conjugate.

A practical synthesis of the complex payload for an anti-Staphylococcus aureus THIOMABTM antibody-antibiotic conjugate (TAC) is described. The route takes advantage of a delicate oxidative condensation, achieved using a semi-continuous flow procedure. It allows for the generation of kilogram quantities of a key intermediate to enable a mild nucleophilic aromatic substitution to the tertiary amine free drug. The linker component is introduced as a benzylic chloride, which allows formation of the quaternary ammonium salt linker-drug. This chemical process surmounts numerous synthetic challenges and navigates deeply colored and unstable compounds to support clinical studies to counter S. aureus bacterial infections.

Asymmetric Synthesis of Akt Kinase Inhibitor Ipatasertib.

A highly efficient asymmetric synthesis of the Akt kinase inhibitor ipatasertib (1) is reported. The bicyclic pyrimidine 2 starting material was prepared via a nitrilase biocatalytic resolution, halogen-metal exchange/anionic cyclization, and a highly diastereoselective biocatalytic ketone reduction as key steps. The route also features a halide activated, Ru-catalyzed asymmetric hydrogenation of a vinylogous carbamic acid to produce α-aryl-ß-amino acid 3 in high yield and enantioselectivity. The API was assembled in a convergent manner through a late-stage amidation/deprotection/monohydrochloride salt formation sequence.

Manganese(I)-Catalyzed Enantioselective Hydrogenation of Ketones Using a Defined Chiral PNP Pincer Ligand.

A new chiral manganese PNP pincer complex is described. The asymmetric hydrogenation of several prochiral ketones with molecular hydrogen in the presence of this complex proceeds under mild conditions (30-40 °C, 4 h, 30 bar H2 ). Besides high catalytic activity for aromatic substrates, aliphatic ketones are hydrogenated with remarkable selectivity (e.r. up to 92:8). DFT calculations support an outer sphere hydrogenation mechanism as well as the experimentally determined stereochemistry.

Biomass-Derived Catalysts for Selective Hydrogenation of Nitroarenes.

Development of catalytically active materials from biowaste represents an important aspect of sustainable chemical research. Three heterogeneous materials were synthesized from inexpensive biomass-based chitosan and abundant Co(OAc)2 using complexation followed by pyrolysis at various temperatures. These materials were applied in the catalytic hydrogenation of nitroarenes using molecular hydrogen. A variety of diversely functionalized nitroarenes including some pharmaceutically active compounds were converted into aromatic amines in high yields, with high selectivity, and with excellent functional group tolerance. This green protocol has also been implemented for the synthesis of a biologically important TRPC3 inhibitor.

A Biomass-Derived Non-Noble Cobalt Catalyst for Selective Hydrodehalogenation of Alkyl and (Hetero)Aryl Halides.

Hydrodehalogenation is a straightforward approach for detoxifications of harmful anthropogenic organohalide-based pollutants, as well as removal of halide protecting groups used in multistep syntheses. A novel sustainable catalytic material was prepared from biowaste (chitosan) in combination with an earth-abundant cobalt salt. The heterogeneous catalyst was fully characterized by transmission electron microscope, X-ray diffraction, and X-ray photoelectron spectroscopy measurements, and successfully applied to hydrodehalogenation of alkyl and (hetero)aryl halides with broad scope (>40 examples) and excellent chemoselectivity using molecular hydrogen as a reductant. The general usefulness of this method is demonstrated by successful detoxification of non-degradable pesticides and fire retardants. Moreover, the potential of the catalyst as a deprotection tool is demonstrated in a multistep synthesis of (±)-peronatin B (alkaloid).

Bond formation kinetics affects self-assembly directed by ligand-receptor interactions.

In this paper we study aggregation kinetics in systems of particles functionalised by complementary linkers. Most of the coarse-grained models currently employed to study large-scale self-assembly of these systems rely on effective potentials between particles as calculated using equilibrium statistical mechanics. In these approaches the kinetic aspects underlying the formation of inter-particle linkages are neglected. We show how the rate at which supramolecular linkages form drastically changes the self-assembly pathway. In order to do this we develop a method that combines Brownian dynamics simulations with a Gillespie algorithm accounting for the evolution of inter-particle linkages. If compared with dynamics based on effective potentials, an explicit description of inter-particle linkages results in aggregates that in the early stages of self-assembly have a lower valency. Relaxation towards equilibrium is hampered by the time required to break existing linkages within one cluster and to reorient them toward free particles. This effect is more important at low temperature and high particle diffusion constant. Our results highlight the importance of including kinetic rates into coarse-grained descriptions of ligand-receptor systems.

Melting transition in lipid vesicles functionalised by mobile DNA linkers.

We study phase behaviour of lipid-bilayer vesicles functionalised by ligand-receptor complexes made of synthetic DNA by introducing a modelling framework and a dedicated experimental platform. In particular, we perform Monte Carlo simulations that combine a coarse grained description of the lipid bilayer with state of art analytical models for multivalent ligand-receptor interactions. Using density of state calculations, we derive the partition function in pairs of vesicles and compute the number of ligand-receptor bonds as a function of temperature. Numerical results are compared to microscopy and fluorimetry experiments on large unilamellar vesicles decorated by DNA linkers carrying complementary overhangs. We find that vesicle aggregation is suppressed when the total number of linkers falls below a threshold value. Within the model proposed here, this is due to the higher configurational costs required to form inter-vesicle bridges as compared to intra-vesicle loops, which are in turn related to membrane deformability. Our findings and our numerical/experimental methodologies are applicable to the rational design of liposomes used as functional materials and drug delivery applications, as well as to study inter-membrane interactions in living systems, such as cell adhesion.

Communication: Free energy of ligand-receptor systems forming multimeric complexes.

Ligand-receptor interactions are ubiquitous in biology and have become popular in materials in view of their applications to programmable self-assembly. Although complex functionalities often emerge from the simultaneous interaction of more than just two linker molecules, state of the art theoretical frameworks enable the calculation of the free energy only in systems featuring one-to-one ligand/receptor binding. In this Communication, we derive a general formula to calculate the free energy of systems featuring simultaneous direct interaction between an arbitrary number of linkers. To exemplify the potential and generality of our approach, we apply it to the systems recently introduced by Parolini et al. [ACS Nano 10, 2392 (2016)] and Halverson and Tkachenko [J. Chem. Phys. 144, 094903 (2016)], both featuring functionalized Brownian particles interacting via three-linker complexes.

Synthesis and Characterization of Iron-Nitrogen-Doped Graphene/Core-Shell Catalysts: Efficient Oxidative Dehydrogenation of N-Heterocycles.

An important goal for nanocatalysis is the development of flexible and efficient methods for preparing active and stable core-shell catalysts. In this respect, we present the synthesis and characterization of iron oxides surrounded by nitrogen-doped-graphene shells immobilized on carbon support (labeled FeOx@NGr-C). Active catalytic materials are obtained in a simple, scalable and two-step method via pyrolysis of iron acetate and phenanthroline and subsequent selective leaching. The optimized FeOx@NGr-C catalyst showed high activity in oxidative dehydrogenations of several N-heterocycles. The utility of this benign methodology is demonstrated by the synthesis of pharmaceutically relevant quinolines. In addition, mechanistic studies prove that the reaction progresses via superoxide radical anions (·O2(-)).