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A modular approach to the synthesis of twisted bicyclic amides and anilines allows for variation in the degree of overlap between the nitrogen lone pair and the relevant π-system, and hence the structural and physical properties of the products.

A three-component synthesis of polysubstituted pyridines, based upon the Diels–Alder reactions of 2-azadienes formed by a novel redox-neutral catalytic intermolecular aza-Wittig reaction.

A convenient and simple three-component synthesis of substituted pyridylacetic acid derivatives is reported. The approach centers on the dual reactivity of Meldrum's acid derivatives, initially as nucleophiles to perform substitution on activated pyridine

Regioselective and stereospecific directed C–H arylation of simple amine substrates, and cyclisation, delivered 30 diverse, three-dimensional scaffolds. The unified approach significantly expanded the range of bridged ring systems that contain both a nitrogen atom and an aromatic ring.

The regioselective γ-C-H amination of the side-chain of saturated 2-alkyl nitrogen heterocycles is reported, proceeding through a sulfamide-directed 1,6-radical translocation. The practicality of this rapid access to 1,3-diamines is highlighted in a short synthesis of the alkaloid tetraponerine T8 and non-natural analogues.

A strategy for the β-sp3 functionalisation of cyclic amines is described. Regioselective conversion of protected amines to enecarbamates is achieved through electrochemical oxidation; these intermediates can be derivatised by functionalised alkyl halides under photoredox catalysis. The potential of the methods is highlighted by direct growth of a DCP2B-binding fragment.

A new modular photochemical continuous-stirred tank reactor design is described, based upon the development of light-source units that can be fitted to the previously described fReactor CSTR platform. In contrast to many tubular or plate-based designs, these units are especially well-suited to handling multiphasic mixtures, exemplified here in solid-liquid and gas-liquid photochemical reactions. The use of slurries as input feeds allows for intensification of a photochemical bromination, while the modular nature of the system facilitates simple integration of downstream reaction steps, exemplified here in a continuous synthesis of an intermediate for the drug valsartan.

An optimized procedure for the direct intra‐ and intermolecular amination of aromatic C‐H bonds with aminium radicals generated from N‐chloroamines under iron catalysis is reported. A range of substituted tetrahydroquinolines could be readily prepared, while extension to the synthesis of benzomorpholines was more limited in scope. A direct one‐pot variant was developed, allowing direct formal oxidative N‐H/C‐H coupling.

3‐Amino‐substituted saturated nitrogen heterocycles are an important subclass of β‐diamines, appearing in a number of clinical agents. Herein, we report a unified approach to these products based upon the regioselective photoredox‐mediated hydroamination of enecarbamates. The amine coupling partner can encompass diverse amine types under a single set of reaction conditions, including primary alkyl amines, ammonia, aryl and heteroaryl amines, and N−H heterocycles. The method enables the synthesis of a wide range of pharmaceutically relevant building blocks., Medicinally important 3‐amino‐substituted cyclic amines can be accessed in a single step by photoredox‐catalysed hydroamination of cyclic enecarbamates. A diverse range of drug‐relevant amine substituents can be introduced under unified reaction conditions, including primary alkyl amines, ammonia, (hetero)aromatic amines, and N‐heterocycles (see scheme).

A unified synthetic approach was developed that enabled the synthesis of diverse tropane-related scaffolds. The key intermediates that were exploited were cycloadducts formed by reaction between 3-hydroxy-pyridinium salts and vinyl sulfones or sulfonamides. The diverse tropane-related scaffolds were formed by addition of substituents to, cyclisation reactions of, and fusion of additional ring(s) to the key bicyclic intermediates. A set of 53 screening compounds was designed, synthesised and evaluated in order to determine the biological relevance of the scaffolds accessible using the synthetic approach. Two inhibitors of Hedgehog signalling, and four compounds with weak activity against the parasite P. falciparum, were discovered. Three of the active compounds may be considered to be indotropane or pyrrotropane pseudo natural products in which a tropane is fused with a fragment from another natural product class. It was concluded that the unified synthetic approach had yielded diverse scaffolds suitable for the design of performance-diverse screening libraries.

High throughput experimentation (HTE) has enabled the rapid identification of ligand/precatalyst combinations that facilitate highly enantioselective hydrogenations of prochiral N‐alkyl α‐aryl ketimines containing a furyl moiety. The chiral amines obtained have proven to be modular precursors in the synthesis of novel unnatural mono N‐alkylated arylalanines and related derivatives.

Vinyl acetate is used as an acetylene equivalent in rhodium(III)-catalysed C-H activation/annulation with aryl ketoxime esters. Extension to an aldoxime ester allows for a concise formal synthesis of decumbenine B.

The direct C−H amination of arenes by aminium radicals generated by photolysis of N‐chloroamines is demonstrated under continuous flow conditions. The reactions proceed with comparable efficiency to small scale batch processes but are superior to larger scale batch operations. The continuous generation of the N‐chloroamine from the amine precursor can be integrated into the process, facilitating the continuous direct conversion of secondary amines to their arylated derivatives.

The power of complementary chemocatalytic and biocatalytic transformations is demonstrated in the asymmetric synthesis of 2-substituted tetrahydroquinolines. A series of racemic tetrahydroquinolines were synthesized through a convergent one-pot Rh(I)-catalyzed addition/condensation sequence of alkyl vinyl ketones and aminophenylboronic acids. The resulting tetrahydroquinolines were thereafter shown to be substrates for the flavin-dependent enzyme cyclohexylamine oxidase, and preparative-scale deracemizations have been demonstrated on these high-value targets.

Aryl dialkyl amines, valuable subunits of a wide range of effect chemicals, are accessed by intramolecular amination of aromatic C–H bonds employing UV photolysis of N-chloroamines. The reactions show good functional group tolerance and allow access to a range of fused and bridged polycyclic structures. The homogeneous reaction conditions allow for the one-pot conversion of secondary amines to their arylated derivatives. Experimental and theoretical evidence supports the involvement of electrophilic aminium radicals which react via direct ortho-attack on the arene.

The organocatalytic asymmetric transfer hydrogenation of N-alkyl aryl imino esters for the direct synthesis of N-alkylated arylglycinate esters is reported. High yields and enantiomeric ratios were obtained, and tolerance to a diverse set of functional groups facilitated the preparation of more complex molecules as well as intermediates for active pharmaceuticals. A simple recycling protocol was developed for the Brønsted acid catalyst which could be reused through five cycles with no loss of activity or selectivity.

The valuable tetrahydro-β- and γ-carboline skeleta can be accessed through Pictet-Spengler cyclisation initiated by acceptorless dehydrogenation of saturated cyclic amines. The substrate scope for the β-isomers is found to be somewhat limited, but access to the γ-isomers through the more reactive 2-(aminoethyl)indoles is more general. The synthetic utility of hydrogen transfer catalysis is highlighted in a two-step preparation of the alkaloid desbromoarborescidine A by sequential redox-neutral alkylation/dehydrogenative cyclisation.

Mit der Verbesserung unserer Kenntnisse zur Bedeutung bestimmter Molekuleigenschaften bei Anwendungen im Rahmen der Wirkstoffsuche wird das Ausmas immer klarer, in dem veroffentlichte Synthesemethoden erwunschten Kriterien genugen (oder nicht genugen). Wir beschreiben hier, wie die Anwendung einfacher (und in vielen Fallen frei verfugbarer) Rechenprogramme genutzt werden kann, um ein semiquantitatives Verstandnis des Potenzials von neuen Methoden in der Wirkstoff-Forschung zu entwickeln. Diese Analyse kann sich unter anderem auf die Planung verbesserter Studien zum Substratspektrum auswirken, die Priorisierung von bestimmten Beispielstrukturen fur die Synthese leiten und Anspruche fur potenzielle kunftige Anwendungen von neuen Methoden begrunden.

Investigation of the use of green organic solvents for the Cu-catalysed arylation of phenols and amides is reported. Alkyl acetates proved to be efficient solvents in the catalytic processes, and therefore excellent alternatives to the typical non-green solvents used for Cu-catalysed arylation reactions. Solvents such as isosorbide dimethyl ether (DMI) and diethyl carbonate also appear to be viable possibilities for the arylation of phenols. Finally, a novel copper catalysed acyl transfer process is reported.

The identification of high-quality starting points for drug discovery is an enduring challenge in medicinal chemistry. Yet, the chemical space explored in discovery programmes tends be limited by the narrow toolkit of robust methods that are exploited in discovery workflows. The European Lead Factory (ELF) was established in 2013 to boost early-stage drug discovery within Europe. In this Feature, we describe an exemplar partnership that has led to the addition of 21 119 distinctive screening compounds to the ELF Joint European Compound Library. The partnership could serve as a blueprint for the translation of innovative academic chemistry into discovery programmes.

Current fragment sets tend to be dominated by flatter molecules, and their shape diversity does not reflect that of the fragments that are theoretically possible. The design and synthesis of a set of bridged fragments containing a bridgehead nitrogen is described. Many of these fragments contain twisted lactams whose modulated electronic properties may present unusual opportunities for interaction with target proteins. The demonstrated novelty, three-dimensionality and molecular properties of the set of 22 fragments may provide valuable, and highly distinctive, starting points for fragment-based drug discovery.

Through careful choice of conditions, 2-(N-indolyl) amides can be directed to undergo selectively either enolate arylation to give oxindoles or direct arylation to give indolo-fused benzodiazepines. The former chemistry facilitates the synthesis of the hexahydropyrrolindole core of psychotrimine.

The use of the “borrowing hydrogen strategy” in the synthesis of a number of typical pharmaceutical intermediates has been investigated. The main aim of this work was to investigate the scope and limitations of current methodology using standard laboratory techniques in an industrial context. Some interesting and significant results were achieved across a diverse set of complex substrates; however several drawbacks with this approach were identified, such as the high loading, poor turnover, and susceptibility to substrate inactivation of the catalysts. These are areas which are highlighted for future investigation and improvements.

A general and efficient method for the synthesis of drug-like fused bicyclic hydantoins is reported. An Ugi–Joullie reaction/cyclisation sequence was exploited as the key complexity-generating process in which trifluoroacetic acid was employed as synthetic equivalent for chloroformic acid. Exemplar diversification of the bicyclic scaffolds was performed to enable subsequent translation to the synthesis of large small molecule libraries, leading to the production of >1000 compounds for addition to the screening collection of the European Lead Factory.

The synthesis of large numbers of diverse molecular scaffolds with controlled molecular properties is a significant challenge in synthetic organic chemistry. A modular unified synthesis was developed, and was exploited in the synthesis of sixteen diverse three-dimensional scaffolds. The approach exploited two cyclisation precursors to be converted, using a toolkit of cyclisation reactions, into spirocyclic and fused-ring scaffolds. Remarkably, Pd-catalysed aminoarylation of substituted N-Boc-hex-5-enylamine cyclisation precursors to yield N-Boc piperidine-containing scaffolds was successful which was ascribed to a significant Thorpe−Ingold effect. Computational property analysis showed that the decorated scaffolds are shape-diverse, and enable diverse lead-like chemical space to be targeted.

© 2018 The Royal Society of Chemistry. Molecular oxygen is without doubt the greenest oxidant for redox reactions, yet aerobic oxidation is one of the most challenging to perform with good chemoselectivity, particularly on an industrial scale. This collaborative review (between teams of chemists and chemical engineers) describes the current scientific and operational hurdles that prevent the utilisation of aerobic oxidation reactions for the production of speciality chemicals and active pharmaceutical ingredients (APIs). The safety aspects of these reactions are discussed, followed by an overview of (continuous flow) reactors suitable for aerobic oxidation reactions that can be applied on scale. Some examples of how these reactions are currently performed in the industrial laboratory (in batch and in flow) are presented, with particular focus on the scale-up strategy. Last but not least, further challenges and future perspectives are presented in the concluding remarks. crosscheck: This document is CrossCheck deposited identifier: Simon Kuhn (ORCID) copyright_licence: The Royal Society of Chemistry has an exclusive publication licence for this journal copyright_licence: This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0) history: Received 30 August 2016; Accepted 13 September 2016; Advance Article published 22 September 2016; Version of Record published 22 November 2016 ispartof: Reaction Chemistry & Engineering vol:1 issue:6 pages:595-612 status: published

A one-pot, three-component synthesis of α-pyridyl, α-substituted amino acid derivatives is described. The key transformation is a direct, precious-metal-free heteroarylation of readily available, amino acid derived azlactones with electrophilically activated pyridine N-oxides. The resulting intermediates can be used directly as efficient acylating agents for a range of nucleophiles, leading to the heteroarylated amino acid derivatives in a single vessel.

For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.

A synthetic approach to diverse scaffolds was developed that was inspired by diterpene biosynthesis. Initial scaffolds, generated using Diels–Alder reactions of furyl-functionalised amines, were transformed into alternative scaffolds using cleavage, ring expansion, annulation and rearrangement reactions. In total, 25 diverse scaffolds were prepared that were shown to have high natural product-likeness.

Complementary cyclisation reactions of hex-2-ene-1,6-diamine derivatives were exploited in the synthesis of alternative molecular scaffolds. The value of the synthetic approach was analysed using LLAMA, an open-access computational tool for assessing the lead-likeness and novelty of molecular scaffolds.

A wide variety of P-stereogenic aryldialkylphosphines were prepared in enantioenriched form by a systematic diversification of the (-)-sparteine-mediated dynamic kinetic resolution of racemic lithiophosphine-boranes reported by Livinghouse. Excellent asymmetric induction was observed provided that the intermediate lithiophosphine/sparteine complex precipitated from solution; more soluble derivatives returned poor ee's or racemic material. The resulting phosphine-boranes were deprotected and used as reagents in the desymmetrizing asymmetric aza-Wittig reaction of 2-alkyl-2-(3-azidopropyl)cyclohexane-1,3-diones, delivering the highest ee's yet observed in this process (up to 84% ee). Phosphines bearing bulky substituents required heating for the aza-Wittig reaction to proceed to completion, which 31P NMR studies showed to be due to interception of the reaction by the formation of unreactive (E)-phosphazides. This was circumvented by use of methyltrioxorhenium to catalyze the formation of iminophosphoranes from the azide and phosphine, allowing reactions to take place at ambient temperature, although the ee's of the asymmetric reactions were reduced in these examples.

A strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from four quaternary α-amino acid building blocks in only 49 synthetic operations, using six connective reactions. The ability of each scaffold to specifically target leadlike chemical space was demonstrated computationally.

The condensation of substituted allylsiloxanes with aldehydes leads to the highly stereoselective construction of 2,3,4,5-tetrasubstituted tetrahydrofurans. With electron-rich aryl and alpha,beta-unsaturated aldehydes as substrates, the stereochemical outcome at C5 can be dictated by appropriate choice of Lewis acid. The reaction has been applied to a concise (nine step) synthesis of (+)-virgatusin (ent-1). [reaction: see text]

4-Silylated oxazoles have been shown to undergo inter- and intramolecular Diels-Alder/retro-Diels-Alder reactions with electron-poor alkynes to generate polysubstituted furans. The ease of synthesis of the requisite oxazoles by the rhodium-catalysed condensation of nitriles with silylated diazoacetate greatly increases the scope of this reaction.

The behavior of electron-rich alkenes in rhodium-catalyzed C–H activation/annulation reactions is investigated. Vinyl acetate emerges as a convenient acetylene equivalent, facilitating the synthesis of sixteen 3,4-unsubstituted isoquinolones, as well as select heteroaryl-fused pyridones. The complementary regiochemical preferences of enol ethers versus enol esters/enamides is discussed.

Rh-catalysed conjugate additions of 2-aminophenyl boronic acid derivatives were exploited in diastereoselective and asymmetric syntheses of tetrahydroquinolines. In both cases, combinatorial variation of the substitution of the tetrahydroquinoline ring system was possible.

The epoxidation of a number of cyclic and linear terminal alkenes by an O 2 –O 3 mixture at room temperatures catalysed by Fe(TMP)Cl is reported. It appears that the alkene forms a primary ozonide which rearranges to a secondary ozonide, and it is the latter which, when catalysed by Fe(TMP)Cl, affects the subsequent alkene epoxidation. A number of other metal complexes were also tested as catalysts, but Fe(TMP)Cl was the most effective.

Medicinally important 3-alkoxy-3-aryloxindoles are conveniently prepared by the rapid microwave-promoted palladium-catalyzed intramolecular enolate arylation of mandelate-derived anilides.

A two-step protocol for the asymmetric synthesis of protected quaternary (E)-vinylglycines from simple aldehydes is reported. The key step is a regiocontrolled deconjugative asymmetric alkylation of dehydroamino acids, giving the targets as single geometric isomers with high diastereoselectivity (92-96% de). The products can be converted to valuable quaternary beta-amino alcohols by chemoselective reduction. [reaction: see text].

[reaction: see text] Putative enantioenriched carbenoid species, (R)-1-chloro-2-phenylethylmagnesium chloride (9) and (S)-1-chloro-2-phenylethyllithium (26), generated in situ by sulfoxide ligand exchange from (-)-(R(S),R)-1-chloro-2-phenylethyl p-tolyl sulfoxide (8), effected the stereocontrolled homologation of boronic esters. sec-Alcohols derived from the product boronates by oxidation with basic hydrogen peroxide exhibited % ee closely approaching that of sulfoxide 8 in examples employing Li-carbenoid 26.

[reaction: see text] A practical and general two-step synthesis of carbamate-protected (E)-vinylglycines from aliphatic aldehydes is reported. The key step involves the kinetic alpha-protonation of dianionic dienolates derived from dehydroamino acids.

BackgroundAllenylsilanes are useful intermediates in organic synthesis. An attractive, convergent but little used approach for their synthesis is the alkylidenation of stable silylketenes. Reactions thus far have been limited to the use of unsubstituted silylketenes (or equivalents) with stabilised or semi-stabilised ylides only. The current study explores the reactions of substituted ketenes prepared through rhodium(II)-mediated rearrangement of silylated diazoketones.ResultsA range of novel 1,3-disubstituted and 1,3,3-trisubstituted allenylsilanes were prepared using stabilised and semi-stabilised ylides. Alkylidenation with non-stabilised phosphorus ylides was not viable, but the use of titanium-based methylenating reagents was successful, allowing access to 1-substituted allenylsilanes.ConclusionMany novel allenylsilanes may be accessed by alkylidenation of substituted silylketenes. Importantly, for the first time, simple methylenation of silylketenes has been achieved using titanium carbenoid-based reagents.