Fluorination methods in drug discovery
Late stage fluorination methods applied to biologically-active drugs have provided the pharmaceutical industry with new leads that show improved properties such as modulation of lipophilicity, electronegativity, basicity, bioavailability, and deceleration of metabolic degradation.
Late stage trifluoromethylthiolation strategies for organic compounds
The introduction of CF3S groups into compounds with known biological activity can alter their properties significantly, as a result of the increased lipophilicity and electronegativity of the trifluoromethylthio group.
The xanthate route to organofluorine derivatives. A brief account
The radical chemistry of xanthates allows numerous approaches to organofluorine compounds.
Modern advances in heterocyclic chemistry in drug discovery
New advances in functionalized heterocyclic chemistry are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs.
Enantioselective synthesis of cyanohydrins catalysed by hydroxynitrile lyases – a review
Ever since their first application in 1908, HNLs have been gaining strength in enantioselective cyanohydrin synthesis.
Total synthesis, biosynthesis and biological profiles of clavine alkaloids
This review highlights noteworthy synthetic and biological aspects of the clavine subfamily of ergot alkaloids.
A practical metal-free homolytic aromatic alkylation protocol for the synthesis of 3-(pyrazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylic acid
As a part of our ongoing synthetic quest to expand the frontiers of contemporary medicinal chemistry, we now report an expedient synthesis of a potentially useful bicyclo[1.1.1]pentane building block, 3-(pyrazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylic acid. This report also showcases the application of this motif as a “spacer” probe in a biological study.
Copper-catalysed oxidative amination of quinoxalin-2(1H)-ones with aliphatic amines
A novel, efficient and practical method for copper-catalysed oxidative C-3 amination of quinoxalin-2(1H)-ones with primary or secondary amines as the nitrogen sources has been developed.
Synthesis of “neoprofen”, a rigidified analogue of ibuprofen, exemplifying synthetic methodology for altering the 3-D topology of pharmaceutical substances
The unique hydrophobic 3-D topology of the neopentylene ring fusion is explored in the context of an analogue of the non-steroidal anti-inflammatory drug, ibuprofen.
A metal-catalyzed enyne-cyclization step for the synthesis of bi- and tricyclic scaffolds amenable to molecular library production
A facile metal-catalyzed diversification step for the synthesis of novel bi- and tricyclic scaffolds from enyne substrates is reported in this study for molecular library production.
Enantioselective N-heterocyclic carbene-catalyzed synthesis of saccharine-derived dihydropyridinones with cis-selectivity
The N-heterocyclic carbene-catalyzed [2 + 4] cyclocondensation of α-chloroaldehydes and saccharine-derived 1-azadienes was developed, giving dihydropyridinones in good yields with exclusive cis-selectivities and excellent enantioselectivities.
Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor
Late-stage photooxygenation can generate novel biologically active lead structures.
Scalable procedure for the fragmentation of hydroperoxides mediated by copper and iron tetrafluoroborate salts
An improved protocol for the formal elimination of propene from organic substrates is reported.
Synthesis of annulated pyridines as inhibitors of aldosterone synthase (CYP11B2)
A series of potent and selective aldosterone synthase (CYP11B2) inhibitors were prepared in one step through an intermolecular Kondrat'eva reaction.
Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and CO: reaction development and application to the formal synthesis of (−)-galanthamine
A Rh-catalyzed [5 + 1] cycloaddition of allenylcyclopropanes and CO has been developed to synthesize functionalized 2-methylidene-3,4-cyclohexenones. This cycloaddition reaction has been utilized as a key step in the formal synthesis of natural product (−)-galanthamine.
An asymmetric approach to bicyclo[2.2.1]heptane-1-carboxylates via a formal [4 + 2] cycloaddition reaction enabled by organocatalysis
An organocatalytic formal [4 + 2] cycloaddition reaction has been developed that permits rapid access to bicyclo[2.2.1]heptane-1-carboxylates with excellent enantioselectivities under mild and operationally simple conditions.
Base-catalyzed controllable reaction of 3-ylideneoxindoles with O-Boc hydroxycarbamates for the synthesis of amidoacrylates and spiroaziridine oxindoles
A base-catalyzed divergent reaction of 3-ylideneoxindoles and O-Boc hydroxycarbamates has been developed to provide various amidoacrylates and spiroaziridine oxindoles with high yields.
The total synthesis and functional evaluation of fourteen stereoisomers of yaku'amide B. The importance of stereochemistry for hydrophobicity and cytotoxicity
Yaku'amide B is a highly unsaturated linear tridecapeptide and an extremely potent cytotoxin.
Synthesis of cycloalkyl substituted purine nucleosides via a metal-free radical route
The selective synthesis of C6-monocycloalkyl or C6,C8-dicycloalkyl substituted purine nucleosides could be realized. Furthermore, uracil and related nucleosides were also suitable substrates, giving the C5-cyclohexyl substituted uracil derivatives in good yields with excellent regioselectivities.
Identification of an active metabolite of PAR-1 antagonist RWJ-58259 and synthesis of analogues to enhance its metabolic stability
Understanding the pharmacokinetic behaviour of PAR-1 antagonist RWJ-58259 and the synthesis of analogues to enhance metabolic stability.
Oxidative coupling between C(sp2)–H and C(sp3)–H bonds of indoles and cyclic ethers/cycloalkanes
Cross-dehydrogenative-coupling (CDC) between C–H/C–H bonds of indoles and cyclic ethers/cycloalkanes is made viable through a simple transition-metal-free pathway.
Radical fluorination powered expedient synthesis of 3-fluorobicyclo[1.1.1]pentan-1-amine
This work describes an expedient synthesis of a potentially useful BCP derivative, 3-fluorobicyclo[1.1.1]pentan-1-amine, by employing a contemporary radical fluorination method.
Tetrazolone as an acid bioisostere: application to marketed drugs containing a carboxylic acid
Matched molecular pair analysis was used to evaluate the ability of a tetrazolone group to act as a bioisostere of a carboxylic acid.
A one-pot synthesis of tetrazolones from acid chlorides: understanding functional group compatibility, and application to the late-stage functionalization of marketed drugs
A one-pot and scalable synthesis of tetrazolones (tetrazol-5-ones) from acid chlorides using azidotrimethylsilane is presented.
Synthesis of trifluoromethylthiolated pyridinones through the copper-mediated trifluoromethylthiolation of iodopyridinones
A simple method for the synthesis of trifluoromethylthiolated pyridinones through the copper-mediated trifluoromethylthiolation of iodopyridinones was developed.
Ravynic acid, an antibiotic polyeneyne tetramic acid from Penicillium sp. elucidated through synthesis
Ravynic acid, an unsaturated tetramic acid possessing antibiotic activity, has been isolated from the fungus Penicillium sp. and identified through synthesis.
Palladium-catalyzed β-(hetero)arylation of α,β-unsaturated valerolactams
A method for the palladium-catalyzed arylation of α,β-unsaturated valerolactams is reported.
Horner–Wadsworth–Emmons approach to piperlongumine analogues with potent anti-cancer activity
Horner–Wadsworth–Emmons approach to a selection of piperlongumine-like compounds from a novel phosphonoacetamide reagent.
Synthesis of cyclopenta-fused polycyclic aromatic hydrocarbons utilizing aryl-substituted anilines
Cyclopenta-fused polycyclic aromatic hydrocarbons were synthesized from readily available 2-aryl-substituted anilines under extremely mild conditions.
Regioselective routes to orthogonally-substituted aromatic MIDA boronates
A series of tetrasubstituted aromatics has been synthesized, many of which are based on elaborated N-methyliminodiacetic acid (MIDA)-boronates.
Synthesis of trifluoromethylated isoxazoles and their elaboration through inter- and intra-molecular C–H arylation
We report conditions for the preparation of a range of trifluoromethylated isoxazole building blocks through the cycloaddition reaction of trifluoromethyl nitrile oxide and their subsequent derivatisation.
Synthesis of furo[3,2-c]coumarin derivatives using visible-light-promoted radical alkyne insertion with bromocoumarins
Heterocyclic framework furo[3,2-c]coumarins were constructed using a visible-light promoted photoredox neutral coupling of 3-bromo-4-hydroxycoumarins with commercially available alkynes.
Iron-mediated oxidative C–H coupling of arenes and alkenes directed by sulfur: an expedient route to dihydrobenzofurans
A route to medicinally-relevant dihydrobenzofurans utilises a sulfur-directed, iron-mediated C–H ortho-coupling of arenes and alkenes, and a palladium-catalysed heterocyclisation.
UV light-mediated difunctionalization of alkenes with CF3SO2Na: synthesis of trifluoromethyl phenanthrene and anthrone derivatives
A metal-free and cost-effective protocol for UV light-mediated difunctionalization of alkenes with CF3SO2Na was developed.
Palladium-catalyzed direct desulfitative C2 arylations of 3-halo-N-protected indoles using (hetero)arenesulfonyl chlorides
Halo-substituents at the indolyl C3 position act as temporary blocking groups allowing the regioselective formation of 2-arylindoles through a direct desulfitative arylation. This method allows one to prepare a wide variety of indole derivatives in a few steps.
Optimization and multigram scalability of a catalytic enantioselective borylative migration for the synthesis of functionalized chiral piperidines
A systematic optimization of a Pd-catalyzed enantioselective borylative migration of an alkenyl nonaflate derivative of the simple precursor, N-Boc-4-piperidone, was achieved.
Metal free C–H functionalization of diazines and related heteroarenes with organoboron species and its application in the synthesis of a CDK inhibitor, meriolin 1
Here, we report a metal-free cross-coupling reaction of diazines and related heteroarenes with organoboron species.
Synthesis of cyclic 1,3-diols as scaffolds for spatially directed libraries
A series of 1,3-diols has been synthesized and used to create a pilot library of spatially diverse compounds.
Enantioselective organocatalytic Michael addition of isorhodanines to α,β-unsaturated aldehydes
The Michael reaction of substituted isorhodanines with α,β-unsaturated aldehydes in the presence of a catalytic amount of a chiral secondary amine is presented.
Synthesis and absolute configuration assignment of albucidin: a late-stage reductive deiodination by visible light photocatalysis
The total synthesis and absolute configuration assignment of albucidin might pave the way for synthetic and medicinal chemists for further research on this type of bioactive molecule.
Conformation-induced regioselective and divergent opening of epoxides by fluoride: facile access to hydroxylated fluoro-piperidines
Utilizing molecular conformation as a controlling factor, epoxide-containing 2-aryl-piperidines can be ring-opened with the reagent combination of TBAF/KHF2 in a regioselective and divergent fashion.
Iron-mediated inter- and intramolecular reductive cross-coupling of unactivated alkyl chlorides with aryl bromides
Efficient inter- and intramolecular reductive cross-coupling of unactivated alkyl chlorides by Fe(PPh3)2Cl3.
An atom-efficient and convergent approach to the preparation of NS5A inhibitors by C–H activation
A novel approach of the convergent functionalisation of aryl dibromides to form NS5A type inhibitors using C–H activation is reported.
Synthesis of novel and potent vorapaxar analogues
Unlocking novel and potent vorapaxar analogues by functionalisation of previously unexplored positions on the parent vorapaxar scaffold.
Catalytic selective deuteration of halo(hetero)arenes
A library of deuterated compounds was synthesized and the mechanism of D-incorporation explored.
Enzymatic transhalogenation of dendritic RGD peptide constructs with the fluorinase
The fluorinase enzyme is used to catalyse transhalogenation reactions on dendritic RGD peptide constructs. The strategy is explored for [18F]-radiolabelling of peptides under neutral aqueous ambient conditions for positron emission tomography (PET).
Flexible synthesis of polyfunctionalised 3-fluoropyrroles
Convergent synthesis of polyfunctionalised 3-fluoropyrroles.
About this collection
This high quality collection aims to demonstrate the importance of synthetic chemistry in drug discovery. Specifically it will highlight how synthetic methods can be used to address hurdles currently being faced in modern medicinal chemistry.
It has been guest edited by Prof. Angela Russell (University of Oxford, UK), Prof. Douglas E. Frantz (The University of Texas at San Antonio, USA) Dr Graham Wynne (University of Oxford, UK) Dr Matthew Duncton (Rigel, San Francisco, USA) and Dr Shane Krska (Merck, Boston, USA).
New articles will be added to this collection as they are published.