Themed collection Contemporary Synthetic Chemistry 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.

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 radical chemistry of xanthates allows numerous approaches to organofluorine compounds.

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.

Ever since their first application in 1908, HNLs have been gaining strength in enantioselective cyanohydrin synthesis.

This review highlights noteworthy synthetic and biological aspects of the clavine subfamily of ergot alkaloids.

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.

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.

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 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.

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.

Late-stage photooxygenation can generate novel biologically active lead structures.

An improved protocol for the formal elimination of propene from organic substrates is reported.

A series of potent and selective aldosterone synthase (CYP11B2) inhibitors were prepared in one step through an intermolecular Kondrat'eva reaction.

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 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.

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.

Yaku'amide B is a highly unsaturated linear tridecapeptide and an extremely potent cytotoxin.

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.

Understanding the pharmacokinetic behaviour of PAR-1 antagonist RWJ-58259 and the synthesis of analogues to enhance metabolic stability.

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.

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.

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 and scalable synthesis of tetrazolones (tetrazol-5-ones) from acid chlorides using azidotrimethylsilane is presented.

A simple method for the synthesis of trifluoromethylthiolated pyridinones through the copper-mediated trifluoromethylthiolation of iodopyridinones was developed.

Ravynic acid, an unsaturated tetramic acid possessing antibiotic activity, has been isolated from the fungus Penicillium sp. and identified through synthesis.

A method for the palladium-catalyzed arylation of α,β-unsaturated valerolactams is reported.

Horner–Wadsworth–Emmons approach to a selection of piperlongumine-like compounds from a novel phosphonoacetamide reagent.

Cyclopenta-fused polycyclic aromatic hydrocarbons were synthesized from readily available 2-aryl-substituted anilines under extremely mild conditions.

A series of tetrasubstituted aromatics has been synthesized, many of which are based on elaborated N-methyliminodiacetic acid (MIDA)-boronates.

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.

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.

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.

A metal-free and cost-effective protocol for UV light-mediated difunctionalization of alkenes with CF₃SO₂Na was developed.

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.

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.

Here, we report a metal-free cross-coupling reaction of diazines and related heteroarenes with organoboron species.

A series of 1,3-diols has been synthesized and used to create a pilot library of spatially diverse compounds.

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.

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.

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.

Efficient inter- and intramolecular reductive cross-coupling of unactivated alkyl chlorides by Fe(PPh₃)₂Cl₃.

A novel approach of the convergent functionalisation of aryl dibromides to form NS5A type inhibitors using C–H activation is reported.

Unlocking novel and potent vorapaxar analogues by functionalisation of previously unexplored positions on the parent vorapaxar scaffold.

A library of deuterated compounds was synthesized and the mechanism of D-incorporation explored.

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).

Convergent synthesis of polyfunctionalised 3-fluoropyrroles.