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Heteroaromatic carboxylic acids have been directly coupled with imines using propylphosphonic anhydride (T3P) and NEt(iPr)2 to form azaspirocycles via intermediate N-acyliminium ions. Spirocyclic indolenines (3H-indoles), azaindolenines, 2H-pyrroles and 3H-pyrroles were all accessed using this metal-free approach. The reactions typically proceed with high diastereoselectivity and 3D shape analysis confirms that the products formed occupy areas of chemical space that are under-represented in existing drugs and high throughput screening libraries.

A regio- and stereoselective one-pot C–H insertion/olefination protocol has been developed for the late stage installation of α-methylene-γ-butyrolactones into conformationally restricted cyclohexanol-derivatives. The method has been successfully applied in the total synthesis of eudesmanolide natural product frameworks, including α-cyclocostunolide.

This Review provides an in-depth account of the synthesis of spirocyclic indolenines. Over the last 77 years, a wide array of diverse synthetic methods has been developed in order to generate these synthetically useful and biologically important spirocyclic scaffolds. The main synthetic strategies discussed are grouped into three main categories, namely interrupted Fischer indolisations, dearomatisation reactions of indoles and condensation reactions. The historical background, common synthetic challenges, current state-of-the-art and future perspectives of this field are examined.

A common indole-tethered propargyl alcohol precursor is converted efficiently into either spirocyclic indolenines or carbazoles by using different Ag(I) catalysts at room temperature.

The synthesis of bis-oxindoles via the copper(II)-mediated double cyclisation of linear bis-anilides is described. Cu(OAc)2·H2O was identified as an efficient and inexpensive catalyst for this process. In contrast to previous methods, which rely on the synthesis of the central core from existing oxindole building blocks, this new approach focusses on concurrent formation of both oxindole rings from a simple linear precursor, allowing the formation of bis-oxindoles containing a diverse range of cyclic and acyclic linkers using a single synthetic method.

A system for the synthesis of α-alkylidene-γ-butyrolactones via a one-pot C–H insertion/olefination sequence is described. The process is based on the rhodium catalysed C–H insertion reaction of α-diazo-α-(diethoxyphosphoryl)acetates. The mild reaction conditions, operational simplicity and ready availability of starting materials are all key features. A wide range of successful reaction systems are reported (41 examples) highlighting the generality of the method. The application of this method in the total synthesis of the natural products (±)-cedarmycins A and B is also described.

A high-yielding silver(I)- or copper(II)-catalyzed dearomatizing spirocyclization strategy allows the conversion of simple aromatic compounds that contain ynone substituents, including indole, anisole, pyrrole, and benzofuran derivatives, into functionalized spirocyclic scaffolds. A high-yielding asymmetric variant furnishes spirocyclic indolenines in up to 89:11 e.r.

The products are generally delivered in high yields and with high to excellent trans-selectivity.

The first total synthesis of (+)-elaeokanidine A is reported. The synthesis features a formic acid-mediated cyclisation to access the indolizidine core and a double conjugate addition of ammonia to construct the piperidone unit. On the basis of 1H NMR spectroscopic data, the relative stereochemistry of elaeokanidine A has been confirmed. Two isomeric species were also formed during the piperidone ring construction, which are potentially elaeokanidines B and C, although their structures could not be assigned unambiguously. The synthetic transformations used to prepare these products are analogous to conditions employed during the extraction procedure, raising questions about the true origins of these compounds.

A facile copper(II)-mediated C–H bond oxidation and C–C bond formation procedure has been applied to the synthesis of indole derivatives. Intramolecular oxidative coupling of 3,3-disubstituted enamines proceeded using a non-expensive and air-stable copper salt, Cu(2-ethylhexanoate)2, to afford the corresponding C-3 quaternary indolenine products in good to excellent yields. 1H-Indoles can be prepared in a similar manner but in this case, Cu(OAc)2·H2O has been found to be the preferred oxidant.

Succinimide-based palladium complex catalysts with either triphenylarsenic or trifuranylphospine ligands are used for the coupling of organostannanes with benzyl halogenides at ambient temperature.

CEH is identified as inexpensive and efficient catalyst for all approaches to the title heterocycles including double cyclizations [cf.

The direct imine acylation (DIA) and subsequent cyclisation of a range of imines with ortho-substituted benzoic acid derivatives is described. Variation in the coupling reagents, imine and benzoic acid were all examined. The DIA procedure was also applied in the total synthesis of (±)-cavidine.

This describes the synthesis of allo-inositol (IV) as well as a similar synthesis of epo-inositol.

Using tetraphenylphorphyrin (TPP) or rose bengal as sensitizers, acyclic and cyclic conjugated dienes as well as furans are converted to the respective 3,6-dihydro-1,2-dioxines, (Z)-4,5-epoxypent-2-enal as well as 5-hydroxy- and 5-alkoxy-2(5H)-furanones.

The key C-H insertion process of various diazo substrates is achieved in the presence of a dirhodium carboxylate catalyst.

Free radicals and oxidative stress play important roles in the deterioration of materials, and free radicals are important intermediates in many biological processes. The ability to detect these reactive species is a key step on the road to their understanding and ultimate control. This short review highlights recent progress in the development of reagents for the detection of free radicals and reactive oxygen species with broad application to materials science as well as biology.

Imines and carboxylic acids have been directly coupled using propylphosphonic acid anhydride and NEt(i-Pr)2 to give N-acyliminium ions, which were intramolecularly trapped with oxygen, nitrogen, sulfur, and carbon nucleophiles to provide a wide range of structurally diverse heterocycles.

The rate-retarding effect of gem-dimethyl substitution on the Cope rearrangements of divinylcyclopropanes is demonstrated for the first time.

The complex macrocycle ‘upenamide was isolated in 2000, stimulating significant effort from synthetic chemists to complete its total synthesis and verify its structure. Progress made by several groups is detailed, culminating in the synthesis of both of the proposed structures of this unique natural product, neither of which matched the natural material according to spectroscopic analysis. The evolution of the synthetic route and the development of associated methodologies are described.

Methanolysis of epoxides (I) and (VI) is achieved in complementary ways by employing either Pd-catalyzed or acid-mediated procedures.

A reliable and versatile tool for the synthesis of a variety of polycyclic heterocyclic scaffolds using the direct acylation of imines with functionalized benzoic acids is described.

The initial stages of drug discovery are increasingly reliant on development and improvement of analytical methods to investigate protein–protein and protein–ligand interactions. For over 20 years, mass spectrometry (MS) has been recognized as providing a fast, sensitive and high-throughput methodology for analysis of weak non-covalent complexes. Careful control of electrospray ionization conditions has enabled investigation of the structure, stability and interactions of proteins and peptides in a solvent free environment. This critical review covers the use of mass spectrometry for kinetic, dynamic and structural studies of proteins and protein complexes. We discuss how conjunction of mass spectrometry with related techniques and methodologies such as ion mobility, hydrogen–deuterium exchange (HDX), protein footprinting or chemical cross-linking can provide us with structural information useful for drug development. Along with other biophysical techniques, such as NMR or X-ray crystallography, mass spectrometry provides a powerful toolbox for investigation of biological problems of medical relevance (204 references).

Conditions A) are suitable for the preparation of various title compounds including precursor (VI) of horsfiline (VII).

A variety of partially reduced heterocycles is easily prepared by cyclization of alkynyl acetals in formic acid.

Novel paramagnetic selective angiotensin AT1 receptor antagonists (sartans) bearing nitroxides (3, 4) have been prepared and their pharmacology evaluated in vitro as well as in vivo. Compounds 3, 4 proved to be effective sartans with pKB estimates in the range 6.2–9.1. In addition, the sodium salt (11) of 4 (R = Bu) is able to protect against vascular injury in hypertensive rats as determined by its ability to attenuate the development of intimal thickening caused by balloon injury of the carotid artery.

An asymmetric decarboxylative palladium-catalyzed allylation of alkyl- and aryl-substituted oxindoles has been developed, enabling the installation of an all-carbon quaternary chiral center at the oxindole 3-position in excellent yields and good to excellent enantioselectivity. An intriguing substrate-dependent reversal in stereoselectivity has been observed, whereby the size of the substituent determines the facial selectivity in the allylation step.

The sequence converts 6-acyl-cyclohex-2-enones of type (I) directly to the required isoquinuclidinones.

Initial investigations towards the synthesis and glutamate receptor activity of triazolyl amino acids are undertaken.

It is demonstrated, that a range of target compounds can be readily accessed in a regioselective manner using PIDA as the oxidant.

The structures and biological activities of naturally occurring 3-alkenyl-oxindoles are reviewed. Important man-made 3-alkenyl-oxindoles are covered, particularly those with pharmaceutical applications such as sunitinib (SU11248), the orally active receptor tyrosine kinase inhibitor marketed by Pfizer as Sutent ® . Traditional synthetic approaches to 3-alkenyl-oxindoles are summarised and then recently developed tandem/telescoped synthetic routes are described.

The preparation of 3,3-disubstituted oxindoles by a formal C−H, Ar−H coupling of anilides is described. Highly efficient conditions have been identified using catalytic (5 mol %) Cu(OAc)2·H2O with atmospheric oxygen as the reoxidant; no additional base is required, and the reaction can be run in toluene or mesitylene. Optimization studies are reported together with a scope and limitation investigation based on variation of the anilide precursors. The application of this methodology to prepare a key intermediate for the total synthesis of the anticancer, analgesic oxindole alkaloid Horsfiline is also described.

Treatment of the 1, 5-dimesylate and 1, 5-ditosylate of 2, 3, 4, 6-tetra-O-benzyl-D-glucitol 1 with tetrabutylammonium acetate in acetonitrile leads, through nucleophilic attack by O-2 at C-5 and normal displacement at C-1, to 1-O-acetyl-2, 5-anhydro-3, 4, 6-tri-O-benzyl-L-iditol. In contrast, the corresponding 1, 5-ditriflate on similar treatment undergoes displacement at C-1 by attack of O-4 and elimination of triflic acid between C-4 and C-5 to afford (3R, 4S)-3, 4-dibenzyloxy-2-(2-benzyloxyethylidene)tetrahydrofuran.

Ring opening of the (bicyclo[1.1.1]pent-1-yl)methyl (4), (bicyclo[2.1.1]hex-1-yl)methyl (5) and (bicyclo[3.1.1]hept-1-yl)methyl (6) radicals has been investigated by semiempirical molecular orbital theory MINDO/3 and AM1) and by experiment. Our results indicate that (4) ring-opens extremely rapidly, with an estimated energy barrier of less than 22 kJ mol-1. The higher homologues (5) and (6) rearrange more slowly with barriers of about 42.2 and 46.0 kJ mol-1 respectively. This trend is also observed in the MINDO/3 and AM1 results, with the latter giving the better agreement with experiment.

The addition of organolithium reagents to pyrylium tetrafluoroborate followed by in situ electrocyclic ring opening of the intermediate 2H-pyrans gives the title Z.E-dienals with high stereoselectivity

1-Iodobicyclo[1.1.1]pentane reacts cleanly with t-butyllithium by a metal-halogen exchange process to give 1-lithiobicyclo[1.1.1]pentane. Both 1-chlorobicyclo[1.1.1]pentane and the parent hydrocarbon bicyclo [1.1.1]pentane are found to be inert to t-butyllithium.

The rearrangement of the bicyclo[1.1.1]pentan-1-ylmethyl radical (9) and the bicyclo[2.1.1]hexan-1-yl-methyl radical (10) to the corresponding methylenecycloalkylmethyl radical (11, 12) has been studied kinetically by EPR spectroscopy and, in the case of 10, by tributyltin hydride reduction. Activation energies of 7.1 ± 1.2 kcal mol–1 and 9.3 ± 0.5 kcal mol–1 have been determined for 9 and 10, respectively, while the corresponding pre-exponential factors have been determined to be 12.3 ± 1.5 and 12.0 ± 1.0, respectively. Rearrangement of 9 has an unusually low activation barrier; this has also been investigated by ab initio molecular-orbital calculations. UHF/3-21 G level of theory predicts a barrier of 7.8 kcal mol–1, in excellent agreement with that obtained experimentally, while a somewhat higher value (11.2 kcal mol–1) is predicted at the UHF/6-31 G* level. All of these data indicate that relief of ring strain is a major contributing factor to the rapid rearrangement of these radicals.