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Formation of valuable spiroheterocycles with multiple contiguous stereogenic centres from palladium-catalysed enantioselective (3 + 2) cycloaddition reactions of sulfamidate-derived azadienes and vinylcyclopropanes.

The first general synthesis of branched tetraenes ([4]dendralenes) involves two or three steps from inexpensive, commodity chemicals. It involves an unprecedented variation on Suzuki-Miyaura cross-coupling, generating two new C-C bonds in a one-flask operation with control of diastereoselectivity. The broad scope of the method is established through the synthesis of more than 60 diversely substituted [4]dendralene molecules, along with substituted buta-1,3-dienes and other [

The readily prepared and vinylated β-carboline

α-Iodo-α,β-unsaturated ketones such as compound

A chemoenzymatic approach to the title framework is reported. The reaction sequence starts with the whole-cell biotransformation of iodobenzene and the conversion of the resulting homochiral metabolite into a triene that engages in an intramolecular Diels–Alder reaction and so affording an adduct embodying the platencin core. Application of an oxa-di-π-methane rearrangement to a derivative of this core affords a cyclopropannulated form of the target framework; the latter is then obtained through a TMSI-mediated cleavage of the three-membered ring. A strategy for the assembly of the enantiomeric framework is also described.

Acyl bicyclobutanes are shown to engage in strain-promoted cycloaddition reactions with a diverse array of triazolinedione reagents. The synthesis of an orthogonally protected urazole building block enabled the facile preparation of amino acid- and peptide-derived triazolinediones that undergo cycloaddition reactions to afford novel peptide conjugates. The additive-free and fully atom-economical nature of the transformation is a promising starting point for the generalization of this cycloaddition reaction for the functionalization of biomolecules.

The potassium aluminyl K[Al(NONDipp)] promotes the reductive homologation of CO to afford the [C4O4]4− (2 isomers) and [C5O5]5− ligands.

A range of palladium complexes featuring electronically modified, imidazole-based abnormal N-heterocyclic carbene (aNHC) ligands have been prepared in the hopes of accessing a new class of cationic aNHC ligands electronically distinct from normal NHCs and aNHCs. These palladium complexes represent the first examples of transition metal-ligated aNHC complexes featuring a cationic moiety adjacent to the abnormal carbene center. It was anticipated that these design principles could facilitate electron transfer between the imidazolinylidene and the cationic heterocycle, thus reducing the electron density at the abnormal carbene center. However, this case study suggests that greater conformational restrictions that allow for heterocycle coplanarity are necessary to achieve significant electron transfer and enable access to a new class of cationic charge-appended aNHCs with unique electronic properties.

The aluminyl compounds [M{Al(NONDipp)}]2 (NONDipp = [O(SiMe2NDipp)2]2–, Dipp = 2,6-iPr2C6H3), which exist as contacted dimeric pairs in both the solution and solid states, have been converted to monomeric ion pairs and separated ion pairs for each of the group 1 metals, M = Li, Na, and K. The monomeric ion pairs contain discrete, highly polarized Al–M bonds between the aluminum and the group 1 metal and have been isolated with monodentate (THF, M = Li and Na) or bidentate (TMEDA, M = Li, Na, and K) ligands at M. The separated ion pairs comprise group 1 cations that are encapsulated by polydentate ligands, rendering the aluminyl anion, [Al(NONDipp)]− “naked”. For M = Li, this structure type was isolated as the [Li(TMEDA)2]+ salt directly from a solution of the corresponding contacted dimeric pair in neat TMEDA, while the polydentate [2.2.2]cryptand ligand was used to generate the separated ion pairs for the heavier group 1 metals M = Na and K. This work shows that starting from the corresponding contacted dimeric pairs, the extent of the Al–M interaction in these aluminyl systems can be readily controlled with appropriate chelating reagents.

The total synthesis of three diastereomeric matrine natural products is reported. The eight-step synthesis commences with simple acyclic precursors, forms all four rings of the tetracyclic natural product framework and forges ten of the twenty covalent bonds of the target structure. The chemical synthesis adopts an unprecedented strategy that encompasses both transform and stereochemical attributes. A cross-conjugated triene is positioned at the core of an acyclic branched structure, which collapses to the tetracyclic natural product framework through an orchestrated sequence of two intramolecular cycloadditions. A subsequent, late-stage hydrogenation is accompanied by strain-release redox epimerizations to deliver the three natural products. Semisynthetic manipulations of matrine provide access to ten additional natural products.

Δ6-Methyltestosterone was reported as the main active ingredient of the purported "dietary supplement" Jungle Warfare. This compound is structurally similar to 17α-methyltestosterone, containing an additional Δ6 double bond, and is reported to possess notable androgenic activity, raising concerns over the potential for abuse of Jungle Warfare in sport. The in vivo metabolism of Δ6-methyltestosterone in greyhounds was investigated. Urinary phase I (unconjugated) and phase II (glucuronide) metabolites were detected following oral administration using liquid chromatography-mass spectrometry. No phase II sulfate metabolites were detected. The major phase I metabolite was confirmed as 16α,17β-dihydroxy-17α-methylandrosta-4,6-dien-3-one by comparison with a synthetically-derived reference material. Minor amounts of the parent drug were also confirmed. Glucuronide conjugated metabolites were also observed, but were found to be resistant to hydrolysis using the Escherichia coli β-glucuronidase enzyme. Qualitative excretion profiles, limits of detection, and extraction recoveries were determined for the parent drug and the major phase I metabolite. These results provide a method for the detection of Jungle Warfare abuse in greyhounds suitable for incorporation into routine screening methods conducted by anti-doping laboratories.

An operationally simple synthesis of Z-configured and C3-unsubstituted N-sulfonyl-2-iminocoumarins (e.g., 8a) that proceeds under mild conditions is achieved by reacting 2-(1-hydroxyprop-2-yn-1-yl)phenols (e.g., 6a) with sulfonyl azides (e.g., 7a). The cascade process involved likely starts with a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. This is followed by ring-opening of the resulting metalated triazole (with accompanying loss of nitrogen), reaction of the ensuing ketenimine with the pendant phenolic hydroxyl group, and finally dehydration of the (Z)-N-(4-hydroxychroman-2-ylidene)sulfonamide so formed.

The regio-isomeric alkynyl-substituted derivatives, 2 and 3, of the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 (1) were prepared and the active one (compound 3) subjected to click reactions ([3 + 2]-cycloaddition reactions) with certain alkyl azides bearing biotin or fluorescent tags. Compounds 2 and 3, as well as four [3 + 2]-cycloadducts of the latter, were subjected to biological evaluation in a human acute myeloid leukemia cell line model. Among the six compounds tested only alkyne 3 remained active but this was less potent than parent 1.

As hydrogen bonded frameworks are held together by relatively weak interactions, they often form several different frameworks under slightly different synthesis conditions and respond dynamically to stimuli such as heat and vacuum. However, these dynamic restructuring processes are often poorly understood. In this work, three isoreticular hydrogen bonded organic frameworks assembled through charge-assisted amidinium⋅⋅⋅carboxylate hydrogen bonds (1

The commercially available, abundant and homochiral cellulose pyrolysis product levoglucosenone (LGO) together with the readily derived isolevoglucosenone (isoLGO) form, in a stereoselective manner...

The bioderived platform molecule levoglucosenone (LGO, 1) and its readily prepared pseudoenantiomer (iso-LGO, 2) have each been subjected to α-iodination reactions with the product halides then being engaged in palladium-catalyzed Ullmann cross-coupling reactions with various bromonitropyridines. The corresponding α-pyridinylated derivatives such as 11 and 24, respectively, are produced as a result. Biological screening of such products reveals that certain of them display potent and selective antimicrobial and/or cytotoxic properties. In contrast, the azaindoles obtained by reductive cyclization of compounds such as 11 and 12 are essentially inactive in these respects. Preliminary mode-of-action studies are reported.

[Image: see text] Synthetically derived samples of (+)-(6aS,11aS)-2,3,9-trimethoxypterocarpan [(+)-1] and its enantiomer [(−)-1], both of which are examples of naturally occurring isoflavonoids, were evaluated, together with the corresponding racemate, as cytotoxic agents against the HL-60, HCT-116, OVCAR-8, and SF-295 tumor cell lines. As a result it was established that compound (+)-1 was particularly active with OVCAR-8 cells being the most sensitive and responding in a dose-dependent manner. A study of cell viability and drug-induced morphological changes revealed the compound causes cell death through a mechanism characteristic of apoptosis. Finally, a computational study of the interactions of compound (+)-1 and (S)-monastrol, an established, synthetically derived, potent, and cell-permeant inhibitor of mitosis, with the kinesin-type protein Eg5 revealed that both bind to this receptor in a similar manner. Significantly, compound (+)-1 binds with greater affinity, an effect attributed to the presence of the associated methoxy groups.

There is a concerted attempt to develop self-assembled metallo-cages of greater structural complexity, and heteroleptic Pd

The aluminyl compounds [

Bicyclo[1.1.0]butanes (BCBs) are highly strained carbocycles that have emerged as versatile synthetic tools, particularly for the construction of functionalized small molecules. This work reports two efficient pathways for the rapid preparation of over 20 structurally diverse BCB ketones, encompassing simple alkyl and aryl derivatives, as well as unprecedented amino acid, dipeptide, bioisostere, and bifunctional linchpin reagents currently inaccessible using literature methods. Analogues are readily forged in two steps and in high yields from simple carboxylic acids or through unsymmetrical ketone synthesis beginning with a convenient carbonyl dication equivalent. The utility of this novel toolbox of strained electrophiles for the selective modification of proteinogenic nucleophiles is highlighted.

Literature reports describe tetraethynylethylene (TEE) as unstable but tetravinylethylene (TVE) as stable. The stabilities of these two known compounds are reinvestigated, along with those of five unprecedented TEE-TVE hybrid compounds. The five new C

The rare flavonoid isolaxifolin, a potent insecticide, has been touted as a potential grain-protecting agent. In order to assess any impact of this natural product on human health and to explore its various other biological properties, we have established a semisynthesis from the simpler but structurally related and more abundant natural product apigenin. The five-step reaction sequence has provided, for the first time, sufficient material for an in-depth evaluation of the cytotoxic properties of the title natural product. The impact of isolaxifolin on certain pro-inflammatory cytokines in murine macrophage RAW 264.7 cells has also been examined. Such studies have revealed that isolaxifolin displays no toxic effects toward normal cells while displaying greater cytotoxicities against certain cancer cell lines than its synthetic precursor apigenin. Furthermore, unlike apigenin, isolaxifolin only reduced NO, TNF-α, and IL-6 secretions in LPS-induced RAW 264.7 cells in a rather modest and dose-independent manner.

Synthetically derived (Z)-ligustilide (1) has been subjected to photochemically-promoted dimerization processes under a range of conditions. By such means, varying distributions of the dimeric natural products tokinolides A–C (4, 3, and 6, respectively) and riligustilide (5) as well certain related (isomeric) compounds have been obtained. The structures of three of them have been confirmed by single-crystal X-ray analysis. The biosynthetic implications of the outcomes of this study are discussed.

We have demonstrated the profound effect that the N-substituent steric bulk of ethylene-linked bis(N-heterocyclic carbene) (bis(NHC)) species has on the mechanism of their formation via Pd(OAc)2-assisted deprotometalations. The binding mode of an ethylene-linked bis(NHC) ligand is chelating when it bears N-2,4-Me2C6H3 substituents but forms a mono(NHC) with a pendant imidazolium group for N-2,6-iPr2C6H3. An N-mesityl-substituted bis(NHC), with steric bulk intermediate between the two aforementioned substituents, generates a mixture of two chelating homoleptic normal/normal and heteroleptic normal/abnormal bis(NHC) complexes, as predicted by DFT calculations. Interestingly, the latter was seen to undergo facile reductive elimination, affording a novel tricyclic monodentate NHC ligand.

An operationally simple synthesis of

Although sulfated xylooligosaccharides are promising therapeutic leads for a multitude of afflictions, the structural complexity and heterogeneity of commercially deployed forms (e. g. Pentosan polysulfate 1) complicates their path to further clinical development. We describe herein the synthesis of the largest homogeneous persulfated xylooligomers prepared to date, comprising up to eight xylose residues, as standards for biological studies. Near quantitative sulfation was accomplished using a remarkably mild and operationally simple protocol which avoids the need for high temperatures and a large excess of the sulfating reagent. Moreover, the sulfated xylooligomer standards so obtained enabled definitive identification of a pyridinium contaminant in a sample of a commercially prepared Pentosan drug and provided significant insights into the conformational preferences of the constituent persulfated monosaccharide residues. As the spatial distribution of sulfates is a key determinant of the binding of sulfated oligosaccharides to endogenous targets, these findings have broad implications for the advancement of Pentosan-based treatments.

Despite their apparent similarity, framework materials based on tetraphenylmethane and tetraphenylsilane building blocks often have quite different structures and topologies. Herein, we describe a new silicon tetraamidinium compound and use it to prepare crystalline hydrogen bonded frameworks with carboxylate anions in water. The silicon-containing frameworks are compared with those prepared from the analogous carbon tetraamidinium: when biphenyldicarboxylate or tetrakis(4-carboxyphenyl)methane anions were used similar channel-containing networks are observed for both the silicon and carbon tetraamidinium. When terephthalate or bicarbonate anions were used, different products form. Insights into possible reasons for the different products are provided by a survey of the Cambridge Structural Database and quantum chemical calculations, both of which indicate that, contrary to expectations, tetraphenylsilane derivatives have less geometrical flexibility than tetraphenylmethane derivatives, i.e. they are less able to distort away from ideal tetrahedral bond angles.

Despite their apparent similarity, framework materials based on tetraphenylmethane and tetraphenylsilane building blocks often have quite different structures and topologies. Herein, we describe a new silicon tetraamidinium compound and use it to prepare crystalline hydrogen bonded frameworks with carboxylate anions in water. The silicon-containing frameworks are compared with those prepared from the analogous carbon tetraamidinium: when biphenyldicarboxylate or tetrakis(4-carboxyphenyl)methane anions were used similar channel-containing networks are observed for both the silicon and carbon tetraamidinium. When terephthalate or bicarbonate anions were used, different products form. Insights into possible reasons for the different products are provided by a survey of the Cambridge Structural Database and quantum chemical calculations, both of which indicate that, contrary to expectations, tetraphenylsilane derivatives have less geometrical flexibility than tetraphenylmethane derivatives, that is, they are less able to distort away from ideal tetrahedral bond angles.

The divergent reactivity of 5-allenyloxazolidinones has been explored. This novel building block undergoes Pd(0)-catalyzed cross-coupling with boronic acids to form a wide range of chiral 1,3-dienes and pharmaceutically useful vinyloxazolidinones, the chemoselectivity being tightly controlled by a simple switch in additive.

Six novel dicationic complexes of the formula [ML2][PF6]2, were prepared from the reaction of MCl2 (M = Pd, Pt) with two equivalents of Tl[PF6] in acetonitrile (MeCN), followed by addition of two equivalents of 2-(alkylchalcogenomethyl)pyridine (N,E) ligands (L) [L = 2-(methylthiomethyl)pyridine (L1), 2-(phenylthiomethyl)pyridine (L2), 2-(methylselenomethyl)pyridine (L3)] at room temperature. Structures of the synthesised complexes [M(L1)2][PF6]2 [M = Pd (1a), Pt (1b)] and [M(L3)2][PF6]2 [M = Pd (3a), Pt (3b)] were characterised by single crystal X-ray diffraction studies, illustrating they crystallise in the triclinic crystal system in the space group P 1 ¯ . The metal centres exhibit a distorted square planar geometry, with the donor atoms of the chelated N,E ligands arranged trans with respect to each other. The orientation of the methyl moieties of the ligands with respect to each other and the square planar metal were varied, with the methyl moieties in [Pt(L3)2][PF6]2 (3b) having anti-geometry in the solid state while those of [M(L1)2][PF6]2 [M = Pd (1a), Pt (1b)] and [Pd(L3)2][PF6]2 (3a) show the methylselenoether groups to have syn-geometries with respect to themselves and the metal plane. All synthesised complexes were further characterised by elemental analysis, FT-IR spectroscopy and liquid secondary ionisation mass spectrometry (LSIMS) techniques.

The advanced development of NHC chemistry has lead to an extensive array of NHC ligand classes varying in structural and electronic properties. Although monodentate NHC ligands are by far the most thoroughly studied, multi-dentate NHC ligands including bidentate, pincer, scorpionate and macrocyclic motifs along with their corresponding transition metal complexes are widely reported in the literature. The unique structural and electronic properties along with high degree of modularity inherent to NHC ligands has made them ideal candidates for the inclusion in chelate rings affording intriguing reactivity consequences in a wide range of transition metal-mediated reactions. This short review focuses on the recent developments of bidentate bis(NHC) transition metal complexes and their applications in contemporary metal-mediated reactions such as alkane oxidation, transfer hydrogenation and photochemical transformations.

This study provides the first report of the construction of tetrahydroindolizines and tetrahydropyrrolo [1,2-a]azepines via Bronsted acid-mediated annulation of pyrroles featuring N-tethered α,β-unsaturated esters. In addition, the Bronsted acid-catalyzed cyclization of pyrroles featuring pendant α,β-unsaturated ketones was applied to complete total syntheses of the indolizidine alkaloids (±)-tashiromine and (±)-indolizidine 209I.

A new iron-based hydrogenase mimic, [Fe(C5(p-C6H4Br)5)(CO)2Br], was synthesised and characterised using X-ray crystallography. Two analogous catalytic precursors, [Fe(C5Ar5)(CO)2Br] (Ar = C6H5; p-C6H4Br), were also analysed electrochemically in order to investigate how bulkier and more electron withdrawing C5Ar5 ligands affect the catalytic generation of hydrogen from trichloroacetic acid. Compared to previously reported iron-based cyclopentadienyl analogues, these complexes were found to have smaller overpotentials and larger turnover numbers. The [Fe(C5(p-C6H4Br)5)(CO)2Br] complex was found to be the most efficient of the two catalytic precursors with a turnover number of 25, an overpotential of around 310 mV and a faster rate of reaction compared to [Fe(C5Ph5)(CO)2Br].

A trans-diastereoselective Pd-catalyzed dearomative [3 + 2] cycloaddition between vinylcyclopropane dicarboxylates and 3-nitroindoles has been developed. The reaction provides densely functionalized cyclopenta[b]indolines with versatile vinyl and nitro-groups. The addition of a halide additive was found to be critical for the diastereoselectivity of the reaction, which is proposed to be a result of a rapid π-σ-π interconversion between the intermediates allowing for Curtin-Hammett control. A switch in diastereoselectivity to afford products with the vinyl and nitro groups cis to each other is observed with a 4-substituted 3-nitroindole.

Four planar tripyridyl ligands (Ltripy), 1,3,5-tris(pyridin-3-ylethynyl)benzene 1 a, 1,3,5-tris[4-(3-pyridyl)phenyl]benzene 2 a, and the hexyloxy chain functionalized derivatives 1,3,5-tris[(3-hexyloxy-5-pyridyl)ethynyl]benzene 1 b, and 1,3,5-tris[4-(3-hexyloxy-5-pyridyl)phenyl]benzene 2 b, were synthesized and used to generate a family of [Pd6(Ltripy)8](BF4)12 octahedral cages (Ltripy=1 a, b or 2 a, b). The ligands and cages were characterized using a combination of 1H, 13C, and DOSY nuclear magnetic resonance (NMR) spectroscopy, high resolution electrospray mass spectrometry (HR-ESI-MS), infrared (IR) spectroscopy, elemental analysis, and in three cases, X-ray crystallography. The molecular recognition properties of the cages with neutral and anionic guests were examined, in dimethyl sulfoxide (DMSO), using NMR spectroscopy, mass spectrometry and molecular modeling. No binding was observed with simple aliphatic and aromatic guest molecules. However, anionic sulfonates were found to interact with the octahedral cages and the binding interaction was size selective. The smaller [Pd6(1 a, b)8]12+ cages were able to interact with three p-toluenesulfonate guest molecules while the larger [Pd6(2 a, b)8]12+ systems could host four of the anionic guest molecules. To probe the importance of the hydrophobic effect, a mixed water–DMSO (1:1) solvent system was used to reexamine the binding of the neutral organic guests adamantane, anthracene, pyrene and 1,8-naphthalimide within the cages. In this solvent system all the guests except adamantane were observed to bind within the cavities of the cages. NMR spectroscopy and molecular modeling indicated that the cages bind multiple copies of the individual guests (between 3–6 guest molecules per cage).

Pyrolysis of variously pretreated or untreated samples of chitin (1) and certain congeners at 150-350 °C afforded a range of platform molecules, as exemplified by compounds 4, 5, 6, 8, 12 and 13. All of these products have been fully characterized, including by single-crystal X-ray analysis. Pathways for the formation of them are proposed and theoretical studies of certain aspects of these described.

The title compounds, (-)

The most pressing challenges for light-driven hydrogel actuators include reliance on UV light, slow response, poor mechanical properties, and limited functionalities. Now, a supramolecular design strategy is used to address these issues. Key is the use of a benzylimine-functionalized anthracene group, which red-shifts the absorption into the visible region and also stabilizes the supramolecular network through π-π interactions. Acid-ether hydrogen bonds are incorporated for energy dissipation under mechanical deformation and maintaining hydrophilicity of the network. This double-crosslinked supramolecular hydrogel developed via a simple synthesis exhibits a unique combination of high strength, rapid self-healing, and fast visible-light-driven shape morphing both in the wet and dry state. As all of the interactions are dynamic, the design enables the structures to be recycled and reprogrammed into different 3D objects.

A crystalline 3D hydrogen bonded framework is assembled in water from tetrahedral tetraamidinium cations and antielectrostatically hydrogen bonded bicarbonate dimers. The framework forms in water, and represents a clear demonstration of the potency of these anti-Coulombic hydrogen bonds. Gentle heating of the framework (50 °C) releases CO2 and water to give the neutral tetraamidine compound.

On exposure to a combination of Cu[I]- and Pd[0]-based catalysts, compounds such as 1 and 7 engage in tandem Ullmann–Goldberg cross-coupling and cyclopalladation-reductive elimination reactions to give benzofurans such as 8. Related reactions involving hetero-Michael additions of o-halogenated phenols or anilines to propiolates and the Pd[0]-catalyzed cyclization of the resulting conjugates provide, in a one-pot process, alternately functionalized benzofurans, indoles, or phthalanes.

Aminobenzaldehydes bearing a pendant 3,5-dinitrophenyl group react thermally with N-substituted α-amino acids to form unprecedented benzoazepine-fused isoindolines. The reaction proceeds via a dearomatization/rearomatization sequence involving an intramolecular (3 + 2)-cycloaddition between the in situ formed azomethine ylide and the dinitroarene. Various glycine derivatives are tolerated as well as branched substrates based on cyclic, α-mono-, and α,α-disubstituted amino acids, giving single diastereomers in many cases. The method is scalable and gives products with a nitro group ready for further manipulation.

An efficient, diastereoselective synthesis of densely functionalized pyrroloindolines is reported. The reaction proceeds via cycloaddition of a vinylaziridine-derived Pd-stabilized 1,3-dipole to electron-deficient 3-nitroindoles. The reactions give the trans diastereoisomer with high selectivity; however, when a 4-substituent is present on the indole ring, a reversal of diastereoselectivity is observed.

Studies of transuranic organometallic complexes provide a particularly valuable insight into covalent contributions to the metal–ligand bonding, in which the subtle differences between the transuranium actinide ions and their lighter lanthanide counterparts are of fundamental importance for the effective remediation of nuclear waste. Unlike the organometallic chemistry of uranium, which has focused strongly on UIII and has seen some spectacular advances, that of the transuranics is significantly technically more challenging and has remained dormant. In the case of neptunium, it is limited mainly to NpIV. Here we report the synthesis of three new NpIII organometallic compounds and the characterization of their molecular and electronic structures. These studies suggest that NpIII complexes could act as single-molecule magnets, and that the lower oxidation state of NpII is chemically accessible. In comparison with lanthanide analogues, significant d- and f-electron contributions to key NpIII orbitals are observed, which shows that fundamental neptunium organometallic chemistry can provide new insights into the behaviour of f-elements. Probing the chemistry of transuranic elements is notoriously challenging. Now, three neptunium(III) organometallic sandwich complexes have been prepared using a flexible macrocycle as ligand, and their molecular and electronic structures characterized, adding to our understanding of the behaviour of f-elements and suggesting that the lower oxidation state Np(II) may be chemically accessible.