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Structurally diverse novel 1,4-benzodiazepine analogues related to selective CCKA antagonist MK-329, and CCKB antagonists L-365,260 and YM022 are prepared via palladium-catalyzed three component domino reactions involving allenylation-carbonylation-anion capture in one-pot cascade protocol in good to excellent yields. The authors thank Mersin University (Turkey), The University of Leeds (UK), and the University of Alicante for support. We also thank the Scientific and Technological Research Council of Turkey (TÜB_ITAK), the Spanish Ministerio de Economía y Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P, and CTQ2016-81797-REDC), the Generalitat Valenciana (PROMETEOII/2014/017), (Consolider Ingenio 2010, CSD2007-00006) for research financing.

γ-Carbolines were prepared from pyrido[4,3- b ]-5 H -indoles via Pd(0)-catalysed, stereo and regioselective allene/uridine allene insertion 3- and 5-component cascades. This versatile reaction sequence gives a range of structurally diverse carboline derivatives and tolerates a broad range of substrates. The power of this approach has been harnessed to produce γ-carboline based HDAC inhibitors.

Histone deacetylase (HDAC) inhibitors prevent neural cell death in in vivo models of cerebral ischaemia, brain injury and neurodegenerative disease. One mechanism by which HDAC inhibitors may do this is by suppressing the excessive inflammatory response of chronically activated microglia. However, the molecular mechanisms underlying this anti-inflammatory effect and the specific HDAC responsible are not fully understood. Recent data from in vivo rodent studies have shown that inhibition of class I HDACs suppresses neuroinflammation and is neuroprotective. In our study, we have identified that selective HDAC inhibition with inhibitors apicidin, MS-275 or MI-192, or specific knockdown of HDAC1 or 2 using siRNA, suppresses the expression of cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in BV-2 murine microglia activated with lipopolysaccharide (LPS). Furthermore, we found that in the absence of HDAC1, HDAC2 is up-regulated and these increased levels are compensatory, suggesting that these two HDACs have redundancy in regulating the inflammatory response of microglia. Investigating the possible underlying anti-inflammatory mechanisms suggests an increase in protein expression is not important. Taken together, this study supports the idea that inhibitors selective towards HDAC1 or HDAC2, may be therapeutically useful for targeting neuroinflammation in brain injuries and neurodegenerative disease.

Histone deacetylase (HDAC) inhibitors prevent neural cell death in in vivo models of cerebral ischaemia, brain injury and neurodegenerative disease. One mechanism by which HDAC inhibitors may do this is by suppressing the excessive inflammatory response of chronically activated microglia. However, the molecular mechanisms underlying this anti-inflammatory effect and the specific HDAC responsible are not fully understood. Recent data from in vivo rodent studies has shown that inhibition of class I HDACs suppresses neuroinflammation and is neuroprotective. In our study we have identified that selective HDAC inhibition with inhibitors apicidin, MS-275 or MI-192, or specific knockdown of HDAC1 or 2 using siRNA, suppresses the expression of cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in BV2 murine microglia activated with lipopolysaccharide (LPS). Furthermore, we found that in the absence of HDAC1, HDAC2 is upregulated and these increased levels are compensatory, suggesting these two HDACs have redundancy in regulating the inflammatory response of microglia. Investigating the possible underlying anti-inflammatory mechanisms suggests an increase in protein expression is not important. Taken together, this study supports the idea that inhibitors selective towards HDAC1 or HDAC2, may be therapeutically useful for targeting neuroinflammation in brain injuries and neurodegenerative disease.Significance StatementThe number of patients suffering a stroke or a neurodegenerative disease, such as Alzheimer’s is increasing These conditions are severely debilitating and are leading causes of mortality, with neural cell death and loss of brain tissue being a major feature. A number of mechanisms contribute to neuronal death, including inflammation in the brain, but we still lack clinical therapies to inhibit this. The work presented here provides further insight into potential molecular therapeutic targets called histone deacetylases (HDACs), which are thought to contribute to neural cell death by promoting inflammation. We show that down regulation of HDAC1 and 2 is sufficient to reduce this inflammatory response. Our findings have clinical relevance because they identify HDAC1 and 2 as promising targets for therapy.

INTRODUCTION: High-grade gliomas feature prominently among the most devastating cancers due to their prevalence in the younger population, highly invasive nature and low 5-year survival. Despite a combined treatment regime of surgical resection, radiation therapy and chemotherapy most patients die within 1 year of initial diagnosis. Alternative, novel ways to treat these tumours are urgently required. Histone deacetylase (HDAC) are important regulators of chromatin remodelling and gene expression and have been shown to be involved in cancer. There is an increasing interest in the study and development of HDAC inhibitors towards clinical application. Moreover, they have been recently reported to inhibit cell migration due to their modulation of tubulin acetylation. Thus HDAC inhibitors represent attractive candidates for chemotherapeutics especially when considering the infiltrative nature of high-grade gliomas. Here, the specific HDAC2/3 inhibitor MI192 developed at Leeds University was investigated for its ability to inhibit 2D and 3D migration of two established adult glioma cell lines. METHODS: U87 and U251 cell lines were used for migration and cytoskeletal studies in 2D and 3D assays. The HDAC inhibitor MI192 was assessed for its ability to inhibit migration alongside LiCl and Bio-Indirubin, two anti-migratory drugs commonly used in glioma in vitro studies. RESULTS: In random migration (2D) the MI192 inhibitor adversely affected the migratory ability of U87 and U251 as evidenced by reduced cell velocity and also cell displacement. This effect was more pronounced in U251 than U87. Immunofluorescence studies of the MI192-treated cells revealed an increase in the acetylation of tubulin in U87, whilst proliferation and apoptosis status remained unchanged. U251 did not appear to show increased levels of tubulin acetylation. In a 3D spheroid invasion assay U87 migration was inhibited by MI192 at 1 uM concentration, but not at 0.1 or 0.01 uM, whereas we did not see a significant change in U251. Immunohistochemistry of the treated spheroids revealed that proliferation was adversely affected in both the core and migratory cells in U87 spheroids with MI192 at a concentration of 1 uM but not in U251 spheroids. Tubulin acetylation appeared more pronounced in U251 after MI192 treatment. In addition, SOX-2 (as a marker of stemness) was reduced in both U251 cores and migratory cells with MI192. CONCLUSION: In addition to its activity as a chromatin remodelling inhibitor, MI192 appears to inhibit glioma cell migration via hyperacetylation of tubulin and possibly microtubule stabilisation in a cell line and topography dependent manner. Thus, the HDAC2/3 inhibitor MI192 may prove useful in targeting migration in certain subtypes of glioma cell.

We report the spatially controlled, protecting group free, catalytic assembly of a library of nineteen 7-component cascade products generated from a novel planar trisallenyl 1,3,5-triazinane-2,4,6-trione core in combination with aryl iodides and amines with excellent regio and good stereoaselectivity for Z,Z,Z-isomers.

We report protecting group free Pd(0) catalyzed cascade syntheses of molecular scaffolds built from heterocyclic bisallenes. These generate novel molecular architecture permitting tri-directional exploration of biochemical space.

Pd-Catalyzed three component reaction of pyrido[4,3-b]-5H-indoles, allenes, and aryl iodides produces the title compounds regioselectively.

Naturally occurring indole-3-carbinol and 3,3-diindolylmethane show bioactivity in a number of disparate disease areas, including cancer, prompting substantial synthetic analogue activity. We describe a new approach to highly functionalised derivatives that starts from allene gas and proceeds via the combination of a three-component Pd(0)-catalysed cascade with a one-pot, three-component carbophilic Pt(II) cascade linked to a stereoselective acid-catalysed Mannich-Michael reaction that generates complex cyclopropyl diindolylmethanes which show selective activity against prostate cancer cell lines.

Histone deacetylase inhibitors (HDACIs) are in advanced clinical development as cancer therapeutic agents. However, first generation HDACIs such as butyrate and valproate are simple short chain aliphatic compounds with moieties resembling acetyl groups, and have a broad spectrum of activity against HDACs. More complex second generation HDACIs undergoing clinical trials, such as the benzamide group compounds MS-275 and MGCD0103, are specific primarily for HDAC1 and HDAC2. To expand the repertoire of available HDACIs and HDAC specificities we created a novel benzamide-based compound named MI-192. When tested against purified recombinant HDACs, MI-192 had marked selectivity for the class I enzymes, HDAC2 and HDAC3. Screening in the NCI60 screen demonstrated that MI-192 had greatly enhanced efficacy against cells of leukaemic origin. When tested in culture against the acute myeloid leukaemic cell lines U937, HL60 and Kasumi-1, MI-192 induced differentiation and was cytotoxic through promotion of apoptosis. MI-192 therefore justifies further investigation and development as a potential therapeutic agent for use in leukaemia.

The reactions of allene gas (1 atm) and of 1,1-dimethylallene with a range protected hydroxylamines and formamide with aryl/heteroaryl iodides, bromides and triflates under Pd(0) catalysis lead to a skeletally diverse range of products in good yield. The cascades tolerate both electron withdrawing and electron donating substrates and 1,1-dimethylallene reacts regioselectively in all cases.

The results of the reaction of aminomethyl heterocycles and 4,6-dimethyl-2-formylpyrimidine and of activated secondary amines with different aryl/heteroaryl or aliphatic aldehydes and N-methylmaleimide or maleimide are described. In the former case the reactions gave single diastereomers via endo-transition states whilst the latter gave a mixture of diastereomers, which are believed to arise from anti-dipoles via endo/exo transition states. The stereochemistry of the cycloadducts was determined by 1H NMR and confirmed by X-ray crystallography.

Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM) that has been approved for the prevention and treatment of postmenopausal osteoporosis. It has antitumor activity; however, its mechanism of action remains unclear. In the present study, we characterized the effects of BZA and several other SERMs on the proliferation of hormone-dependent MCF-7 and T47D breast cancer cells and hormone-independent MCF-7:5C and MCF-7:2A cells and examined its mechanism of action in these cells. We found that all of the SERMs inhibited the growth of MCF-7, T47D, and MCF-7:2A cells; however, only BZA and fulvestrant (FUL) inhibited the growth of hormone-independent MCF-7:5C cells. Cell cycle analysis revealed that BZA and FUL induced G(1) blockade in MCF-7:5C cells; however, BZA down-regulated cyclin D1, which was constitutively overexpressed in these cells, whereas FUL suppressed cyclin A. Further analysis revealed that small interfering RNA knockdown of cyclin D1 reduced the basal growth of MCF-7:5C cells, and it blocked the ability of BZA to induce G(1) arrest in these cells. BZA also down-regulated estrogen receptor-α (ERα) protein by increasing its degradation and suppressing cyclin D1 promoter activity in MCF-7:5C cells. Finally, molecular modeling studies demonstrated that BZA bound to ERα in an orientation similar to raloxifene; however, a number of residues adopted different conformations in the induced-fit docking poses compared with the experimental structure of ERα-raloxifene. Together, these findings indicate that BZA is distinct from other SERMs in its ability to inhibit hormone-independent breast cancer cell growth and to regulate ERα and cyclin D1 expression in resistant cells.

Twenty-six novel naphthoquinone aliphatic esters were synthesized by esterification of 1,4-naphthoquinone alcohols with various aliphatic acids. The 1,4-naphthoquinone alcohols were prepared from 1-hydroxy-2-naphthoic acid in nine steps with excellent yields. Twenty-four of the novel synthetic naphthoquinone esters showed significant antimalarial activity with IC(50) values in the range of 0.03-16.63 microM. The length of the aliphatic chain and the presence of C-2' substituents on the propyl chain affected the activity. Interestingly, compounds 31 and 37 showed very good antimalarial activity and were not toxic to normal Vero cells, and the PTI values of 31 (>1990.38) and 37 (1825.94) are excellent. Both 31 and 37 showed potent inhibition against P. falciparum 3D7 cyt bc(1) and no inhibition on rat cyt bc(1). They showed IC(50) values in the nanomolar range, providing full inhibition of cyt bc(1) with one molecule inhibitor bound per cyt bc(1) monomer at the Q(o) site.

Iodination of 1-C-(tetra-O-acetyl-beta-d-galactopyranosyl)allene affords an E/Z-mixture of 1-C-(tetra-O-acetyl-beta-d-galactopyranosyl)-2,3-diiodo-1-propene. S(N)2 displacement of the allylic iodide with primary amines affords an E/Z-mixture of allylic amines under a variety of conditions. Due to its experimental simplicity and low cost of reagents, this procedure may find wide use in the laboratory for functionalization of sugar allenes.

A series of Ni(II), Pd(II) and Cu(II) metal complexes of highly functionalized aroylaminocarbo-N-thioyl pyrrolidines were prepared and characterized by microanalysis, spectroscopic methods, magnetic susceptibility measurements and single crystal X-ray diffraction studies. The antifungal activity of the metal complexes against the yeast Saccharomyces cerevisae and against the fungus Penicillium digitatum was studied.

Ir catalysed alkylation of 4-hydroxy coumarin, 4-hydroxy-2-quinolones and quinolin-4(1H)-one with a range of substituted benzyl and aliphatic alcohols under solvent free thermal conditions afforded the corresponding monoalkylated products in high to excellent yield and in certain cases produced bis-(3,3′-1-methyl-4-hydroxy)methenes.

5-Chloro-7-[1,3]oxazolo[4,5-b]pyridin-2-ylquinolin-8-ol was synthesized by a Pd-catalyzed arylation, which proceeds efficiently with 2 equivalents of benzylated clioquinol and 1 equivalent of oxazolo[4,5-b]pyridine. The product was smoothly debenzylated by boron trichloride in dichloromethane.

Ir-catalysed alkylation of oxindole and N-methyl oxindole with a range of substituted benzyl and heteroaryl alcohols under solvent free thermal or microwave conditions afforded the corresponding C-3-monoalkylated products in high to excellent yield.

Ir-catalysed alkylation of tert -butyl cyanoacetate with a range of substituted benzyl and heteroaryl alcohols under solvent free conditions afforded the corresponding monoalkylated products in moderate to high yields.

A palladium-catalyzed three-component cascade process for the synthesis of isoindolone and phthalazone derivatives is reported. The cascade process involves carbonylation of an aryl iodide/Michael acceptor to give an acylpalladium species which is intercepted by a hydrazine nucleophile. Intramolecular Michael addition follows to give either N-aminoisoindolones or mono- N- and di-N,N'-phthalazones depending on whether a monosubstituted or 1,2-disubstituted hydrazine nucleophile is used.

1,3-Dipolar reactions of imines of both acyclic and cyclic α-amino esters with a range of nitroolefins using a combination of AgOAc or Ag2O with NEt3 are described. In most cases the reactions were highly regio- and stereospecific and endo-cycloadducts were obtained in good yield. However, in a few cases the initially formed cycloadducts underwent base catalysed epimerisation. The stereochemistry of the cycloadducts was assigned from NOE data and established unequivocally in several cases by X-ray crystallography.\ud \ud

We report novel iridium(III)-catalyzed reactions that afford substituted indoles via the indirect functionalization of alcohols via C-3 selective alkylation of indoles with alcohols and a one-pot cascade strategy from amino- or nitro-phenyl ethyl alcohols, which incorporates oxidative cyclization and C-3 alkylation.

Novel palladium catalysed two- and three-component thermal (conventional heating and microwave) cascade processes are described involving allenylation of an aryl iodide to generate a (π-allyl)palladium species, which are intercepted (inter- or intramolecularly) by a carbon or nitrogen nucleophile followed by intramolecular Michael addition to afford carbo- and heterocycles in good yields.

Histone deacetylase 3 removes acetyl groups from lysine residues, thereby modifying protein function. It is found in both the nucleus and the cytoplasm. We have discovered that it can indirectly deacetylate tubulin, a cytoplasmic protein that forms microtubules, thus modifying the microtubule., Histone deacetylase 3 (HDAC3), a member of the Class I subfamily of HDACs, is found in both the nucleus and the cytoplasm. Its roles in the nucleus have been well characterized, but its cytoplasmic roles are still not elucidated fully. We found that blocking HDAC3 activity using MI192, a compound specific for HDAC3, modulated tubulin acetylation in the human prostate cancer cell line PC3. A brief 1 h treatment of PC3 cells with MI192 significantly increased levels of tubulin acetylation and ablated the dynamic behaviour of microtubules in live cells. siRNA-mediated knockdown (KD) of HDAC3 in PC3 cells, significantly increased levels of tubulin acetylation, and overexpression reduced it. However, the active HDAC3–silencing mediator of retinoic and thyroid receptors (SMRT)–deacetylase-activating domain (DAD) complex did not directly deacetylate tubulin in vitro. These data suggest that HDAC3 indirectly modulates tubulin acetylation.

A new series of Rh, Ir and Ru precatalysts for the [2+2+2] cyclotrimerisation of 1,6-diynes with monoynes is reported. The precatalysts are reduced in situ to the active catalysts by reduction with alcohols. The precatalysts activity is in the order Ru>Rh>Ir which reflects the ease of this reduction. The Rh and Ir precatalysts require temperature in excess of 140 C allowing their preparation in 2-methoxymethanol at 125 C. The mechanism of this process is discussed.

A palladium-catalysed one-pot reaction for the in situ generation of 'zippers' and subsequent cyclisation-anion capture with phenyl boronic acid produces tricyclic heterocycles with the formation of three C-C bonds, one C-N bond, two rings, two stereocentres and one tetrasubstituted C-centre.

A range of room temperature 1,3-dipolar cycloaddition reactions of imines of 2-amino-γ-lactone and thiolactone, catalysed by a combination of AgOAc or Ag2O with NEt3 or DBU, are described. The spiro lactones/thiolactones are formed regio- and stereoselectively as single cycloadducts in good yield via the syn dipoles and an endo-transition states.

Catalytic bis- and tris-cyclisation of a series of acyclic carbo- and heterocyclic precursors results in formation of two or three rings, two or three C–C bonds and two asymmetric tetrasubstituted C-centres regio- and stereoselectively in excellent yield.

Purpose: Selective estrogen receptor modulators (SERM) are used for the treatment and prevention of breast cancer (tamoxifen) and osteoporosis (raloxifene). Mechanisms of tamoxifen-resistance in breast cancer are incompletely understood but current research is focused on crosstalk between growth factor receptors and the estrogen receptor α (ERα) pathway. There is increasing clinical use of raloxifene for the treatment of osteoporosis, but the widespread use of this SERM will have consequences for the treatment of breast cancer in raloxifene-exposed women. Experimental Design: We took the strategic step of developing a raloxifene-resistant tumor (MCF-7RALT) model in vivo and investigating the mechanisms responsible for resistance. Results: MCF-7RALT tumors exhibited phase I SERM resistance, growing in response to SERMs and 17β-estradiol. Epidermal growth factor receptor/HER1 and HER2/neu mRNAs were increased in MCF-7RALT tumors. The HER2/neu blocker, trastuzumab, but not the epidermal growth factor receptor blocker, gefitinib, decreased the growth of MCF-7RALT tumors in vivo. Consequently, trastuzumab decreased prosurvival/proliferative proteins: phospho-HER2/neu, total HER2/neu, phospho-Akt (protein kinase B), glycogen synthetase kinase-3, cyclin D1, and the antiapoptotic protein X chromosome-linked inhibitor of apoptosis, whereas increasing the proapoptotic protein, caspase-7, in raloxifene-treated MCF-7RALT tumors. Interestingly, ERα protein was overexpressed in untreated MCF-7RALT tumors and hyperactivated in cells derived from these tumors. Only fulvestrant completely inhibited the growth and ERα activity of MCF-7RALT tumors. The coactivator of ERα, amplified in breast cancer-1 protein was modestly increased in the raloxifene-treated MCF-7RALT tumors and increased both basal and estradiol-induced activity of ERα in cells derived from the MCF-7RALT tumors. Conclusions: These results suggest that overexpression and increased activity of HER2/neu might be responsible for the development of raloxifene-resistant breast cancer. The results also suggest that increased expression of basal activity of ERα could contribute to the hypersensitivity of MCF-7RALT tumors in response to estradiol because only fulvestrant blocked growth and ERα activity.

A sequential one-pot process is reported involving in situ, palladium catalysed, formation of a series of tributylstannyl-1,2-carbo and heterocyclic dialkylidene-5-membered rings from the corresponding 1,6-diynes and Bu 3 SnH. These substrates and other organostannanes are then combined with carbamyl chlorides and iodobenzenes containing proximate alkene and alkynyl groups in palladium catalysed cyclisation–anion capture cascades affording a diverse range of heterocycles in good yield.

A palladium-catalysed four-component process is described involving carbon monoxide, allene and aryl/heteroaryl iodides generating (π-allyl) palladium species, which are intercepted by alkene tethered nitrogen nucleophiles to afford 1,6- and 1,7-dienones. Subsequent ring closing metathesis affords five- and six-membered N-heterocyclic enones. The N-heterocyclic enones are active dipolarophiles in 1,3-dipolar cycloaddition reactions as exemplified by azomethine ylide and nitrone cycloadditions.

Metallo-azomethine ylides, generated from iminophosphonates in combination with LiBr or AgOAc and bases Et3N, DBU, t-butyl tetramethylguanidine(BTMG) undergo cycloaddition to give dialkyl pyrrolidine-2-phosphonates along with the corresponding Michael adduct in some cases. Cycloadditions with the chiral dipolarophile 5R-(1′R,2′S,5′R-menthyloxy)-2-(5H)-furanone (MOF) afforded enantiopure cycloadducts.

A novel sequential Pd-catalysed termolecular allenylation cascade/Ru catalysed RCM process affords a diverse range of Δ 3 -aryl/heteroaryl substituted five–seven membered nitrogen and oxygen heterocycles. Further elaboration, via 1,3-dipolar cycloaddition, in selected cases, afforded fused heterocyclic ring systems.

Cyclopalladated, phosphine free, 8-methyl quinoline based complexes ( 2a – j ) are excellent catalysts for the Heck vinylation of aryl iodides and bromides with turnover numbers of greater than 25 million observed in some cases. The catalysts are air and moisture stable.

A range of regio- and stereo-selective 1,3-dipolar reactions of imines of α-amino esters, generating polysubstituted prolines, catalysed by silver(I) exchanged zeolites or silver(I) supported on titania, both in combination with DBU, are described. The use of a catalytic amount of silver(I) oxide, Ni(II) complexes and cuprous iodide as catalysts for the cycloaddition reactions are also disclosed.

Palladium catalysed 3-component cascades are described involving aryl/heteroaryl iodides, allene and benzyl malononitrile. Catalytic monohydration and monoamination of malononitriles to the corresponding monoamides and monoamidines are also described together with several examples of mono-oxazoline formation.

Rhinacanthin-M, -N and -Q, natural products isolated from the medicinal plant Rhinacanthus nasutus, and 39 novel naphthoquinone esters have been synthesized in excellent yield by esterification of naphthoquinone-3-(propan-3'-ols) with benzoic or naphthoic acids. Almost all the naphthoquinone esters that contain a C-3 hydroxy group showed significant cytotoxicities against KB, HeLa, and HepG2 cell lines. In contrast, ester derivatives lacking the C-3 hydroxy group were inactive to the cancer cell lines. Two methyl substituents on the C-2' of propyl chain conferred more potent cytotoxicity than when there is only one or no methyl group. Naphthoate esters exhibited greater cytotoxicity than benzoate esters. Computer modeling has been done to obtain a first look at the mode of action in connection with these observations.

Mono 3-(2′-arylallyl) derivatives of 4-hydroxycoumarin 1a,b , 4-hydroxy-6-methyl-pyran-2-one ( 3 ) and 6-hydroxy-1,4-dimethyl-1,2-dihydropyrid-2-one-3-carbonitrile ( 4 ) are produced in 3-component cascades involving aryl/heteroaryl/vinyl iodides and allene (1 atm) using Pd(PPh3)4/Cs2CO3/MeCN/80 °C or Pd2(dba)3/tris(2-furyl)phosphine/K2CO3/DMF/80 °C as the catalyst system. 4-Hydroxy-2-quinolone ( 2 ) afforded a mixture of mono- and bis-allylation products under these conditions. Mono C-allylation products 5a–e and 15a–e undergo facile acid catalysed cyclisation to afford dihydrofurocoumarins 11a–e and dihydrofurodihydropyrid-2-ones 16a–e in good overall yield.

Cascade thermal and decarboxylative cycloaddition reactions of uracil polyoxin C (UPoC) with mono- and di-carbonyl compounds in the presence of a dipolarophile leads, via stabilised and non-stabilised azomethine ylides respectively, to a series of polyoxin cycloadducts related to Nikkomycin B in good to excellent yields and high diastereoselectivity.

Treatment of PdCys or palladium salts with carbon monoxide (1 atm) in DMF or toluene at room temperature results in a solution of palladium nanoparticles whose morphology depends on the PdCy or palladium salt. Unusual triangular shaped 2–12 nm nanoparticles result from PdCys 1 and 3.

Preparation of some novel spiro-oxazolidines related to 3 , which is known to posses anorectic and antidepressant activity, via 1,3-APT–1,3-DC cascades of the oxime of benzobicyclo[3.3.1]non-5-en-9-one 1 is described. Substrate 1 allows the influence of the two bridges on the cascade to be assessed with respect to the configuration of the nitrone that is generated and the facial selectivity of the subsequent cycloaddition.

A new general three-component Pd/In bimetallic cascade reaction with four synthetic variants involving aryl iodides, allenes and C=X compounds affording homoallylic alcohols/amines as products is described and exemplified for Class 1 processes (intermolecular Pd–intermolecular In steps). Remarkable increases in yield and reaction rates were observed in the presence of amine additives. Excellent diastereoselection is exhibited when 2-hydroxycyclohexanone is employed, and semi-empirical and ab initio calculations are used to rationalise the observed syn : anti diastereoselectivity.

The Pd/Cu-catalysed cross-coupling reaction of heterocyclic terminal alkynes and allene/allenyl heterocycles affords novel trisubstituted en-ynes in good yield.

Imines of (1S,9S)-t-butyl-9-amino-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate undergo thermal (toluene, 110°C) or LiBr-DBU catalysed (MeCN, room temperature) regio- and stereo-specific cycloaddition to a range of chiral dipolarophiles giving enantiopure spiro-cycloadducts in excellent yield. The reactions proceed via intermediate NH azomethine ylides and litho azomethine ylides, respectively and results in the multiplication of chiral centres from 2 (one of which is lost in the process) to 5.

The effect of adding 1 equiv. of an amine or 0.2 equiv. of CuI to a Pd/In bimetallic cascade reaction is described. In the class 1 cascade reaction of aldehydes, aryl iodides and allene, generating homoallylic alcohols, the reaction time is reduced from 16 to 2 h and is accompanied by an impressive increase in yield.