Ronald Grigg

Palladium catalysed cascade cyclisation-anion capture, relay switches and molecular queues ☆

Abstract Cyclic carbopalladation can be achieved by a group of related reactions that provide versatile and powerful methodology for the construction of carbocyclic and heterocyclic rings. These ring forming processes are marked by their tolerance of a wide range of functionality together with their ability to process a variety of starter species and to effect cyclisation onto all types of C–C unsaturated bonds. Substantial additional pre- and post-cyclisation functionality can be incorporated via cyclisation-anion capture and/or polycomponent cascades that switch between inter- and intra-molecular processes. The polycomponent cascades can be regarded as proceeding via molecular queuing processes and when gaseous reactants are employed the queuing processes are sensitive to pressure. These wide ranging processes occur with excellent chemo-, regio- and stereo-selectivity and allow incorporation of precisely located complex functionality whilst generating bridged, fused and spirocyclic systems and multiple C–C/C-heteroatom bonds.

Chiral Co(II) and Mn(II) catalysts for the 1,3-dipolar cycloaddition reactions of azomethine ylides derived from arylidene imines of glycine

Abstract Anhydrous MnBr 2 and CoCl 2 in conjunction with chiral ephedrine ligands effect substantial asymmetric induction in cycloadducts derived from methyl acrylate and imines of glycine methyl ester. CoCl 2 is most effective and gives 96% e.e.

The synthesis of fused ring nitrogen heterocycles via regiospecific intramolecular heck reactions

Abstract A series of palladium (and in some cases rhodium) catalysed regiospecific 5-exo-, 6-endo-and 6-exo-trig cyclisations of aryl iodides and vinyl bromides onto proximate alkenes or heteroaromatic rings (indole, pyrrole) lead to a wide variety of fused ring systems. In appropriate cases the methodology provides a facile approach to the creation of tetrasubstituted carbon centres. Double bond isomerisation in the product is only observed in a few cases.

Asymmetric cascade 1,3-dipolar cycloaddition reactions of imines

Abstract Mechanistic and preparative features of a variety of successful approaches to homochiral pyrrolidines based on imine → azomethine ylide → cycloaddition cascades are discussed.

X = Y - ZH systems as potential 1,3-dipoles part 35. Generation of nitrones from oximes. Class 3 processes. Tandem intramolecular michael addition (1,3-azaprotio cyclotransfer) - intermolecular 1,3-dipolar cycloaddition reactions.☆☆☆

Abstract Aldoximes and ketoximes possessing γ- or δ-alkenyl substituents undergo thermal conversion to 5- and 6- membered cyclic nitrones via a 1,3-azaprotio cyclotransfer, a 2n + 2σ + 2π concerted process, rather than a Michael addition. The reactions can be performed as a tandem nitrone formation-cycloaddition sequence or, if required, the intermediate nitrones can be isolated. The cycloadditions usually proceed via an exo-transition state and show both regio- and diastereofacial-specificity. Preliminary attempts at chiral induction via a menthyl auxiliary are reported.

Suppression of alkene isomerisation in products from intramolecular heck reactions by addition of Tl(1) salts.

Abstract Palladium catalysed cyclisations creating products possessing spiro-, fused- and bridged-rings, and tetrasubstituted carbon centres as mixtures of double bond isomers are modified to give single products in the presence of Tl(1) salts.

X-Y-ZH Systems as potential 1,3-dipoles : Part 15. Amine generated azaallyl anios versus metallo-1,3-dipoles in cycloadditions of α-amino acid esters. Facile regio- and stereo-specific formation of pyrrolidines

Abstract Kinetic studies of the deprotonation of arylidene imines of alanine and phenylglycine esters by tertiary amines and pyridine and cycloaddition of the resultant 4π-azaallyl anions to N-phenylmaleimide show the expected dependance on the p-substituent in the aryl ring. e.g. p-NO2 > H > OMe >fs NMe2. A combination of metal salt (silver, lithium. or zinc) and triethylamine in THF, dipolar aprotic solvents (MeCN, DMSO, DMF) or N-methylacetamide effects regio- and stereo-specific or highly stereo-selective inter- and intra-molecular cycloaddition of imines of phenylglycine. alanine and glycine esters to a range of dipolarophiles probably via metallo-1,3-dipole formation at room temperature. Silver acetate is a more efficient and selective catalyst than lithium bromide and reactions in acetonitrile, DMSO or N-methylacetamide, are especially rapid (O.1–3.5h).

Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3–selective inhibitor reduces interleukin‐6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients

OBJECTIVE To characterize the role of histone deacetylase (HDAC) activity in rheumatoid arthritis (RA) and to evaluate the effects of MI192, a novel HDAC-3-selective inhibitor, compared with the established nonselective HDAC inhibitor trichostatin A (TSA), on proinflammatory cytokine production. METHODS Activity of HDAC and histone acetyltransferase was measured in peripheral blood mononuclear cells (PBMCs) from RA patients by spectrophotometric assay, prior to and after 12 weeks of etanercept therapy. The effects of HDAC inhibitor treatment on cytokine production in both RA and healthy PBMCs were assessed by enzyme-linked immunosorbent assay. RESULTS RA PBMCs exhibited significantly increased HDAC activity (P = 0.007) compared to PBMCs from healthy individuals, and the increase was unaltered after 12 weeks of etanercept therapy. TSA was a potent inhibitor of tumor necrosis factor (TNF) and interleukin-6 (IL-6) production in both RA and healthy PBMCs and of interferon-γ (IFNγ) production in healthy PBMCs; IFNγ was not produced by RA PBMCs. MI192 inhibited TNF production at high concentrations and dose-dependently inhibited IL-6 in RA PBMCs but not healthy PBMCs, across a dose range of 10 μM-5 nM. CONCLUSION HDAC activity is dysregulated in RA PBMCs and is a potential target for therapeutic intervention, as it is not affected by conventional anti-TNF treatment with etanercept. Both the selective and the nonselective HDAC inhibitors (MI192 and TSA, respectively) were found to regulate cytokine production from PBMCs, but their effects were cell type and compound specific. HDAC inhibitors have potential in the treatment of RA, and HDAC-selective inhibition may improve the therapeutic margin of safety; however, further clinical characterization and evaluation for adverse effects is needed.

Palladium catalysed tandem cyclisation-anion capture processes. Part 1 : Background and hydride ion capture by alkyl- and π-allyl-palladium species

Abstract A new, wide ranging, synthetically powerful, catalytic tandem cyclisation-anion capture process is proposed which depends on the rate of cyclisation of an organopalladium specifies (RPdX) onto a proximate alkene or diene being significantly faster than anion exchange and reductive elimination in the sequence RPdX → RPdY → RY + Pd(0). The catalytic cyclisation - anion capture sequence is illustrated for hydride capture by a wide variety of substrates giving rise to fused- and spiro-, carbo- and hetero-cyclic systems, regio- and stereo-specifically.

Rhodium catalysed [2+2+2] cycloadditions of acetylenes

Wilkinsons catalyst RhCl(PPh3)3 is an effective catalyst (0.5 – 2 mole %) for the rapid intermolecular trimerisation of 1,6-heptadiynes with monoacetylenes under mild conditions.