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Mixed ligand, palladium(II) and platinum(II) complexes of tertiary diphosphineswithS-1H benzo[d] imidazole-2-yl benzothioate

Palladium(II) and platinum(II) complexes containing the mixed ligands tertiary diphosphinesdppm. dppp and dppf with Thioester ligand S-1H benzo[d] imidazole-2-yl benzothioate (HSBIBT) have been prepared by the reaction of PdCl2 and PtCl2 with one equiv of tertiary diphosphines ligands to form [Pd(k2-dppf)Cl2], [Pd(k2-dppp)Cl2] and [Pt(k2-dppmCl)Cl2] complexes and then add the ligand HSBIBT to these complexes to form mixed ligand complexes. The prepared complexes have been characterized by single-crystal X-ray diffraction, elemental analysis, magnetic susceptibility, molar conductance, IR spectral data and UV-Visible. The results suggested that the ligand HSBIBT bonded to the metal through N atom and square planner geometries were assigned for the complexes.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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The stereocontrolled total synthesis of spirastrellolide A methyl ester. Fragment coupling studies and completion of the synthesis

The spirastrellolides are a novel family of structurally unprecedented marine macrolides which show promising anticancer properties due to their potent inhibition of protein phosphatase 2A. In the preceding paper, a modular strategy for the synthesis of spirastellolide A methyl ester which allowed for the initial stereochemical uncertainties was outlined, together with the synthesis of a series of suitably functionalised fragments. In this paper, the realisation of this synthesis is described. Two alternative coupling strategies were explored for elaborating the C26-C40 DEF bis-spiroacetal fragment: a modified Julia olefination of a C26 aldehyde with a C17-C25 sulfone, and a Suzuki coupling of a C25 trialkylborane with a C17-C24 vinyl iodide, which also required the development of a double hydroboration reaction to install the C23/C24 stereocentres. The latter proved a significantly superior strategy, and was fully optimised to provide a C17 aldehyde which was coupled with a C1-C16 alkyne fragment to afford the C1-C40 carbon framework. The BC spiroacetal was then installed within this advanced intermediate by oxidative cleavage of two PMB ethers with spontaneous spiroacetalisation, which also led to unanticipated deprotection of the C23 TES ether. The ensuing truncated seco-acid was cyclised in high yield to construct the 38-membered macrolactone under Yamaguchi macrolactonisation conditions, suggesting favourable conformational pre-organisation. Exhaustive desilylation provided a crystalline macrocyclic pentaol, revealing much about the likely conformation of the macrolactone in solution. Attachment of the remainder of the side chain proved challenging, potentially due to steric hindrance by this macrocycle; an olefin cross-metathesis to install an electrophilic allylic carbonate and subsequent pi-allyl Stille coupling with a C43-C47 stannane achieved this goal. Global deprotection completed the first total synthesis of (+)-spirastrellolide A methyl ester which, following detailed NMR correlation with an authentic sample, validated the full configurational assignment. A series of simplified analogues of spirastrellolide incorporating the C26-C47 region were also prepared by pi-allyl Stille coupling reactions.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Heterocyclylalkylpiperidine derivatives, their preparation and compositions containing them

Heterocyclylalkylpiperidine derivatives of general formula (I) 1in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and/or, where appropriate, in their syn or anti form or a mixture thereof, as well as any salt thereof.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Revealing a second transmetalation step in the Negishi coupling and its competition with reductive elimination: Improvement in the interpretation of the mechanism of biaryl syntheses

This paper presents an experimental and theoretical investigation of the Pd-catalyzed Negishi coupling reaction and reveals a novel second transmetalation reaction between an Ar1-Pd-Ar2 species and the organozinc reagent Ar2-ZnX. Understanding of this second step reveals how homocoupling and dehalogenation products are formed. Thus, the second transmetalation generates Ar2PdAr2 and Ar 1ZnCl, which upon reductive elimination and hydrolysis, respectively, give the homocoupling product Ar2-Ar2 and the dehalogenation product Ar1H. The ratio of the cross-coupling product Ar1-Ar2 and the homocoupling product Ar 2-Ar2 is determined by competition between the second transmetalation and reductive elimination steps. This mechanism is further supported by density functional theoretical calculations. Calculations on a series of reactions suggest a strategy in controlling the selectivity of cross-coupling and homocoupling pathways, which we have experimentally verified.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Probing the molecular orbitals and charge redistribution in organometallic (PP)Pd(XX) complexes. A Pd K-edge XANES study

Pd K-edge X-ray absorption near-edge spectroscopy (XANES) is used to probe the unoccupied molecular orbitals in bidentate diphosphine Pd complexes. Complexes containing a series of bidentate diphosphine ligands (PP) are examined to study the effect of the ligand bite angle on the charge redistribution in these complexes. Different coordinating moieties (XX) have been used to induce a range of Pd oxidation states. A full interpretation of the Pd K-edge XANES data is presented. The negative second derivative of these XANES data provides direct information on the energy and electronic distribution of the different unoccupied molecular orbitals probed. The charge redistributions within the complexes, as reflected in the effective Pd oxidation state, are indicated by both the intensity of the first edge feature, the “Pd d peak”, and the energy of the second edge feature, the “Pd p peak”, which can be easily observed in the negative second derivative of the XANES data. Additionally, the changing covalent interaction between the Pd and coordinated moieties via the Pd p orbitals is reflected directly in the energy splitting of the “Pd p” peak. Thus, investigation of these (PP)Pd(XX) complexes, some used as catalysts in organic synthesis, with XANES spectroscopy provides new essential information on their electronic properties. Further, the XANES analysis techniques described in this paper can be applied to investigate the unoccupied molecular orbitals and charge redistributions within a wide range of samples.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Palladium-Catalyzed Three-Component Reaction: A Novel Method for the Synthesis of N-Acyl Propiolamides

Palladium-catalyzed three-component reactions between terminal alkynes, isonitriles, and sodium carboxylates have been developed. This novel and operationally simple methodology provides an alternative for the synthesis of N-acyl propiolamide derivatives under mild conditions using isonitriles as the amine source and sodium carboxylates as the oxygen and acyl source.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Discovery of GSK2656157: An optimized PERK inhibitor selected for preclinical development

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Pd-catalyzed C-arylation of unsaturated compounds with pentavalent triarylantimony dicarboxylates

Triarylantimony (V) derivatives Ar3SbX2 (X = Hal or acyloxy) were prepared by reaction of Ar3Sb with equimolar amounts of a peroxide ROOH (R = t-Bu, H) in the presence of an acid or an anhydride in good to excellent yields. Ar3Sb(O2CR)2 are mild and efficient C-arylation reagents of unsaturated compounds (methyl acrylate, styrene, 2-phenylpropene and acrylonitrile) under palladium catalysis at 50 C, with PdCl2 being the most effective catalyst. Ar3SbHal2 do not react under these conditions.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Total synthesis of an atropdiastereomer of RP-66453 and determination of its absolute configuration

The absolute configuration (aR, S, S, S, S, S) was assigned to the natural product RP-66453 (1) after the total synthesis of its atropdiastereomer and spectroscopic studies on the two compounds. A sequence of SNAr-based cyclo-etherification and an intramolecular atropdiastereoselective Suzuki-Miyaura coupling were used for the construction of the elusive A-B-O-C bicyclic skeleton of RP-66453.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Modular Synthesis of Enantioenriched 1,1,2-Triarylethanes by an Enantioselective Arylboration and Cross-Coupling Sequence

An enantioselective Cu/Pd-catalyzed borylative coupling of styrenes with aryl/alkenyl iodides was realized using a chiral sulfoxide-phosphine (SOP) ligand. Enantioenriched 1,1-diarylethyl and beta-aryl-homoallylic boronates are readily prepared. A streamlined procedure merging arylboration and subsequent Pd-catalyzed Suzuki-Miyaura cross-coupling enables the modular assembly of enantioenriched 1,1,2-triarylethanes, including two medicinally important chiral small-molecule targets.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method