Tsuji-Trost Reaction of Non-Derivatized Allylic Alcohols.

Palladium-catalyzed allylic substitution of non-derivatized enantioenriched allylic alcohols with a variety of uncharged N-, S-, C- and O-centered nucleophiles using a bidentate BiPhePhos ligand is described. A remarkable effect of the counter ion (X) of the XPd[κ2 -BiPhePhos][η3 -C3 H5 ] was observed. When ClPd[κ2 -BiPhePhos][η3 -C3 H5 ] (complex I) was used as catalyst, non-reproducible results were obtained. Study of the complex by X-ray crystallography, 31 P NMR spectroscopy, and ESI-MS showed that a decomposition occurred where one of the phosphite ligands was oxidized to the corresponding phosphate, generating ClPd[κ1 -BiPhePhosphite-phosphate][η3 -C3 H5 ] species (complex II). When the chloride was exchanged to the weaker coordinating OTf- counter ion the more stable Pd[κ2 -BiPhePhos][η3 -C3 H5 ]+ +[OTf] - (complex III) was formed. Complex III performed better and gave higher enantiospecificities in the substitution reactions. Complex III was evaluated in Tsuji-Trost reactions of stereogenic non-derivatized allylic alcohols. The desired products were obtained in good to excellent yields (71-98 %) and enantiospecificities (73-99 %) for both inter- and intramolecular substitution reactions with only water generated as a by-product. The methodology was applied to key steps in total synthesis of (S)-cuspareine and (+)-lentiginosine. A reaction mechanism involving a palladium hydride as a key intermediate in the activation of the hydroxyl group is proposed in the overall transformation.

Pd-Catalyzed Substitution of the OH Group of Nonderivatized Allylic Alcohols by Phenols.

Nonactivated phenols have been employed as nucleophiles in the allylation of nonderivatized allylic alcohols to generate allylated phenolic ethers with water as the only byproduct. A Pd[BiPhePhos] catalyst was found to be reactive to give the O-allylated phenols in good to excellent yields in the presence of molecular sieves. The reactions are chemoselective in which the kinetically favored O-allylated products are formed exclusively over the thermodynamically favored C-allylated products.

A General Route to ß-Substituted Pyrroles by Transition-Metal Catalysis.

An atom-efficient route to pyrroles substituted in the ß-position has been achieved in four high yielding steps by a combination of Pd, Ru, and Fe catalysis with only water and ethene as side-products. The reaction is general and gives pyrroles substituted in the ß-position with linear and branched alkyl, benzyl, or aryl groups in overall good yields. The synthetic route includes a Pd-catalyzed monoallylation step of amines with substituted allylic alcohols that proceeds to yield the monoallylated products in moderate to excellent yields. In a second step, unsymmetrical diallylated aromatic amines are generated from the reaction of a second allylic alcohol with high selectivity in moderate to good yields by control of the reaction temperature. Ru-catalyzed ring-closing metathesis performed on the diallylated aromatic amines yields the pyrrolines substituted in the ß-position in excellent yields. By addition of ferric chloride to the reaction mixture, a selective aromatization to yield the corresponding pyrroles substituted in the ß-position was achieved. A reaction mechanism involving a palladium hydride, generated from insertion of palladium to O-H of an allyl alcohol, that is responsible for the C-O bond cleavage to generate the π-allyl intermediate is proposed.

Mechanistic insights into the Pd-catalyzed direct amination of allyl alcohols: evidence for an outer-sphere mechanism involving a palladium hydride intermediate.

The mechanism of direct amination of allyl alcohol by a palladium triphenylphosphite complex has been explored. Labelling studies show that the reaction proceeds through a π-allylpalladium intermediate. A second-order dependence of reaction rate on allyl alcohol concentration was observed. Kinetic isotope effect studies and ESI-MS studies are in agreement with a reaction proceeding through a palladium hydride intermediate in which both O-H bond and C-O bond cleavages are involved in rate-determining steps. A stereochemical study supports an outer-sphere nucleophilic attack of the π-allylpalladium intermediate giving complete chiral transfer from starting material to product.

An atom efficient route to N-aryl and N-alkyl pyrrolines by transition metal catalysis.

The synthesis of N-aryl, N-tosyl, and N-alkyl pyrrolines from allyl alcohols and amines has been developed. The reaction sequence includes a palladium-catalyzed allylation step in which non-manipulated allyl alcohol is used to generate the diallylated amine in good to excellent yield. An excess of allyl alcohol was necessary for efficient diallylation of the amine, where the excess alcohol could be recycled three times. For aryl and tosyl amines, Pd[P(OPh)(3)](4) was used and for benzyl and alkyl amines a catalytic system comprising Pd(OAc)(2), P(n)Bu(3), and BEt(3) was used. Both the electronic properties and the steric influence of the amine affected the efficiency of the allylation. The isolated diallylated amines were transformed into their corresponding pyrrolines by ring-closing metathesis catalyzed by (H(2)IMes)(PCy(3))Cl(2)RuCHPh in good to excellent yield. A one-pot reaction was developed in which aniline was transformed into the corresponding pyrroline without isolating the diallylated intermediate. This one-pot reaction was successfully scaled-up to 1 mL of aniline in which the N-phenyl pyrroline was isolated in 95% yield. The versatility of the reaction in which 3-methyl-1-phenyl pyrroline was prepared in two-steps was demonstrated.

Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass.

INTRODUCTION: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic ß-cells where it is believed to play a role in insulin release. Reduction in ß-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify ß-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes. METHODS: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. Saturable tracer binding was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat. RESULTS: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270 ±â€¯120 MBq) and a radiochemical purity of 93 ±â€¯2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was reduced in tissues with known expression of CRTH2 after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data. CONCLUSIONS: Initial preclinical in vitro and in vivo evaluations of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in ß-cell mass imaging and CRTH2 drug development.

Green Diesel from Kraft Lignin in Three Steps.

Precipitated kraft lignin from black liquor was converted into green diesel in three steps. A mild Ni-catalyzed transfer hydrogenation/hydrogenolysis using 2-propanol generated a lignin residue in which the ethers, carbonyls, and olefins were reduced. An organocatalyzed esterification of the lignin residue with an in situ prepared tall oil fatty acid anhydride gave an esterified lignin residue that was soluble in light gas oil. The esterified lignin residue was coprocessed with light gas oil in a continous hydrotreater to produce a green diesel. This approach will enable the development of new techniques to process commercial lignin in existing oil refinery infrastructures to standardized transportation fuels in the future.

Equilibrium Study of Pd(dba)2 and P(OPh)3 in the Pd-Catalyzed Allylation of Aniline by Allyl Alcohol.

Reaction of Pd(dba)2 and P(OPh)3 shows a unique equilibrium where the Pd[P(OPh)3]3 complex is favored over both Pd(dba)[P(OPh)3]2 and Pd[P(OPh)3]4 complexes at room temperature. At a lower temperature, Pd[P(OPh)3]4 becomes the most abundant complex in solution. X-ray studies of Pd[P(OPh)3]3 and Pd(dba)[P(OPh)3]2 complexes show that both complexes have a trigonal geometry with a Pd-P distance of 2.25 Å due to the π-acidity of the phosphite ligand. In solution, pure Pd(dba)[P(OPh)3]2 complex equilibrates to the favored Pd[P(OPh)3]3 complex, which is the most stable complex of those studied, and also forms the most active catalytic species. This catalyst precursor dissociates one ligand to give the reactive Pd[P(OPh)3]2, which performs an oxidative addition of nonmanipulated allyl alcohol to generate the π-allyl-Pd[P(OPh)3]2 intermediate according to ESI-MS studies.

Atropisomeric myristinins: selective COX-2 inhibitors and antifungal agents from Myristica cinnamomea.

The first naturally occurring atropisomeric flavans, myristinins B (2), C (2a), E (4), and F (4a), together with their corresponding trans-isomers, myristinins A (1) and D (3), were isolated from the CH(2)Cl(2) extract of Myristica cinnamomea fruits. Compounds 1, the mixture of 2 and 2a, and the mixture of 4 and 4a, exhibited antifungal activity against Candida albicans with IC(50) values ranging from 5.9 to 8.8 microg/mL, and they selectively inhibited the enzyme cyclooxygenase-2 (COX-2).

Antiviral and antiplasmodial spirodihydrobenzofuran terpenes from the fungus Stachybotrys nephrospora.

Two known spirodihydrobenzofuran terpenes (1 and 2) were isolated from a mycelium extract of the fungus Stachybotrys nephrospora BCC 3900. Compound 1 (Mer-NF5003F or stachybotrydial) exhibited potent antiviral activity (the IC50 value of 4.32 microg/mL) comparable to the standard drug, acyclovir, while compound 2 was inactive against the HSV-1 virus. Both 1 and 2 possessed antiplasmodial activity (IC50 values of 0.85 and 0.15 microg/mL for 1 and 2, respectively), and were not toxic towards the Vero cell line. A regiospecific conversion of the dialdehyde 1 to the lactone 2 proceeded simply under acidic conditions.