Combined bead polymerization and Cinchona organocatalyst immobilization by thiol-ene addition.

In this work, we report an unusually concise immobilization of Cinchona organocatalysts using thiol-ene chemistry, in which catalyst immobilization and bead polymerization is combined in a single step. A solution of azo initiator, polyfunctional thiol, polyfunctional alkene and an unmodified Cinchona-derived organocatalyst in a solvent is suspended in water and copolymerized on heating by thiol-ene additions. The resultant spherical and gel-type polymer beads have been evaluated as organocatalysts in catalytic asymmetric transformations.

Halodiazophosphonates, a new class of diazo compounds for the diastereoselective intermolecular Rh(II) catalyzed cyclopropanation.

(Halodiazomethyl)phosphonates 2A-C have been generated by a one-pot procedure via a clean, efficient, and rapid deprotonation/electrophilic halogenation sequence from diethyl diazomethylphosphonate 1 (EDP). Subsequent intermolecular Rh(II)-catalyzed cyclopropanation afforded the corresponding halocyclopropylphosphonates 3-10 in moderate to high yields and high diastereomeric ratios. Catalyst loadings down to 0.

2-Diazo-1-(1,1-dioxothio-morpholin-4-yl)ethanone.

In the mol-ecule of the title compound, C(6)H(9)N(3)O(3)S, at 105 K, the six-membered ring is predominantly found in the chair conformation, with 1.89 (14)% in the boat conformation. In the crystal structure, there are five inter-molecular C-H⋯O=C and C-H⋯O=S contacts less than 2.

1,1'-(4,4'-Bipiperidine-1,1'-di-yl)bis-(2,2,2-trifluoro-ethanone).

The title compound, C(14)H(18)F(6)N(2)O(2), has a central center of symmetry with both piperidine rings occurring in regular chair conformations. Even though the structure is fairly compact with no sizable voids, the shortest H⋯O distance is as long as 2.58 Å.

Identification of a new series of non-peptidic NK3 receptor antagonists.

The identification and structure-activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxamides as novel NK(3) receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK(3) receptor and brain exposure, leading to activity in vivo in the senktide-induced hypoactivity model in gerbils.

Computational study of cyclopropanation reactions with halodiazoacetates.

The mechanism of rhodium(II)-catalyzed cyclopropanation reactions with ethyl bromo-, chloro-, and iododiazoacetate has been studied with density functional theory calculations. The halodiazoacetates were shown to be remarkably kinetically active compared to ethyl diazoacetate, as demonstrated experimentally in a study of reaction rates and supported by the calculated low potential energy barriers for the rate-determining loss of dinitrogen. In the rhodium carbenoids formed from the halodiazoacetates, pi-interactions between the halogen, the carbenoid carbon, and one rhodium atom were found.

A general approach for preparation of polymer-supported chiral organocatalysts via acrylic copolymerization.

Polymer-supported chiral organocatalysts, as well as most other forms of immobilized catalysts, are traditionally prepared by a postmodification approach where modified catalyst precursors are anchored onto prefabricated polymer beads. Herein, we report an alternative and more scalable approach where polymer-supported chiral enamine and iminium organocatalysts are prepared in a bottom-up fashion where methacrylic functional monomers are prepared in an entirely nonchromatographic manner and subsequently copolymerized with suitable comonomers to give cross-linked polymer beads. All syntheses have been conducted on multigram scale for all intermediates and finished polymer products, and the catalysts have proven successful in reactions taking place in solvents spanning a wide range of solvent polarity.

tert-Butyl 4-(2-diazo-acet-yl)piperazine-1-carboxyl-ate.

The title crystal structure, C(11)H(18)N(4)O(3), is the first diazo-acetamide in which the diazo-acetyl group is attached to an N atom. The piperazine ring is in a chair form and hence the mol-ecule has an extended conformation. Both ring N atoms are bonded in an essentially planar configuration with the sum of the C-N-C angles being 359.

Synthesis of acrylic polymer beads for solid-supported proline-derived organocatalysts.

A completely non-chromatographic and highly large-scale adaptable synthesis of acrylic polymer beads containing proline and prolineamides has been developed. Novel monomeric proline (meth)acrylates are prepared from hydroxyproline in only one step. Free-radical copolymerization then gives solid-supported proline organocatalysts directly in as little as two steps overall, without using any prefabricated solid supports, by using either droplet or dispersion polymerization.

(1S,5R)-1-(3,4-Dichloro-phen-yl)-3-oxa-bicyclo-[3.1.0]hexan-2-one.

The absolute structure has been determined by X-ray analysis for the title compound, C(11)H(8)Cl(2)O(2). The five-membered ring of the mol-ecule is best described as a flattened envelope conformation with the methyl-ene C atom located 0.208 (2) Å below the plane formed by the other four atoms.

(1S,5R)-1-(4-Fluoro-phen-yl)-3-azonia-bicyclo-[3.1.0]hexane chloride.

The absolute structure of the title compound, C(11)H(13)FN(+)·Cl(-), has been determined. The five-membered ring has an envelope conformation with the N atom at the flap position. In the crystal structure, the Cl(-) anion links with the organic cation via N-H⋯Cl hydrogen bonding.

Highly efficient formation of halodiazoacetates and their use in stereoselective synthesis of halocyclopropanes.

Halogenated analogues of ethyl diazoacetate are synthesised by a novel and highly efficient procedure and give halocyclopropanes in good to excellent yields when exposed to a Rh(ii) catalyst in the presence of alkenes.

(2SR,3RS)-Benz-yl[4-chloro-1-(4-chloro-phen-yl)-1-methoxy-carbon-yl-2-but-yl]-ammonium chloride.

In the racemic hydro-chloride salt of the title ester, C(19)H(22)Cl(2)NO(2) (+)·Cl(-), the penta-noic acid chain shows a mixture of trans and gauche orientations to give an overall helical conformation. The dihedral angle between the two aromatic rings is 26.11 (10)°.

Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters.

A series of Milnacipran analogs with variation in the aromatic moiety were prepared in high enantiomeric excess. Structure-activity relationships for two parallel enantiomeric series are described. The (-)-(1R,2S)-naphthyl analog (8h) showed the highest potency in the two series and is a triple reuptake inhibitor of the SERT, NET, and DAT.

Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites.

The rhodium(II)-catalyzed intermolecular C-H insertion of methyl aryldiazoacetates with either N-Boc-piperidine or N-Boc-pyrrolidine followed by deprotection with trifluoroacetic acid is a very direct method for the synthesis of methylphenidate analogues. By using either dirhodium tetraacetate or dirhodium tetraprolinate derivatives as catalyst, either the racemic or enantioenriched methylphenidate analogues can be prepared. The binding affinities of the methylphenidate analogues to both the dopamine and the serotonin transporters are described.

Formation of optically active chromanes by catalytic asymmetric tandem oxa-Michael addition-Friedel-Crafts alkylation reactions.

A novel tandem reaction involving an oxa-Michael addition, followed by a Friedel-Crafts alkylation has been developed. This catalytic tandem reaction, which provides facile and efficient access to optically active functionalised chromanes, proceeds under the influence of bisoxazoline-based catalysts to give diastereomerically pure products in enantioselectivities up to 81% and excellent yields. The optimisation studies, the scope of the reaction, and a model that on the basis of PM3 calculations predicts the outcome of the reaction will be detailed.

New strategic reactions for organic synthesis: catalytic asymmetric C-H activation alpha to nitrogen as a surrogate for the mannich reaction.

The asymmetric C-H activation reactions of methyl aryldiazoacetates are readily induced by the rhodium prolinate catalyst Rh(2)(S-DOSP)(4) (1) or the bridged prolinate catalysts Rh(2)(S-biDOSP)(2) (2a) and Rh(2)(S-biTISP)(2) (2b). The C-H activation of N-Boc-protected cyclic amines demonstrates that the donor/acceptor-substituted carbenoids display remarkable chemoselectivity, which allows for highly regioselective, diastereoselective, and enantioselective reactions to be achieved. Furthermore, the reactions can display high levels of double stereodifferentiation and kinetic resolution.