ortho-Alkylation of Pyridine N-Oxides with Alkynes by Photocatalysis: Pyridine N-Oxide as a Redox Auxiliary.

A photocatalyzed ortho-alkylation of pyridine N-oxide with ynamides and arylacetylenes has been developed, which yields a series of α-(2-pyridinyl) benzyl amides/ketones. Mechanistic studies, including electrochemical studies, radical-trapping experiments, and Stern-Volmer fluorescence quenching studies demonstrate that pyridine N-oxide serves as both a redox auxiliary and radical acceptor to achieve the mild photocatalytic single-electron oxidation of carbon-carbon triple bonds with the generation of a cationic vinyl radical intermediate.

Towards the Complete Synthetic O-Antigen of Vibrio cholerae O1, Serotype Inaba: Improved Synthesis of the Conjugation-ready Upstream Terminal Hexasaccharide Determinant.

Synthesis of the upstream terminal hexasaccharide part of the lipopolysaccharides (LPS) of Vibrio cholerae O1, serotype Inaba has been improved. The key improvements include but are not limited to optimized conditions for the stereoselectivity of glycosylation reactions involved and fewer number of synthetic steps, compared to previous approaches. Particularly noteworthy is conducting the glycosylation of the very reactive glycosyl acceptor 8-azido-3,6-dioxaoctanol with the fully assembled hexasaccharide trichloroacetimidate under thermodynamic control. It produced the desired α glycoside with an α:ß ratio of 7:1, compared with the ratio of 1.1:1, observed when the coupling was conducted conventionally. Several substances, which were previously obtained in purity acceptable only for synthetic intermediates, were now obtained in the analytically pure state and were fully characterized. The structure of the key trisaccharide glycosyl acceptor was confirmed by single-crystal x-ray structure determination.

Synthesis and molecular structure of the 5-methoxycarbonylpentyl α-glycoside of the upstream, terminal moiety of the O-specific polysaccharide of Vibrio cholerae O1, serotype Inaba.

The trimethylsilyl trifluoromethanesulfonate (TMSOTf)-catalyzed reaction of methyl 6-hydroxyhexanoate with 3-O-benzyl-4-(2,4-di-O-acetyl-3-deoxy-L-glycero-tetronamido)-4,6-dideoxy-2-O-levulinoyl-α-d-mannopyranosyl trichloroacetimidate followed by a two-step deprotection (hydrogenolysis over Pd/C catalyst and Zemplén deacylation, to simultaneously remove the acetyl and levulinoyl groups) gave 5-(methoxycarbonyl)pentyl 4-(3-deoxy-L-glycero-tetronamido)-4,6-dideoxy-α-D-mannopyranoside. The structure of the latter, for which crystals were obtained in the analytically pure state for the first time, followed from its NMR and high-resolution mass spectra and was confirmed by X-ray crystallography. The molecule has two approximately linear components; a line through the aglycon intersects a line through the mannosyl and tetronylamido groups at 120°. The crystal packing separates the aglycon groups from the tetronylamido and mannosyl groups, with only C-H...O hydrogen bonding among the aglycon groups and N-H...O, O-H...O and C-H...O links among the tetronylamido and mannosyl groups. A carbonyl oxygen atom accepts the strongest O-H...O hydrogen bond and two strong C-H...O hydrogen bonds. The geometric properties were compared with those of related molecules.

3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters.

A series of 3-aryl-3-arylmethoxy-azetidines were synthesized and evaluated for binding affinities at dopamine and serotonin transporters. The 3-aryl-3-arylmethoxyazetidines were generally SERT selective with the dichloro substituted congener 7c (Ki=1.0 nM) and the tetrachloro substituted derivative 7i (Ki=1.3 nM) possessing low nanomolar affinity for the SERT. The 3-(3,4-dichlorophenyl-3-phenylmethoxyazetidine (7g) exhibited moderate affinity at both DAT and SERT transporters and suggests that substitution of the aryl rings can be used to tune the mononamine transporter affinity.

Di(phenylpropylamino)gossypol: a derivative of the dimeric natural product gossypol.

Di(phenylpropylamino)gossypol [systematic name: 2,2'-bis{1,6-dihydroxy-5-isopropyl-8-[(3-phenylpropylamino)methylidene]naphthalen-7-one}, C48H52N2O6, was formed by reaction of the dimeric natural product gossypol with 3-phenylpropylamine. The structure of this compound has its two naphthalene ring systems oriented approximately perpendicular to each other, and the two pendant phenylpropyl groups have different conformations. One of these side groups is considerably disordered at room temperature but less so at 120 K. The enantiomeric molecules form centrosymmetric dimers that are supported by intermolecular hydrogen bonds and by hydrophobic interactions between a pair of naphthalene rings. Two additional hydrogen bonds tie the dimer pairs into layers. Unlike gossypol and many gossypol Schiff base derivatives, the title compound crystallizes without the inclusion of solvent, which appears to occur because of the size and flexibility of its phenylpropyl pendent groups.

Synthesis and antifungal activity of functionalized 2,3-spirostane isomers.

Invasive fungal infections are a major complication for individuals with compromised immune systems. One of the most significant challenges in the treatment of invasive fungal infections is the increased resistance of many organisms to widely used antifungals, making the development of novel antifungal agents essential. Many naturally occurring products have been found to be effective antimicrobial agents. In particular, saponins with spirostane glycosidic moieties-isolated from plant or marine species-have been shown to possess a range of antimicrobial properties. In this report, we outline a novel approach to the synthesis of a number of functionalized spirostane molecules that can be further used as building blocks for novel spirostane-linked glycosides and present results from the in vitro screenings of the antifungal potential of each derivative against four fungal species, including Candida albicans, Cryptococcus neoformans, Candida glabrata, and the filamentous fungus Aspergillus fumigatus.

6,6'-Dimethoxygossypolone.

6,6'-Dimethoxygossypolone (systematic name: 7,7'-dihydroxy-5,5'-diisopropyl-6,6'-dimethoxy-3,3'-dimethyl-1,1',4,4'-tetraoxo-2,2'-binaphthalene-8,8'-dicarbaldehyde), C(32)H(30)O(10), is a dimeric molecule formed by oxidation of 6,6'-dimethoxygossypol. When crystallized from acetone, 6,6'-dimethoxygossypolone has monoclinic (P2(1)/c) symmetry, and there are two molecules within the asymmetric unit. Of the four independent quinoid rings, three display flattened boat conformations and one displays a flattened chair/half-chair conformation. The angles between the planes of the two bridged naphthoquinone structures are fairly acute, with values of about 68 and 69°. The structure has several intramolecular O-H...O and C-H...O hydrogen bonds and several weak intermolecular C-H...O hydrogen bonds, but no intermolecular O-H...O hydrogen bonds.

[(NHC)CuX] complexes: synthesis, characterization and catalytic activities in reduction reactions and Click chemistry. On the advantage of using well-defined catalytic systems.

The preparation of three series of [(NHC)CuX] complexes (NHC = N-heterocyclic carbene, X = Cl, Br, or I) is reported. These syntheses are high yielding and only use readily available starting materials. The prepared complexes were spectroscopically and structurally characterized. Notably, two of them present a bridging NHC ligand between two copper centers in the solid state, an extremely rare coordination mode for these ligands. These complexes were then applied to two distinct organic reactions: the hydrosilylation of ketones and the 1,3-dipolar cycloaddition of azides and alkynes. In both transformations, outstanding catalytic systems were found for preparing the corresponding products in excellent yields and short reaction times. Most remarkably, the screening of well-defined systems in the hydrosilylation reaction allowed for the identification of a pre-catalyst previously overlooked since, originally, catalytic species were in situ generated. Under such conditions, major formation of [(NHC)(2)Cu](+) species, inactive in this reduction reaction, occurred instead of the expected copper hydride. These results highlight one of the most important advantages of employing well-defined complexes in catalysis: gaining an improved control of the nature of the catalytically relevant species in the reaction media.

Ethynyl and Propynylpyrene Inhibitors of Cytochrome P450.

The single-crystal X-ray structures and in vivo activities of three aryl acetylenic inhibitors of cytochromes P450 1A1, 1A2, 2A6, and 2B1 have been determined and are reported herein. These are 1-ethynylpyrene, 1-propy-nylpyrene, and 4-propynylpyrene. To investigate electronic influences on the mechanism of enzyme inhibition, the experimental electron density distribution of 1-ethynylpy-rene has been determined using low-temperature X-ray diffraction measurements, and the resulting net atomic charges compared with various theoretical calculations. A total of 82,390 reflections were measured with Mo Kα radiation to a (sinθ/λ)(max) = 0.985 Å(-1). Averaging symmetry equivalent reflections yielded 8,889 unique reflections. A least squares refinement procedure was used in which multipole parameters were added to describe the distortions of the atomic electron distributions from spherical symmetry. A map of the model electron density distribution of 1-ethynylpyrene was obtained. Net atomic charges calculated from refined monopole population parameters yielded charges that showed that the terminal acetylenic carbon atom (C18) is more negative than the internal carbon (C17). Net atomic charges calculated by ab initio, density functional theory, and semi-empirical methods are consistent with this trend suggesting that the terminal acetylenic carbon atom is more likely to be the site of oxidation. This is consistent with the inhibition mechanism pathway that results in the formation of a reactive ketene intermediate. This is also consistent with assay results that determined that 1-ethynylpyrene acts as a mechanism-based inhibitor of P450s 1A1 and 1A2 and as a reversible inhibitor of P450 2B1. Crystallographic data: 1-ethynylpyrene, C(18)H(10), P2(1)/c, a = 14.571(2) Å, b = 3.9094(5) Å, c = 20.242(3) Å, ß = 105.042(2)°, V = 1,113.5(2) Å(3); 1-propynylpyrene, C(19)H(12), P2(1)/n, a = 8.970(2) Å, b = 10.136(1) Å, c = 14.080(3) Å, ß = 99.77(2)°, V = 1,261.5(4) Å(3); 4-propynylpyrene, C(19)H(12), Pbca, a = 9.904(1) Å, b = 13.174(2) Å, c = 19.401(1) Å, V = 2,531.4(5) Å(3).

Experimental and theoretical electron density distribution of alpha,alpha-trehalose dihydrate.

alpha,alpha-Trehalose is of interest because of its cryoprotective and antidessicant properties, and because it possesses various technical anomalies such as (13)C NMR spectra that give misleading indications of intramolecular structural symmetry. It is a non-reducing disaccharide, with the glycosidic oxygen atom shared by the anomeric carbon atoms of the two glucose rings, and is therefore subject to a proposed 'overlapping'exo-anomeric effect. We report here a study of the electron density of trehalose with X-ray diffraction and quantum mechanics calculations, similar to a recent study of sucrose, also a non-reducing molecule. In particular we studied the electron density around the glycosidic linkage and the hydrogen bonding with both deformation density and Atoms in Molecules (AIM) analyses. A total of 129,952 single crystal X-ray intensity measurements were collected on alpha,alpha-trehalose dihydrate to a resolution of sintheta/lambda=1.18A(-1) at 100K and refined with an aspherical multipole model to a final agreement factor of R(1)=0.0160. Wavefunctions were calculated at three levels of theory. Redistribution of electron density due to anomeric effects was reduced in trehalose, compared to sucrose. Five new C-Hcdots, three dots, centeredO hydrogen bonds were confirmed with bond critical points and bond paths from AIM analyses, as were the previously proposed O-Hcdots, three dots, centeredO hydrogen bonds.

Modified [(IPr)Pd(R-acac)Cl] complexes: influence of the acac substitution on the catalytic activity in aryl amination.

The synthesis of a series of [(IPr)Pd(R-acac)Cl] precatalysts (acac=acetylacetonato; IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), where the acac ligand on palladium has been systematically modified through terminal substitution, is reported. The following substituted acac ligands are employed in this study: dibenzoylmethanato (dbm), benzoylacetonato (bac), tetramethylheptanedionato (tmhd), and hexafluoroacetylacetonato (hfac). Full spectroscopic characterization of the new complexes is provided along with X-ray studies for three of these. Investigation of their catalytic activity in cross-coupling is also presented through a comparative study in an aryl amination reaction. The catalytic results show a strong correlation between the increased steric bulk of the acac substituents and an increased activation rate of the precatalyst, going from the acac to the tmhd ligand. This observation, along with the inertness of the hfac compound, seems to support our previous proposal for the activation mechanism of these complexes under cross-coupling conditions.

Unusual reactivities of N-heterocyclic carbenes upon coordination to the platinum(II)-dimethyl moiety.

Unsaturated NHCs of varying steric bulk undergo a series of unusual oxidative addition and reductive elimination processes upon binding to the Pt(Me)(2) fragment.

Synthesis and monoamine transporter affinity of 3alpha-arylmethoxy-3beta-arylnortropanes.

A series of 3-arylnortrop-2-enes and 3alpha-arylmethoxy-3beta-arylnortropanes were synthesized and evaluated for binding affinity at monoamine transporters. The 3-(3,4-dichlorophenyl)nortrop-2-ene (6e) exhibited high affinity for the SERT (K(i)=0.3 nM). The 3alpha-arylmethoxy-3beta-arylnortropanes were generally SERT selective with the 3alpha-(3.4-dichlorophenylmethoxy)-3betaphenylnortrop-2-ene (7c) possessing subnanomolar potency (K(i)=0.061 nM). However, 3alpha-(3,4-dichlorophenylmethoxy)-3beta-phenylnortrop-2-ene (7b) exhibited high affinity at all three transporters [(DAT K(i)=22 nM), (SERT K(i)=6 nM) and (NET K(i)=101 nM)].

Synthesis and structural analysis of a series of D-glucose derivatives as low molecular weight gelators.

Low molecular weight gelators are an interesting new type of compounds that are important in supramolecular chemistry and advanced materials. Previously, we had synthesized several acyl derivatives of methyl 4,6-O-benzylidene-alpha-D-glucopyranoside and found that a number of terminal acetylene-containing esters are good gelators. To understand the structure requirement of the acyl chains, we synthesized a series of analogs containing different functional groups including aryl, alkenyl, and halogen derivatives. X-ray crystal structures of a monoester and a diester derivative were also obtained to help understand the relationship between structure and gelation. For good gelation properties, the carboxyl derivatives should possess alkyl groups containing a terminal acetylene group and aryl derivatives.

Synthesis and CB1 cannabinoid receptor affinity of 4-alkoxycarbonyl-1,5-diaryl-1,2,3-triazoles.

A series of 4-alkoxycarbonyl-1,5-diaryl-1,2,3-triazoles were synthesized regioselectively using click chemistry and evaluated at CB1 cannabinoid receptors. The n-propyl ester 11 (K(i)=4.6 nM) and phenyl ester 14 (K(i)=11 nM) exhibited the most potent affinity of the series.

N-(4-Hydroxy-phen-yl)-2-(1,1,3-trioxo-2,3-di-hydro-1,2-benzothia-zol-2-yl)-acet-amide.

In the title compound, C(15)H(12)N(2)O(5)S, the benzisothia-zole group is approximately planar (r.m.s. deviation excluding H atoms and the two O atoms bonded to S = 0.023 Å). The dihedral angle between the benzisothia-zole ring and the terminal phenol ring is 84.9 (1)°. In the crystal, mol-ecules are joined by N-H⋯O and O-H⋯O hydrogen bonds, and π-stacking inter-actions are observed between alternating phenol and benzisothia-zole rings [centroid-centroid distances = 3.929 (3) and 3.943 (3) Å].

A [(NHC)CuCl] complex as a latent Click catalyst.

A latent catalyst for the [3+2] cycloaddition reaction of azides and alkynes has been developed in accordance with the principles of Click chemistry.

Synthesis and characterization of [Cu(NHC)2]X complexes: catalytic and mechanistic studies of hydrosilylation reactions.

The preparation of two series of [Cu(NHC)2]X complexes (NHC=N-heterocyclic carbene, X=PF6 or BF4) in high yields from readily available materials is reported. These complexes have been spectroscopically and structurally characterized. The activity of these cationic bis-NHC complexes in the hydrosilylation of ketones was examined, and both the ligand and the counterion showed a significant influence on the catalytic performance. Moreover, when compared with related [Cu(NHC)]-based systems, these cationic complexes proved to be more efficient under similar reaction conditions. The activation step of [Cu(NHC)2]X precatalysts towards hydrosilylation was investigated by means of 1H NMR spectroscopy. Notably, it was shown that one of the N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) ligands in [Cu(IPr)2]BF4 is displaced by tBuO(-) in the presence of NaOtBu, producing the neutral [Cu(IPr)(OtBu)]. This copper alkoxide is known to be a direct precursor of an NHC-copper hydride, the actual active species in this transformation. Furthermore, reagent loading and counterion effects have been rationalized in light of the species formed during the reaction.

Octa-O-propanoyl-beta-maltose: crystal structure, acyl stacking, related structures, and conformational analysis.

The crystal structure of beta-maltose octapropanoate (1) was solved to improve understanding of di-, oligo-, and polysaccharide conformations. The O6 and O6' atoms are in gg and gt orientations, respectively. Extrapolation of the coordinates of the non-reducing residue and observed linkage bond and torsion angles of 1 [Formula: see text] yields a left-handed helix similar to amylose triacetate I. The phi and psi values of 1 are also similar to those of other crystalline, acylated maltose compounds as well as some hydroxyl-bearing molecules. Acylated maltose moieties are often stabilized by stacking of the carbonyl groups and alpha-carbons on O3 and O2' as well as by the exo-anomeric effect. The conformation of 1 is within the 1-kcal/mol contour on a hybrid energy map built with a dielectric constant of 7.5, but corresponds to higher energies on maps made with lower dielectric constants. In one region of phi,psi space, both hydroxyl-bearing and derivatized maltose moieties are found but no inter-residue, intramolecular hydrogen-bonding occurs. In another region, only hydroxyl-bearing molecules crystallize and O2'...O3 hydrogen bonds are always found. In agreement with the energy surfaces, amylose helices extrapolated from available linkage geometries were almost all left-handed.

Synthesis, isolation and characterization of cationic gold(I) N-heterocyclic carbene (NHC) complexes.

A number of cationic gold(I) complexes have been synthesized and found to be stabilized by the use of N-heterocyclic carbene ligands. These species are often employed as in situ-generated reactive intermediates in gold catalyzed organic transformations. An isolated, well-defined species was tested in gold-mediated carbene transfer reactions from ethyl diazoacetate.