Synthesis of 12ß-Methyl-18-nor-bile Acids.

Decoupling the roles of the farnesoid X nuclear receptor and Takeda G-protein-coupled bile acid receptor 5 is essential for the development of novel bile acid therapeutics targeting metabolic and neurodegenerative diseases. Herein, we describe the synthesis of 12ß-methyl-18-nor-bile acids which may serve as probes in the search for new bile acid analogues with clinical applicability. A Nametkin-type rearrangement was applied to protected cholic acid derivatives, giving rise to tetra-substituted Δ13,14- and Δ13,17-unsaturated 12ß-methyl-18-nor-bile acid intermediates (24a and 25a). Subsequent catalytic hydrogenation and deprotection yielded 12ß-methyl-18-nor-chenodeoxycholic acid (27a) and its 17-epi-epimer (28a) as the two major reaction products. Optimization of the synthetic sequence enabled a chromatography-free route to prepare these bile acids at a multi-gram scale. In addition, the first cis-C-D ring-junctured bile acid and a new 14(13 → 12)-abeo-bile acid are described. Furthermore, deuteration experiments were performed to provide mechanistic insights into the formation of the formal anti-hydrogenation product 12ß-methyl-18-nor-chenodeoxycholic acid (27a).

Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds.

In this study, we report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of the adenosine triphosphate (ATP) binding site driven by structure-based drug design. For an upscale compatible multigram synthesis of the functionalized pyrrolidine scaffolds, we used a chiral pool synthetic route starting from methionine. Biological evaluation of key compounds in kinase and cellular assays revealed significant effects of the scaffolds towards activity and selectivity, however, the absolute configuration of the chiral moieties only exhibited a limited effect on inhibitory activity. X-ray crystallographic analysis of ligand-CK1δ complexes confirmed the expected binding mode of the 3,4-diaryl-isoxazole inhibitors. Surprisingly, the original compounds underwent spontaneous Pictet-Spengler cyclization with traces of formaldehyde during the co-crystallization process to form highly potent new ligands. Our data suggests chiral "ribose-like" pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds.

N-(2-Acetamido-2-de-oxy-ß-d-gluco-pyranos-yl)-N-(3-azido-prop-yl)-O-methyl-hydroxyl-amine.

The structure of the title compound, C12H23N5O6, solved using adequate data from a thin crystal plate, confirmed that this useful glycoconjugate was obtained in the ring-closed ß-pyran-ose configuration with (4) C 1 conformation. The mol-ecules are bound by O-H⋯O(OH) hydrogen bonds, notably in a zigzag C(2) chain along the short b (screw) axis, supplemented with an R 2 (2)(12) O-H⋯O(carbon-yl) link along the a axis and other C(2) links. The absolute configuration was not unambiguously determined but was known from the synthetic chemistry, which used natural 2-acetamido-2-de-oxy-d-glucose as the starting material.

Total synthesis of Lewis(X) using a late-stage crystalline intermediate.

Herein, we report on a highly efficient synthesis of a crystalline protected Lewis(X) trisaccharide that was converted to Lewis(X) following global deprotection. The trisaccharide was prepared in a highly convergent synthesis (seven steps, longest linear sequence) and in a 38% overall yield using a strategy that involved the regioselective glycosylation of a GlcNAc acceptor with a galactose thioglycoside donor, followed by fucosylation of the remaining free GlcNAc hydroxyl as key steps. The core trisaccharide also has the potential to be converted to other members of the Type-2 Lewis family of antigens due to the orthogonal nature of the protecting groups employed.

Crystal packing in three related disaccharides: precursors to heparan sulfate oligosaccharides.

The three title compounds form part of a set of important precursor dissacharides which lead to novel therapeutics, in particular for Alzheimer's disease. All three crystallize as poorly diffracting crystals with one independent mol-ecule in the asymmetric unit. Two of them are isostructural: 4-meth-oxy-phenyl 4-O-[6-O-acetyl-2-azido-3-O-benzyl-2-de-oxy-4-O-(9-fluor-en-yl-methyl-oxycarbon-yl)-α-d-gluco-pyranos-yl]-2-O-benzoyl-3-O-benzyl-6-O-chloro-acetyl-α-l-ido-pyran-oside, C59H56ClN3O16, (I), the ido-relative of a reported gluco-disaccharide [Gainsford et al., 2013 ▶). Acta Cryst. C69, 679-682] and 4-meth-oxy-phenyl 4-O-[6-O-acetyl-2-azido-3-O-benzyl-2-de-oxy-4-O-(9-fluorenyl-methyl-oxycarbon-yl)-α-d-gluco-pyranos-yl]-2-O-benzoyl-3-O-benzyl-6-O-meth-oxy-acetyl-α-l-ido-pyran-oside, C60H59N3O17, (II). Both exhibit similar conformational disorder of pendant groups. The third compound 4-meth-oxy-phenyl 4-O-[6-O-acetyl-2-azido-3,4-di-O-benzyl-2-de-oxy-α-d-gluco-pyranos-yl]-2-O-benzoyl-3-O-benzyl-6-O-meth-oxy-oacetyl-ß-d-gluco-pyran-oside, C52H55N3O15, (III), illustrates that a slightly larger set of weak inter-molecular inter-actions can result in a less disordered mol-ecular arrangement. The mol-ecules are bound by weak C-H⋯O(ether) hydrogen bonds in (I) and (II), augmented by C-H⋯π inter-actions in (III). The absolute configurations were determined, although at varying levels of significance from the limited observed data.

2-{2-[5-(4-Cyano-5-di-cyano-methyl-idene-2,2-dimethyl-2,5-di-hydro-furan-3-yl)penta-2,4-dienyl-idene]-3,3-dimethyl-2,3-di-hydro-1H-indol-1-yl}ethyl 3,5-bis-(benz-yloxy)benzoate.

In the title mol-ecule, C48H42N4O5, a potential non-linear optical compound, the furan ring [r.m.s. deviation = 0.010 (1) Å] and the indolyl-idene ring system [r.m.s. deviation = 0.013 (2) Å] are inclined to one another by 18.52 (6)°. This is similar to the arrangement [16.51 (18)°] found for the N-hy-droxy-ethyl adduct of the title compound [Bhuiyan et al. (2011 ▶). Mol. Cryst. Liq. Cryst. 548, 1-12]. Replacing the hy-droxy-ethyl group with 3,5-di-benzyl-oxybenzoate has not resulted in a non-centrosymmetric lattice arrangement or significant changes to the basic mol-ecular structure. In the crystal, mol-ecules are linked via pairs of C-H⋯N hydrogen bonds, forming inversion dimers with an R (2) 2(20) ring motif. The dimers are linked via C-H⋯O hydrogen bonds, forming C(17) chains along [010]. The chains are linked by further C-H⋯N hydrogen bonds, forming layers parallel to (001) and enclosing R 2 (2)(44) ring motifs. There are also C-H⋯π inter-actions present, stabilizing the inter-layer orientation of the pendant bis-(benz-yloxy)benzo-yloxy group.

2-(3-Cyano-4-{3-[1-(2-hy-droxy-eth-yl)-3,3-dimethyl-1,3-di-hydro-indol-2-yl-idene]prop-2-en-yl}-5,5-dimethyl-5H-furan-2-yl-idene)malono-nitrile.

The title compound, C25H24N4O2, adopts a cisoid configuration and has twofold orientational disorder of the 2-hy-droxy-ethyl group. The mol-ecule is twisted from planarity so that the dihedral angle between the terminating indol-2-yl-idene and the furan-2-yl-idene moiety mean planes is 12.75 (7)°. Conformational disorder occurs at the indol-2-yl-idene N atom, which results in two orientations for the hy-droxy-ethyl group [occupancy ratio = 0.896 (2):0.104 (2)], and the hy-droxy O atom of the 2-hy-droxy-ethyl group is located over three sites [occupancy ratio = 0.548 (2):0.348 (2):0.104 (2)]. An intra-molecular C-H⋯O hydrogen bond involving the lowest occupancy hy-droxy O atom is observed. In the crystal, the mol-ecules pack in parallel dimeric sheets about centres of symmetry, utilizing O-H⋯N(cyano), C-H⋯N(cyano) and O-H⋯O hydrogen bonds, in two sets parallel to (02-1) and (021) planes.

1-(2,3-Di-hydroxy-prop-yl)-4-{2-[4-(di-methyl-amino)-phen-yl]vin-yl}pyridinium chloride.

The title compound, C18H23N2O2 (+)·Cl(-), crystallizes with two independent cations and anions per cell. Each cation has twofold rotational disorder about the linking vinyl groups but with unequal occupancies [0.963 (5):0.037 (5) and 0.860 (8):0.140 (8)]. The two independent cations are close to being related by an inversion centre but the data does not support the expected centrosymmetric space-group assignment. The conclusion is that the differing rotational disorder has lead to an overall non-centrosymmetric lattice. In the crystal, the mol-ecules pack in layers parallel to (133) and (-13-3), chain-linked with motif C (1) 2(7) by the di-hydroxy-propyl O-H⋯Cl⋯H-O hydrogen bonds. Other lattice binding is provided by O-H⋯Cl, C-H⋯Cl and C-H⋯N inter-actions.

1-(4-{[(1,3,3-Tri-methyl-indolin-2-yl-idene)meth-yl]diazen-yl}phen-yl)ethanone.

The title compound, C20H21N3O, has crystallographic mirror symmetry with all non-H atoms apart from the methyl C atom of the CMe2 group lying on the mirror plane. Mol-ecules are linked into planar sheets parallel to (010) by phen-yl-azo C-H⋯N and phen-yl-ethanone C-H⋯O inter-actions. Methyl C-H⋯π inter-actions provide crosslinking between the planes.

4-Methyl-5-(4-nitro-benzyl-idene)-2-oxo-2,5-di-hydro-1H-pyrrole-3-carbo-nitrile.

Mol-ecules of the potential non-linear optical title compound, C13H9N3O3, form dimeric stacks of mol-ecules along the a axis cross-linked around inversion centers by N-H⋯O hydrogen bonds and weak (phen-yl)C-H⋯O inter-molecular inter-actions, forming a 'collaboration' of R 2 (2)(8) and R 2 (2)(16) ring motifs. The mol-ecules are then further linked by weak C-H⋯O and C-H⋯N inter-actions into sheets parallel to (121).

Acet-oxy-γ-valerolactone.

Levulinyl cellulose esters have been produced as an effective renewable binder for architectural coatings. The title compound, C7H10O4 (systematic name: 2-methyl-5-oxo-tetra-hydro-furan-2-yl acetate), assigned as the esterifying species, was isolated and crystallized to confirm the structure. In the crystal, the mol-ecules pack in layers parallel to (102) utilizing weak C-H⋯O inter-actions.

Alkyl levulinates as `green chemistry' precursors: butane-1,4-diyl bis(4-oxopentanoate) and hexane-1,6-diyl bis(4-oxopentanoate).

Levulinic acid derivatives are potential `green chemistry' renewably sourced molecules with utility in industrial coatings applications. Suitable single crystals of the centrosymmetric title compounds, C14H22O6 and C16H26O6, respectively, were obtained with difficulty. The data for the latter hexane-1,6-diyl compound were extracted from the major fragment of a three-component twinned crystal. Both compounds crystallize in similar-sized unit cells with identical symmetry, utilizing the same weak nonconventional attractive C-H···O(ketone) hydrogen bonds via C(4) and C(5) motifs, which expand to R(2)(2)(30) ring and C(2)(2)(14) chain motifs. Their different packing orientations in similar-sized unit cells suggest that crystal growth involving packing mixes could lead to intergrowths or twins.

Translationally related nearly identical molecules: 4-methoxyphenyl 4-O-[6-O-acetyl-2-azido-3-O-benzyl-2-deoxy-4-O-(fluoren-9-ylmethoxycarbonyl)-α-D-glucopyranosyl]-2-O-benzoyl-3-O-benzyl-6-O-chloroacetyl-ß-D-glucopyranoside.

The title compound, C59H56ClN3O16, is an important dissacharide precursor to novel therapeutics for the treatment of Alzheimer's disease. It crystallizes with two independent enantiomerically identical molecules in almost exactly the same orientation in the cell, being one half cell-edge apart. Apart from the conformation of a single benzyl group, the molecules are superimposable. They are bound efficiently using complementary C-H···O(carbonyl) hydrogen bonds, principally along the `duplicating' axis. The absolute configurations were determined.

(E)-5-[3-Cyano-2-(dicyano-methyl-ene)-1-oxaspiro-[4.5]dec-3-en-4-yl]-3-(1-methyl-1,4-dihydro-pyridin-4-yl-idene)pent-4-en-1-yl 3,5-bis-(benz-yloxy)benzoate.

In the title compound, C45H40N4O5, the cyclo-hexane entity on the (3-cyano-2,5-dihydro-furan-2-yl-idene)propane-dinitrile group, which replaces the usual dimethyl substituents, has not perturbed the delocalization geometry significantly. Weak inter-molecular inter-actions, viz. C-H⋯N(cyano), C-H⋯O(ether), C-H⋯π and π-π [between the aromatic rings with the shortest centroid-centroid distance of 3.603 (3) Å], consolidate the crystal packing, which exhibits voids of 57 Å(3).

2-[4-(2-{5-tert-Butyl-2-chloro-3-[2-(3-pentyl-1,3-benzothia-zol-2-yl-idene)ethyl-idene]cyclo-hex-1-en-yl}ethen-yl)-3-cyano-5,5-dimethyl-furan-2-yl-idene]malono-nitrile.

In the title mol-ecule, C36H39ClN4OS, the non-aromatic part of the cyclo-hex-1-enyl ring and the attached tert-butyl group are disordered over two conformations with occupancy ratios of 0.52 (3):0.48 (3) and 0.53 (3):0.47 (3), respectively. The polyene chain single- and double-bond dimensions contrast with a closely related compound [Bouit et al. (2007 ▶). Chem. Mater.19, 5325-5335] with an approximate 19° twist between donor and acceptor ends of the mol-ecule, related to the additional intra-molecular C-H⋯S inter-action. In the title compound, the mol-ecules pack into dimeric units about centres of symmetry utilizing weak C-H⋯N(cyano) and C-H⋯O attractive inter-actions, building both chain and ring motifs about the centres [R2(2)(8) and R2(2)(9)]. Adjacent dimeric sets then form a herringbone configuration.

Bis(2-carb-oxy-N-{[1-(2-hy-droxy-eth-yl)-3,3-dimethyl-indolin-2-yl-idene]methyl-imino}-anilinium) sulfate monohydrate.

The asymmetric unit of the title compound, 2C20H22N3O3(+)·SO4(2-)·H2O, contains four cations, two sulfate anions and two lattice water mol-ecules. One of the four cations shows a different conformation of the hy-droxy-ethyl group; the remaining three are all essentially superimposable. Two cations exhibit two-site orientational disorder [ratios = 0.524 (5):0.476 (5) and 0.616 (6):0.384 (6)] of the last two atoms of their hy-droxy-ethyl groups, and one water mol-ecule is disordered over two positions in a 0.634 (13):0.366 (13) ratio. Each imine H atom is intra-molecularly in contact with the adjacent carboxyl O atom, forming an S(6) motif, while all the carb-oxy-lic acid H atoms are hydrogen bonded to O atoms of the sulfate anions. Other notable hydrogen-bond inter-actions involve (methyl-ene, phenyl and imine chain) C-H⋯O (sulfate and carbox-yl) and O-H⋯O(water) contacts, making up a comprehensive three-dimensional network involving D2(2)(n), with n = 4-6 and 15-16, and C2(2)(17) classical hydrogen-bond motifs. The crystal investigated was twinned by pseudomerohedry with a twin component ratio of 0.4745 (12):0.5255 (12).

Synthesis of cyclic pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway.

Cyclic pyranopterin monophosphate (1), isolated from bacterial culture, has previously been shown to be effective in restoring normal function of molybdenum enzymes in molybdenum cofactor (MoCo)-deficient mice and human patients. Described here is a synthesis of 1 hydrobromide (1·HBr) employing in the key step a Viscontini reaction between 2,5,6-triamino-3,4-dihydropyrimidin-4-one dihydrochloride and D-galactose phenylhydrazone to give the pyranopterin (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one (10) and establishing all four stereocenters found in 1. Compound 10, characterized spectroscopically and by X-ray crystallography, was transformed through a selectively protected tri-tert-butoxycarbonylamino intermediate into a highly crystalline tetracyclic phosphate ester (15). The latter underwent a Swern oxidation and then deprotection to give 1·HBr. Synthesized 1·HBr had in vitro efficacy comparable to that of 1 of bacterial origin as demonstrated by its enzymatic conversion into mature MoCo and subsequent reconstitution of MoCo-free human sulfite oxidase-molybdenum domain yielding a fully active enzyme. The described synthesis has the potential for scale up.

2-(Acet-oxy-meth-yl)benzoic acid.

The title compound, C(10)H(10)O(4), crystallizes with the well-known carb-oxy-lic acid dimer-forming R(2) (2)(8) hydrogen-bond motif. Chains approximately parallel to (-1-12) are then built through C(methyl-ene,phen-yl)-H⋯O(carbon-yl) inter-actions [C(6) and C(8) motifs] with one (meth-yl)C-H⋯π inter-action providing inter-planar binding. The weakness of the latter inter-action is consistent with the difficulty experienced in obtaining suitable single crystals.

2-(3-Cyano-4-methyl-5,5-diphenyl-5H-furan-2-yl-idene)malono-nitrile.

The title compound, C21H13N3O, crystallizes with two independent molecules with similar conformations per asymmetric unit. The dihydrofuran rings are essentially planar with maximum deviations of 0.017 (1) and 0.006 (1) Šfor the O atoms. The dihedral angles between the di-hydro-furan ring and the attached phenyl rings are 79.90 (6) and 82.07 (6)° in one mol-ecule and 79.36 (6) and 72.26 (6)° in the other. In the crystal, the molecules are linked by weak C-H⋯π and C-H⋯N inter-actions similar to those in other closely related crystals. The replacement of appended methyl by phenyl groups has not significantly affected the dihydrofuran ring structure or the crystal packing interactions.

2-{3-Cyano-4-[2-(4-diethylamino-2-hy-droxyphenyl)ethenyl]-5,5-dimethyl-2,5-dihydrofuran-2-ylidene}malononitrile acetone 0.25-solvate.

In the title compound, C(22)H(22)N(4)O(2)·0.25C(3)H(6)O, the disordered acetone mol-ecule lies with partial occupancy about the 2 axis. The mol-ecule of the malononitrile derivative is essentially planar excluding the methyl groups, with the largest deviation from the mean plane through the non-H atoms being 0.1955 (13) Å. Two rotamers with different orientations of the benzene ring are observed in the ratio of 0.919 (2):0.081 (2), and as a result the OH group is disordered over two sets of sites. In the crystal, the mol-ecules form ribbons along (101) utilizing a strong O-H⋯N(cyano) hydrogen bond. Inter-leaving of the nearly planar ribbons is provided by the twofold disordered acetone molecule through C-H⋯O inter-actions.