Synthesis of 12β-Methyl-18--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 12β-methyl-18--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 Δ- and Δ-unsaturated 12β-methyl-18--bile acid intermediates ( and ).

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.

N-(2-Acetamido-2-de-oxy-β-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 β-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.

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.

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)°.

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.

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.

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.

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-β-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.

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.

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.

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.

(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.

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.

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).

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.

tert-Butyl (2R,4aR,5aR,11aS,12R,12aR)-8-[bis-(tert-but-oxycarbon-yl)amino]-12-hydroxy-2-meth-oxy-2,10-dioxo-4,4a,5a,6,9,10,11,11a,12,12a-deca-hydro-2H-1,3,5-trioxa-6,7,9,11-tetra-aza-2λ(5)-phosphatetra-cene-6-carboxyl-ate methanol monosolvate monohydrate.

The title compound, C(26)H(40)N(5)O(13)P·CH(3)OH·H(2)O, crystallizes with one water and one methanol mol-ecule providing important crystal-binding inter-actions. The compound has the unusual feature of having two but-oxy-carbonyl groups bound to one N atom. The conventional attractive hydrogen bonds involving hy-droxy, amine and water donors include bifurcations at both donors and acceptors with novel R(1) (2)(6) and R(2) (1)(6) motifs.

(4R,5S)-4-Hy-droxy-meth-yl-5-[(methyl-sulfanyl)-meth-yl]-1,3-oxazolidin-2-one.

The title compound, C(6)H(11)NO(3)S, crystallizes utilizing a three-dimensional set of O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds. The 1,3-oxazolidin-2-one ring adopts an envelope conformation with the C atom bearing the hy-droxy-methyl group as the flap.

1d-1-O-tert-Butyl-diphenyl-silyl-2,3,6-O-tris-(meth-oxy-methyl-ene)-myo-inositol 4,5-bis-(dibenzyl-phosphate).

THE TITLE COMPOUND [SYSTEMATIC NAME: tetra-benzyl (1R,2R,3S,4R,5R,6S)-4-(tert-butyl-diphenyl-sil-yloxy)-3,5,6-tris-(meth-oxy-meth-oxy)cyclo-hexane-1,2-diyl bis-phosphate], C(56)H(68)O(15)P(2)Si, was isolated as an inter-mediate in the preparation of a phosphatidylinositol phosphate for biological studies. In the crystal, the mol-ecules are connected via one methyl-ene C-H⋯π and two weak phen-yl-ether C-H⋯O inter-actions. One benz-yloxy group is disordered over two overlapping positions with an occupancy ratio of 0.

(9H-Fluoren-9-yl)methyl N-{(2R,3R,4S)-4-hy-droxy-2-[(2S,5R)-2-isopropyl-5-methyl-cyclo-hex-yloxy]-5-oxooxolan-3-yl}carbamate propan-2-ol 0.334-solvate.

The title compound, C(29)H(35)NO(6).0.334C(3)H(8)O, a novel chiral N-(fluoren-9-yl-methyl-oxyxcarbon-yl) precursor, crystallizes with two independent carbamate (M) mol-ecules and propan-2-ol solvent mol-ecules in the unit cell.

C-H⋯π packing inter-actions in 2-[5,5-bis-(4-benzyl-oxyphen-yl)-3-cyano-4-methyl-2,5-dihydro-furan-2-yl-idene]malononitrile.

The title mol-ecule, C(35)H(25)N(3)O(3), packs utilizing C-H⋯π attractive inter-actions causing the identical 4-benzyl-oxyphenyl groups to pack with different conformational angles. This difference is consistent with the variable inter-planar dihedral angles found in closely related structures.