Oxazole Moiety Research Articles

Total Synthesis of Phorboxazole A via de Novo Oxazole Formation: Convergent Total Synthesis

The phorboxazoles are mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic products that embody polyketide domains joined via two serine-derived oxazole moieties. Total syntheses of phorboxazole A and analogues have been developed that rely upon the convergent coupling of three fragments via biomimetically inspired de novo oxazole formation. First, the macrolide-containing domain of phorboxazole A was assembled from C3-C17 and C18-C30 building blocks via formation of the C16-C18 oxazole, followed by macrolide ring closure involving an intramolecular Still-Genarri olefination at C2-C3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural product's (2Z)-acrylate with remarkable geometrical selectivity. The C31-C46 side-chain domain was then appended to the macrolide by a second serine amide-derived oxazole assembly. Minimal deprotection then afforded phorboxazole A. This generally effective strategy was then dramatically abbreviated by employing a total synthesis approach wherein both of the natural product's oxazole moieties were installed simultaneously. A key bis-amide precursor to the bis-oxazole was formed in a chemoselective one-pot, bis-amidation sequence without the use of amino or carboxyl protecting groups. Thereafter, both oxazoles were formed from the key C18 and C31 bis-N-(1-hydroxyalkan-2-yl)amide in a simultaneous fashion, involving oxidation-cyclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3-C17 and C18-C30 synthetic fragments. It illustrates the utility of a synthetic design to form a mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic product based upon biomimetic oxazole formation initiated by amide bond formation to join synthetic building blocks.

ChemInform Abstract: Isolation, Structural Elucidation, and Absolute Stereochemistry of Enigmazole A, a Cytotoxic Phosphomacrolide from the Papua New Guinea Marine Sponge Cinachyrella enigmatica.

Enigmazole A (1), a novel phosphate-containing macrolide, was isolated from a Papua New Guinea collection of the marine sponge Cinachyrella enigmatica. The structure of 1, including the absolute stereochemistry at all eight chiral centers, was determined by a combination of spectroscopic analyses and a series of microscale chemical derivatization studies. Compound 1 is comprised of an 18-membered phosphomacrolide that contains an embedded exomethylene-substituted tetrahydropyran ring and an acyclic portion that spans an embedded oxazole moiety. Two additional analogues, 15-O-methylenigmazole A and 13-hydroxy-15-O-methylenigmazole A, were also isolated and assigned. The enigmazoles are the first phosphomacrolides from a marine source and 1 exhibited significant cytotoxicity in the NCI 60-cell line antitumor screen, with a mean GI(50) of 1.7 microM.

Synthesis of morphinans with diversely functionalized benzoxazole moieties

Three independent strategies have been established for the synthesis of morphinans with oxazole moieties derived from the aminophenol function of 2-aminomorphine. All the procedures possess the ability to furnish diversely substituted 2′-oxazole moieties which are considered significant in view of the presented density functional studies on the spatial and electrostatic properties of the proximal functions of the 3-hydroxyl of the morphinan backbone. These data are considered important for neuropharmacological development of potential kappa antagonist morphinans. The second strategy was extended to the direct vinylation of oxazoles to form more complex benzoxazole-type morphinans.

Organic Selenium Compounds, Part IV: Synthesis and Applications of Some New Diaryl Selenides Containing Azomethine and Oxazole Moieties

3,3′-Diacetyloxy (2), 3,3′-dihydroxy (3), 4,4′-diamino (4), and 4-amino (5) diphenylselenide derivatives were prepared as new precursors for the title studies. Compound 6 was obtained by condensation of 4 with an appropriate aromatic aldehyde. Unsymmetrical diphenylselenides 7 and 8 were obtained by condensation of 4 and/or 5 with an aromatic aldehyde. Compound 7 undergoes facile condensation with the same aldehyde present in its arylidene moiety to yield 6, while condensation with another different aromatic aldehyde yielded unsymmetrical 4-arylideneamino diphenylselenide derivative 9. Oxidation of 6, 8, and 9 using lead tetra acetate and/or N-bromosuccinimide yielded symmetrical bis-(2-aryl benzoxazol-6-yl) (10), unsymmetrical 3′-hydroxy, 2-aryl benzoxazol-6-yl selenides (11), and 2-aryl benzoxazol-6-yl, 2′-aryl′ benzoxazol-6′-yl selenide derivatives (12), respectively. Compound 10 was prepared in one-pot unequivocal synthesis by fusion of 4 with the appropriate aromatic aldehyde, while 12 was prepared by fusion of 4 with two different aromatic aldehydes. In certain cases, 6 and 9 were heated on a direct flame until complete homogeneity afforded the corresponding 10 and 12. The structures of the synthesized compounds are based on physical data, IR, 1H NMR, 13C NMR, chemical means, and mass spectral data. Some of the synthesized compounds were biologically tested. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Design and Synthesis of Novel 1,3-Dioxane-2-carboxylic Acid Derivatives as PPARα/γ Dual Agonists

1,3-dioxane carboxylic acid derivatives were prepared based on our previous studies directed towards identifying novel pharmacophore for the development of PPAR α/γ dual agonists. Based on the typical topology of PPAR agonists we focused our design approach on modifying lipophilic tail and prepared a series of compounds by replacing the oxazole moiety of our previously reported compound with optimized lipophilic groups. Compound 8a was found to be a weak PPAR activator but exhibited potent hypolipidemic and anti-hyperglycemic activities in vivo due to superior bioavailability, whereas 8f exhibited potent in vitro and invivo effects. The activity of 8f is further supported by molecular docking study. Keywords: PPAR agonist, PPAR α/γ dual agonists, Type 2 diabetes, 1,3-dioxane carboxylic acid

Isolation, structural elucidation, and absolute stereochemistry of enigmazole A, a cytotoxic phosphomacrolide from the Papua New Guinea marine sponge Cinachyrella enigmatica.

Enigmazole A (1), a novel phosphate-containing macrolide, was isolated from a Papua New Guinea collection of the marine sponge Cinachyrella enigmatica. The structure of 1, including the absolute stereochemistry at all eight chiral centers, was determined by a combination of spectroscopic analyses and a series of microscale chemical derivatization studies. Compound 1 is comprised of an 18-membered phosphomacrolide that contains an embedded exomethylene-substituted tetrahydropyran ring and an acyclic portion that spans an embedded oxazole moiety. Two additional analogues, 15-O-methylenigmazole A and 13-hydroxy-15-O-methylenigmazole A, were also isolated and assigned. The enigmazoles are the first phosphomacrolides from a marine source and 1 exhibited significant cytotoxicity in the NCI 60-cell line antitumor screen, with a mean GI(50) of 1.7 microM.

Studies toward Intramolecular Cycloaddition of o-Quinodimethane with an Oxazole Moiety

Thermal reaction of benzocyclobutene derivatives having an oxazole moiety was investigated. Intramolecular [4+2] cycloaddition of o-quinodimethane, generated by thermolysis of the benzocyclobutene, with the oxazole did not proceed, and instead, [1,5]-sigmatropic rearrangement occurred dominantly.

Synthesis and Structural Investigation of C4‐ and C2‐Symmetric Molecular Scaffolds Based on Imidazole Peptides

AbstractThe syntheses of a C4‐ and a C2‐symmetric scaffold are presented. The first is composed of four imidazole units, while the second contains two imidazole and two oxazole moieties. The synthesis of the key building block for both systems has been fundamentally improved. Starting from these scaffolds, various platforms possessing two or four arms can easily be prepared. The structures of the scaffolds, together with that of a C4‐symmetric oxazole scaffold, were investigated in the solid state and in the gas phase. We found that these 24‐membered cyclic peptides exist as two different structure types. In one case (type I), the nitrogen atoms of the azole units pointing into the interior of the macrocycle form a square, whereas in the second case (type II), they form a parallelogram. The type of molecular structure does not depend on the symmetry of the system, but on the type of azole used. Cyclic systems composed of four imidazole units are present in the type I structure, whereas systems consisting of four oxazole units exhibit the type II nature. Structure type II is also present in cycles composed of two oxazole units and two imidazole units. The existence of the different structure types can be explained in terms of the different orbital energies of the imidazole and oxazole systems. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Ceric Ammonium Nitrate Promoted Oxidation of Oxazoles

The ceric ammonium nitrate promoted oxidations of 4,5-diphenyloxazoles and oxazoles with various substitution patterns have been investigated. This transformation results in the formation of the corresponding imide in good yield and tolerates a wide variety of functional groups and substituents on the oxazole moiety. [reaction: see text].

Synthesis and G-quadruplex stabilizing properties of a series of oxazole-containing macrocycles

The synthesis of 24-membered macrocycles containing four, six, and seven oxazole moieties is described. Selected compounds were evaluated for their ability to specifically bind and stabilize G-quadruplex DNA and for cytotoxic activity. An unexpected oxidative cleavage reaction afforded a macrocyclic imide that was also evaluated for G-quadruplex stabilizing and cytotoxic activity.

Synthesis of oxazolyl-substituted morpholinium salts

Morpholinium salts coupled to oxazolyl moieties have been synthesized via nucleophilic substitution of a series of oxazolyl chlorides with morpholine. The oxazole moieties were first synthesized and then coupled with morpholine. The corresponding hydrochloride and methyl iodide salts were obtained, purified, characterized and then tested for muscarinic receptor binding affinity. Biological test results from MDS Pharma Services revealed no significant muscarinic receptor affinity.

Application of Dialkyltin Hydrides Containing the Chiral 2‐(4‐Isopropyl‐2‐oxazolinyl)‐5‐phenyl Ligand in Radical Cyclizations at the Steady State.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Recent Advances in the Total Syntheses of Oxazole-Containing Natural Products

For Abstract see ChemInform Abstract in Full Text.

Ethyl 1-acetyl-2′-methyl-2-oxo-4′,5′-dihydro-1H-indoline-3-spiro-5′-oxazole-4′-carboxylate

In the title compound, C16H16N2O5, the indoline and oxazole moieties are almost planar, while the five-membered ring in the indoline moiety is slightly distorted towards an envelope conformation. The only intramolecular C—H⋯O contact forms a six-membered ring. The crystal packing is stabilized by dipole–dipole and van der Waals forces.

Synthesis of a high-affinity Fluorescent PPARγ ligand for high-throughput fluorescence polarization assays

Members of the peroxisome proliferator activated receptor (PPAR) family of transcription factors are under investigation as molecular targets for the treatment of numerous diseases including Alzheimer's, asthma, atherosclerosis, inflammation, multiple sclerosis, cancer, and diabetes. We employed the X-ray crystal structure of the PPARγ subtype complexed with the potent small molecule agonist GI262570 (farglitazar) to design and synthesize a novel fluorescent and high-affinity probe for homogeneous and high-throughput fluorescent polarization (FP) assays. Examination of this X-ray structure revealed that the phenyl carbon atom meta to the oxazole moiety of GI262570 is exposed to solvent at the bottom of a narrow protein cavity. A derivative of GI262570 was synthesized bearing a linear phenylacetylene-derived side chain comprising propargylamine coupled to fluorescein. This fluorescent analogue was designed to project the fluorophore into the adjacent protein cavity with minimal effects on receptor affinity and maximal effects on fluorescence polarization properties. The recombinant PPARγ ligand binding domain protein bound tightly and specifically to this probe with K d=61±14 nM as determined by FP measurements. Competition binding assays with known PPARγ ligands provided K i values that were highly correlated with analogous values obtained by scintillation proximity (SP) assays. This fluorescent PPARγ probe enables high-throughput and homogenous FP assays for the identification of novel endogenous and exogenous PPARγ ligands, and this rational ligand design approach may be applied to other therapeutically important members of the nuclear hormone receptor superfamily.

7-Nitro-1,2,3a,4-tetrahydrobenzo[b][1,3]oxazolo[3,2-d]oxazine: a new heterocycle

The title compound, C10H10N2O4, crystallizes with two independent mol­ecules (A and B) in the asymmetric unit. The five-membered ring of the oxazole moiety adopts a half-chair conformation in mol­ecule A and an envelope conformation in mol­ecule B. The oxazine ring adopts a sofa conformation in both mol­ecules.

Syntheses of analogues of the insect neuropeptide proctolin containing an oxazole ring as an amide bond replacement.

[structure: see text]. Three oxazole analogues of the insect neuropeptide proctolin (H-Arg-Tyr-Leu-Pro-Thr-OH) have been prepared, containing a single oxazole between Tyr and Pro and between Pro and Thr, respectively. A compound containing an oxazole moiety between Tyr and Pro and between Pro and Thr has also been prepared. All compounds have been tested for myotropic activity.

New natural epothilones from Sorangium cellulosum, strains So ce90/B2 and So ce90/D13: isolation, structure elucidation, and SAR studies.

In addition to epothilones A (1) and B (2), 37 natural epothilone variants and epothilone-related compounds were isolated from the culture broth of a 700 L fermentation of Sorangium cellulosum, strain So ce90/B2. Of these, only the 12,13-desoxyepothilones, epothilone C (14) and D (15), were produced in significant amounts (3-6 mg/L); the 21-hydroxy derivatives and epothilones E (3) and F (4), in low and variable amounts due to further degradation by the producing organism. Most of the other epothilone variants were produced only in 1-100 microg/L amounts. The new compounds are very similar in structure to the parent compounds 1, 2 and 14, 15 and are presumably the result of the imperfect selectivity of the biosynthetic enzymes for acetate and propionate. Further, epothilones containing an oxazole moiety (10-13) in the side chain instead of a thiazole as well as ring-expanded 18-membered macrolides, epothilones I (30-35), and a ring contracted 14-membered macrolide, epothilone K (36), were found as very minor metabolites. The mutant strain, So ce90/D13, instead of macrolactones, produced short-chain carboxylic acids 40, 41, and 42 bearing the characteristic thiazole side chain. The structures of the new epothilones were elucidated on the basis of comprehensive NMR and MS data. The new epothilone variants were tested in a cytotoxicity assay with mouse fibroblasts (cell line L929), and structure-activity relationships were established. Several new natural epothilones showed activity comparable to 1 and 2, but in no case exceeded that of 2.

Nostocyclamide M: a cyanobacterial cyclic peptide with allelopathic activity from Nostoc 31

A cyclic peptide containing thiazole and oxazole moieties was isolated from Nostoc 31 and its structure determined by chemical degradation detailed NMR and mass spectroscopic analyses. The compound is stereochemically pure and closely related to nostocyclamide in which d-valine is replaced by d-methionine. Therefore, it differs from tenuecyclamide C reported to contain l-methionine. It shows allelopathic activity against Anabaena 7120, but is inactive against grazers.

New Oxazole‐Based Conformationally Restricted Peptidomimetics: Design and Synthesis of Pseudopeptides

A general synthesis of a new class of optically active amino acids containing an oxazole moiety is described along with a strategy for their insertion into a peptidomimetic chain. A modified portion of endothelin-1 is prepared as a potential receptor antagonist. The procedure presented is based on readily available materials and can be performed in multigram quantities.