Stereoselective Synthesis of 1,6,9-Tri-oxaspiro[4.5]decanes From d-Glucose: Novel Structural Motifs of Spiroacetal Natural Products

Spiroacetals are the central structural core element of numerous natural products and are essential for their biological activity. A typical structural representative of a spiroacetal is the bicyclic 1,6-dioxaspiro[4.5]decane ring system. It represents the complete or partial structure of many biologically potent natural products such as the Paravespula pheromone 1, the antibiotic (+)-monensin A 2, the anticancer agent (−)-berkelic acid 3, the antimitotic ingredient spirastrellolide F, characterized after methylation as (+)-methyl ester 4, and the marine toxin (−)-calyculin A 5. In these compounds, the 1,6-dioxaspiro[4.5]decane ring system is found in either spiro ( R)-6 or ( S) - 6 configuration. The corresponding 1,6,9-trioxaspiro[4.5]decane framework ( S)-7 and ( R)-7 with opposite chirality at the spiro center due to an additional oxygen atom at position 9 in the pyran portion has so far not been found in living organisms or been synthesized. To close this gap and enable structure–activity relationship studies, potentially leading to novel antibiotics and selective anticancer agents, we have developed an efficient and stereocontrolled route to the ( R)- and ( S)-configurated 1,6,9-trioxaspiro[4.5]decane ring system leading to oxa analog motifs of the above natural products.

Evidence for Naturally Produced Beauvericins Containing N-Methyl-Tyrosine in Hypocreales Fungi

Beauvericin is a depsipeptide mycotoxin. The production of several beauvericin analogues has previously been shown among various genera among Hypocreales fungi. This includes so-called beauvenniatins, in which one or more N-methyl-phenylalanine residues is exchanged with other amino acids. In addition, a range of “unnatural” beauvericins has been prepared by a precursor addition to growth medium. Our aim was to get insight into the natural production of beauvericin analogues among different Hypocreales fungi, such as Fusarium and Isaria spp. In addition to beauvericin, we tentatively identified six earlier described analogues in the extracts; these were beauvericin A and/or its structural isomer beauvericin F, beauvericin C, beauvericin J, beauvericin D, and beauvenniatin A. Other analogues contained at least one additional oxygen atom. We show that the additional oxygen atom(s) were due to the presence of one to three N-methyl-tyrosine moieties in the depsipeptide molecules by using different liquid chromatography–mass spectrometry-based approaches. In addition, we also tentatively identified a beauvenniatin that contained N-methyl-leucine, which we named beauvenniatin L. This compound has not been reported before. Our data show that N-methyl-tyrosine containing beauvericins may be among the major naturally produced analogues in certain fungal strains.

Detection of intracellular superoxide formation in endothelial cells and intact tissues using dihydroethidium and an HPLC-based assay

Recently, it was demonstrated that superoxide oxidizes dihydroethidium to a specific fluorescent product (oxyethidium) that differs from ethidium by the presence of an additional oxygen atom in its molecular structure (Zhao H, Kalivendi S, Zhang H, Joseph J, Nithipatikom K, Vásquez-Vivar J, and Kalyanaraman B. Free Radic Biol Med 34: 1359–1368, 2003). We have adapted this new HPLC-based assay to quantify this product as a tool to estimate intracellular superoxide in intact tissues. Ethidium and oxyethidium were separated using a C-18 column and quantified using fluorescence detection. Initial cell-free experiments with potassium superoxide and xanthine oxidase confirmed the formation of oxyethidium from dihydroethidium. The formation of oxyethidium was inhibited by superoxide dismutase but not catalase and did not occur upon the addition of H2O2, peroxynitrite, or hypochlorous acid. In bovine aortic endothelial cells (BAEC) and murine aortas, the redox cycling drug menadione increased the formation of oxyethidium from dihydroethidium ninefold (0.4 nmol/mg in control vs. 3.6 nmol/mg with 20 μM menadione), and polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) significantly inhibited this effect. Treatment of BAEC with angiotensin II caused a twofold increase in oxyethidium formation, and this effect also was reduced by PEG-SOD (0.5 nmol/mg). In addition, in the aortas of mice with angiotensin II-induced hypertension and DOCA-salt hypertension, the formation of oxyethidium was increased in a manner corresponding to superoxide production estimated on the basis of cytochrome c reduction. Detection of oxyethidium using HPLC represents a new, convenient, quantitative method for the detection of superoxide in intact cells and tissues.

Synthesis and Structure of a New Chiral Oxaziridine from (3-Oxo-camphorsulfonyl)imine

Oxidation of (3-oxo-camphorsulfonyl)imine (1) by magnesium monoperoxyphthalate does not lead to the oxaziridine obtained with 3-chloro-perbenzoic acid, but to a new chiral oxaziridine containing an additional oxygen atom (Baeyer-Villiger type oxidation). The structure of the product is established by X-ray crystallography, and reaction pathways for the oxidation of 1 by peracids are discussed.

Alkaloids of the Australian Apocynaceae: Kopsia longiflora Merr. III. Preliminary Degradation of the Alkaloids

Graded alkaline hydrolysis of the monoacid tertiary bases kopsiflorine (C23H28O5N2), kopsilongine (C24H30O6N2), and kopsamine (C24H28O7N2) shows that they contain two methoxycarbonyl groups. All but one of the residual oxygen atoms are accounted for as aromatic ether linkages. One of the methoxycarbonyl groups is responsible for the deactivation of the other nitrogen atom (N(a)) present, since anew basic centre is generated by partial hydrolysis and subsequent decarboxylation of the acid produced. The alkaloids are tentatively formulated as blocked indoline bases containing a urethane grouping at N(a). The fourth alkaloid, kopsinine (C21H26O2N2) is similarly formulated, but in this case N(a) is weakly basic, the urethane methoxycarbonyl group and the additional oxygen atom being absent.

Problems bearing on residual affinity

Valency implies the existence of something equivalent to the possession by an atom of points of attachment, and is inseparable from the idea of chemical combination; but it must not be confused, as has often been done, with the force acting at those points. The properties of a mass of matter are the sum of those of its constituents, and, since molecules combine together, the affinities and valencies effecting their union must be those of the constituent atoms. The satisfaction of such additional valencies will represent a comparatively small expenditure of energy, for, even when principal valencies are concerned, as when an element forms pairs of oxides or halides, the heat evolution on combining with the additional oxygen atom is, on the average, only 38 per cent. of what it is on combining with the first atom or atoms (17 cases), and 52 per cent. in the case of the halides (10 cases). At this rate residual affinity must soon become reduced to a quantity insufficient for the attachment of another free atom, but might still be sufficient to unite with it if it were already in combination, and had only its own residual affinity available. Platinum is hexavalent in Cl 4 Pt ClK ClK , though Cl 6 Pt cannot exist. It is, therefore, only in so-called molecular compounds that the highest valencies of an atom can be expected, though no fundamental differences can be imagined between the higher and the principal valencies; this is admitted even by those who have coined a distinctive name for the higher valencies ( e. g. , Werner’s “co-ordination values”). The general rule that additional valencies come into existence in pairs is not invalidated by certain apparent exceptions. Thus, the most stable arrangement of five atoms round a central one is two in one plane, and three in the plane at right angles; according as the positions occupied are those in the one, the other, or both planes, the atom will show valencies of 2, 3 or 5, and by the suppression or development of pairs of valencies, other values of 1, 4, 7, 9, etc., might be shown.