Fluoroproline flip-flop: regiochemical reversal of a stereoelectronic effect on peptide and protein structures.
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Molecular Conformation↗
Biomedical subjects
Kenneth I Hardcastle
Publications and source records attributed to Kenneth I Hardcastle.
Reduced fluorescence quenching of cyclodextrin-acetylene dye rotaxanes.
An acetylene dye rotaxane with alpha-CD has been synthesized using the Heck-Cassar-Sonogashira-Hagihara-type reaction in aqueous solution. Free dye with tetracarboxylic acids is found to be highly sensitive to various metal ions, showing high Stern-Volmer constants, KSV. As CD encapsulation protects and stabilizes the threaded chromophore against an outside quencher, metal-insensitive biological tags are an obvious application for this class of molecules.
Journal Article↗
Functional lactide monomers: methodology and polymerization.
Side-chain-functionalized lactide analogues have been synthesized from commercially available amino acids and polymerized using stannous octoate as a catalyst. The synthetic strategy presented allows for the incorporation of any protected amino acid for the preparation of functionalized diastereomerically pure lactide monomers. The resulting functionalized cyclic monomers can be homopolymerized and copolymerized with lactides and then quantitatively deprotected forming new functional poly(lactide)-based materials. This strategy allows for the introduction of functional groups along a poly(lactide) (PLA) backbone that after deprotection can be viewed as chemical handles for further functionalization of PLA, yielding improved biomaterials for a variety of applications.
Amino Acids↗
Electron exchange between alpha-Keggin tungstoaluminates and a well-defined cluster-anion probe for studies in electron transfer.
Fully oxidized alpha-AlIIIW12O40(5-) (1ox), and one-electron-reduced alpha-AlIIIW12O40(6-) (1red), are well-behaved (stable and free of ion pairing) over a wide range of pH and ionic-strength values at room temperature in water. Having established this, 27Al NMR spectroscopy is used to measure rates of electron exchange between 1ox (27Al NMR: 72.2 ppm relative to Al(H2O)63+; nu(1/2) = 0.77 Hz) and 1red (74.1 ppm; nu(1/2) = 0.76 Hz). Bimolecular rate constants, k, are obtained from line broadening in 27Al NMR signals as ionic strength, mu, is increased by addition of NaCl at the slow-exchange limit of the NMR time scale. The dependence of k on is plotted using the extended Debye-Hückel equation: log k = log k0 + 2alphaz1z2mu(1/2)/(1 + betarnu(1/2)), where z1 and z2 are the charges of 1ox and 1red, alpha and beta are constants, and r, the distance of closest contact, is fixed at 1.12 nm, the crystallographic diameter of a Keggin anion. Although not derived for highly charged ions, this equation gives a straight line (R2 = 0.996), whose slope gives a charge product, z1z2, of 29 +/- 2, statistically identical to the theoretical value of 30. Extrapolation to mu = 0 gives a rate constant k11 of (6.5 +/- 1.5) x 10(-3) M(-1) s(-1), more than 7 orders of magnitude smaller than the rate constant [(1.1 +/- 0.2) x 10(5) M(-1) s(-1)] determined by 31P NMR for self-exchange between P(V)W12O40(3-) and its one-electron-reduced form, P(V)W12O40(4-). Sutin's semiclassical model reveals that this dramatic difference arises from the large negative charges of 1ox and 1red. These results, including independent verification of k11, recommend 1red as a well-behaved electron donor for investigating outer-sphere electron transfer to molecules or nanostructures in water, while addressing a larger issue, the prediction of collision rates between uniformly charged nanospheres, for which 1ox and 1red provide a working model.
Journal Article↗
Antineoplastic diterpene-benzoate macrolides from the Fijian red alga Callophycus serratus.
[structures: see text] Three diterpene-benzoate natural products, with novel carbon skeletons and an unusual proposed biosynthesis, were isolated from extracts of the Fijian red alga Callophycus serratus and identified by a combination of X-ray crystallographic, NMR, and mass spectral analyses. Bromophycolide A (1) displayed cytotoxicity against several human tumor cell lines via specific apoptotic cell death. This represents the first discovery of natural products incorporating a diterpene and benzoate skeleton into a macrolide system.
Anti-Bacterial Agents↗
A palladium-oxo complex. Stabilization of this proposed catalytic intermediate by an encapsulating polytungstate ligand.
A terminal Pd-oxo unit is reported. The unit is encapsulated in a cavity defined by two [A-alpha-PW9O34]9- units fused together by one [WO(OH2)]4+ center and forms from Pd(II) in buffered media in the presence of O2. Both X-ray diffraction and EXAFS data are consistent with a Pd-oxo bond distance of ca. 1.65 A. 17O NMR studies confirm that the solid-state structure is maintained in solution.
Catalysis↗
Biomimetic synthesis of trans,syn,trans-fused polyoxepanes: remarkable substituent effects on the endo-regioselective oxacyclization of polyepoxides.
The biogenesis of trans,syn,trans-fused polycyclic ether substructures of neurotoxic natural products of the brevetoxin-ciguatoxin family may involve regio- and stereoselective oxacyclizations of polyepoxides. We report that a biomimetic Lewis acid-promoted cyclization of 1 to 2 proceeds with endo-regioselectivity and anti-stereospecificity at each position of nucleophilic addition (C3, C7, C11, and C15 in 1) when the tandem cyclization cascade is terminated by a carbonyl oxygen nucleophile. In contrast to expectations from earlier reports with simpler epoxide substrates, alkyl substituents are not required at internal epoxide positions corresponding to C7 and C11 in polyepoxide 1. Furthermore, we report that trimethylsilyl serves as a removable regioselectivity-directing substituent at positions corresponding to C3 of 1. These results greatly expand the potential applications of this biomimetic oxacyclization cascade to the synthesis of fused polycyclic ether natural products.
Biomimetic Materials↗
Alkene substituents for selective activation of endo-regioselective polyepoxide oxacyclizations.
The presence of an alkenyl substituent on the terminal epoxide of a polyepoxide substrate enhances the yield of all-endo-regioselective tandem oxacyclization to trans-syn-trans-fused polycyclic ethers. For a substrate in which the epoxide and alkene functional groups are separated by two methylene substituents, a novel bromonium ion-induced endo-regioselective cyclization to bromooxepane is also described. [reaction: see text]
Alkenes↗
Multi-iron silicotungstates: synthesis, characterization, and stability studies of polyoxometalate dimers.
The reaction of Fe(III) with Na(+) and K(+) salts of the trivacant [alpha-SiW(9)O(34)](10)(-) ligand have been investigated at pH 6 and pH 1. A new dimer, [(alpha-SiFe(3)W(9)(OH)(3)O(34))(2)(OH)(3)](11-) (1), is synthesized by reacting Na(7)H(3)[alpha-SiW(9)O(34)] or K(10)[alpha-SiW(9)O(34)] with exactly 3 equiv of Fe(III) in a 0.5 M sodium acetate solution (pH 6). The structure of 1, determined by single-crystal X-ray diffraction (a = 22.454(2) A, b = 12.387(2) A, c = 37.421(2), beta = 100.107(8) degrees , monoclinic, C2/c, Z = 4, R(1) = 5.11% based on 12739 independent reflections), consists of two [alpha-SiFe(3)W(9)(OH)(3)O(34)](4-) units linked by three Fe-mu-OH-Fe bonds. Reaction of K(10)[alpha-SiW(9)O(34)] with 3 equiv of Fe(III) in water (pH 1) yields [(alpha-Si(FeOH(2))(2)FeW(9)(OH)(3)O(34))(2)](8)(-2). The structure of 2 was also determined by single-crystal X-ray diffraction (a = 36.903(2) A, b = 13.9868(9) A, c = 21.7839(13) A, beta = 122.709(1) degrees , monoclinic, C2/c, Z = 4, R(1) = 4.57% based on 11787 independent reflections). It consists of two [alpha-Si(FeOH(2))(2)FeW(9)(OH)(3)O(34)](4-) Keggin units linked by a single edge. The terminal ligand on Fe1 in each trisubstituted Keggin unit becomes a mu(2) oxo ligand bridging to a [WO(6)](2-) moiety. The UV-vis spectra of both complexes show the characteristic oxygen-to-metal-charge-transfer bands of polyoxometalates as well as an Fe(III)-centered band at 436 nm (epsilon = 146 M(-1) cm(-1)) and 456 nm (epsilon = 104 M(-1) cm(-1)) for complexes 1 and 2, respectively. Differential scanning calorimetry data show that complex 1 decomposes between 575 and 600 degrees C whereas no decomposition is observed for complex 2 up to temperatures of 600 degrees C.
Journal Article↗
Semi-vacant Wells-Dawson anions. Synthesis of tri-tungsten-vacant derivatives and crystallographic studies of [alphabetabetaalpha-(Cu(II)OH2)2(Cu(II))2(AsW15(OH2)3(OH)O52)2]12-.
The tri-tungsten-vacant polyoxometalate, [alpha-AsW15(OH)4O52]13-, derived from the semi-vacant Wells-Dawson complex [alpha-AsW18(OH)4O58]7-, reacts with the late-transition metal cations, Cu(II) or Zn(II), to form sandwich-type species; the X-ray crystal structure of [alphabetabetaalpha]-(Cu(II)OH2)2(Cu(II))2(AsW15(OH2)3(OH)O52)2]12-, prepared by the acidification of [alphabetabetaalpha]-(Cu(II)OH2)2(Cu(II))2(AsW15(OH)4O52)2]18-, reveals that the missing heteroatoms are distal to the central Cu4 unit and the vertices of the vacant tetrahedron are occupied by one OH- and three OH2 groups.
Journal Article↗
Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin.
Hyperphosphatemia is thought to underlie medial vascular calcification in advanced renal failure, but calcification can occur in other conditions in the absence of hyperphosphatemia, indicating that additional factors are important. To identify these factors, a model of medial calcification in rat aorta in vitro was developed. Aortic rings from rats were incubated in serum-free medium for 9 d, and calcification was measured as incorporation of (45)Ca and confirmed by histology and x-ray diffraction. No calcification occurred in normal vessels despite elevated free Ca(2+) and PO(4)(3-) concentrations of 1.8 mM and 3.8 mM, respectively, but mechanical injury resulted in extensive calcification in the media. Co-incubation studies revealed that normal aortas produced a soluble inhibitor of calcification in injured vessels that was destroyed by alkaline phosphatase. Culture of normal aortas with alkaline phosphatase resulted in calcification of the elastic lamina identified as hydroxyapatite by x-ray diffraction. This effect of alkaline phosphatase was not due to dephosphorylation of osteopontin (OPN), and calcification was not increased in aortas from OPN-deficient mice. The inhibitor was identified as pyrophosphate on the basis of the calcification induced in aortas cultured with inorganic pyrophosphatase, the inhibition of calcification in injured aortas by pyrophosphate, and the production of inhibitory levels of pyrophosphate by normal aortas. No calcification occurred under any conditions at a normal PO(4)(3-) concentration. It is concluded that elevated concentrations of Ca(2+) and PO(4)(3-) are not sufficient for medial vascular calcification because of inhibition by pyrophosphate. Alkaline phosphatase can promote calcification by hydrolyzing pyrophosphate, but OPN is not an endogenous inhibitor of calcification in rat aorta.
Alkaline Phosphatase↗
Cupric decamolybdodivanadophosphate. A coordination polymer heterogeneous catalyst for rapid, high conversion, high selectivity sulfoxidation using the ambient environment.
A new type of coordination network polymer involving the redox-active polyanion, PV(2)Mo(10)O(40)(5)(-), and bridging -Cu(II)(OH(2))(4)- units, [[(Cu(II)(OH(2))(4))(3)(OH)]PV(2)Mo(10)O(40)](n)() (1), has been characterized by X-ray crystallography and several other methods. It is the first efficient heterogeneous (insoluble) catalyst for selective and rapid sulfoxidation using only the ambient environment (air at room temperature). Catalytic activity is enhanced by soluble nitrate in nontoxic perfluoropolyether (PFPE) media.
Journal Article↗
Biomimetic synthesis of fused polypyrans: oxacyclization stereo- and regioselectivity is a function of the nucleophile.
[reaction: see text] The stereoselectivity of Lewis acid-induced endo-regioselective oxacyclizations of 1,4-diepoxides is dependent upon the nature of the terminating nucleophile. For instance, the tert-butyl carbonate-substituted diepoxide of 3,6-dimethylhepta-2,5-dien-1-ol provides a cis-fused bicyclic product, whereas the N,N-dimethylcarbamate derivative affords the trans-fused diastereomer. Stereospecific and regioselective conversion of the tertiary carbamate-terminated 1,4,7-triepoxide (I) to tricyclic all-trans-fused polypyran (II) is also demonstrated.
Biomimetics↗
Multi-iron tungstodiarsenates. Synthesis, characterization, and electrocatalytic studies of alphabetabetaalpha-(Fe(III)OH(2))(2)Fe(III)(2)(As(2)W(15)O(56))(2)(12)(-).
Reaction of the trivacant lacunary complex, alpha-Na(12)[As(2)W(15)O(56)], with an aqueous solution of Fe(NO(3))(3).9H(2)O yields the sandwich-type polyoxometalate, alphabetabetaalpha-Na(12)(Fe(III)OH(2))(2)Fe(III)(2)(As(2)W(15)O(56))(2) (Na1). The structure of this complex, determined by single-crystal X-ray crystallography (a = 13.434(1) A, b = 13.763(1) A, c = 22.999(2) A, alpha = 90.246(2) degrees, beta = 102.887(2) degrees, gamma = 116.972(1) degrees, triclinic, Ponemacr;, R1 = 5.5%, based on 25342 independent reflections), consists of an Fe(III)(4) unit sandwiched between two trivacant alpha-As(2)W(15)O(56)(12)(-) moieties. UV-vis, infrared, cyclic voltammetry, and elemental analysis data are all consistent with the structure determined from X-ray analysis. Magnetization studies confirm that the four Fe(III) centers are antiferromagnetically coupled. A cyclic voltammogram of Na1 reveals that a three-wave W(VI) system replaces the two-wave W(VI) system found in the precursor alpha-As(2)W(15)O(56)(12)(-) complex. The observed modifications in the CV patterns of Na1 and alpha-As(2)W(15)O(56)(12)(-) are most likely due to subsequent changes in the acid-base properties of two reduced POMs that occur as a result of Fe(III) incorporation. Na1 is shown to be more efficient than the monosubstituted complex alpha(2)-As(2)(Fe(III)OH(2))W(17)O(61)(7)(-) in the electrocatalytic reduction of dioxygen. This is attributed to cooperativity effects among the adjacent Fe(III) centers in Na1.
Journal Article↗
A short diastereoselective synthesis of the putative alkaloid jamtine, using a tandem pummerer/mannich cyclization sequence.
Treatment of 2-phenylhex-5-enal with benzylamine followed by sequential reaction with ethylthioacetyl chloride and sodium periodate oxidation afforded a E/Z mixture of alpha-sulfinylamides. As anticipated from a 4pi-conrotatory mechanism, cyclization of each olefin afforded fused isoquinoline lactams as single diastereomers epimeric at the ethylthio position without any cross contamination. Some preliminary studies were directed toward the synthesis of mesembrine using a 3,4-dimethoxy aryl group. In this case, the Z-enamide prefers to undergo electrophilic aromatic substitution to give a substituted azepinone as the preferred product in 87% yield. In contrast, the E-enamide isomer provided the desired hydroindolone. The convergency and stereochemical control associated with the tandem Pummerer /Mannich cyclization make it particularly suited for the assembly of jamtine, a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties. The key step in the synthesis involves a domino thionium/N-acyliminium ion cyclization to provide the tricyclic ring skeleton 27a as the major diastereomer. Deprotonation of 27a with NaH gave 28a, which contains the fully assembled skeleton of jamtine. Completion of the synthesis entailed installation of the double bond and reduction of the lactam. Oxidation of a synthetic sample of jamtine with MCPBA afforded the corresponding N-oxide, which does not match the spectral data reported in the literature for this alkaloid. Our synthetic efforts raise the possibility of a revision of the earlier assignment.
Alkaloids↗
Stability and structure in alpha- and beta-Keggin Heteropolytungstates, [X(n)(+)W12O40)](8-n)(-), X = p-block cation.
beta-[SiW(12)O(40)](4)(-) (C(3)(v) symmetry) is sufficiently higher in energy than its alpha-isomer analogue that effectively complete conversion to alpha-[SiW(12)O(40)](4)(-) (T(d)) is observed. By contrast, beta- and alpha-[AlW(12)O(40)](5)(-) (beta- and alpha-1; C(3)(v) and T(d), respectively) are sufficiently close in energy that both isomers are readily seen in (27)Al NMR spectra of equilibrated (alpha-beta) mixtures. Recently published DFT calculations ascribe the stability of beta-1 to an electronic effect of the large, electron-donating [AlO(4)](5)(-) (T(d)) moiety encapsulated within the polarizable, fixed-diameter beta-W(12)O(36) (C(3)(v)) shell. Hence, no unique structural distortion of beta-1 is needed or invoked to explain its unprecedented stability. The results of these DFT calculations are confirmed by detailed comparison of the X-ray crystal structure of beta-1 (beta-Cs(4.5)K(0.5)[Al(III)W(12)O(40)].7.5H(2)O; orthorhombic, space group Pmc2(1), a = 16.0441(10) A, b = 13.2270(8) A, c = 20.5919(13) A, Z = 4 (T = 100(2) K)) with previously reported structures of alpha-1, alpha- and beta-[SiW(12)O(40)](4)(-), and beta(1)-[SiMoW(11)O(40)](4)(-).
Journal Article↗
Reactions of trivacant Wells-Dawson heteropolytungstates. Ionic strength and Jahn-Teller effects on formation in multi-iron complexes.
Reaction of alpha-P(2)W(15)O(56)(12-) and Fe(III) in a saturated NaCl solution produces a trisubstituted Wells-Dawson structure with three low-valent metals, alpha-(Fe(III)Cl)(2)(Fe(III)OH(2))P(2)W(15)O(59)(11-) (1). Dissolution of this species into 1 M NaBr (Br(-) is non-coordinating) gives the triaquated species alpha-(Fe(III)OH(2))(3)P(2)W(15)O(59)(9-) (2). Ionic strength values of 1 M or greater are necessary to avoid decomposition of 1 or 2 to the conventional sandwich-type complex, alpha beta beta alpha-(Fe(III)OH(2))(2)Fe(III)(2)(P(2)W(15)O(56))(2)(12-) (3). If the pH is greater than 5, a new triferric sandwich, alpha alpha beta alpha-(NaOH(2))(Fe(III)OH(2))Fe(III)(2)(P(2)W(15)O(56))(2)(14-) (4), forms rather than 3. Like the previously reported Wells-Dawson-derived sandwich-type structures with three metals in the central unit ([TM(II)Fe(III)(2)(P(2)W(15)O(56))(P(2)TM(II)(2)W(13)O(52))],(16-) TM = Cu, Co), this complex has a central alpha-junction and a central beta-junction. Thermal studies suggest that 4 is more stable than 3 over a wide range of temperatures and pH values. The intrinsic Jahn-Teller distortion of d-electron-containing metal ions incorporated into the external sites of the central multi-metal unit impacts the stoichiometry of their incorporation (with a consequent change in the inter-POM-unit connectivity, where POM = polyoxometalate). Reaction of non-distorting Ni(II) with the diferric lacunary sandwich-type POM alpha alpha alpha alpha-(NaOH(2))(2)Fe(III)(2)(P(2)W(15)O(56))(2)(16-) (5) produces alpha beta beta alpha-(Ni(II)OH(2))(2)Fe(III)(2)(P(2)W(15)O(56))(2)(14-) (6), a Wells-Dawson sandwich-type structure with two Ni(II) and two Fe(III) in the central unit. All structures are characterized by (31)P NMR, IR, UV-vis, magnetic susceptibility, and X-ray crystallography. Complexes 4 and 6 are highly selective and effective catalysts for the H(2)O(2)-based epoxidation of alkenes.
Alkenes↗
Carbenoid reactions of 2-halomethyl-4,6-dimethyl-s-triazines.
Reactions of lithium, sodium, and potassium salts of 2,4,6-trimethyl-s-triazine (1) with 2-halomethyl-4,6-dimethyl-s-triazine (2) (X = Cl, Br) in glyme have been studied and found to give 1,2-bis(4,6-dimethyl-s-triazin-2-yl)ethane (3), 1,2-bis(4,6-dimethyl-s-triazin-2-yl)ethene (5), 1,2,3-tris(4,6-dimethyl-s-triazin-2-yl)cyclopropane (6), 1,2,3-tris(4,6-dimethyl-s-triazin-2-yl)propane (7), and 1,2,3,4-tetrakis(4,6-dimethyl-s-triazin-2-yl)butane (8). It is proposed that product 3 is formed primarily via an S(N)2 reaction, whereas the remaining products are formed primarily via carbenoid reactions that are enumerated.
Cyclization↗