Mild and practical method for the alpha-arylation of nitriles with heteroaryl halides

[reaction: see text] A mild and transition-metal-free method for the alpha-arylation of aliphatic nitriles with activated heteroaryl halides was developed using NaHMDS or KHMDS as base at ambient temperature. The key to the success of this method is generation of the nitrile anion in the presence of the heteroaryl halide. The method is applicable to both primary and secondary carbonitriles and a wide range of heteroaryl halides. Selective monoarylation was observed with primary carbonitriles. The operational simplicity and the mild reaction conditions add to the value of this method as a practical alternative to the preparation of alpha-heteroaryl carbonitriles.     

Antihydrophobic cosolvent effects for alkylation reactions in water solution, particularly oxygen versus carbon alkylations of phenoxide ions

Antihydrophobic cosolvents such as ethanol increase the solubility of hydrophobic molecules in water, and they also affect the rates of reactions involving hydrophobic surfaces. In simple reactions of hydrocarbons, such as the Diels-Alder dimerization of 1,3-cyclopentadiene, the rate and solubility data directly reflect the geometry of the transition state, in which some hydrophobic surface becomes hidden. In reactions involving polar groups, such as alkylations of phenoxide ions or S(N)1 ionizations of alkyl halides, cosolvents in water can have other effects as well. However, solvation of hydrophobic surfaces is still important. By the use of structure-reactivity relationships, and comparing the effects of ethanol and DMSO as solvents, it has been possible to sort out these effects. The conclusions are reinforced by an ab initio computer model for hydrophobic solvation. The result is a sensible transition state for phenoxide ion as a nucleophile, using its oxygen n electrons to avoid loss of conjugation. The geometry of alkylation of aniline is very different, involving packing (stacking) of the aniline ring onto the phenyl ring of a benzyl group in the benzylation reaction. The alkylation of phenoxide ions by benzylic chlorides can occur both at the phenoxide oxygen and on ortho and para positions of the ring. Carbon alkylation occurs in water, but not in nonpolar organic solvents, and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para. The effects of phenol substituents and of antihydrophobic cosolvents on the rates of the competing alkylation processes indicate that in water the carbon alkylation involves a transition state with hydrophobic packing of the benzyl group onto the phenol ring. The results also support our conclusion that oxygen alkylation uses the n electrons of the phenoxide oxygen as the nucleophile and does not have hydrophobic overlap in the transition state. The mechanisms and explanations for competing oxygen and carbon alkylations differ from previous proposals by others.     

Reactivity of DNA guanyl radicals with phenolate anions

Guanine bases are the most easily oxidized sites in DNA. Electron-deficient guanine species are major intermediates produced in DNA by the direct effect of ionizing radiation (ionization of the DNA itself) because of preferential hole migration within DNA to guanine bases. By using thiocyanate ions to modify the indirect effect (ionization of the solvent), we are able to produce these single-electron-oxidized guanine radical species in dilute aqueous solutions of plasmid DNA where the direct effect is negligible. The guanyl radical species produce stable modified guanine products. They can be detected in the plasmid by converting them to strand breaks after incubation with a DNA repair enzyme. If a phenol is present during irradiation, the yield of modified guanines is decreased. The mechanism is reduction of the guanine radical species by the phenol. It is possible to derive a rate constant for the reaction of the phenol with the guanyl radical. The pH dependence shows that phenolate anions are more reactive than their conjugate acids, although the difference for guanyl radicals is smaller than with other single-electron-oxidizing agents. At physiological pH values, the reduction of a guanyl radical entails the transfer of a proton in addition to the electron. The relatively small dependence of the rate constant on the driving force implies that the electron cannot be transferred before the proton. These results emphasize the potential importance of acidic tyrosine residues and the intimate involvement of protons in DNA repair.     

Asymmetric total synthesis of rollicosin

[structure: see text] The first total synthesis of rollicosin, a member of a rare subgroup of Annonaceous acetogenins containing two terminal gamma-lactones, is reported. The approach features a highly regio- and stereoselective tandem ring-closing/cross-metathesis reaction for construction of the east-wing lactone and incorporation of the alkyl spacer. Establishment of the C4 stereocenter and addition of the west-wing lactone were achieved by Sharpless asymmetric dihydroxylation and enolate alkylation.     

Self-assembling of helical poly(phenylacetylene) carrying L-valine pendants in solution, on mica substrate, and on water surface

In the present work, we investigated self-assembling of a poly(phenylacetylene) carrying L-valine pendants (PPA-Val) in a water/methanol solution, upon evaporation of the solution on mica, and on the water surface. With intercalation of a fluorescence probe of Ru(phen)2(dppx)2+ (phen = 1,10-phenanthroline, dppx=7,8-dimethyldipyridophenazine) into the hydrophobic cavities associated by the PPA-Val chains, their helical structures were directly detected in solution with an in situ fluorescence microscope. Helical aggregates were observed with AFM upon evaporation of the solvents, suggesting that the helical structures in the solution are the building blocks of the helical aggregates. Self-assembling structures of PPA-Val on the water surface were, however, very different from that formed upon evaporation of its THF solution on the mica surface. The polymer chains associated into a monolayer of extended fibers on the water surface, whereas superhelical fibers formed on the mica surface. Water molecules play a critical role in inducing the polymer to form diverse morphological structures in its bulk solution and on its surface. In solution, the isotropic hydrophobic effect drove the polymer chains to form superhelical aggregates, while on the water surface, the hydrophobic effect concentrated mainly on the lateral part of the polymer, thus giving a monolayer of extended fibers.     

Flexible ligand docking without parameter adjustment across four ligand–receptor complexes

Understanding molecular recognition is one of the fundamental problems in molecular biology. Computationally, molecular recognition is formulated as a docking problem. Ideally, a molecular docking algorithm should be computationally efficient, provide reasonably thorough search of conformational space, obtain solutions with reasonable consistency, and not require parameter adjustments. With these goals in mind, we developed DIVALI (Docking wIth eVolutionary AlgorIthms), a program which efficiently and reliably searches for the possible binding modes of a ligand within a fixed receptor. We use an AMBER-type potential function and search for good ligand conformations using a genetic algorithm (GA). We apply our system to study the docking of both rigid and flexible ligands in four different complexes. Our results indicate that it is possible to find diverse binding modes, including structures like the crystal structure, all with comparable potential function values. To achieve this, certain modifications to the standard GA recipe are essential. © 1995 John Wiley & Sons, Inc.     

Two-, three-, and four-coordinate Ag(I) coordination polymers formed by the novel phosphinite PPh2(3-OCH2C5H4N)

The novel phosphinite PPh(2)(3-OCH(2)C(5)H(4)N) (1) has been synthesized, and its coordination properties to Ag(I) have been studied. When reacted in a 1:1 ratio with Ag(I), coordination polymers with different coordination numbers about the Ag are found depending on the anion. For PPh(2)(3-OCH(2)C(5)H(4)N)AgBF(4) (2), a two-coordinate Ag is observed with a P-Ag-N angle of 167 degrees. Mixed three and four coordination about Ag is observed for PPh(2)(3-OCH(2)C(5)H(4)N)AgOTf (3), and for the trifluoroacetate derivative, PPh(2)(3-OCH(2)C(5)H(4)N)Agtfa (4), only a four-coordinate Ag is produced. X-ray crystal-structure determinations for compounds 2-4 have been carried out. The X-ray structures show a wide range of Ag-Ag distances in the polymers, which are dependent on the conformation of the bridging ligand.     

Acid-Catalyzed Amine-Borane Reduction of Nitrite

The rate of reduction of nitrite by trimethylamine-borane was followed by observing the decrease in nitrite absorbance under pseudo-first-order conditions. The reaction is acid-catalyzed and exhibits a first-order dependence on both amine-borane and total nitrite concentration. The molar equivalence of NaNO(2) to (CH(3))(3)NBH(3) = 2:1. Equimolar amounts of hydrogen and nitrous oxide are formed, and the molar ratio of nitrite reacted to N(2)O produced is 2:1. In concentrated HCl or H(2)SO(4), a correlation of rate with the Hammett acidity function, h(o), is observed. The reaction is subject to a pronounced inversesolvent isotope effect (k(D)()2(O)/k(H)()2(O) approximately 2.7) and a modest normal substrate effect (k((CH)()3())()3(N.BH)()3/k((CH)()3())()3(N.BD)()3 approximately 1.4). The reaction is first-order in H(3)O(+) in the region pH 0.7-2.7, but a second-order dependence is observed above pH 4 with the transition occurring at pH approximately pK(a) for HNO(2). Results are consistent with a mechanistic model involving preequilibration protonation of molecular nitrous acid followed by rate-limiting hydride attack on H(2)ONO(+) or free NO(+) to produce nitrosyl hydride as a reactive intermediate.     

Ordering the reductive and cytochrome P450 oxidative steps in demethylsterigmatocystin formation yields general insights into the biosynthesis of aflatoxin and related fungal metabolites

The biosynthesis of the potent environmental carcinogen aflatoxin B1 involves ca. 15 steps beyond the first polyketide intermediate. Central among these is the rearrangement of the anthraqinone versicolorin A to the xanthone demethylsterigmatocystin. Genetic evidence strongly suggests that two enzymes are required for this process, a cytochrome P450, AflN, and a probable NADPH-dependent oxidoreductase, AflM. Given the overall redox change evident in this skeletal rearrangement, two rounds of oxidation and a reduction necessarily occur. Earlier experiments indicated that reductive deoxygenation of versicolorin A is not the first step. In the present report we consider a mechanistic alternative that AflM-mediated reduction is instead the last of these three reactions prior to formation of the xanthone intermediate. To this end, 9-hydroxydihydrodemethylsterigmatocystin was prepared by total synthesis as was its 9-deoxy analogue, an established aflatoxin precursor. During the final isolation of the "angular" synthetic xanthone targets it was found that acid catalysis promoted their isomerization to thermodynamically favored "linear" xanthones. Whole-cell and ground-cell incubations of the 9-hydroxy- and 9-deoxyxanthones were conducted with a mutant strain of Aspergillus parasiticus blocked at the first step of the pathway and examined for their ability to support aflatoxin production. The 9-deoxyxanthone gave dramatically enhanced levels of the mycotoxin. The 9-hydroxyxanthone, on the other hand, afforded no detectable increase in aflatoxins above controls, indicating that reductive deoxygenation at C-9 of a xanthone precursor does not take place in aflatoxin biosynthesis. Constraints imposed by earlier studies and the experiments in this paper serve to eliminate simple and intuitive conversions of versicolorin A to demethylsterigmatocystin and lead inescapably to a more subtle reaction sequence of oxidation-reduction-oxidation. Previous puzzling observations of extensive A-ring hydrogen exchange in the course of the rearrangement of versicolorin A to demethylsterigmatocystin have now been explained by a new mechanism that is consistent with all extant data. We propose that P450-mediated aryl epoxidation (AflN) initially disrupts the aromatic A-ring of versicolorin A. Oxirane opening enables A-ring proton exchange, as does the subsequent AflM-mediated reductive step. A second cycle of P450 oxidation (AflN), this time a Baeyer-Villiger cleavage, enables decarboxylation and the formation of demethylsterigmatocystin. Mechanistic and stereoelectronic principles that underlie this proposal are described and may prove general as illustrated in biogenetic hypotheses for four other fungal anthraquinone --> xanthone transformations.     

Effects of alkali metal halide salts on the hydrogen bond network of liquid water

Measurements of the oxygen K-edge X-ray absorption spectrum (XAS) of aqueous sodium halide solutions demonstrate that ions significantly perturb the electronic structure of adjacent water molecules. The addition of halide salts to water engenders an increase in the preedge intensity and a decrease in the postedge intensity of the XAS, analogous to those observed when increasing the temperature of pure water. The main-edge feature exhibits unique behavior and becomes more intense when salt is added. Density functional theory calculations of the XAS indicate that the observed red shift of the water transitions as a function of salt concentration arises from a strong, direct perturbation of the unoccupied molecular orbitals on water by anions, and does not require significant distortion of the hydrogen bond network beyond the first solvation shell. This contrasts the temperature-dependent spectral variations, which result primarily from intensity changes of specific transitions due to geometric rearrangement of the hydrogen bond network.