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ABSTRACT: Reductive heterocycle-heterocycle (heterocycle → heterocycle; H-H) transformations that give 4-aminoquinolines, 3-acylindoles, and quinolin-4(1H)-ones from 2-nitrophenyl substituted isoxazoles are reported. When this methodology is applied to 3,5-, 4,5-, and 3,4-bis(2-nitrophenyl)isoxazoles, chemoselective heterocyclization gives quinolin-4(1H)-ones, and 4-aminoquinolines, exclusively.
Organic Letters 04/2013; · 5.86 Impact Factor
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ABSTRACT: The yohimbinoid alkaloids continue to receive considerable attention from the synthetic community because of their interesting chemical structures and varied biological activity. Although there are several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class are hampered by a lack of complete control in setting the C(3) stereocentre at a late stage. Herein, we report that a functionalized hydrindanone enables a divergent strategy that builds on existing precedent to address this long-standing challenge. Utilizing an aminonitrile intermediate, the stereochemistry at C(3) of the yohimbinoid skeleton can be controlled effectively in a Pictet-Spengler reaction. We applied this approach to the first total syntheses of the C(3) epimeric natural products venenatine and alstovenine.
Nature Chemistry 02/2013; 5(2):126-31. · 20.52 Impact Factor
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ABSTRACT: Quantum chemical calculations (B3LYP and MP2) are described for the formation and rearrangements of carbocations derived from the biological methylation reaction that produces 24-propyl sterols in Pelagophyte algae. Previous mechanistic proposals are discussed in light of the results of these calculations. Of particular note is the prediction of a new triple-shift rearrangement that is inherently preferred for the biosynthetically relevant carbocations. Our calculations also reveal how these reactions may be affected by intermolecular interactions with S-adenosylmethionine.
The Journal of Organic Chemistry 12/2012; · 4.45 Impact Factor
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ABSTRACT: The Davis-Beirut reaction, which provides an efficient synthesis of 2H-indazoles and, subsequently, indazolones, is shown to proceed rapidly from o-nitrosobenzaldehyde and primary amines under both acid or base catalysis. Experimental and theoretical evidence in support of a reaction mechanism is provided in which o-nitrosobenzylidine imine is a pivotal intermediate in this N,N-bond forming heterocyclization reaction. The Davis-Beirut reaction is also shown to effectively synthesize a number of novel 3-amino-2H-indazole derivatives.
Tetrahedron Letters 11/2012; 53(48):6475-6478. · 2.68 Impact Factor
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ABSTRACT: The Prins cyclization of syn-beta-hydroxy allylsilanes and aldehydes gives cis-2,6-disubstituted 4-alkylidene tetrahydropyrans as sole products in excellent yields regardless of the aldehyde (R") or syn-beta-hydroxy allylsilane substituent (R') used. By reversing the R" and R' groups, complementary exocyclic stereocontrol can be achieved. When the anti-beta-hydroxy allylsilanes are used, the Prins cyclization gives predominantly cis-2,6-disubstituted 4-alkylidene tetrahydropyrans, now with the opposite olefin geometry in excellent yield. The proposed reaction mechanism and the observed stereoselectivity for these processes are supported by DFT calculations.
The Journal of Organic Chemistry 11/2012; · 4.45 Impact Factor
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ABSTRACT: Quantum chemical computations (B3LYP/LACVP**) were applied to assess the impact of Au(I) complexation on activation barriers for sequential electrocyclization reactions (one a 1,2-dihydroazete ring-opening and another a pentadienyl cation ring-closure) proposed to occur during a complex reaction cascade that converts alkynes and imines to cyclopentenimines.
Journal of Molecular Modeling 09/2012; · 1.80 Impact Factor
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ABSTRACT: The nature of the recently described "triple shift" rearrangement of a biologically relevant carbocation (computed in the absence of a surrounding enzyme) is characterized by examining the evolution of charge distribution, molecular volume, accessible surface area, and multicenter bonding indices along its reaction coordinate. Implications for interaction of the rearranging carbocation with a terpene synthase active site are discussed.
The Journal of Physical Chemistry A 08/2012; 116(35):8902-9. · 2.95 Impact Factor
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ABSTRACT: Dyotropic rearrangements of fused, tricyclic β-lactones are described that proceed via unprecedented stereospecific, 1,2-acyl migrations delivering bridged, spiro-γ-butyrolactones. A unique example of this dyotropic process involves a fused bis-lactone possessing both β- and δ-lactone moieties which enabled rapid access to the core structures of curcumanolide A and curcumalactone. Our current mechanistic understanding of the latter dyotropic process, based on computational studies, is also described. Other key transformations in the described divergent syntheses of (-)-curcumanolide A and (-)-curcumalactone from a common intermediate (11 and 12 steps from 2-methyl-1,3-cyclopentanedione, respectively), include a catalytic, asymmetric nucleophile (Lewis base)-catalyzed aldol-lactonization (NCAL) leading to a tricyclic β-lactone, a Baeyer-Villiger oxidation in the presence of a β-lactone, and highly facial-selective and stereocomplementary reductions of an intermediate spirocyclic enoate. The described dyotropic rearrangements significantly alter the topology of the starting tricyclic β-lactone, providing access to complex spirocyclic cyclopentyl-γ-lactones and bis-γ-lactones in a single synthetic operation.
Journal of the American Chemical Society 08/2012; 134(32):13348-56. · 9.91 Impact Factor
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ABSTRACT: DFT (both B3LYP and M06-2X), CASSCF, and CASPT2 calculations were used to investigate competing [3, 3] and [3, 5] sigmatropic shifts and intramolecular [4+2] cycloaddition of 1,3,7-octatriene. In accord with previous results on 1,5-hexadiene, CASSCF calculations found both stepwise and concerted pathways for the [3, 3] rearrangement. For the competing [3, 5] sigmatropic rearrangement, CASSCF and CASPT2 calculations revealed three stepwise pathways with similar barriers. UB3LYP and UM06-2X calculations predicted a different potential energy landscape: no stepwise [3, 3] pathway, only two competing [3, 5] sigmatropic shifts, and an intramolecular Diels-Alder cycloaddition/homolytic ring-opening pathway. Significant lowering of barriers for all rearrangements was predicted for some 1,3,7-octatrienes with substituents at the 4- and 7-positions.
Chemistry 07/2012; 18(35):11029-35. · 5.93 Impact Factor
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ABSTRACT: Density functional theory calculations are used to predict structures and reactivity (barriers for sigmatropic shifts and retrocycloadditions) of 1,5-hexadienes fused to cubanes.
Physical Chemistry Chemical Physics 07/2012; 14(43):14756-9. · 3.57 Impact Factor
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ABSTRACT: Mechanistic proposals for the carbocation cascade reaction leading to the tricyclic sesquiterpene pentalenene are assessed in light of the results of isotopically sensitive branching experiments with the H309A mutant of pentalenene synthase. These experimental results support a mechanism for pentalenene formation involving a 7-protoilludyl cation whose intermediacy was first predicted using quantum-chemical calculations.
Journal of the American Chemical Society 06/2012; 134(28):11369-71. · 9.91 Impact Factor
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ABSTRACT: Quantum chemical calculations on possible decomposition processes for ladderane lipids are described. Based on the results of these calculations, it is proposed that hydrogen atom abstraction next to the ladderane core can lead to opening of the cyclobutane rings comprising the ladderane substructure, and protonation leads directly to fragmentation. Potential biological implications of these processes are discussed.
Organic & Biomolecular Chemistry 06/2012; 10(29):5514-7. · 3.70 Impact Factor
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ABSTRACT: Several small molecule species formally known primarily as toxic gases have, over the past 20 years, been shown to be endogenously generated signaling molecules. The biological signaling associated with the small molecules NO, CO, H₂S (and the nonendogenously generated O₂), and their derived species have become a topic of extreme interest. It has become increasingly clear that these small molecule signaling agents form an integrated signaling web that affects/regulates numerous physiological processes. The chemical interactions between these species and each other or biological targets is an important factor in their roles as signaling agents. Thus, a fundamental understanding of the chemistry of these molecules is essential to understanding their biological/physiological utility. This review focuses on this chemistry and attempts to establish the chemical basis for their signaling functions.
Chemical Research in Toxicology 02/2012; 25(4):769-93. · 3.78 Impact Factor
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ABSTRACT: Subtle differences between carbocation rearrangements leading to the pinene/camphene, ylangene/sativene and bergamotene/santalene terpenes are revealed.
Chemical Communications 02/2012; 48(10):1571-3. · 6.17 Impact Factor
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ABSTRACT: We report the total synthesis of (-)-N-methylwelwitindolinone C isonitrile, in addition to the total syntheses of the 3-hydroxylated welwitindolinones. Our routes to these elusive natural products feature the strategic use of a deuterium kinetic isotope effect to improve the efficiency of a late-stage nitrene insertion reaction. We also provide a computational prediction for the stereochemical configuration at C3 of the hydroxylated welwitindolinones, which was confirmed by experimental studies.
Journal of the American Chemical Society 01/2012; 134(3):1396-9. · 9.91 Impact Factor
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ABSTRACT: Strategies for the formation of carbon-carbon bonds from the α-thioaryl carbonyl products of substituted lactams are described. Although direct functionalization is possible, a two step process of oxidation and magnesium-sulfoxide exchange has proven optimal. The oxidation step results in the formation of two diastereomers that exhibit markedly different levels of stability toward elimination, which is rationalized on the basis of quantum mechanical calculations and X-ray crystallography. Treatment of the sulfoxide with i-PrMgCl results in the formation of a magnesium enolate that will undergo an intramolecular Michael addition reaction to form two new stereogenic centers. The relationship between the substitution patterns of the sulfoxide substrate and the efficiency of the magnesium exchange reaction are also described.
The Journal of Organic Chemistry 01/2012; 77(1):160-72. · 4.45 Impact Factor
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ABSTRACT: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing ΔF508-CFTR targeting) and potentiator ("Po", normalizing ΔF508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only, and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search ⇒ force-field lowest energy assessment ⇒ geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo's may adopt two distinct π-stacking conformations to elicit corrector and potentiator activities.
Journal of Medicinal Chemistry 01/2012; 55(3):1242-51. · 4.80 Impact Factor
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Journal of chemical education 01/2012; 89(11):1400–1404. · 0.74 Impact Factor
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The Journal of Organic Chemistry 11/2011; · 4.45 Impact Factor
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Chemical Reviews 11/2011; 112(3):1839-62. · 40.20 Impact Factor
