Synthetic Applications and Mechanistic Studies of the Hydroxide-Mediated Cleavage of Carbon–Carbon Bonds in Ketones

The hydroxide-mediated cleavage of ketones into alkanes and carboxylic acids has been reinvestigated and the substrate scope extended to benzyl carbonyl compounds. The transformation is performed with a 0.05 M ketone solution in refluxing xylene in the presence of 10 equiv of potassium hydroxide. The reaction constitutes a straightforward protocol for the synthesis of certain phenyl-substituted carboxylic acids from 2-phenylcycloalkanones. The mechanism was investigated by kinetic experiments which indicated a first order reaction in hydroxide and a full negative charge in the rate-determining step. The studies were complemented by a theoretical investigation where two possible pathways were characterized by DFT/M06-2X. The calculations showed that the scission takes place by nucleophilic attack of hydroxide on the ketone followed by fragmentation of the resulting oxyanion into the carboxylic acid and a benzyl anion

Dehydrogenative Synthesis of Carboxylic Acids from Primary Alcohols and Hydroxide Catalyzed by a Ruthenium N‑Heterocyclic Carbene Complex

Primary alcohols have been reacted with hydroxide and the ruthenium complex [RuCl₂(I<i>i</i>Pr)­(<i>p</i>-cymene)] to afford carboxylic acids and dihydrogen. The dehydrogenative reaction is performed in toluene, which allows for a simple isolation of the products by precipitation and extraction. The transformation can be applied to a range of benzylic and saturated aliphatic alcohols containing halide and (thio)­ether substituents, while olefins and ester groups are not compatible with the reaction conditions. Benzylic alcohols undergo faster conversion than other substrates, and a competing Cannizzaro reaction is most likely involved in this case. The kinetic isotope effect was determined to be 0.67 using 1-butanol as the substrate. A plausible catalytic cycle was characterized by DFT/B3LYP-D3 and involved coordination of the alcohol to the metal, β-hydride elimination, hydroxide attack on the coordinated aldehyde, and a second β-hydride elimination to furnish the carboxylate

Mechanistic Investigation of Palladium-Catalyzed Allylic C–H Activation

The mechanism for the palladium-catalyzed allylic C–H activation was investigated using a combination of experimental and theoretical methods. A Hammett study revealed a buildup of a partial negative charge in the rate-determining step, and determination of the kinetic isotope effect (KIE) indicated that the C–H bond is broken in the turnover-limiting transition state. These experimental findings were further substantiated by carrying out a detailed density functional theory (DFT)-based investigation of the entire catalytic cycle. The DFT modeling supports a mechanism in which a coordinated acetate acts as a base in an intramolecular fashion during the C–H activation step. The reoxidation of palladium was found to reach an energy level similar to that of the C–H activation. Calculations of turnover frequencies for the entire catalytic cycle for the C–H alkylation were used to acquire a better understanding of the experimental KIE value. The good correspondence between the experimental KIE and the computed KIE values allows discrimination between scenarios where the acetate is acting in an intramolecular fashion (C–H alkylation) and an intermolecular fashion (C–H acetoxylation and C–H amination)

Maša Mlinarič - Forma v gibanju

Mrežno ali geometrijsko naravnani prostor slikovnega polja in njegov »podaljšek« v razširjeno sliko – v slikarski objekt (B. Riley, V. Richter, D. Jejčič), se v povezovalnem študijskem procesu formira najprej kot izkušnja z risbo in nato kot slikarska izkušnja. Oboje se ob izpitu nato vzporedno artikulira v znanju, s široko oporo likovne teorije (V. Vasarelly- Op Art in entnografska povezava z tradicionalnimi vezeninami), s področjem umetnostne zgodovine ter z drugimi povezavami, kot je prostorsko oblikovanje ali področje glasbe (P. Mondrian-»Bugi Wugi«) ali skozi signalistično poezijo (Zagoričnik-»West Est«), ki se nato kot refleksija izgovarja kot priprava v učnih načrtih

<i>Cis</i>–<i>Trans</i> Amide Bond Rotamers in β‑Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains

Non-natural peptide analogs have significant potential for the development of new materials and pharmacologically active ligands. One such architecture, the β-peptoids (N-alkyl-β-alanines), has found use in a variety of biologically active compounds but has been sparsely studied with respect to folding propensity. Thus, we here report an investigation of the effect of structural variations on the <i>cis</i>–<i>trans</i> amide bond rotamer equilibria in a selection of monomer model systems. In addition to various side chain effects, which correlated well with previous studies of α-peptoids, we present the synthesis and investigation of <i>cis</i>–<i>trans</i> isomerism in the first examples of peptoids and β-peptoids containing thioamide bonds as well as trifluoroacetylated peptoids and β-peptoids. These systems revealed an increase in the preference for <i>cis</i>-amides as compared to their parent compounds and thus provide novel strategies for affecting the folding of peptoid constructs. By using NMR spectroscopy, X-ray crystallographic analysis, and density functional theory calculations, we present evidence for the presence of thioamide–aromatic interactions through C_sp²–H···S_amide hydrogen bonding, which stabilize certain peptoid conformations

<i>Cis</i>–<i>Trans</i> Amide Bond Rotamers in β‑Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains

Non-natural peptide analogs have significant potential for the development of new materials and pharmacologically active ligands. One such architecture, the β-peptoids (N-alkyl-β-alanines), has found use in a variety of biologically active compounds but has been sparsely studied with respect to folding propensity. Thus, we here report an investigation of the effect of structural variations on the <i>cis</i>–<i>trans</i> amide bond rotamer equilibria in a selection of monomer model systems. In addition to various side chain effects, which correlated well with previous studies of α-peptoids, we present the synthesis and investigation of <i>cis</i>–<i>trans</i> isomerism in the first examples of peptoids and β-peptoids containing thioamide bonds as well as trifluoroacetylated peptoids and β-peptoids. These systems revealed an increase in the preference for <i>cis</i>-amides as compared to their parent compounds and thus provide novel strategies for affecting the folding of peptoid constructs. By using NMR spectroscopy, X-ray crystallographic analysis, and density functional theory calculations, we present evidence for the presence of thioamide–aromatic interactions through C_sp²–H···S_amide hydrogen bonding, which stabilize certain peptoid conformations

Methyl Effect in Azumamides Provides Insight Into Histone Deacetylase Inhibition by Macrocycles

Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides (J. Med. Chem. 2013, 56, 6512). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme–ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1–3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes

Resolution and Determination of the Absolute Configuration of a Twisted Bis-Lactam Analogue of Tröger’s Base: A Comparative Spectroscopic and Computational Study

The first reported twisted bis-lactam, a racemic Tröger’s base (TB) analogue (<b>2</b>), was resolved into its enantiomers on a chiral stationary phase HPLC column. The absolute configuration of (+)-<b>2</b> was determined to be (<i>R</i>,<i>R</i>)-<b>2</b> by comparing experimental and calculated vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectra. The absolute configuration of (−)-<b>2</b> was determined by comparing experimental and calculated electronic circular dichroism (ECD) spectra. The corresponding theoretical spectra were calculated using the lowest energy conformation of (<i>R</i>,<i>R</i>)-<b>2</b> and (<i>S</i>,<i>S</i>)-<b>2</b> at the B3LYP/6-31G­(d,p) level of theory. The absolute configuration of (+)-<b>2</b> was also determined to (<i>R</i>,<i>R</i>)-<b>2</b> by anomalous X-ray diffraction (AXRD) in a chiral space group <i>P</i>2₁2₁2₁ using Cu-irradiation resulting in a very low Flack parameter of −0.06(3), despite the heaviest element being an oxygen atom, thus unambiguously confirming the results from the spectroscopic studies. We conclude that, for the Tröger’s base (TB) analogue (<b>2</b>), we may rank the reliability of the individual methods for AC determination as AXRD ≫ VCD > ECD, while the synergy of all three methods provides very strong confidence in the assigned ACs of (+)-(<i>R</i>,<i>R</i>)-<b>2</b> and (−)-(<i>S</i>,<i>S</i>)-<b>2</b>

Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and Structure–Activity Relationship

Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure–activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound <b>15</b>: IC₅₀ 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm³), compound <b>15</b> reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1–9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT