9 research outputs found
Synthetic Applications and Mechanistic Studies of the Hydroxide-Mediated Cleavage of CarbonāCarbon 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 NāHeterocyclic Carbene Complex
Primary alcohols
have been reacted with hydroxide and the ruthenium
complex [RuCl<sub>2</sub>(I<i>i</i>Pr)Ā(<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)Āether 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, Ī²-hydride
elimination, hydroxide attack on the coordinated aldehyde, and a second
Ī²-hydride elimination to furnish the carboxylate
Mechanistic Investigation of Palladium-Catalyzed Allylic CāH Activation
The mechanism for the palladium-catalyzed allylic CāH
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 CāH 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 CāH activation
step. The reoxidation of palladium was found to reach an energy level
similar to that of the CāH activation. Calculations of turnover
frequencies for the entire catalytic cycle for the CāH 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 (CāH alkylation)
and an intermolecular fashion (CāH acetoxylation and CāH
amination)
MaÅ”a MlinariÄ - Forma v gibanju
Mrežno ali geometrijsko naravnani prostor slikovnega polja in njegov Ā»podaljÅ”ekĀ« v razÅ”irjeno sliko ā v slikarski objekt (B. Riley, V. Richter, D. JejÄiÄ), se v povezovalnem Å”tudijskem procesu formira najprej kot izkuÅ”nja z risbo in nato kot slikarska izkuÅ”nja. Oboje se ob izpitu nato vzporedno artikulira v znanju, s Å”iroko oporo likovne teorije (V. Vasarelly- Op Art in entnografska povezava z tradicionalnimi vezeninami), s podroÄjem umetnostne zgodovine ter z drugimi povezavami, kot je prostorsko oblikovanje ali podroÄje glasbe (P. Mondrian-Ā»Bugi WugiĀ«) ali skozi signalistiÄno poezijo (ZagoriÄnik-Ā»West EstĀ«), ki se nato kot refleksija izgovarja kot priprava v uÄnih naÄrtih
<i>Cis</i>ā<i>Trans</i> Amide Bond Rotamers in Ī²āPeptoids 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 Ī²-peptoids (N-alkyl-Ī²-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>ā<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 Ī±-peptoids, we present the synthesis and investigation
of <i>cis</i>ā<i>trans</i> isomerism in
the first examples of peptoids and Ī²-peptoids containing thioamide
bonds as well as trifluoroacetylated peptoids and Ī²-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 thioamideāaromatic
interactions through C<sub>sp<sup>2</sup></sub>āHĀ·Ā·Ā·S<sub>amide</sub> hydrogen bonding, which stabilize certain peptoid conformations
<i>Cis</i>ā<i>Trans</i> Amide Bond Rotamers in Ī²āPeptoids 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 Ī²-peptoids (N-alkyl-Ī²-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>ā<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 Ī±-peptoids, we present the synthesis and investigation
of <i>cis</i>ā<i>trans</i> isomerism in
the first examples of peptoids and Ī²-peptoids containing thioamide
bonds as well as trifluoroacetylated peptoids and Ī²-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 thioamideāaromatic
interactions through C<sub>sp<sup>2</sup></sub>āHĀ·Ā·Ā·S<sub>amide</sub> 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 enzymeāligand
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 1ā3,
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 TroĢgerās Base: A Comparative Spectroscopic and Computational Study
The first reported twisted bis-lactam,
a racemic TroĢgerās
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 (ā)-<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/6-31GĀ(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>2<sub>1</sub>2<sub>1</sub>2<sub>1</sub> using Cu-irradiation resulting
in a very low Flack parameter of ā0.06(3), despite the heaviest
element being an oxygen atom, thus unambiguously confirming the results
from the spectroscopic studies. We conclude that, for the TroĢgerās
base (TB) analogue (<b>2</b>), we may rank the reliability of
the individual methods for AC determination as AXRD ā« 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 (ā)-(<i>S</i>,<i>S</i>)-<b>2</b>
Nicotinamide Phosphoribosyltransferase Inhibitors, Design, Preparation, and StructureāActivity Relationship
Existing pharmacological
inhibitors for nicotinamide phosphoribosyltransferase
(NAMPT) are promising therapeutics for treating cancer. By using medicinal
and computational chemistry methods, the structureāactivity
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>: IC<sub>50</sub> 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 mm<sup>3</sup>), 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 1ā9. 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