54 research outputs found
Enantioselective Total Synthesis of (–)-Myrifabral A and B
A catalytic enantioselective approach to the Myrioneuron alkaloids (−)-myrifabral A and (−)-myrifabral B is described. The synthesis was enabled by a palladium-catalyzed enantioselective allylic alkylation, that generates the C(10) all-carbon quaternary center. A key N-acyl iminium ion cyclization forged the cyclohexane fused tricyclic core, while vinyl boronate cross metathesis and oxidation afforded the lactol ring of (−)-myrifabral A. Adaptation of previously reported conditions allowed for the conversion of (−)-myrifabral A to (−)-myrifabral B
Enantioselective synthesis of highly oxygenated acyclic quaternary center-containing building blocks via palladium-catalyzed decarboxylative allylic alkylation of cyclic siloxyketones
The development of a palladium-catalyzed enantioselective decarboxylative allylic alkylation of cyclic siloxyketones to produce enantioenriched silicon-tethered heterocycles is reported. The reaction proceeds smoothly to provide products bearing a quaternary stereocenter in excellent yields (up to 91% yield) with high levels of enantioselectivity (up to 94% ee). We further utilized the unique reactivity of the siloxy functionality to access chiral, highly oxygenated acyclic quaternary building blocks. In addition, we subsequently demonstrated the utility of these compounds through the synthesis of a lactone bearing vicinal quaternary-trisubstituted stereocenters
Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity
gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry
Stacking with No Planarity?
This viewpoint describes the results
obtained from matched molecular pair analyses and quantum mechanics
calculations that show unsaturated rings found in drug-like molecules
may be replaced with their saturated counterparts without losing potency
even if they are engaged in stacking interactions with the side chains
of aromatic residues
Reactions Of 1,3-Dibromo-1,1-Difluoro Compounds With 1,8-Diazabicyclo[5.4.0]Undec-7-Ene
Difluorodienes result from the double dehydrobromination of 4-aryl-1,3-dibromo-1,1-difluorobutanes with DBU. Attempted syntheses of analogous 4-alkyl or 4-alkoxy dienes yield monoelimination products under mild conditions and unexpected trifluoro compounds under more vigorous conditions. 4-Aryl-1,1-difluoro-1,3-butadienes react rapidly with 4-phenyl-1,2,4-triazoline-3,5-dione in Diels-Alder reactions, but these dienes are unreactive toward several other electron-deficient and electron-rich dienophiles
Enantioselective synthesis of highly oxygenated acyclic quaternary center-containing building blocks via palladium-catalyzed decarboxylative allylic alkylation of cyclic siloxyketones
The development of a palladium-catalyzed enantioselective decarboxylative allylic alkylation of cyclic siloxyketones to produce enantioenriched silicon-tethered heterocycles is reported. The reaction proceeds smoothly to provide products bearing a quaternary stereocenter in excellent yields (up to 91% yield) with high levels of enantioselectivity (up to 94% ee). We further utilized the unique reactivity of the siloxy functionality to access chiral, highly oxygenated acyclic quaternary building blocks. In addition, we subsequently demonstrated the utility of these compounds through the synthesis of a lactone bearing vicinal quaternary-trisubstituted stereocenters
Accelerating Effect of Triazolyl and Related Heteroaryl Substituents on S<sub>N</sub>Ar Reactions: Evidence of Hydrogen-Bond Stabilized Transition States
The
remarkable accelerating effect of 1,2,3-triazolyl substituents
on S<sub>N</sub>Ar reactions has been investigated through systematic
experiments and density functional theory calculations. The lone pair
electrons of an <i>ortho</i>-triazolo substituent play a
key role in lowering the activation energy for nucleophilic addition
via formation of a preferential hydrogen bond with the amine nucleophile
at the transition state for addition. In an extension of this finding,
a series of related heteroaryl groups with similar electron pair donor
properties have also been found to facilitate S<sub>N</sub>Ar reactions.
The experimentally determined solvent effect provides further support
for this rationale, which was utilized to achieve an <i>ortho</i>-selective substitution on a difluoroarene substrate
Application of 1,1-ADEQUATE, HMBC, and Density Functional Theory To Determine Regioselectivity in the Halogenation of Pyridine <i>N</i>‑Oxides
The 1,1-ADEQUATE
spectrum clearly shows specific two-bond proton
to carbon correlations to unequivocally distinguish the major and
minor regioisomers of ortho-halogenated pyridines and to aid in assignment
of the corresponding proton and carbon chemical shifts. M06-2X/6-31+GÂ(d,p)
free energies of the regioisomeric intermediates arising from deprotonation
correctly predict the experimentally observed preference and thus
can be used to tune the substituent pattern to yield a desired regiochemical
outcome
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The Magnitude of [C−H···O] Hydrogen Bonding in Molecular and Supramolecular Assemblies
Ab initio calculations at the MP2/6-311++G** level on model systems (N-methylpyridinium complexes of dimethyl ether and dimethyl phosphate anion) provide quantitative measures of the large stabilization energies that arise from [C−H···O] contacts in charged systems. These attractive interactions control (i) the self-assembly of bipyridinium-based catenanes and rotaxanes in solution, (ii) the self-organization of left-handed Z-DNA with alternating [dC−dG] sequences in the solid state, and (iii) the binding of pyridinium derivatives with single- and double-stranded DNA. Slightly attractive interactions occur between the donor ether and phosphate moieties and a neutral pyridine molecule in the gas phase. Electrostatic potential and solvation calculations demonstrate that [C−H···O] interactions which involve a cationic [C−H] donor are dominated by electrostatic terms
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