Intramolecular Interaction of Adjacent Hydroxymethyl, Formyl, and Carboxyl Groups: Proximity Effect in the Swern Oxidation of <i>cis</i>,<i>cis</i>-1,3,5-Tris(hydroxymethyl)-1,3,5-trimethylcyclohexane

The proximity effect in the Swern oxidation of cis,cis-1,3,5-tris(hydroxymethyl)-1,3,5-trimethylcyclohexane (4) with TFAA was examined. The oxidation reaction of triol 4 with DMSO, TFAA, and relatively small amounts of triethylamine gave 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid hemiacetal (7a) as well as 1,7,9-trimethyl-3,5,12-trioxawurtzitane (6), 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone (5), and polymers of cis,cis-1,3,5-triformyl-1,3,5-trimethylcyclohexane (2). Hemiacetal 7a underwent novel solvent-dependent conversions to hemiacetal 7b, lactone 5, or 1,7,9-trimethyl-2-oxo-3,5-dioxatricyclo[5.3.1.04,9]undecane (8) via 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid. In the cases of relatively large amounts of triethylamine, trialdehyde 2 was given in moderate yield

Hydride-Transfer Domino Rearrangement of Glycine-Containing Dioxa-azawurtzitane

The novel synthetic method for dioxa-azawurtzitanes to selectively cap amino groups in amino acids or peptides is described. Mixing the CH3CN solution of cis,cis-1,3,5-triformyl-1,3,5-trimethylcyclohexane (2) with the aqueous solution of the equimolar amounts of glycine and NaHCO3 yields glycine-containing dioxa-azawurtzitane 7-Na. Dioxa-azawurtzitane 7-Na almost quantitatively isomerizes to lactone-imine 9-Na through the hydride-transfer rearrangement in CH3CN/H2O. Lactone-imine 9-Na also isomerizes to lactam-aldehyde 12-Na in DMSO

Chiroptical Properties of Organic Radical Cations. The Electronic and Vibrational Circular Dichroism Spectra of α-Tocopherol Derivatives and Sterically Hindered Chiral Hydroquinone Ethers

Qualitatively and quantitatively reliable electronic and vibrational circular dichroism (ECD and VCD) spectra of chiral organic radical cations were obtained for the first time with α-tocopherol derivatives and sterically hindered chiral hydroquinone ethers. The isolation and spectral measurements of chiral radical cation salts were made possible by using nitrosonium or antimony derivatives as electron-transfer oxidants, which can cleanly oxidize the substrate donors without giving any byproducts in the sample solution. Such reliable ECD spectra enabled us to fully examine the chiroptical properties of organic radical cations and also compare them with those of the corresponding neutral compounds. The observed VCD spectra of neutral and radical cationic species of chiral hydroquinone ether were nicely simulated by density functional theory (DFT) calculations, from which the relative contribution of each radical cation conformer in solution was evaluated. Thus, the combined synthetic, spectroscopic, and theoretical protocol, composed of chiral modification, clean oxidation to form stable radical cations, ECD/VCD spectral analyses, and DFT calculations, was demonstrated to be a powerful, indispensable tool for elucidating a comprehensive picture of radical cationic species in solution

Effect of Conformational Variability on Seasonable Thermal Stability and Cell Entry of Omicron Variants

The Omicron BA.1 variant of SARS-CoV-2 preferentially infects through the cathepsin-mediated endocytic pathway, but the mechanism of cell entry has not been solved yet because BA.4/5 is more fusogenic and more efficiently spread in human lung cells than BA.2. It has been unclear why the Omicron spike is inefficiently cleaved in virions compared with Delta, and how the relatively effective reproduction proceeds without the cell entry through plasma membrane fusion. Conformational variability from deep neural network-based prediction correlates well with the thermodynamic stability of variants. The difference of seasonable pandemic variants in summer and those in winter is distinguishable by this conformational stability, and the geographical optimization of variants is also traceable. Further, the predicted conformational variability maps rationalize the less efficient S1/S2 cleavage of Omicron variants and provide a valuable insight into the cell entry through the endocytic pathway. It is concluded that conformational variability prediction is able to complement transformation information on motifs in protein structures for drug discovery

Fliplike Motion in the Thalidomide Dimer: Conformational Analysis of (<i>R</i>)-Thalidomide Using Vibrational Circular Dichroism Spectroscopy

The dynamic fliplike motion in the (R)-thalidomide dimer has been reported for the first time. The vibrational circular dichroism (VCD) spectrum of (R)-thalidomide in DMSO-d6 indicates the characteristic νCO bands with opposite signs and reflects the structural property of the equatorial configuration of the phthalimide ring. On the other hand, the VCD spectrum of (R)-thalidomide in CDCl3 exhibits a different pattern of νCO bands and suggests the fliplike motion in dimer forms. This novel insight for the dimer forms would be helpful for the understanding of the structure−activity relationship for thalidomide

Analysis of peak areas (as a per cent of the total) for 35 representative constituents of wolf urine samples A, B and C.

<p>The median area is shown for six MS experiments. *Positively identified by GC-quadropole MS and by matching the retention times against identified chemicals in wolf urine. The chemicals without symbols were tentatively rather than positively identified by GC-quadropole MS. ^†Signifies a significantly higher peak area, whereas #signifies a significantly lower peak area, in sample C compared with either sample A or B, as assessed by the Kruskal-Wallis test and the Steel-Dwass post-hoc test.</p

Effect of Conformational Variability on the Drug Resistance of Candida auris ERG11p and FKS1

Candida auris infection has been recognized as an urgent threat to antifungal drug resistance, and the Eagle effect of C. auris FKS1 (1,3-β-d-glucan synthase) wild-type isolates has also been noted. The Eagle effect, namely, where higher concentrations of antifungals reduce fungicidal activity relative to lower concentrations, is a confounding factor of apparent antifungal resistance, but the detailed mechanism remains unclear. Here, we present the conformational variability of mutation sites for ERG11p (lanosterol 14α-demethylase) and FKS1 from deep neural network-based prediction along with the reported X-ray crystallographic and cryo-electron microscopy (cryo-EM) structures of antifungals. The sequence variability maps provide valuable insights into the inconsistent correlation between azole resistance and the mysterious Eagle effect with the dispersion of minimal inhibitory concentration (MIC) for echinocandin resistance. The conformational variability prediction supports the hypothesis that mutations K143R of clade I, VF125AL of clade III, and Y132F of clade IV for C. auris ERG11p make the corresponding site variable and that an increased population of invisible variable conformations potentially contributes to triazole resistance. In contrast, the predicted rigid conformation by the S639F mutation of hot spot region 1 (HS1) for FKS1 suggests that caspofungin (CAS) is involved in an uncompetitive inhibition, and a decreased population of the CAS-bound state of FKS1 with Rho1 leads to drug resistance. The predicted variable HS1 region for FKS1 WT isolates and the rigid one for FKS1 S639F mutants support the in vivo drug response and the in vitro MIC dispersion. A plausible mechanism of the Eagle effect is hereby proposed, namely, that a high concentration of CAS with a high membrane affinity reduces the population of the CAS-bound state of FKS1 with Rho1, as well as accompanying events such as aggregation or association depending on the conformational variability of HS1

Synthesis and Cyclization Reaction of <i>cis,cis</i>-1,3,5-Triformyl-1,3,5-trimethylcyclohexane

Synthesis and Cyclization Reaction of cis,cis-1,3,5-Triformyl-1,3,5-trimethylcyclohexan

Comparison of freezing (immobilization) duration in mice during a 3 min exposure to (a) undiluted wolf urine samples and (b) 5-fold diluted wolf urine samples.

<p>The statistical significance of the differences between the freezing duration in response to wolf urine samples compared with control (water) was assessed by ANOVA followed by Fisher’s PLSD post-hoc test (*P<0.05, **P<0.01 vs. control).</p

Revisiting Vibrational Circular Dichroism Spectra of (S)-(+)-Carvone and (1S,2R,5S)-(+)-Menthol Using SimIR/VCD Method

The VCD spectra of (<i>S</i>)-(+)-carvone and (1<i>S</i>,2<i>R</i>,5<i>S</i>)-(+)-menthol are recalculated using the DFT method with extended conformation and configuration spaces. The calculated individual and averaged spectra are compared against observed ones using the previously reported similarity index, <i>S</i>_V. It is found that the <i>S</i>_V population forms approximately two normal distributions, depending on whether a spectrum matches the observed one or not. This statistical character can be used to estimate the error in absolute configuration (AC) assessments. To avoid erroneous AC assignments and incomplete conformation searching, it is advisible to employ a minimum |<i>S</i>_V| of 0.2 and maximize it using conformation averaging. It is demonstrated that this approach is suitable and robust for flexible chiral molecules