Inducible knockdown of a gene essential for cortical development impaired radial migration.

<p>(A) Immunoblot analysis of the inducible knockdown against the exogenously expressed Dab1 in HEK293T cells. Dab1 was decreased in the presence of the <i>Tol2</i>-inducible knockdown vector pT2K-TBI-shRNAmir-Dab1#2 following the application of Dox. (B) Quantitative real-time PCR data showing the efficiency of inducible knockdown against the endogenous Dab1 in cortical neurons. In the EGFP-positive cells that had been electroporated with pT2K-TBI-shRNAmir-Dab1#2, the expression level of Dab1 was significantly decreased compared with the control. (C) Inducible knockdown of Dab1 during cortical development. The empty control vector did not inhibit neuronal migration. The induction of mir-Dab1#2 expression resulted in impaired radial migration in the presence of Dox but not without Dox. Scale bar, 100 µm.</p

Computational Study on the Reaction Pathway of α-Bromoacetophenones with Hydroxide Ion: Possible Path Bifurcation in the Addition/Substitution Mechanism

The reaction of an α-haloketone with a nucleophile has three reaction channels: carbonyl addition, direct substitution, and proton abstraction. DFT calculations for the reaction of PhCOCH2Br with OH– showed that there exists an addition/substitution TS on the potential energy surface, in which OH– interacts with both the α- and carbonyl carbons. The intrinsic reaction coordinate calculations revealed that the TS serves as the TS for direct substitution for XC6H4COCH2Br with an electron-donating X or a X less electron-withdrawing than m-Cl, whereas the TS serves as the TS for carbonyl addition for derivatives with a X more electron-withdrawing than m-CF3. Trajectory calculations starting at respective TS indicated that the single TS can serve for the two mechanisms, substitution and addition, through path bifurcation after the TS for borderline substrates. The reaction is the first example of dynamic path bifurcation for fundamental reaction types of carbonyl addition and substitution

Proton-Transfer Reactions of Nitroalkanes: The Role of <i>aci</i>-Nitro Species

Proton-transfer reactions of two systems, ionization of a series of small carbon acids in water (the Pearson system) and reactions of substituted phenylnitromethanes, were examined in detail computationally. Comparison of experimental reactivity and pKa with calculated relative activation barrier and reaction energy for the Pearson system suggested that the origin of the well-know nitroalkane anomaly does not reside in the reactivity but in the equilibrium. For the reactions of substituted phenylnitromethanes, proton transfers among three species, PhCH2NO2, PhCHNO2−, and PhCHNO2H, were examined, and the role of the aci-nitro species (PhCHNO2H) was evaluated on the basis of its stability and reactivity. Protonation of PhCHNO2− by H2O was suggested to occur kinetically on the oxygen site, but due to its instability PhCHNO2H does not contribute to the overall reaction energetics. The protonation of PhCHNO2− under acidic conditions occurs on the oxygen site to give PhCHNO2H both kinetically and thermodynamically. The aci-nitro species thus formed appears to give PhCH2NO2 via intramolecular H2O-mediated proton transfer, but a possibility of the route through PhCHNO2−−C-protonation would not be fully eliminated

Catalyst-Directed Guidance of Sulfur-Substituted Enediolates to Stereoselective Carbon–Carbon Bond Formation with Aldehydes

A highly chemo-, regio-, and stereoselective glycolate aldol reaction of sulfur-substituted enediolates with aldehydes was developed by employing a l-cyclohexylglycine-derived chiral iminophosphorane as a catalyst. The key for establishing this protocol is the distinct ability of the iminophosphorane catalyst to precisely direct the equilibrium mixture of the enediolates toward the intermolecular carbon–carbon bond formation with simultaneous yet rigorous control of relative and absolute stereochemistry. The critical importance of the cyclohexyl substituents on the catalyst backbone in dictating the reaction pathway and the stereochemical outcome was elucidated through an extensive quantum analysis by density functional theory calculations

Catalyst-Directed Guidance of Sulfur-Substituted Enediolates to Stereoselective Carbon–Carbon Bond Formation with Aldehydes

A highly chemo-, regio-, and stereoselective glycolate aldol reaction of sulfur-substituted enediolates with aldehydes was developed by employing a l-cyclohexylglycine-derived chiral iminophosphorane as a catalyst. The key for establishing this protocol is the distinct ability of the iminophosphorane catalyst to precisely direct the equilibrium mixture of the enediolates toward the intermolecular carbon–carbon bond formation with simultaneous yet rigorous control of relative and absolute stereochemistry. The critical importance of the cyclohexyl substituents on the catalyst backbone in dictating the reaction pathway and the stereochemical outcome was elucidated through an extensive quantum analysis by density functional theory calculations

Reaction Pathways and Possible Path Bifurcation for the Schmidt Reaction

The N2 liberation from iminodiazonium ion (2-X) is a key step of the Schmidt rearrangement of ketones. Molecular orbital calculations showed that two concurrent reaction channels, syn-benzyl fragmentation and anti-Me rearrangement, exist for syn-2, whereas anti-2-X proceeds via a single TS. Substituent effect analyses of the reactions of syn-2-X gave concave-upward plots, typical for a concurrent reaction mechanism. On the other hand, the reactions of anti-2-X gave linear Hammett plots, indicative of a single reaction mechanism for all anti-2-X. IRC calculations, however, revealed that the TS led to either an anti-benzyl rearrangement or an anti-benzyl fragmentation product depending on the substituent. Thus, the change of the mechanism (identity of the product) could not be detected by the Hammett plots. Ab initio dynamics simulations for anti-2-X were found to follow the IRC path for X = p-NO2, giving the rearrangement product, and almost so for X = p-MeO, giving the fragmentation products. However, in borderline cases where X is less donating than p-MeO and less withdrawing than p-NO2, the trajectories did not follow the minimum energy path on the potential energy surface but gave both rearrangement and fragmentation products directly from the single TS. This is a novel example of path bifurcation for a closed shell anionic reaction. It was concluded that a reactivity-selectivity argument based on the traditional TS theory might not always be applicable even to a well-known textbook organic reaction

Catalyst-Directed Guidance of Sulfur-Substituted Enediolates to Stereoselective Carbon–Carbon Bond Formation with Aldehydes

A highly chemo-, regio-, and stereoselective glycolate aldol reaction of sulfur-substituted enediolates with aldehydes was developed by employing a l-cyclohexylglycine-derived chiral iminophosphorane as a catalyst. The key for establishing this protocol is the distinct ability of the iminophosphorane catalyst to precisely direct the equilibrium mixture of the enediolates toward the intermolecular carbon–carbon bond formation with simultaneous yet rigorous control of relative and absolute stereochemistry. The critical importance of the cyclohexyl substituents on the catalyst backbone in dictating the reaction pathway and the stereochemical outcome was elucidated through an extensive quantum analysis by density functional theory calculations

Catalyst-Directed Guidance of Sulfur-Substituted Enediolates to Stereoselective Carbon–Carbon Bond Formation with Aldehydes

A highly chemo-, regio-, and stereoselective glycolate aldol reaction of sulfur-substituted enediolates with aldehydes was developed by employing a l-cyclohexylglycine-derived chiral iminophosphorane as a catalyst. The key for establishing this protocol is the distinct ability of the iminophosphorane catalyst to precisely direct the equilibrium mixture of the enediolates toward the intermolecular carbon–carbon bond formation with simultaneous yet rigorous control of relative and absolute stereochemistry. The critical importance of the cyclohexyl substituents on the catalyst backbone in dictating the reaction pathway and the stereochemical outcome was elucidated through an extensive quantum analysis by density functional theory calculations

Deprotonation of 3(2H)-Furanone and 3(2H)-Thiophenone by Carbanions in the Gas Phase: Disproportionately High Aromaticity of the Transition State: An <i>Ab Initio</i> Study

The reversible deprotonation of 3(2H)-furanone (3H−O) and 3(2H)-thiophenone (3H−S) by a series of delocalized carbanions and by CN−, and the identity proton transfer of 3H−O to its conjugate base (3−−O) and of 3H−S to 3−−S have been studied at the MP2//6−31+G** level. The main objective has been to examine to what extent the aromaticity of 3−−O and 3−−S is expressed at the transition state of these reactions and how the intrinsic barriers are affected by the transition state aromaticity. Aromaticity parameters such as NICS values, HOMA and Bird Indices indicate a disproportionately high degree of aromatic stabilization of the transition state. This stabilization results in a reduction of the intrinsic barriers which is most clearly manifested in the identity reactions. However, these reductions are relatively modest compared to those reported previously for the identity proton transfers from the benzenium ion to benzene and of cyclopentadiene to its conjugate base, reflecting the smaller aromatic stabilization of 3−−O and 3−−S compared to those of benzene and cyclopentadienyl anion

Catalyst-Directed Guidance of Sulfur-Substituted Enediolates to Stereoselective Carbon–Carbon Bond Formation with Aldehydes

A highly chemo-, regio-, and stereoselective glycolate aldol reaction of sulfur-substituted enediolates with aldehydes was developed by employing a l-cyclohexylglycine-derived chiral iminophosphorane as a catalyst. The key for establishing this protocol is the distinct ability of the iminophosphorane catalyst to precisely direct the equilibrium mixture of the enediolates toward the intermolecular carbon–carbon bond formation with simultaneous yet rigorous control of relative and absolute stereochemistry. The critical importance of the cyclohexyl substituents on the catalyst backbone in dictating the reaction pathway and the stereochemical outcome was elucidated through an extensive quantum analysis by density functional theory calculations