The mechanism of Cu^I-catalyzed allylic alkylation and the influence of the leaving groups (OPiv, SPiv, Cl, SPO(OiPr)₂; Piv: pivavloyl) on the regioselectivity of the reaction have been explored by using density functional theory (DFT). A comprehensive comparison of many possible reaction pathways shows that [(iPr)₂Cu]⁻ prefers to bind first oxidatively to the double bond of the allylic substrate at the anti position with respect to the leaving group, and this is followed by dissociation of the leaving group. If the leaving group is not taken into account, the reaction then undergoes an isomerization and a reductive elimination process to give the α- or γ-selective product. If OPiv, SPiv, Cl, or SPO(OiPr)₂ groups are present, the optimal route for the formation of both α- and γ-substituted products changes from the stepwise elimination to the direct process, in which the leaving group plays a stabilizing role for the reactant and destabilizes the transition state. The differences to the energy barrier for the α- and γ-substituted products are 2.75 kcal mol⁻¹ with SPO(OiPr)₂, 2.44 kcal mol⁻¹ with SPiv, 2.33 kcal mol⁻¹ with OPiv, and 1.98 kcal mol⁻¹ with Cl, respectively; these values show that α regioselectivity in the allylic alkylation follows a SPO(OiPr)₂>SPiv>OPiv>Cl trend, which is in satisfactory agreement with the experimental findings. This trend mainly originates in the differences between the attractive electrostatic forces and the repelling steric interactions of the SPO(OiPr)₂, SPiv, OPiv, and Cl groups on the Cu group.

Quantum chemical calculations have been performed to explore the mechanism of intramolecular cyclization of 2-benzyloxyphenyl trimethylsilyl ketone (acylsilane) to give the benzofuran derivatives stereoselectively. This reaction involves a formation of siloxycarbene intermediate and a C–H bond insertion of siloxycarbene. The comparative studies on three possible insertion of siloxycarbene show that the concerted insertion of siloxycarbene into C–H bond (pathway a), which needs overcoming an energy barrier of 45.1 kcal/mol, is the most unlikely pathway, and the stepwise insertion of siloxycarbene without spin multiplicity change (pathway c) is energetically more favorable than the stepwise insertion of siloxycarbene with spin multiplicity change (pathway b). More importantly, this work can provide an insight into the stereoselectivity in this reaction in atomic molecular level. The formation of siloxycarbene is calculated to be endergonic by 22.9 kcal/mol with an energy barrier of 30.2 kcal/mol, being the rate-determining step of the whole process. Copyright © 2011 John Wiley & Sons, Ltd.

The conformation change picture of human islet amyloid polypeptide (hIAPP) is outlined using molecular dynamics simulation, and the structural influences of L16Q, S20G, and L16Q-S20G mutations on the conformation of hIAPP are analyzed. Particularly, the conformational changes of the amyloidogenic-related regions of residues 15–17 and 20–29 are emphasized. Our studies find that, for WT hIAPP, residues 15–17 always maintain a stable α-helix structure, residues 20–25 structurally fluctuate between turn and 5-helix, and residues 26–29 mainly adopt coil and bend structures. The hydrogen bonds between the polar groups of hIAPP, long-rang van der Waals forces between the residues, and hydrophobic interactions between the residues of hIAPP are important driving forces to maintain the secondary structure of hIAPP. The replacement of leucine16 by glutamine stabilizes the helix structure of residues 15–17 and 20–23 of hIAPP monomer, and the structure of residues 24–29 fluctuates between helix and turn. The relatively stable helix structures of residues 15–17 and 20–29 are supposed to be beneficial for L16Q hIAPP to resist the aggregation as observed in the experiment. The substitution of serine20 by glycine drives residues 15–17 and 20–29 of hIAPP to transform from helix structure to β-strands or coil structures with higher extension and flexibility, which may promote the aggregation of hIAPP as the experiments reported. These results are significant to understand the aggregation mechanism of hIAPP monomer into the dimer, trimer, oligomers and fibrils associated with the type 2 diabetes at the atomic level.

The silver(I)-catalyzed synthesis picture of axially chiral allenes based on propargylamines has been outlined using density functional theory (DFT) method for the first time. Our calculations find that, the coordination of silver(I) into triple bond of propargylamines at anti-position of nitrogen shows a stronger activation on the triple bond than that at cis-position, which is favorable for the subsequent hydrogen transfer. The NBO charge analysis for the hydrogen transfer affirms the experimental speculation that this step is a hydride transfer process. The energy barrier of the anti-periplanar elimination of vinyl-silver is 26.9 kJ·mol⁻¹ lower than that of the syn-periplanar elimination, supporting that (−)-allene is the main product of this reaction. In a word, the most possible route for this reaction is that the silver(I) coordinates into the triple bond of propargylamines at anti-position of nitrogen, then the formed silver(I) complex undergoes a hydride transfer to give a vinyl-silver, finally the vinyl-silver goes through an anti-periplanar elimination to give (−)-allene. The hydride transfer with the energy barrier of 44.8 kJ·mol⁻¹ is the rate-limiting step in whole catalytic process. This work provides insight into why this reaction has a very high enantioselectivity.

Density functional calculations have been performed to comparatively investigate two possible pathways of Au(I)-catalyzed Conia-ene reaction of β-ketoesters with alkynes. Our studies find that, under the assistance of trifluoromethanesulfonate (TfO), the β-ketoester is the most likely to undergo Model II to isomerize into its enol form, in which TfO plays a proton transfer role through a 6-membered ring transition state. The coordination of the Au(I) catalyst to the alkynes triple bond can enhance the eletrophilic capability and reaction activity of the alkynes moiety, which triggers the nucleophilic addition of the enol moiety on the alkynes moiety to give a vinyl-Au intermediate. This cycloisomerizaion step is exothermal by 21.3 kJ/mol with an energy barrier of 56.0 kJ/mol. In the whole catalytic process, the protonation of vinyl-Au is almost spontaneous, and the formation of enol is a rate-limiting step. The generation of enol and the activation of Au(I) catalyst on the alkynes are the key reasons why the Conia-ene reaction can occur in mild condition. These calculations support that Au(I)-catalyzed Conia-ene reactions of β-ketoesters with alkynes go through the pathway 2 proposed by Toste.