A Computational Study of Regioselectivity in a Cyclodextrin‐Mediated Diels–Alder Reaction: Revelation of Site Selectivity and the Importance of Shallow Binding and Multiple Binding Modes

Abstract

The use of a cyclodextrin.Diels-Alder transition structure complex (CD.TS) as a model in molecular dynamics simulations has enabled us to gain insight into the controlling factors in the cyclodextrin-mediated Diels-Alder reaction of methyl-p-benzoquinone with isoprene. MD simulations were carried out with multiple binding configurations of the CD.TS (TS=meta-TS, para-TS) complexes at the top and bottom rims of beta-CD. We discovered that i) only shallow binding with the CD is necessary for the regioselectivity, and multiple binding geometries are possible; ii) the narrow bottom rim, with the primary hydroxyl groups, of the CD binds both regio-TSs better than at the wider top rim (secondary hydroxyl groups), which was unexpected from the perspective of shape complementarity that governs the stability of most CD.guest complexes. Overall, the bottom rim of the CD exhibits higher regioisomer discrimination for the meta-TS; iii) structural clustering analyses of the CD.TS configurations (sampled during MD simulations) have enabled us to evaluate the binding energies of the different binding configurations. The result indicates that there is a direct correlation between meta-product selectivity and a higher number of binding configurations favoring the formation of the CD.meta-TS complex. The main forces of stabilization in the CD.TS complexes are the van der Waals interactions when the TS is bound at the top rim. At the bottom rim, closer contacts between polar functional groups of the TS and CD have increased the importance of electrostatic interactions. We found that van der Waals, solvation, and torsional forces are less favorable for complexation at the bottom rim; however, this is compensated by large favorable electrostatic interactions. With insights obtained from the study of CD.TS complexes and MD simulations of the modified heptakis-[6-O-(2-hydroxy)propyl]-beta-CD, we were able to explain why a low selectivity was observed when the Diels-Alder reaction was carried out in this modified CD. Two types of search method [Monte Carlo and multiple minimum (MCMM) and molecular dynamics (MD)] to explore and evaluate the different possible binding geometries of the TS within beta-CD, were discussed.

Is [N+−H···O] Hydrogen Bonding the Most Important Noncovalent Interaction in Macrocycle−Dibenzylammonium Ion Complexes?

“…The sampled structures were then minimized with use of the PR conjugated gradient method to obtain the lowest energy structure in each simulation. A previous study on β-cyclodextrin complexes has shown this method of locating low-energy structures to be superior to using the Monte Carlo multiple minimum (MCMM) search in MacroModel . During the MD simulations, the guest changes orientation and position in the host, but no decomplexation was observed.…”

Computational study on new natural compound agonists of dopamine receptor

“…According to the results, the Root Mean Square Deviation (RMSD) was 0.6Å. It was between the complex's crystal structure and the docked pose [22]. It indicated that CDOCKER module was very believable in this study.…”