Transannular Diels–Alder Reactivities of 14-Membered Macrocylic Trienes and Their Relationship with the Conformational Preferences of the Reactants: A Combined Quantum Chemical and Molecular Dynamics Study

Abstract

Transannular Diels-Alder (TADA) reactions that occur between the diene and dienophile moieties located on a single macrocyclic triene molecule have been recognized as effective synthetic routes toward realizing complex tricyclic molecules in a single step. In this paper, we report a comprehensive study on the TADA reactions of 14-membered cyclic triene macrocycles to yield A.B.C[6.6.6] tricycles using quantum chemical methods and using classical molecular dynamics simulations. A benchmark study has been performed to examine the reliability of the commonly used ab initio methods and hybrid density functional levels of theory in comparison with results from CCSD(T) calculations to accurately model TADA reactions. The energy barriers obtained using the M06-2X functional were found to be in quantitative agreement with the CCSD(T) level of theory using a reasonably large basis set. Conformational properties of the reactants have been systematically studied using extensive molecular dynamics (MD) simulations. For this purpose, model systems were conceived, and force field parameters corresponding to the dihedral terms in the potential energy function were obtained. Linear relationship between the activation energies corresponding to the TADA reactions and the probability of finding the reactant in certain conformational states was obtained. A clustering method along with optimizations at the molecular mechanics and density functional M06-2X levels has been used to locate the most stable conformation of each of the trienes.

Computational Study of a Model System of Enzyme-Mediated [4+2] Cycloaddition Reaction

“…The increase of molecular complexity led to a more pronounced asynchrony of the C-C bonds formation. The result is in a good agreement with the earlier DFT calculations of the [4+2] transition states [ 41 , 42 , 43 , 44 , 45 , 46 , 83 ].…”

“…DFT methods were proven to provide reliable and accurate results for the correct description of different types of cycloaddition reactions, in particular the [4+2] cycloaddition [ 61 , 62 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ] and its transannular variant, implemented in the synthesis of Spinosyn A [ 83 ]. Reaction ( a ) was investigated in several previous studies (see refs.…”

Unusual In‐Situ Preorganization and Postoxidation Steps Observed in Diels‐Alder Reactions of Styrylcyclohexene Dienes

“…The ability of the reaction to form up to four stereogenic centers with predictable regiochemistry and absolute configuration, [3] combined with the ease of operation and convenient execution of chiral auxilaries [4] and catalysts [5] have facilitated successful applications of this pericyclic process in stereoselective synthesis of enantioenriched natural products, [6] biologically active compounds, [7] and desired complex molecular structures [8] . Employment of high pressure techniques [9] and Lewis acid mediated methods [10] along with the development of intramolecular, [11] transannular, [12] temporary tethered, [13] self‐assembled, [14] and hetero [15] variants of the reaction have further extended the scope of this remarkable process.…”

Role of conformational properties on the transannular Diels–Alder reactivity of macrocyclic trienes with varying linker lengths

“…The structures from the trajectories of the REMD simulations on all six systems were grouped based on their conformations using a clustering method proposed in our recent study. 49 The dihedral angles involving the carbon atoms in the ring systems were calculated for all the structures in the trajectories. Based on a dihedral bin size of 30u, multi-dimensional histograms were generated: 552, 562, 662, 572, 672 and 772 ring systems have 12, 13, 14, 14, 15 and 16 dihedrals respectively.…”

“…The conformational properties of these trienes were investigated using MD simulations and it was found that these properties play a major role in determining the TADA reactivity. 49 In the present paper, the effect of -CH 2 -linker length between the diene and the dienophile of the macrocyclic ring on TADA reactivity, and the conformational preferences of the reactants are investigated. The number of -CH 2 -linkers were varied from three to five resulting in six different sets of macrocyclic trienes, which are depicted in Fig.…”