Origins of the diastereoselectivity in hydrogen bonding directed Diels–Alder reactions of chiral dienes with achiral dienophiles: a computational study

Abstract

In this study, the origins of diastereoselectivity in the hydrogen bonding assisted Diels-Alder reactions of chiral dienes with achiral dienophiles have been investigated with density functional methods. The distortion/interaction model has been applied to shed light on the origins of selectivity. C9-Substituted chiral anthracene templates (R = (CH(3))(OCH(3))(H), R = (CH(3))(OH)(H), R = (CH(3))(CH(2)CH(3))(H) and R = (-CH(2)-C(CH(3))(OCH(3))(H)) are used to rationalize the role of a stereogenic center and H-bonding on the product distribution ratio. Even though hydrogen bonding increases the reactivity of the diene, the stereoselectivity is reduced because of the hydrogen bonding capacity of both diastereomeric transition states. The interaction energies of the studied anthracene templates with N-methyl maleimide at the transition state correlate linearly with an increase in reactivity. The selectivity is determined by both favorable distortion and interaction energies. The π-facial selectivity induced by the presence of a chiral auxiliary in 1-substituted 1,3-pentadienes (R1 = (CH(3))(OCH(3))(H) and R1 = (CH(3))(OH)(H)) has also been modeled in order to rationalize the role of the stereogenic center and H-bonding on the stereoselectivity of an aliphatic diene. In both parts, the product distribution ratios calculated from Boltzmann distributions based on Gibbs free energies are in reasonable agreement with the experimental results. Finally the role of OH-substituted five-membered pyrrolidine on C9 of anthracene is investigated since the successful usage of the conformationally rigid pyrrolidines in asymmetric synthesis is well known. Overall, both in the acyclic system and in anthracene, the facilitation due to H-bonding is reflected in the interaction energies: the higher the difference in interaction energies in the transition structures of the two diastereomers, the more selective the H-bonding assisted Diels-Alder reaction is.

The activation strain model and molecular orbital theory

“…Conveniently, there is no special computer code required to perform activation strain analyses: all necessary quantities can be computed using any of the regular quantum‐chemical software packages available. As a result, the activation strain model has been applied by various research groups, on a range of chemical processes, such as nucleophilic substitution, cycloaddition, oxidative addition, isomerization, and many other processes from organic and organometallic chemistry.…”

“…9 Conveniently, there is no special computer code required to perform activation strain analyses: all necessary quantities can be computed using any of the regular quantum-chemical software packages available. As a result, the activation strain model has been applied by various research groups, on a range of chemical processes, such as nucleophilic substitution, 1,[10][11][12][13][14][15][16][17][18][19] cycloaddition, [20][21][22][23][24][25][26][27][28][29][30][31][32][33] oxidative addition, [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] isomerization, [50][51][52][53][54][55] and many other processes from organic…”

Diels‐Alder Reactivity of a Chiral Anthracene Template with Symmetrical and Unsymmetrical Dienophiles: A DFT Study

“…A critical feature of the DA reactions studied here is the presence of hydrogen bond interactions in both the RC and TS structures (Figures and S4). Such intermolecular hydrogen bonds have been suggested to be the origin of the diastereoselectivity in reactions involving chiral dienes, and this topic has already been assessed using computational chemistry . Therefore, we shall not focus on the role of hydrogen bonding in the studied DA reactions, but rather on the reactivity trends and electronic properties that characterize such cycloadditions.…”

High diastereoselectivity induced by intermolecular hydrogen bonding in [3 + 2] cycloaddition reaction: experimental and computational mechanistic approaches

“…There are some studies on H‐bonding–induced diastereoselectivity in different reactions . Kilic et al reported that diastereoselectivity can be obtained through H‐bonding in some aziridination reactions .…”

“…Kilic et al reported that diastereoselectivity can be obtained through H‐bonding in some aziridination reactions . On the other hand, according to Jones et al and Aviyente et al diastereoselective [4 + 2] cycloadditions can also be performed guided by H‐bonding. One study reported that internally H‐bonded chiral methylene nitrones undergo diastereoselective [3 + 2] cycloaddition .…”