Diels‐Alder Reaction of Levoglucosenone with a Protected cis‐Cyclohexadienediol: Structural and Electronic Basis behind the Unexpected Stereoselectivity

Abstract

Recently, we found that the Diels–Alder reaction between levoglucosenone and the acetonide of (1S,2R)‐3‐methylcyclohexa‐3,5‐diene‐1,2‐diol occurs through the most hindered face of the diene. This unexpected facial selectivity has no precedent for di‐O‐isopropylidene‐protected dienes, and the reasons behind it remain unclear. Here, we expand on our earlier findings, computationally assessing the structural and electronic factors responsible for this unforeseen stereoselectivity. The B3LYP/6‐31+G(d,p) results identify the three main adducts (β‐endo‐ortho:α‐endo‐meta:α‐exo‐ortho), giving a product ratio (63:9:28) that is in line with the experimental value (64:16:10). The β‐endo attack allows to maximize the electrostatic attraction between the reactants, giving rise to dipolar C−O⋅⋅⋅H−C interactions with the isopropylidene group at the transition state. The endo/exo preference can be rationalized through electrostatic repulsion and steric hindrance between the isopropylidene and methylene fragments. Finally, the non‐classical C=O⋅⋅⋅H−C hydrogen bonding stabilizes the ortho transition structures, making them more polar and asynchronous.