Abstract
Nature has evolved selective enzymes for the efficient biosynthesis of complex products. This exceptional ability stems from adapted enzymatic pockets, which geometrically constrain reactants and stabilize specific reactive intermediates by placing electron-donating/accepting residues nearby. Here we perform an abiotic electrophilic aromatic substitution reaction, which is directed precisely through space. Ester arms—positioned above the planes of aromatic rings—enable it to distinguish between nearly identical, neighbouring reactive positions. Quantum mechanical calculations show that, in two competing reaction pathways, both [C–H···O]–hydrogen bonding and electrophile preorganization by coordination to a carbonyl group likely play a role in controlling the reaction. These through-space-directed mechanisms are inspired by dimethylallyl tryptophan synthases, which direct biological electrophilic aromatic substitutions by preorganizing dimethylallyl cations and by stabilizing reactive intermediates with [C–H···N]–hydrogen bonding. Our results demonstrate how the third dimension above and underneath aromatic rings can be exploited to precisely control electrophilic aromatic substitutions.
Highlights
Nature has evolved selective enzymes for the efficient biosynthesis of complex products
We investigate the fundamental question of how aromatic reactivity can be directed with high precision from above and below the planes of aromatic rings
By advancing towards this general goal, we aim to add a new dimension of control to the large class of electrophilic aromatic substitution (SEAr) reactions
Summary
Nature has evolved selective enzymes for the efficient biosynthesis of complex products. Quantum mechanical calculations show that, in two competing reaction pathways, both [C–HO]–hydrogen bonding and electrophile preorganization by coordination to a carbonyl group likely play a role in controlling the reaction These through-space-directed mechanisms are inspired by dimethylallyl tryptophan synthases, which direct biological electrophilic aromatic substitutions by preorganizing dimethylallyl cations and by stabilizing reactive intermediates with [C–HN]–hydrogen bonding. On the basis of high-resolution X-ray crystal structures, it was proposed[5,6] that DMATS from Aspergillus fumigatus achieves (Fig. 1a) its regioselectivity owing to (i) preorganization of the dimethylallyl cation inside its active site as well as (ii) a key through-space [C–HN] hydrogen bond Such a non-classical hydrogen bond between Lys[174] of the enzyme and the acidic proton being substituted likely stabilizes the cationic Wheland reaction intermediate of the SEAr reaction selectively. It operates by orienting the electrophile with O to electrophile coordination, akin to how DMATS’s enzymatic pocket aligns a dimethylallyl cation with its tryptophan substrate
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