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Precise through-space control of an abiotic electrophilic aromatic substitution reaction

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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.

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Different strategies to direct SEAr reactions from above and underneath aromatic rings.(a) Proposed5 mechanism of through-space control in dimethylallyl tryptophan synthase (DMATS). The enzymatic pocket is illustrated schematically in blue. Note how (i) the precise positioning of the dimethylallyl cation inside the enzyme as well as (ii) a [C–H···N] hydrogen bond in the Wheland intermediate likely play a role in determining the selectivity of the reaction. (b) Placing a negatively polarized fluorine atom above the centre of an aromatic ring activates9 two symmetrically equivalent positions on the ring for SEAr reactions. On the other hand, carbonyl groups located directly above two atoms of an aromatic ring (c,d, this work) can precisely direct the substitution to one specific location. Key stabilizing interactions involving electron donation from O/N lone pairs to carbocations and positively polarized H/N atoms are illustrated with dashed lines.
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f1: Different strategies to direct SEAr reactions from above and underneath aromatic rings.(a) Proposed5 mechanism of through-space control in dimethylallyl tryptophan synthase (DMATS). The enzymatic pocket is illustrated schematically in blue. Note how (i) the precise positioning of the dimethylallyl cation inside the enzyme as well as (ii) a [C–H···N] hydrogen bond in the Wheland intermediate likely play a role in determining the selectivity of the reaction. (b) Placing a negatively polarized fluorine atom above the centre of an aromatic ring activates9 two symmetrically equivalent positions on the ring for SEAr reactions. On the other hand, carbonyl groups located directly above two atoms of an aromatic ring (c,d, this work) can precisely direct the substitution to one specific location. Key stabilizing interactions involving electron donation from O/N lone pairs to carbocations and positively polarized H/N atoms are illustrated with dashed lines.

Mentions: In this work, 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. While synthetic chemists still rely1 largely on traditional covalent electron-donating and -withdrawing groups to direct SEAr reactions, nature has already mastered the third dimension in this regard. Enzymes, for instance, make heavy use of the areas above and underneath aromatic rings to (i) align electrophiles above/underneath a desired position of attack and (ii) stabilize reactive SEAr intermediates through space with protein residues. This three-dimensional approach provides exquisite reaction selectivities and has enabled evolution to tailor enzymatic pockets to form different products selectively from the same starting materials. Different orthologs of dimethylallyl tryptophan synthase (DMATS) catalyse, for example, Friedel-Crafts alkylations of L-tryptophan with dimethylallyl diphosphate with varying regioselectivities23. This family of enzymes is involved in the biosynthesis of ergot alkaloids, which find use in a variety of pharmaceuticals currently on the market4. On the basis of high-resolution X-ray crystal structures, it was proposed56 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–H···N] hydrogen bond. Such a non-classical hydrogen bond between Lys174 of the enzyme and the acidic proton being substituted likely stabilizes the cationic Wheland reaction intermediate of the SEAr reaction selectively.


Precise through-space control of an abiotic electrophilic aromatic substitution reaction
Different strategies to direct SEAr reactions from above and underneath aromatic rings.(a) Proposed5 mechanism of through-space control in dimethylallyl tryptophan synthase (DMATS). The enzymatic pocket is illustrated schematically in blue. Note how (i) the precise positioning of the dimethylallyl cation inside the enzyme as well as (ii) a [C–H···N] hydrogen bond in the Wheland intermediate likely play a role in determining the selectivity of the reaction. (b) Placing a negatively polarized fluorine atom above the centre of an aromatic ring activates9 two symmetrically equivalent positions on the ring for SEAr reactions. On the other hand, carbonyl groups located directly above two atoms of an aromatic ring (c,d, this work) can precisely direct the substitution to one specific location. Key stabilizing interactions involving electron donation from O/N lone pairs to carbocations and positively polarized H/N atoms are illustrated with dashed lines.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382318&req=5

f1: Different strategies to direct SEAr reactions from above and underneath aromatic rings.(a) Proposed5 mechanism of through-space control in dimethylallyl tryptophan synthase (DMATS). The enzymatic pocket is illustrated schematically in blue. Note how (i) the precise positioning of the dimethylallyl cation inside the enzyme as well as (ii) a [C–H···N] hydrogen bond in the Wheland intermediate likely play a role in determining the selectivity of the reaction. (b) Placing a negatively polarized fluorine atom above the centre of an aromatic ring activates9 two symmetrically equivalent positions on the ring for SEAr reactions. On the other hand, carbonyl groups located directly above two atoms of an aromatic ring (c,d, this work) can precisely direct the substitution to one specific location. Key stabilizing interactions involving electron donation from O/N lone pairs to carbocations and positively polarized H/N atoms are illustrated with dashed lines.
Mentions: In this work, 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. While synthetic chemists still rely1 largely on traditional covalent electron-donating and -withdrawing groups to direct SEAr reactions, nature has already mastered the third dimension in this regard. Enzymes, for instance, make heavy use of the areas above and underneath aromatic rings to (i) align electrophiles above/underneath a desired position of attack and (ii) stabilize reactive SEAr intermediates through space with protein residues. This three-dimensional approach provides exquisite reaction selectivities and has enabled evolution to tailor enzymatic pockets to form different products selectively from the same starting materials. Different orthologs of dimethylallyl tryptophan synthase (DMATS) catalyse, for example, Friedel-Crafts alkylations of L-tryptophan with dimethylallyl diphosphate with varying regioselectivities23. This family of enzymes is involved in the biosynthesis of ergot alkaloids, which find use in a variety of pharmaceuticals currently on the market4. On the basis of high-resolution X-ray crystal structures, it was proposed56 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–H···N] hydrogen bond. Such a non-classical hydrogen bond between Lys174 of the enzyme and the acidic proton being substituted likely stabilizes the cationic Wheland reaction intermediate of the SEAr reaction selectively.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus