Semibiocatalytic Approach toward Regioisomerically Enriched Ethyl Dimethylpyrazines Important in Flavor Industries

Alkylpyrazines are important heterocyclic compounds used as flavorants in food and beverage industries. In this study, a regioselective semibiocatalytic process was developed to synthesize 2-ethyl-3,5-dimethylpyrazine (235-EDMP) over its 3-ethyl-2,5-dimethyl pyrazine (325-EDMP) isomer and vice versa. We initially explored how sterics could direct the coupling orientations between diamines and diketones to access 235- or 325-EDMP selectively. Also, the physical parameters of the reaction conditions were changed, such as reduced temperature, the order-of-addition of the reactants, and supplementation with chiral zeolites to template the orientation of the coupling partners to direct the reaction regiochemistry. Each reaction trial resulted in 50:50 mixtures of the EDMP isomers. An alternative approach was explored to control the regioselectivity of the reactions; alpha-hydroxy ketones replaced the diketones as the electrophilic coupling reactant used in previous trial experiments. The hydroxy ketone reactants were made biocatalytically with pyruvate decarboxylase. The coupling reaction between 2-hydroxypentan-3-one and propane-1,2-diamine resulted in the desired 235-EDMP at >70% (similar to 77 mg) relative to 325-EDMP in the mixture. The 3-hydroxypentan-2-one congener was biocatalyzed and reacted with propane-1,2-diamine as a proof of principle to synthesize 325-EDMP (similar to 60% relative abundance, similar to 73 mg) over 235-EDMP. These results suggested a mechanism that was directed by the hydroxy ketone electrophilicity and the sterics at the diamine nucleophilic centers.

Automated summary

In this study, a regioselective semibiocatalytic process was developed to synthesize important alkylpyrazine isomers for flavorants in food and beverage industries. Experimentation showed that changing physical parameters of the reaction conditions and substituting different reactants can effectively control the selectivity of the reactions.