Sulfite-Catalyzed Nucleophilic Substitution Reactions with Thiamin and Analogous Pyrimidine Donors Proceed via an S_NAE Mechanism

Abstract

When treated with SO3 2–, thiamin undergoes a substitution reaction to release a thiazole leaving group and the corresponding sulfonate. Although this reaction could proceed via a simple SN2-like mechanism, a multistep addition–elimination (SNAE) mechanism involving the addition of SO3 2– to C6′ of the 4-aminopyrimidine of thiamin has also been proposed. Although this reaction has potential utility in the synthesis of substituted pyrimidines and provides a direct analogue to reactions catalyzed by thiaminases, a detailed mechanistic picture of the SO3 2–-catalyzed cleavage of thiamin has remained elusive. Here, DFT calculations have been used to probe the relative energetics and the factors that shape the potential energy surfaces that define the possible mechanisms of substitution. These calculations provide clear support for the SNAE mechanism over an SN2-like process and illustrate that the unique ability of SO3 2– to activate thiamin toward nucleophilic displacement is due to the combined nucleophilicity and relatively poor leaving group ability of SO3 2–. Both of these factors favor the forward partitioning of the sulfite adduct toward the cleavage products whereas adducts formed with other nucleophiles overwhelmingly revert to reactants. Calculations performed with a range of substrates with various electrophilicities and nucleofugalities consistently suggest that the SNAE pathway is significantly lower in energy than the direct substitution, illustrating that this SO3 2–-catalyzed multistep process is likely to be broadly applicable both in solution and in catalysis by thiaminases.

Intramolecular Cyclization and a Retro-Ene Reaction Enable the Rapid Fragmentation of a Vitamin B1-derived Breslow Intermediate

“…Recently, we reported our efforts to characterize the mechanism of the sulfite-catalyzed cleavage of 1a using DFT calculations. [9] During that study, an exploratory calculation suggested that 4a was susceptible to cyclization via intramolecular nucleophilic attack of the C2α position onto the electrophilic C6ʹ of the aminopyrimidine moiety to give tricyclic species 12a (Scheme 4). This unexpected reactivity suggested a potential alternative pathway for the formation of 6 and 7a involving i) cyclization, ii) cleavage of the C-N bond between the thiazolium and the bridging methylene, and iii) a retro-ene reaction that ultimately releases the products (Scheme 4).…”