Thermodynamics Determine the Diastereochemical Outcome of Catalytic Reactions

Abstract

Diastereomers are characterised by an intrinsic energy difference, and thermodynamics dictate their distribution within a dynamic equilibrium. The characteristic mechanistic reversibility and non-ideal stereoselectivity of catalysts therefore simultaneously promote both synthesis and epimerization of products during the formation of diastereomers. This feature can even result in the thermodynamic inversion of a chiral centre against the catalyst's stereoselectivity. Here, we provide a comprehensive experimental and theoretical study of factors that govern thermodynamic epimerization in catalysis, using enzymes as example. Our analysis highlights, that the deduction of a catalyst's stereoselectivity based on the absolute configuration of the isolated product constitutes a potential pitfall. The selective formation of either the thermodynamic-, or the kinetic product is less determined by the catalyst, but rather by the reaction conditions. Next to low temperatures, a high maximal extent of conversion was identified to promote kinetically controlled conditions. For bimolecular reactions, conversions can be conveniently modulated via the use of one substrate in excess. Quantum mechanical calculations accurately predicted the diastereomeric excess under equilibrium conditions, which opens the prospect of a rational choice between thermodynamic and kinetic reaction control at an early stage of process design. Our findings are of critical importance for multi-step syntheses of stereocomplex molecules via catalytic cascade reactions or artificial metabolic pathways, as the final stereochemistry may be determined by the absolute configuration of the product that is overall lowest in energy.

Biocatalysis making waves in organic chemistry

“…Indeed, it applies to all catalytic reactions during which two or more stereocentres are generated, independent of whether they are biocatalytic or not. 85 The aldolases are grouped by the nucleophile they activate into four groups (Scheme 3). 6,35,80 Overall three mechanisms are utilized.…”

“…While the E/Z control over the enolate seems perfect, the attack of the acceptor is prone to lower selectivity. 85,110 Another special type of pyruvate dependent enzymes have in recent years attracted attention. The hydratase-aldolase produce conjugated systems and therefore catalyse an aldol condensation rather than an aldol reaction.…”

“…This is possibly due to a thermodynamically controlled product distribution in this case (see also Scheme 8B) as the observed lack of selectivity is diastereoselectivity and not enantioselectivity. 85 While this lack of selectivity is typically considered a disadvantage, it recently has been utilised to prepare rare sugars such as L-psicose and L-sorbose. 122 The DHAP aldolases are a versatile tool for the synthesis of sugars and sugar derivatives but their application is hampered by the low stability and high price of DHAP.…”

One Step Forward in Exploration of Class II Pyruvate Aldolases Nucleophile and Electrophile Substrate Specificity

“…The reaction catalyzed by A5VH82 led to 80 % of (3 S ,4 R ) adduct versus 65 % of (3 S ,4 S ) for the two other enzymes, once more confirming its interesting role as a complementary stereoselective tool compared to B4XH86 or A5VAX1. Importantly, because high conversion rates were reached, it could be assumed that some reactions converged toward the thermodynamic equilibrium which could explain a loss of stereocontrol in C4, as recently reported [22] …”

“…Importantly, because high conversion rates were reached, it could be assumed that some reactions converged toward the thermodynamic equilibrium which could explain a loss of stereocontrol in C4, as recently reported. [22] Although slower than with aldehydes, it was possible to convert 1 in the presence of a ketone, namely DHA 7 (Scheme 4). Since 7 was not chiral, the reaction was carried out only with one enzyme, B4XH86.…”