Diisopropylzinc alkylation of pyrimidine aldehydes – the Soai reaction, is a <i>sui generis</i> process in organic chemistry that brings to life the kinetic scheme of amplifying asymmetric autocatalysis. Soai’s seminal discoveries have received widespread attention in diverse chemical fields and have profoundly impacted chemists’ perspective of autocatalysis, chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Our work combines structural, spectroscopic, kinetic and computational studies to provide answers to longstanding questions about the mechanism<i> </i>of the Soai reaction. Fundamental insights were facilitated by the unprecedented observation of asymmetry amplifying autocatalysis in the diisopropylzinc alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde – thus extending this phenomenon to pyridine substrates. Kinetic studies with a surrogate reactant and spectroscopic analysis of a series of zinc-alkoxides incorporating specific structural mutations revealed that the (auto)catalyst is assembled via a pyridine-assisted cube escape. This new tetrameric cluster activates the substrate through a two-point binding mode and poises a coordinated diisopropylzinc moiety for alkyl group transfer. Transition-state models leading to both the homochiral and heterochiral products were validated by density functional theory calculations; additional experimental and computational analysis of the heterochiral complex provide an explanation for the non-linear behavior of this system. Furthermore, the paradigm of mixed catalyst-substrate experiments allowed extensive study of structure activity relationships in the pyrimidine and pyridine systems. This approach identified the unique roles played by reactant and autocatalyst structural constituents in effecting catalysis and selectivity. Collectively, the results reveal the structural logic behind the autocatalyst assembly, its mode of action, a rationalization of its non-linear behavior as well as an understanding of the substrate constraints that control this iconic transformation.

Demystifying the asymmetry-amplifying, autocatalytic Soai reaction

ACS Spring Meeting 2021

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