Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies

Abstract

The Soai reaction has profoundly impacted chemists’ perspective of chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Herein, we describe the unprecedented observation of asymmetry amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc. Kinetic studies with a surrogate substrate and spectroscopic analysis of a series of zinc-alkoxides that incorporate specific structural mutations reveal a ‘pyridine-assisted cube escape’. The new tetrameric cluster functions as a catalyst that 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. Moreover, experimental and computational analysis of the heterochiral complex provides a definitive explanation for the non-linear behavior of this system. Our deconstruction of the Soai system reveals the structural logic for autocatalyst evolution, function and substrate compatibility – a central mechanistic aspect of this iconic transformation.

In Situ Mass Spectrometric and Kinetic Investigations of Soai's Asymmetric Autocatalysis

“…More recently, Denmark and co‐workers [40] performed investigations of the Soai reaction with focus on the role of the nitrogen atoms in the pyrimidine/ pyridyl moiety, the structure of the Zn‐alkoxides in solution by NMR spectroscopic studies and in situ IR kinetic studies using pyridyl‐3‐carbaldehyde as surrogate, (“Trojan‐Horse” substrate). An alternative mechanism is proposed, considering a “cube escape” model.…”

Unravelling Structural Mysteries of Simple Organozinc Alkoxides

“…In this regard, the multifaced chemistry of zinc alkoxides has a particularly long history and can be traced back to Frankland's pioneering studies [3] . This interest in zinc alkoxides has been driven by several perspectives including synthetic methodology, [4–9] molecular structure, [4–20] reactivity, [9–11, 16, 18, 20–29] potential applications of zinc alkoxides both in catalytic reactions, [21, 23, 24, 30, 31] and more recently in materials science as predesigned precursors of zinc oxide nanostructures [15, 22, 26–29, 32–34] . Over time, a wide variety of their structural motifs (see below) and diverse transformations in the solid state and solution emerged.…”

“…In the Soai amplifying autocatalytic reaction, the catalytic sites arise from a combination of the dialkylzinc reagent ( i Pr 2 Zn) and the enantiomerically pure alkylzinc alkoxide species derived from the aldehyde reactant incorporating the distal N‐donor pyrimidine sites. Owing to the complex structural landscape of zinc alkoxide aggregates, the fundamental relationships between structure, reactivity, and catalytic activity have been discussed for over two decades [23, 24, 30, 31, 37] . Very recently, Denmark and co‐workers, using diverse dialkylzinc reagents and surrogate alkanol substrates, performed extensive kinetic and spectroscopic investigations.…”

“…They demonstrated that the reaction system in question is highly sensitive to subtle changes in the character of both the zinc‐bonded alkyl group and the alkoxide unit. These factors appeared to have a profound effect on the solution‐state structures of the respective zinc alkoxides as well as on the evolution of the catalytically active aggregates [30] . Undoubtedly, further basic research is needed for a thorough understanding of the multifaceted yet peculiar chemistry of zinc alkoxides and, ultimately, critical for the rational design of zinc alkoxide‐based applications.…”

Efficient Amplification in Soai's Asymmetric Autocatalysis by a Transient Stereodynamic Catalyst

“…Asymmetric autocatalytic amplification of the enriched enantiomer yields the pyrimidine alcohol 1 with enhanced ee . Several mechanistic models were proposed to explain the extraordinary behavior of this reaction (Blackmond et al, 2001 ; Blackmond, 2006 ; Ercolani and Schiaffino, 2011 ; Gehring et al, 2012 ; Micheau et al, 2012 ; Gridnev and Vorobiev, 2015 ; Athavale et al, 2020 ).…”