Observation of a Transient Intermediate in Soai’s Asymmetric Autocatalysis: Insights from ¹H NMR Turnover in Real Time

Abstract

The amplifying asymmetric autocatalysis of alkylzinc addition to aldehydes discovered by Soai and co-workers in 1995 remains the only effective example of this genre, [1,2] despite widespread continuing interest in asymmetric amplification, primarily in the context of studies probing the origin of biological homochirality.[3] The autocatalytic process is highly circumscribed, being effective only within a narrowly defined regime: only 2-substituted pyrimidin-5-als such as 1 function as reactant [4] and only di-isopropylzinc 2 functions as reagent. The active catalyst is thought to be a higher-order alkoxide species derived from alkoxide 3 and is normally generated in situ from the alcohol 4. Significant advances in the period since the initial discovery include absolute asymmetric synthesis, [5,6] amplification from extremely low to high levels of enantiomer excess, [7] and initiation by diverse chiral entities or by isotopically chiral promoters. [8,9] Kinetic and spectroscopic studies have provided much information about the nature of the autocatalytic process, and kinetic and computational modeling have contributed to our understanding. To date, however, neither experimental observations of intermediate species, nor evidence of the nature of the catalytic entity, have been reported. Hence the molecular mechanisms by which amplifying autocatalysis occur are not yet properly understood.We report the direct observation of active species during catalytic turnover in the Soai autocatalytic Zn alkylation by 1 H NMR spectroscopy. This work confirms the surprising dependence on reaction temperature reported previously and reveals the first temporal observation of an intermediate species present during the reaction, which is transient at 0 8C but stable below À20 8C. The species is observed from the onset of the accelerating phase of autocatalytic turnover. Our earlier kinetic work indicated an equilibrating reaction product, formed without selectivity between homo-and heterochiral dimers, for which only the homochiral form was catalytically active.[10] Further studies demonstrated that the reaction was first-order in catalyst, close to second-order in aldehyde, but zero-order in the zinc alkyl reagent.

Asymmetric Amplification Coupling Enantioselective Autocatalysis and Asymmetric Induction for Alkylation of Azaaryl Aldehydes

“…[5] Such behaviour could be rationalized by a kinetically controlled amplification that leads to high ee for (R)-2 and www.eurjoc.org (R)-4f in a single reaction step, which is a breach to the essential feature of the Soai reaction, i.e. a sequential procedure of 3-4 reactions.…”

“…[4] While the exact details remain under investigation, results obtained in kinetic studies proposed the involvement of homoand heterochiral dimers of Zn-2. [5] However, this chemical model alone cannot rationalize such marked ee amplification as in the Soai reaction.…”

A Quantification of the Soai Reaction

“…As our model was converted into ordinary differential equations (ODEs), it can deliver a numerical simulation of the time evolution of all reactants, intermediates, and products. Therefore, among the available kinetic records, experiments that display the time evolution of both the reactant A and the ee of the carbinol products were important because they provide a quantitative and a qualitative description of the reaction simultaneously.…”

Mechanismen der Autokatalyse

“…[163,[195][196][197][198][199] Obwohl die genauen Einzelheiten weiter erforscht werden, liefert die Arbeit von Blackmond und Brown [191,[200][201][202][203][204][205][206][207][208][209][210] Autokatalyse ponenten erfolgt schnell und reversibel, wobei die Alkylierung des Aldehyds mit Diisopropylzink der geschwindigkeitsbestimmende Schritt ist. [163,[195][196][197][198][199] Obwohl die genauen Einzelheiten weiter erforscht werden, liefert die Arbeit von Blackmond und Brown [191,[200][201][202][203][204][205][206][207][208][209][210] Autokatalyse ponenten erfolgt schnell und reversibel, wobei die Alkylierung des Aldehyds mit Diisopropylzink der geschwindigkeitsbestimmende Schritt ist.…”

“…Der Mechanismus der Soai-Reaktion wurde von mehreren Gruppen untersucht. [163,[195][196][197][198][199] Obwohl die genauen Einzelheiten weiter erforscht werden, liefert die Arbeit von Blackmond und Brown [191,[200][201][202][203][204][205][206][207][208][209][210] Autokatalyse ponenten erfolgt schnell und reversibel, wobei die Alkylierung des Aldehyds mit Diisopropylzink der geschwindigkeitsbestimmende Schritt ist.…”