Biocatalytic Parallel Interconnected Dynamic Asymmetric Disproportionation of α‐Substituted Aldehydes: Atom‐Efficient Access to Enantiopure (S)‐Profens and Profenols

Abstract

The biocatalytic asymmetric disproportionation of aldehydes catalyzed by horse liver alcohol dehydrogenase (HLADH) was assessed in detail on a series of racemic 2‐arylpropanals. Statistical optimization by means of design of experiments (DoE) allowed the identification of critical interdependencies between several reaction parameters and revealed a specific experimental window for reaching an ′optimal compromise′ in the reaction outcome. The biocatalytic system could be applied to a variety of 2‐arylpropanals and granted access in a redox‐neutral manner to enantioenriched (S)‐profens and profenols following a parallel interconnected dynamic asymmetric transformation (PIDAT). The reaction can be performed in aqueous buffer at ambient conditions, does not rely on a sacrificial co‐substrate, and requires only catalytic amounts of cofactor and a single enzyme. The high atom‐efficiency was exemplified by the conversion of 75 mM of rac‐2‐phenylpropanal with 0.03 mol% of HLADH in the presence of ∼0.013 eq. of oxidized nicotinamide adenine dinucleotide (NAD+), yielding 28.1 mM of (S)‐2‐phenylpropanol in 96% ee and 26.5 mM of (S)‐2‐phenylpropionic acid in 89% ee, in 73% overall conversion. Isolated yield of 62% was obtained on 100 mg‐scale, with intact enantiopurities.

Enzymatic Dynamic Reductive Kinetic Resolution Towards 115 g/L (S)-2-Phenylpropanol

“…A dependence of product enantiopurity on reaction progress, especially at high enzyme loading, was experienced by us and others despite DKR conditions. Substrate racemization velocity was identi ed as main limitation towards high product enantiopurity (12,28). Here, substrate-to-catalyst ratio turned out as main factor determining product enantiopurity.…”

Biokatalytische Reduktionen aus der Sicht eines Chemikers

“…[98] Schließlich ist in diesem Zusammenhang auch die kürzlich wiederentdeckte biokatalytische Variante der Cannizzaro-Reaktion in der razemische Profenaldehyde in enantiomerenreine Alkohole und Carbonsäuren disproportioniert werden erwähnenswert. [99] 4.2. Reduktion von Ketonen 4.2.1. zu Alkoholen ADHs sind die Katalysatoren der Wahl für die stereoselektive Reduktion von Ketonen zu Alkoholen.…”

Enzymatic self-sufficient hydride transfer processes

“…Exemplary biocatalytic synthetic disproportionation was reported with the case of parallel interconnected dynamic asymmetric transformation (PIDAT), practically taking place concurrently between two molecules of the same substrate. 106 Here, the enzyme concurrently catalyzes with high enantioselectivity the same redox reaction on the same functional group in opposite redox directions. The reported biocatalytic Cannizzarotype reaction 107 was applied to a series of substituted rac-2-arylpropanals employing purified horse liver alcohol dehydrogenase (HLADH) and allowed the formation of enantioenriched (S)-profens and profenols (up to 99% ee) in a high atomefficient manner (Scheme 24).…”