Asymmetric Synthesis of 1-Phenylethylamine from Styrene via Combined Wacker Oxidation and Enzymatic Reductive Amination

Abstract

An enantioselective chemoenzymatic two-step one-pot transformation of styrene to 1-phenylethylamine has been developed based on combining an initial Pd/Cu-catalyzed Wacker oxidation of styrene with a subsequent reductive amination of the in situ formed acetophenone. As a nitrogen source only ammonia is needed. The incompatible catalysts were separated by means of a polydimethylsiloxane membrane, thus leading to quantitative conversion and an excellent enantiomeric excess of the corresponding amine. The overall one-pot process formally corresponds to an asymmetric hydroamination of styrene with ammonia.

New Advances in the Synthetic Application of Enantiomeric 1-Phenylethylamine (α-PEA): Privileged Chiral Inducer and Auxiliary

“…The catalysts were separated through membrane filtration, giving almost quantitative styrene conversion and 99% enantiomeric excess of the amine. The entire process ultimately represents the asymmetric hydroamination of styrene with ammonia ( Scheme 2 ) [ 8 ].…”

Biotransformations in Pure Organic Medium: Organic Solvent‐Labile Enzymes in the Batch and Flow Synthesis of Nitriles

“…This concept enables the combination of non-compatible reactions comprising biocatalytic steps and, e.g., polydimethylsiloxane (PDMS) membranes were successfully used for this purpose. [16][17][18] Another solution to overcome the instability problems of biocatalysts in organic media is immobilization. Besides immobilization of enzymes in crude extracts or purified enzymes themselves, [19][20][21][22] techniques of whole cell immobilization are known as well.…”

“…One opportunity is compartmentalization of the reaction medium. This concept enables the combination of non‐compatible reactions comprising biocatalytic steps and, e.g., polydimethylsiloxane (PDMS) membranes were successfully used for this purpose . Another solution to overcome the instability problems of biocatalysts in organic media is immobilization.…”

Merging Heterocyclic Chemistry and Biocatalysis in One-Pot Processes through Compartmentalization of the Reaction Steps

“…Originally pioneered by the Bowden group [ 10 , 11 , 12 ] for merging chemocatalytic and “classic” chemical reactions, the Gröger group demonstrated the usefulness of this concept also for combining non-compatible chemo- and biocatalytic transformations, exemplified for the combination of a Wacker-oxidation with an enzymatic reduction [ 13 ]. In the meantime, this methodology was applied to a range of other combinations of metal-catalyzed transformations (Suzuki reactions, Wacker oxidations) and biotransformations (e.g., halogenases, transaminases, amine dehydrogenases) [ 14 , 15 , 16 ].…”

“…In continuation with our recent studies on the chemoenzymatic enantioselective synthesis of sulfur-containing heterocyclic amines consisting of an initial formation of heterocyclic imines and subsequent enzymatic reduction [ 17 ], we became interested to combine these reactions within a one-pot cascade process. As the “process windows“ for these two reactions differ strongly from each other (e.g., in terms of required pH conditions), we envisioned that the compartmentalization concept using PDMS thimbles applied already successfully for a range of combinations of chemo- and biocatalytic transformations [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ] might be an option for such a combination of heterocyclic chemistry and biocatalysis. In the following, we report our results in this field demonstrating a proof of concept for such an engineered process, which to the best of our knowledge represents the first example of a one-pot process merging a heterocycle formation through a classic chemical process at strongly basic conditions with a biocatalytic reaction running at neutral pH conditions.…”