Formal Enantioselective Hydroamination of Non‐Activated Alkenes: Transformation of Styrenes into Enantiomerically Pure 1‐Phenylethylamines in Chemoenzymatic One‐Pot Synthesis

Abstract

to his 75th birthday As ac omplementary approach to current asymmetrics ynthetic methods, ad irect transformation of styrenes into 1-phenylethylamines was developed. The one-pot process represents af ormal hydroamination of an on-activated alkene with ammonia andi sb ased on the combination of aP d/Cu-catalyzed Wacker-oxidation with an enzymatic transamination.Akey feature of this processi st he compartmentation of the catalytic systems, which turned out to be essential to avoid deactivation of the transaminase by the Cu-component. This one-pot synthesis can be applied to ab road substrate range, which leads to the chiral amines with high conversionsa nd excellent enantioselectivities of > 99 % ee.

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

“…The PDMS thimbles were prepared according to Uthoff et al [ 14 ]. The surface of a glass vial (1.5 mL) is passivated by addition of a few drops of trichloro-(1H, 1H, 2H, 2H-perfluoroctyl)silane onto the glass vial and incubation in a desiccator at 45 mbar over night.…”

“…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.…”

Expanding the boundary of biocatalysis: design and optimization of in vitro tandem catalytic reactions for biochemical production

“…They coupled these two enzymes with ruthenium-catalyzed metathesis and a proline-derivative-catalyzed aldol reaction for efficient preparation of antioxidants 4,4’-dihydroxystilbene and 1,3-diols separately. In another study, they combined Wacker oxidation with enzymatic reduction or hydroamination in a one-pot process in aqueous media by withholding the detrimental effect of Cu ions from biotransformation in the interior of a polydimethylsiloxane thimble (PDMS) that only enabled the free exchange of organic chemical (Figure 6) (Sato et al, 2015; Uthoff et al, 2017). …”

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.…”