Stereoselective Synthesis of 1‐Arylpropan‐2‐amines from Allylbenzenes through a Wacker‐Tsuji Oxidation‐Biotransamination Sequential Process

Abstract

Herein, a sequential and selective chemoenzymatic approach is described involving the metalcatalysed Wacker-Tsuji oxidation of allylbenzenes followed by the amine transaminase-catalysed biotransamination of the resulting 1-arylpropan-2-ones. Thus, a series of nine optically active 1-arylpropan-2-amines were obtained with good to very high conversions (74-92%) and excellent selectivities (> 99% enantiomeric excess) in aqueous medium. The Wacker-Tsuji reaction has been exhaustively optimised searching for compatible conditions with the biotransamination experiments, using palladium(II) complexes as catalysts and iron(III) salts as terminal oxidants in aqueous media. The compatibility of palladium/iron systems for the chemical oxidation with commercially available and made in house amine transaminases was analysed, finding ideal conditions for the development of a general and stereoselective cascade sequence. Depending on the selectivity displayed by selected amine transaminase, it was possible to produce both 1-arylpropan-2-amines enantiomers under mild reaction conditions, compounds that present therapeutic properties or can be employed as synthetic intermediates of chiral drugs from the amphetamine family.

Construction of Chemoenzymatic Linear Cascades for the Synthesis of Chiral Compounds

“…[38] The combination of the Wacker-Tsuji oxidation with different enzymes to make chiral alcohols and amines has also been significantly studied using either Cu or Fe as the terminal oxidant. [22,39,40] An alternative approach has recently been reported by Gotor-Fernández and coworkers in which Pd(II) was regenerated by using the photosensitizer [Acr-Mes]ClO 4 and blue led light irradiation (Scheme 2c). [41] Sequential combination with enantiocomplementary KREDs and ω-TAs allowed access to a collection of chiral alcohols and primary amines, respectively, in moderate to high yields (42-83 %) and excellent enantiomeric excesses (> 99 %) in all cases.…”

“…The combination of the Wacker‐Tsuji oxidation with different enzymes to make chiral alcohols and amines has also been significantly studied using either Cu or Fe as the terminal oxidant [22,39,40] . An alternative approach has recently been reported by Gotor‐Fernández and coworkers in which Pd(II) was regenerated by using the photosensitizer [Acr‐Mes]ClO 4 and blue led light irradiation (Scheme 2c) [41] .…”

Transaminase-mediated synthesis of enantiopure drug-like 1-(3′,4′-disubstituted phenyl)propan-2-amines

“…For the transamination of 7a, commercially available puri-ed TAs, 30,60 lyophilized whole cells 41 or cell-free extracts (CFEs) directly 29 were applied as TA-biocatalysts. In case of lyophilized whole cells, 250% w/w TA-biocatalyst was used for transforming 17 mM of 7a with 1 M IPA ($60 equiv.)…”

“…27,28 TA-mediated amine syntheses have been widely reported as a one-enzyme system using a variety of amine donors without further transformation of the ketone coproduct. [29][30][31][32][33] Furthermore, there were reports on TAs coupled in cascades with pyruvate-reducing enzyme lactate dehydrogenase (LDH) and NADH-regenerating glucose dehydrogenase (GDH). 34,35 Amine dehydrogenases (G, AmDH) can utilise ammonia for the synthesis of the desired amines by reductive amination of the prochiral ketone.…”

Markovnikov Wacker‐Tsuji Oxidation of Allyl(hetero)arenes and Application in a One‐Pot Photo‐Metal‐Biocatalytic Approach to Enantioenriched Amines and Alcohols

“…Among the different substrates included in this study, trans ‐β‐methylstyrene provided 1‐phenylpropan‐2‐ol although at low extent [38] . Our research group recently developed the stereoselective synthesis of a family of 1‐arylpropan‐2‐amines in good yields starting from allylarenes following a sequential strategy which involved a Wacker‐Tsuji oxidation and a biotransamination step (Scheme 1b) [8d] . Interestingly, palladium(II) trifluoroacetate and an iron(III) salt, used as co‐oxidant, in the presence of sodium trifluoroacetate efficiently catalyzed the formation of the ketone intermediates at 30–60 °C, which were subsequently aminated by an amine transaminase.…”