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Cutting Short the Asymmetric Synthesis of the Ramatroban Precursor by Employing ω‐Transaminases
Author(s) -
Busto Eduardo,
Simon Robert C.,
Grischek Barbara,
GotorFernández Vicente,
Kroutil Wolfgang
Publication year - 2014
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201300993
Subject(s) - chemistry , ketone , amine gas treating , reductive amination , enantiopure drug , biocatalysis , amination , transaminase , organic chemistry , yield (engineering) , combinatorial chemistry , enantiomeric excess , substrate (aquarium) , enantioselective synthesis , catalysis , reaction mechanism , enzyme , materials science , metallurgy , oceanography , geology
Starting from an adequate ketone precursor previous reports required three steps for the preparation of ( R )‐2,3,4,9‐tetrahydro‐1 H ‐carbazol‐3‐amine, a key intermediate for the synthesis of the antiallergic drug ramatroban. A single biocatalytic step was sufficient to prepare the target amine with >97% ee (HPLC) via reductive amination of the corresponding ketone using an ω‐transaminase as biocatalyst. Since the ketone was barely soluble under the reaction conditions employed, it was provided as a solid and still the reaction went to completion within 4 h at 50 mM substrate concentration. Although 2‐propylamine is regarded as an ideal amine donor, it turned out to be detrimental for the specific ketone precursor leading to the formation of various side products. These could be avoided by using ( R )‐1‐phenylethylamine as the best suited amine donor. An alternative work‐up was developed via freeze‐drying of the reaction mixture, enabling the isolation of the desired ( R )‐amine in excellent yield (96%) and enantiopure form on a preparative scale (500 mg). No purification steps (e.g., column chromatography, crystallisation) were required.