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A Chemoenzymatic Approach to Enantiomerically Pure Amines Using Dynamic Kinetic Resolution: Application to the Synthesis of Norsertraline
Author(s) -
Thalén Lisa K.,
Zhao Dongbo,
Sortais JeanBaptiste,
Paetzold Jens,
Hoben Christine,
Bäckvall JanE.
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200802303
Subject(s) - racemization , kinetic resolution , chemistry , candida antarctica , lipase , organic chemistry , amine gas treating , catalysis , enantioselective synthesis , enzyme
Dynamic transformation : A racemization catalyst and the enzyme Candida antarctica lipase B (CALB) were combined in a one‐pot dynamic kinetic resolution (DKR) of primary amines, which were transformed to their corresponding amides in up to 95 % yield and >99 % ee. This chemoenzymatic DKR was also applied to the synthesis of norsertraline (see scheme).Racemization catalyst 5 c and the enzyme Candida antarctica lipase B were combined in a one‐pot dynamic kinetic resolution (DKR) of primary amines in which a wide range of amines were transformed to their corresponding amides in up to 95 % isolated yield and >99 % ee . The DKR protocol was applicable with either isopropyl acetate or dibenzyl carbonate as the acyl donor. In the latter case, release of the free amine from the carbamate products was carried out under very mild conditions. The racemization of ( S )‐1‐phenylethylamine with several different Ru catalysts was also evaluated. Catalyst 5 c , of the Shvo type, was able to selectively racemize amines and was also compatible with the reaction conditions used for DKR. A racemization study of three different amines with varying electronic properties was also performed. Competitive racemization of a 1:1 mixture of the deuterated and non‐deuterated amine was carried out with 5 c and a primary kinetic isotope effect was observed for all three amines, providing support that the rate‐determining step is β‐hydride elimination. The chemoenzymatic DKR protocol was applied to the synthesis of norsertraline ( 16 ) by using a novel route starting from readily available 1,2,3,4‐tetrahydro‐1‐naphthylamine ( 1 o ).