Asymmetric Chemoenzymatic
Synthesis of Ramatroban
Using Lipases and Oxidoreductases
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Abstract
A chemoenzymatic asymmetric route for the preparation
of enantiopure
(<i>R</i>)-ramatroban has been developed for the first time.
The action of lipases and oxidoreductases has been independently studied,
and both were found as excellent biocatalysts for the production of
adequate chiral intermediates under very mild reaction conditions.
CAL-B efficiently catalyzed the resolution of (±)-2,3,4,9-tetrahydro-1<i>H</i>-carbazol-3-ol that was acylated with high stereocontrol.
On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1<i>H</i>-carbazol-3(2<i>H</i>)-one provided an alternative
access to the same enantiopure alcohol previously obtained through
lipase-catalyzed resolution, a useful synthetic building block in
the synthesis of ramatroban. Inversion of the absolute configuration
of (<i>S</i>)-2,3,4,9-tetrahydro-1<i>H</i>-carbazol-3-ol
has been identified as a key point in the synthetic route, optimizing
this process to avoid racemization of the azide intermediate, finally
yielding (<i>R</i>)-ramatroban in enantiopure form by the
formation of the corresponding amine and the convenient functionalization
of both exocyclic and indole nitrogen atoms