23 research outputs found
Broadening the substrate scope of strictosidine synthases by site-directed mutagenesis
The condensation of ß-arylethylamines with carbonyl compounds (Pictet-Spengler reaction) is employed in the synthesis of tetrahydro-β-carboline and isoquinoline scaffolds which are common motifs in many naturally occurring alkaloids. These compounds exhibit a range of biological activities and are thus interesting targets for organic synthesis and medicinal chemistry.
Nature’s equivalent to the Pictet-Spengler reaction is catalyzed by the so called Pictet-Spenglerases. Within this class of enzymes, strictosidine synthases (STRs, EC 4.3.3.2) have attracted attention [1-4]. These enzymes catalyse the formation of the 1,2,3,4-tetrahydro-β-carboline (S)-strictosidine, a key intermediate in the monoterpenoid indole alkaloid biosynthetic pathway in higher plants.
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Catalytic Promiscuity of Transaminases : Preparation of Enantioenriched β-Fluoroamines by Formal Tandem Hydrodefluorination/Deamination
Transaminases are valuable enzymes for industrial biocatalysis and enable the preparation of optically pure amines. For these transformations they require either an amine donor (amination of ketones) or an amine acceptor (deamination of racemic amines). Herein transaminases are shown to react with aromatic β-fluoroamines, thus leading to simultaneous enantioselective dehalogenation and deamination to form the corresponding acetophenone derivatives in the absence of an amine acceptor. A series of racemic β-fluoroamines was resolved in a kinetic resolution by tandem hydrodefluorination/deamination, thus giving the corresponding amines with up to greater than 99 % ee. This protocol is the first example of exploiting the catalytic promiscuity of transaminases as a tool for novel transformations
Stereoselective Cascade to C3-Methylated Strictosidine Derivatives Employing Transaminases and Strictosidine Synthases
(<i>S</i>)-Strictosidine
represents the first key intermediate
in the biosynthesis of several pharmaceutically relevant monoterpenoid
indole alkaloids. Optically pure C3-methyl-substituted strictosidine
derivatives were prepared by setting up the two stereogenic centers
at the β-carboline core via two enzymatic steps catalyzed by
the enzymes transaminase and strictosidine synthase in a one-pot cascade
fashion. The two enzymatic steps were performed simultaneously as
well as in a stepwise fashion. The amination of the prochiral ketones
led to optically pure amines with up to >98% enantiomeric excess.
Depending on the enzyme used, the (<i>S</i>)- and (<i>R</i>)-enantiomers were prepared in most cases. Selected amines
were then condensed with secologanin in a Pictet–Spengler reaction
catalyzed by strictosidine synthase leading to diastereomerically
pure products (>98% diastereomeric excess)
Asymmetric Amination of Tetralone and Chromanone Derivatives Employing ω‑Transaminases
Various (<i>S</i>)-selective
and (<i>R</i>)-selective
ω-transaminases were investigated for the amination of 1- and
2-tetralone and derivatives as well as of 3- and 4-chromanone. All
ketones tested were aminated to give the corresponding enantiopure
amines (<i>ee</i> > 99%) employing at least one of the
enzymes
investigated. In most of the cases the (<i>S</i>)- as well
as the (<i>R</i>)-enantiomer was obtained in optically pure
form. The amination of 3-chromanone was performed on a 100 mg scale
leading to optically pure (<i>R</i>)-3-aminochromane (<i>ee</i> > 99%) with complete conversion and 78% isolated yield