Stereoselective Cascade to C3-Methylated Strictosidine Derivatives Employing Transaminases and Strictosidine Synthases

Abstract

(S)-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 (S)- and (R)-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).

Stereoselective biocatalysis: A mature technology for the asymmetric synthesis of pharmaceutical building blocks

“…Finally, the combination of a transaminase and a strictosidine synthase will be discussed for the preparation of C-3 methylated strictosidine derivatives through a cascade approach (Fischereder 2016).…”

Enzyme catalysed Pictet-Spengler formation of chiral 1,1’-disubstituted- and spiro-tetrahydroisoquinolines

“…The plant enzymes have a central role in engineered microbial systems for the production of alkaloids1819202122. Furthermore, the wide substrate promiscuity of these enzymes has led to their use in biocatalytic syntheses, but the carbonyl substrates employed have always been aldehydes23242526272829303132. The only example of a Pictet–Spenglerase accepting non-aldehyde carbonyl substrates was the report of a norcoclaurine synthase (NCS) from Coptis japonica ( Cj NCS2, also known as Cj PR10A) turning over 4-hydroxyphenylpyruvate and pyruvic acid, activated α-keto acids10.…”

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

“…Both enantiomers of methyl tryptamine were prepared by either (R)-selective transaminase from Arthrobacter species or (S)-selective transaminase from Silibacter pomeroyi or Bacillus megaterium, thus providing the first stereogenic center at the β-carboline core with up to >98% enantiomeric excess. The chiral tryptamines were then condensed with secologanin in a diastereoselective Pictet-Spengler reaction catalyzed by strictosidine synthase from Ophiorriza pumila or Rauvofolia serpentina (Scheme 26) [78]. Strictosidine synthase clearly controlled the diastereoselectivity, in fact both enantiomers at C-3 of the amine led to an (S)-configured center at C-1 of the carboline.…”