Multienzyme One‐Pot Cascades Incorporating Methyltransferases for the Strategic Diversification of Tetrahydroisoquinoline Alkaloids

Abstract

The tetrahydroisoquinoline (THIQ) ring system is present in a large variety of structurally diverse natural products exhibiting a wide range of biological activities. Routes to mimic the biosynthetic pathways to such alkaloids, by building cascade reactions in vitro, represents a successful strategy and can offer better stereoselectivities than traditional synthetic methods. S‐Adenosylmethionine (SAM)‐dependent methyltransferases are crucial in the biosynthesis and diversification of THIQs; however, their application is often limited in vitro by the high cost of SAM and low substrate scope. In this study, we describe the use of methyltransferases in vitro in multi‐enzyme cascades, including for the generation of SAM in situ. Up to seven enzymes were used for the regioselective diversification of natural and non‐natural THIQs on an enzymatic preparative scale. Regioselectivites of the methyltransferases were dependent on the group at C‐1 and presence of fluorine in the THIQs. An interesting dual activity was also discovered for the catechol methyltransferases used, which were found to be able to regioselectively methylate two different catechols in a single molecule.

Enzymatic Oxy‐ and Amino‐Functionalization in Biocatalytic Cascade Synthesis: Recent Advances and Future Perspectives

“…Hailes and co-workers recently extended this work, adding different O-and N-methyltransferases (MTs) to obtain several THIQ methylated derivatives (Scheme 5q). [172] The methyltransferases chosen were SAM dependent. However, SAM is a cost-intensive cofactor, and it limits the applicability of MT-catalyzed reactions on large scale.…”

Enzyme Kits to Facilitate the Integration of Biocatalysis into Organic Chemistry – First Aid for Synthetic Chemists

“…[30,140] In general, enzyme kits of other classes such as hydrolases (e. g., lipases and esterases) and ketoreductases have existed for decades [1,2] and are commercially available from many different companies. [3,4] Furthermore, enzyme kits of yet less well investigated classes such as methyltransferases [141][142][143] for the selective alkylation (e. g., methylation and carboxymethylation) of natural products of lead drugs should be highly valuable for synthetic (pharmaceutical) chemists, [144][145][146] especially since the discovery of the 'magic methyl effect'. [147,148] Scheme 4.…”

Expanding the Substrate Scope of N‐ and O‐Methyltransferases from Plants for Chemoselective Alkylation**

“…In previous studies it was found that the COMT from Myxococcus xanthus (MxSafC) was also able to perform a double methylation of tetrahydroisoqunolines while the related enzyme from Rattus norvegicus (RnCOMT) transferred only one methyl group regioselectively. [32] Different classification systems have been suggested to distinguish between similar enzymes. Regarding plant hydroxyl O-MTs, Joshi et al introduced a classification system dividing O-MTs into class I and II, according to their amino acid sequence, size and dependence on metal ions.…”

“…This includes catechol O‐ MTs (COMTs) known for the O‐ methylation of dopamine. In previous studies it was found that the COMT from Myxococcus xanthus (Mx SafC) was also able to perform a double methylation of tetrahydroisoqunolines while the related enzyme from Rattus norvegicus ( Rn COMT) transferred only one methyl group regioselectively [32] . Different classification systems have been suggested to distinguish between similar enzymes.…”