Methyltransferases: Green Catalysts for Friedel–Crafts Alkylations

Abstract

A set of S‐adenosyl‐l‐methionine (SAM) dependent methyltransferases has been characterized as versatile catalysts for the enzymatic Friedel–Crafts (alkylation) reaction. Although the substrate specificity of the enzymes range from high (in the case of SfmM2, SacF, and ORF19) to moderate (in the case of NovO and CouO), the cofactor spectrum is broad. Modified cofactors decorated with alkyl groups other than methyl were used for biocatalytic Friedel–Crafts alkylation, and conversions up to 99 % were achieved. In contrast to the classical chemical reaction the biotransformation is very selective and environmentally compatible.

A Tandem Enzymatic sp2‐C‐Methylation Process: Coupling in Situ S‐Adenosyl‐l‐Methionine Formation with Methyl Transfer

“…In contrast, nature routinely employs S ‐adenosyl‐ l ‐methionine (SAM)‐dependent methyltransferases (MTs) to methylate at O‐, N‐, S‐ and C‐sites. Thus, MTs hold considerable potential for the development of a biocatalytic alkylation platform for small molecules …”

“…We and others have shown that regiospecific methylation of the 8‐position of 1 b is catalysed by a novel His‐Arg motif, which facilitates the deprotonation of the phenolic proton in the 7‐position, followed by methylation at position 8 by SAM to form 2 b . NovO is also effective in catalysing Friedel–Crafts alkylations by using non‐natural SAM analogues to alkylate 1 b – d regiospecifically . Furthermore, NovO accepts non‐natural substrates such as 3 to form exclusively 4 (Scheme B), which is currently only accessible by this process …”

“…At present, the broader applicability of small‐molecule MTs is hampered by the inherent instability of SAM (942 min at pH 8) as the corresponding methylating agent . Additionally, the synthesis of SAM by chemical methods results in the formation of a diastereomeric mixture; this increases the cost of the process and has the potential for undesirable C‐MT inhibition by the unwanted diastereomer …”

S‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C‐Alkylation

“…[14][15][16][17] Ther epertoire of C-methylation extends to small molecules,which opens up opportunities to tailor these enzymes as ag eneral platform for biocatalytic C À Cb ond formation (Figure 1a). [20,21] One limitation of this process is the need to prepare these cofactors by chemical synthesis,w hich is laborious,l ow yielding,a nd produces both epimers at the sulfur center. [18][19][20] Ahallmark of NovO is its substrate promiscuity (e.g., 1)and the ability to utilize S-alkylated analogues of SAM to form products such as 2 ( Figure 1a).…”

“…[18][19][20] Ahallmark of NovO is its substrate promiscuity (e.g., 1)and the ability to utilize S-alkylated analogues of SAM to form products such as 2 ( Figure 1a). [20,21] One limitation of this process is the need to prepare these cofactors by chemical synthesis,w hich is laborious,l ow yielding,a nd produces both epimers at the sulfur center. [22][23][24][25][26] Furthermore,S AM analogues are inherently unstable in buffered solution (t 1/2 942 min for SAM at pH 8).…”