A new strategy for aromatic ring alkylation in cylindrocyclophane biosynthesis

Abstract

Alkylation of aromatic rings with alkyl halides is an important transformation in organic synthesis, yet an enzymatic equivalent is unknown. Here, we report that cylindrocyclophane biosynthesis in Cylindrospermum licheniforme ATCC 29412 involves chlorination of an unactivated carbon center by a novel halogenase, followed by a previously uncharacterized enzymatic dimerization reaction featuring sequential, stereospecific alkylations of resorcinol aromatic rings. Discovery of the enzymatic machinery underlying this unique biosynthetic carbon-carbon bond formation has implications for biocatalysis and metabolic engineering.

Biocatalytic Oxidation Reactions: A Chemist's Perspective

“…Selection of selectiveh alogenationr eactions mediated by halogenases.PCP:p eptidyl carrier protein;ACP:a cyl carrier protein; SyrB2:h alogenase from Pseudomonas syringae; [74] Barb2:halogenase from Lyngbya majuscule (involved in barbamide biosynthesis); [75] CmaB:h alogenase from Pseudomonas syringae (involved in coronatine biosynthesis); [76] WelO5:h alogenase from Hapalosiphon welwitschii (involved in welwitindolinone biosynthesis); [77] CylC:non-a-KG-dependent halogenase from Cylindrospermuml icheniforme. [78] Urlacher and co-workers for the P450BM3-catalysed epoxidation of limonene (Scheme 21). [86] Increasing attention is being paid to hydrolase-mediated chemoenzymatic epoxidation reactions.I nt he presence of H 2 O 2 ,many hydrolases catalyse the conversion of carboxylic acid (esters) into the corresponding peracids (perhydrolase activity).…”

Enzymatic Cascade Reactions in Biosynthesis

“…To date,n ok nown biosynthetic analogues of metalcoordinated olefin metathesis equivalents are known in enzymatic catalysis.O nt he other hand, cyanobacteria do produce cylindrocyclophaneF , [107] albeit by aq uite different cascade logic. [108] Balskus and co-workers established that the primary metabolite decanoic acid is the starting substrate for tethering by thioester linkage to a1 0kDa acyl carrier protein. [108] Then anovel member of the diiron-dicarboxylate enzyme family CylC carries out ar egio-and stereospecific chlorination of the unactivated methylene group at C 6 of the 10-carbon acyl chain to yield the 6R-chloro-decanoyl-S-acyl carrier protein.…”

“…[108] Balskus and co-workers established that the primary metabolite decanoic acid is the starting substrate for tethering by thioester linkage to a1 0kDa acyl carrier protein. [108] Then anovel member of the diiron-dicarboxylate enzyme family CylC carries out ar egio-and stereospecific chlorination of the unactivated methylene group at C 6 of the 10-carbon acyl chain to yield the 6R-chloro-decanoyl-S-acyl carrier protein. This is the substrate for aP KS assembly line that builds and then releases the S-methyl-R-chloroalkyl resorcinol (Scheme 41 B).…”

Enzymkaskadenreaktionen in der Biosynthese

“…Andererseits produzieren Cyanobakterien Cylindrocyclophan F [107] nach einer vçllig anderen Kaskadenlogik. [108] Balskus und Mitarbeiter wiesen nach, dass der primäre Metabolit Decansäure das Ausgangssubstrat für die Bindung an ein Acyl-Carrier-Protein von 10 kDa über eine Thioesterbindung ist. [108] Danach erfolgt eine regio-und stereospezifische Chlorierung der nichtaktivierten Methylen-Gruppe am C6-Atom der Acyl-Kette mit zehn Kohlenstoff-Atomen durch einen neuartigen Vertreter der Dieisen-Dicarboxylat-Enzymfamilie,C ylC,u nter Bildung von (6R)-Chlordecanoyl-S-Acyl-Carrier-Protein.…”