title: Regioselective cope rearrangement and prenyl transfers on indole scaffold mimicking fungal and bacterial dimethylallyltryptophan synthases.
abstract: Aromatic prenyltransferases are an actively mined enzymatic class whose biosynthetic repertoire is growing. Indole prenyltransferases catalyze the formation of a diverse set of prenylated tryptophan and diketopiperazines, leading to the formation of fungal toxins with prolific biological activities. At a fundamental level, the mechanism of C4-prenylation of l-tryptophan recently has surfaced to engage a debate between a "direct" electrophilic alkylation mechanism (for wt DMATS and FgaPT2) versus an indole C3-C4 "Cope" rearrangement followed by rearomatization (for mutant FgaPT2). Herein we provide the first series of regioselectively tunable conditions for a Cope rearrangement between C3 and C4 positions. Biomimetic conditions are reported that effect a [3,3]-sigmatropic shift whose two-step process is interrogated for intramolecularity and rate-limiting general base-promoted mechanism. Solvent polarity serves a crucial role in changing the regioselectivity, resulting in sole [1,3]-shifts under decalin. An intermolecular variant is also reported that effectively prenylates the C3 position of l-tryptophan, resulting in products that mimic the structures accessed by bacterial indole prenyltransferases. We report an elaborate investigation that includes screening various substituents and measuring steric and electronic effects and stereoselectivity with synthetically useful transformations.
authors.affiliation: Department of Chemistry, Case Western Reserve University , Millis Science Center Room 214, 2074 Adelbert Road, Cleveland Ohio 44106-7078, United States.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Thandavamurthy
authors.forename: Deepti
authors.initials: D
authors.lastname: Sharma
authors.forename: Suheel K
authors.initials: SK
authors.lastname: Porwal
authors.forename: Dale
authors.initials: D
authors.lastname: Ray
authors.forename: Rajesh
authors.initials: R
authors.lastname: Viswanathan
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000737:chemistry* / Q000378:metabolism*; D001232:Aspergillus fumigatus; D001669:Biochemical Phenomena; D002384:Catalysis; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism*; D005658:Fungi / Q000737:chemistry* / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry*; D015394:Molecular Structure; D009387:Neoprene / Q000737:chemistry*; D014364:Tryptophan / Q000737:chemistry
chemical_list: D005656:Fungal Proteins; D007211:Indoles; C016077:prenyl; C030374:indole; D014364:Tryptophan; D009387:Neoprene; D019883:Alkyl and Aryl Transferases; C032409:tryptophan dimethylallyltransferase