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Regioselective Cope Rearrangement and Prenyl Transfers on Indole Scaffold Mimicking Fungal and Bacterial Dimethylallyltryptophan Synthases
journal contribution
posted on 2014-11-07, 00:00 authored by Karthikeyan Thandavamurthy, Deepti Sharma, Suheel K. Porwal, Dale Ray, Rajesh ViswanathanAromatic
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.
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Keywords
biosynthetic repertoireC 3 positionPrenyl TransfersBiomimetic conditionsSolvent polarityFgaPTBacterial Dimethylallyltryptophan SynthasesAromatic prenyltransferasesIndole prenyltransferases catalyzeformationC 4 positionsshiftindole prenyltransferasesprenylated tryptophanRegioselective Cope RearrangementC 3wt DMATSregioselectively tunable conditionsmechanismCope rearrangementIndole Scaffold Mimicking Fungal
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