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.

Synergism between genome sequencing, tandem mass spectrometry and bio-inspired synthesis reveals insights into nocardioazine B biogenesis

“…The overall yield for formation of 13 was 24.9%. Similarly, the assembly of 16 began with 20a undergoing a tandem epimerization-hydrolysis event under aqueous lithium hydroxide, Through a biomimetic prenylation method we published recently, 21 employment of the methyl ester of L-tryptophan (9) served as a precursor to engage in a domino process initiated by a C3′-prenylation event (with prenyl bromide as the electrophile), subsequently resulting in a C-N bond-forming pyrroloindoline cyclization, under sodium acetate-acetic acid conditions ( pH = 2.7) at room temperature, to result in the formation of 27a and 27b as a 4 : 1 mixture of exo and endo diastereomers. The overall yield for this transformation was 67% considering full recovery of unreacted 9.…”

Synthesis of 2-oxindoles via 'transition-metal-free' intramolecular dehydrogenative coupling (IDC) of sp2 C–H and sp3 C–H bonds

“…A few substrates were treated under decarboxylative allylation (DcA) conditions in the presence of 10 mol % of Pd(PPh 3 ) 4 in refluxing tetrahydrofuran (7–8 h), which afforded products 26a – d in up to 99% yield ( Scheme 11 ). Interestingly, oxidative coupling products with dimethylallyl esters 8j underwent smooth decarboxylative prenylation and reverse -prenylation in the presence of 5 mol % of Pd 2 (dba) 3 and 15 mol % dppp in refluxing toluene (7–8 h, 96% yields) to afford prenylated ( 27a ) and reverse -prenylated ( 27b ) structures in 64% and 32% yield, respectively ( Scheme 11 ) [ 92 – 93 ]. These structures commonly occur in many hexahydropyrrolo[2,3- b ]indole-based alkaloids.…”

Access to 3-Prenylated Oxindoles by α-Regioselective Prenylation: Application to the Synthesis of (±)-Debromoflustramine E

“…In principle, the direct incorporation of a prenyl group into the 3-position of the oxindoles represents the most reliable method to prepare 3-prenylated oxindoles. However, a major problem in direct prenylation can be the formation of two regioisomeric products, i.e., α-product and γ-product . In particular, the selective formation of a α-product has proven to be challenging …”