Reverse Prenyl Transferases Exhibit Poor Facial Discrimination in the Biosynthesis of Paraherquamide A, Brevianamide A, and Austamide

Abstract

The mode of attachment of dimethylallyl pyrophosphate (DMAPP) in the biosynthesis of the indole alkaloids paraherquamide A, austamide, and brevianamide A has been studied. Feeding experiments on Penicillium fellutanum, Penicillium brevicompactum, and Aspergillus ustus using [13C2]-acetate showed isotopic scrambling of the geminal methyl groups originating from C-2 of the indole ring precursors in paraherquamide A, brevianamide A, and austamide biosynthesis. The labeling patterns suggest that the methyl groups of dimethylallyl pyrophosphate become equivalent during the biosyntheses; a non-face-selective SN‘ mechanism has been invoked to account for these observations.

Acetylaszonalenin Biosynthesis in Neosartorya fischeri

“…The structures of the enzymatic products were elucidated by NMR and mass spectroscopy analysis. AnaPT was found to catalyze the reverse prenylation of (R) Prenylated indole derivatives are hybrid natural products containing both aromatic and isoprenoid moieties and are found especially in fungi of the genera Aspergillus and Penicillium (1,2). Besides L-tryptophan, the precursor of indole rings, most of these substances contain a second amino acid, forming cyclic dipeptides with a diketopiperazine structure or a derivative thereof (1).…”

“…Besides L-tryptophan, the precursor of indole rings, most of these substances contain a second amino acid, forming cyclic dipeptides with a diketopiperazine structure or a derivative thereof (1). Several members of this group carry reverse prenyl moieties (3Ј-(3Ј, 3Ј)-dimethylallyl (3Ј-DMA) 2 ) at position C3 of the indoline ring and a ring system between the indoline and the diketopiperazine ring (Fig. 1).…”

Study on the NBS-Induced Rearrangement of 2-tert-Prenyltryptamines

“…5 Williams also showed that the biosynthesis of 3-tert-prenylated tryptophan derivatives can proceed via 2-tert-prenylated precursors, as in the case of the paraherquamides. 6 Since regioselective introduction of tert-prenyl moieties at the indole nucleus is important for the synthesis of many tryptophan-derived natural products, 7 we investigated the scope of the facile NBS-induced oxidative cyclization/rearrangement. Debromoflustrabromine (3,Scheme 2) was chosen as starting material, which was obtained in four steps from tryptamine by applying Danishefsky's tert-prenylation 8 to N b -formyl-N b -methyltryptamine.…”

Total Synthesis and Biosynthesis of the Paraherquamides: An Intriguing Story of the Biological Diels–Alder Construction

“…12). 99) In summary, isotopic enrichment experiments with [ 13 C 2 ]-acetate have shown that the isoprene units in the secondary metabolites paraherquamide A (1), brevianamide A (2) and austamide (10) all arise via the classical mevalonate pathway. In all three systems, a loss of stereochemical integrity at the isoprene-derived quaternary center attached to the 2-position of the indole ring was observed.…”

“…Two possible mechanisms for the formation of this novel ring system have been proposed by Williams et al (Chart 30). 98,99) In the biosynthesis of austamide (10), there are also approximately equal levels of specific 13 C enrichment from in- 99) tact C2 units at the isoprene derived geminal methyl groups. Brevianamide A (2), on the other hand, exhibits significant but incomplete loss of stereochemical integrity in the construction of the reverse prenyl unit.…”