Isoprenylated indole

Our group proposed a biosynthesis of the flinderoles that also proceeds via the intermediacy of cation 9 and isoprenylated indole 10 (Scheme 2). Cation 9 would... 

Dihydroquinolines can be synthesized by the palladium-catalyzed reaction of o-allyl- or o-isoprenyl-iV-tosylanilides with vinyl halides or triflates (Equation 135) <1998TL1885, 1998TL2515, 1998T9961, 1998TL2965, 1998JOC4554>. By-products can be formed in the instance of n-vinylanilide, including indoles and extended chains. 

Tanabe (772) and Acklin et al. (173) independently, and results were in good agreement. They showed that these related metabolites are derived from tryptophan and geranylgeraniol. Acklin etal. (173) reported that the probable biosynthetic sequence is paspaline (93) paspalicine (97) — paspalinine (94) (Scheme 18). It might be further speculated that paspalinine is converted to aflatrem by addition of an isoprene unit at the 4 position of the indole aromatic ring and that paspalitrem A (98) is derived via isoprenylation at the 5 position. 

Shortly after the studies reported by Allen, Casnati et al. reported the fate of the aromatic protons in the indole ring during the subsequent isoprenylation steps [57]. This study was undertaken to investigate the possible role of arene oxides and the diagnostic NIH shift that was discovered in the early 1970s. 

In the course of their studies on the biosynthesis of ergot alkaloids. Robbers and Floss isolated clavidpitic acid, a new indolic amino acid [89]. Based on the X-ray crystal data of the major isomer and the assumption that the stereocenter at C-5 retains its stereochemistry from L-tryptophan, the structure shown in Scheme 59 was assigned [90]. By performing feeding experiments on Claviceps sp. SD 58 with clavicipitic acid (biosynthetically labeled), the laboratories of Floss [90] and Anderson [91] independently determined that clavicipitic acid is not a precursor to elymoclavine. Instead, Floss argues that it arises from ... a derailment of the metabolism leading to the tetracyclic ergolines between the first and second pathway-specific steps, the isoprenylation of tryptophan and the N-methylation of 4-(y,y-dimethylallyl)-tryptophan (DMAT). Anderson and co-workers isolated an enzyme, DMAT oxidase, from Claviceps sp. which catalyzes the formation of clavicipitic acid from DMAT [92]. The enzyme, which requires... 

Other enzymes involved in terpene biosynthesis have also been harnessed for biocatalytic reactions of arenes. Prenyltransferase enzymes that can affect the addition of Cj isoprenyl units both at carbon and at heteroatoms have been used for biocatalytic arene alkylations. For example, L-tryptophan 49 undergoes prenylation at various positions on the indole core in a wholly regiose-lective fashion, depending on the enzyme used [28] (Scheme 32.6). 

The conclusion of Shibuya et al. (1990) from these experiments was that isoprenylation of L-tryptophan involved displacement of the pyrophosphate moiety of DMAPP by the indole residue with inversion at C-1 of the isoprene moiety. In the ternary enzyme substrate complex, dissociation of the C-1/ pyrophosphate bond of DMAPP would yield an ion pair or an allylic carbocation stabilised by the countercharge of the enzyme-bound pyrophosphate as shown in Figure 7. From C-4 of enzyme-bound L-tryptophan on the face opposite to the pyrophosphate, attack would create DMAT with inversion at C-1 and retention of double bond geometry. If the scrambling between allylic hydrogens occurred during these event, this can be readily accounted for by Figure 7... 

The mechanism of the conversion of Trp into cAATrp remains to be investigated. The biochemical process in this case may be similar to that suggested earlier for the biosynthesis of tenuazonic acid. The mechanism of the isoprenylation at the least nucleophilic position of the indole ring system of cAATrp has not as yet been elucidated. The corresponding isoprenylation of Trp in ergot alkaloid biosynthesis has received considerable attention (cf. Bellatti et al., 1977), but the mechanistic problem remains unsolved. 

---