Dimethylallyltryptophan

Some H NMR data for ergot derivatives of differing types— paspaclavine [360], (222) iV-methyl-4-dimethylallyltryptophan [361], (223) and the TV-acetyl methyl ester of clavicipitic acid [362] (224)— are shown in the structures. 

Dimethylallyltryptophan (3 C16H20N2O2 mp 210°) had already been synthesized in 1963 (4) and shortly afterward it was recognized as an important intermediate in biosynthesis of ergot alkaloids (5). 

It had already been stated earlier that clavine alkaloids are formed from L-tryptophan and mevalonic acid, the methyl group in position 6 originating from methionine (53, 54). There was also evidence that 4-dimethylallyltryptophan (3) is an early intermediate in the biosynthetic pathway (58). 

Ergot Alkaloids.—In connection with the biosynthesis of the ergot alkaloids it is of interest to note that 7V-methyl-4-dimethylallyltryptophan (49) has been isolated from cultures of Claviceps fusiformis grown anaerobically the presence of (49) could not be detected in cultures grown under normal aerobic conditions. An early stage in the biosynthesis of the alkaloids is the introduction of the allylic hydroxy-group, e.g. (50)- (51) whether the -methylation precedes or follows hydroxyla-tion is not known, but it seems certain that iV-methylation occurs before the cyclization-decarboxylation stage that results in formation of the tricyclic chano-clavines. 

Dimethylallyltryptophan (118) is the first intermediate after tryptophan on the pathway to the clavine alkaloids. Support for hydroxylation of one of the methyl groups as the next step was gained by the incorporation of (127)... 

Chemoenzymatic synthesis. As for other indole positions, enzymatic prenylation appears to become competitive. Li employed the 4-dimethylallyltryptophan synthase FgaPT2 [211] and the 7-dimethylallyltryptophan synthase DM ATS [212] (both from Aspergillus fumigatus) to prenylate tryptophan derivatives (286) on the 100 nanomolar scale. In all cases shown in Scheme 54, yields >90% were obtained overnight, based on recovered starting material. As coupling partner, ammonium prenylpyrophosphate (8) was used as always. 

Scheme 54 Chemoenzymatic 4- and 7-prenylations of tryptophan derivatives 286 (FgaPT2 4-dimethylallyltryptophan synthase, DMATS 7-dimethylallyltryptophan synthase from Aspergillus fumigatus) by Li and co-workers [211, 212]...

The biosynthesis of ergot alkaloids is initiated by prenyla-tion of tryptophan with dimethylallyl pyrophosphate (DMAPP) to yield 4-dimethylallyltryptophane (DMAT) (4) (Fig. 35.2) (Floss, 1980). This alkylation step is believed to be rate limiting, and the enzyme that catalyzes this reaction, DMAT synthetase, has been purified more than 60 times (Maier and Groger, 1976 Waller and Dermer, 1981). The enzyme appears to be specific for L-tryptophan and is inhibited by agroclavine (2) and elymoclavine (5) the end products of the reaction. 

Rigbers O, Li S-M (2008) Ergot alkaloid biosynthesis in Aspergillus fumigatus overproduction and biochemical characterisation of a 4-dimethylallyltryptophan N-methyltransferase, J Biol Chem 283 26859-26868... 

JV-methyl-4-dimethylallyltryptophan, 699 NMR. See Nuclear magnetic resonance (NMR) NO. See Nitric oxide (NO) Nitrite oxide (NO) NOAEL. See No observed adverse effect effect-levels (NOAEL) Nocardiafarcinica, 1635 Nociceptive, 1371, 1374 Nodulation, 3595... 

Agurell, S. (1966a) Biosynthesis of ergot alkaloids in Claviceps paspali. I. Incorporation of DL-4-dimethylallyltryptophan- C. Acta Pharm. Suec., 3,11-22. 

Barrow, K.D. and Quigley, ER. (1975) Ergot alkaloids III The isolation of N-Methyl-4-dimethylallyltryptophan from Claviceps fusiformis. Tetrahedron Lett., 1975,4269-4270. 

Robbers, J.E. and Floss, H.G. (1968) Biosynthesis of ergot alkaloids formation of 4-dimethylallyltryptophan by the ergot fungus. Arcb. Biochem. Biophys., 126, 967-969. 

Four enzymes which are involved in the biosynthesis of the ergot alkaloids have now been isolated from Claviceps. The other three are 4-dimethylallyltryptophan synthase , chanoclavine-I cyclase , and agroclavine hydroxylase . ... 

---