Indoles clavicipitic acid

The usefulness of Pd-catalysed reactions is demonstrated amply in the total synthesis of clavicipitic acid [76]. The first step is intramolecular aminopalladation of the 2-vinyltosylamide 92 with Pd(II) to give the indole 93. Then stepwise Heck reactions of the iodide and bromide of 94 with two different alkenes 95 and 96 in the absence and presence of a phosphine ligand give 97. In the last step of the synthesis, the intramolecular aminopalladation of 97 with a catalytic amount of Pd(II) gives the cyclized product 99. It should be noted that the aminopalladation is a stoichiometric... 

Some effected the coupling of phenyl-, 2-fuiyl-. and 1-hexenylboronic acids with 4-thallated indole-3-carboxaldehyde (Pd(OAc),/DMF) to give 4-substituted 3-formylin-doles [148]. Regioselective thallation of indole-3-carboxaldehyde is achieved using thallium tris-trifluoroacetate in 77% yield. Indole 129, which is available by the Buchwald zirconium indoline synthesis, was used by Buchwald to synthesize 130 via a Suzuki protocol [149]. Boronate ester 130 is prepared by the hydroboration of3-methyl-1-butyne with catechol borane. Indole 131 had been used in earlier studies to synthesize the clavicipitic acids. 

Functionalization of indoles at C-4 can be achieved by the addition of nucleophiles to indole tricarbonylchromium complexes, followed by oxidative removal of the chromium. A recent example, from 1992, shows the formation of the 4-allylindole (164) following carbanion addition (Scheme 54) <92AJC99>. This technique has also been applied to formation of a 4-indolylbutenone, a key intermediate in the synthesis of clavicipitic acid <93TL5051>. 7-Substitution of the indole ring can... 

Several other syntheses of the lif-azepino[5,4,3-c,c/ indole ring system have been reported, including the Mitsunobo reaction <85TL4043>, an intramolecular, acid-catalyzed aminoalkylation <88JOC5128> and intramolecular imine formation <87H(26)1197> leading to total synthesis of clavicipitic acid. Palladium-catalyzed ring closure of (127) afforded the cyclized derivative (128) (Equa-... 

Robbers JE, Floss HG (1969) Clavicipitic Acid, a New 4-Substituted Indolic Amino Acid Obtained from Submerged Cultures of the Ergot Fungus. Tetrahedron Lett 10 1857... 

In the total synthesis of clavicipitic acid and aurantioclavine, Jia and co-workers have successfully prepared the key intermediate 56 via a Mori-Ban reaction by direct coupling of 3-nitro-2-iodoaniline with (5)-2-iV,A(-di-rer/-butoxycarbonyl-5-oxopentane under standard Pd-catalyzed indole synthesis conditions, yielding the optically pure 4-nitrotryptophan derivative 56 in 80% yield. ... 

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... 

This method of making indoles has been used in a synthesis of the methyl ester of Clavicipitic acid 637." Palladium catalysis was employed for many key steps (Scheme 6.17). Heck reactions were planned to add... 

Robbers, J.E. and Floss, H.G. (1969) Clavicipitic acid, a new 4-substituted indolic amino acid obtained from submerged cultures of the ergot fungus. Tetrahedron Lett., 23, 1857-1858. 

Nichols group (25) successfully applied an acid-catalyzed intramolecular aminoalkylation reaction between an amine and alcohol to form the azepino ring system, the characteristic structure of this indolic amino acid in the route, via a functional equivalent of 10-hydroxylated DMAT 15. This hypothetical biochemical precursor of the alkaloid, which was not prepared previously, was the key intermediate for their efficient synthesis to clavicipitic acid. Nichols group first prepared the requisite alcohol 12 by the Grignard reaction of N-tosylated indole-4-carboxaldehyde 11 with 2-methyl-1-propenylmagnesium... 

Hie activating effect of n-complexation of a Cr(CO)3 complex allows for selective nucleophilic substitution in indoles, such as OTptophan, providing intermediates for the synthesis of clavicipitic acid. Indole was readily transformed into the corresponding tricarbonylchromium complex and silylated to the orange-colored complex 17. The addition of 17 to a solution of the lilhiated sulfone followed by oxidative quenching with iodine and desilyladon furnished the C-4 substituted indole 18 in 90% yield. The conversion of 18 to the enone 19 was achieved in 78% yield by sequential acid and base treatment. 

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