Clavicipitic acid synthesis

Hegedus synthesis of ( )-clavicipitic acid //-acetyl methyl ester culminated in the Pd-induced cyclization of 238 to 239, the latter of which was reduced to the target mixture [251], Substrate 238 was prepared via a Heck reaction with the corresponding 4-bromo compound 223 and 2-methyl-3-buten-2-ol (83%). The cyclization also occurs with tosic acid (97%). 

In a related approach, Murakami synthesized clavicipitic acid and costaclavine [79], and later extended this chemistry to a synthesis of chanoclavine-I featuring the intramolecular Heck vinylation 240 to 241 [266], The corresponding enone failed to cyclize under these conditions. Noteworthy is that radical cyclizations, which often compete successfully with Heck reactions, were poor in this system. 

Kozikowski et al. have described a synthesis of clavicipitic acids where a key step involved preparation of the imine (202).112 Azide cyclization at 190 C presumably afforded a triazoline which, however, was nonisolable affording (202) in 62% yield. 

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... 

Ergot Alkaloids.—The enzyme which catalyses the first step in ergot alkaloid biosynthesis, namely the conversion of tryptophan into dimethylallyltryptophan (126),110 has been isolated from a Claviceps species and characterized.111 The biosynthesis of clavicipitic acid (127) may be a major alternative to the synthesis of other ergot metabolites, and further results in a study112 of an enzyme from C. purpurea which catalyses the formation of clavicipitic acid (127) from (126) have been published.113... 

We end this section with a synthesis of N-acetyl clavicipitic acid methyl ester, an ergot alkaloid, by Hegedus. The power of orga no-transition-metal chemistry is illustrated in five steps of this seven-step process. Each of the organometallic steps catalysed by Pd(0) or Pd(II) has been described in this chapter. The overall yield is 18%, a good result for a molecule of such complexity. 

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. 

Hegedus synthesis of ( )-clavicipitic acid jV-acetyl methyl ester culminated in the... 

Scheme 28. An illustration of the efficacy of palladium chemistry in the total synthesis of N-acetyl-( )-clavicipitic acid methyl ester...

Scheme 29. Synthesis of optically pure clavicipitic acid...

An asymmetric version of the total synthesis of clavicipitic acid was reported by Yokoyama et al. [82-84]. As illustrated in Scheme 29 asymmetric hydrogenation of the known 4-bromodehydrotryptophan 163 was best achieved (94% ee) using the optically active Monsanto bidentate phosphine, DIPAMP. The Heck vinylation in the presence of Ag,CO, gave the C(4)-vinylated product 168 without racemization. Treatment of 168 with HCl-EtOAc effected the cyclization to give the tricyclic azepinoindole 170 (62%), al.- ig with diene 169 (29%). Cleavage of the sulfonamide (Mg/MeOH) afforded 171 which underwent saponification (KOH) to give optically active clavicipitic acid (167). 

As described in Section 4.1. (Scheme 29), in the frequently reviewed synthesis of N-acetyl ( )-clavicipitic acid methyl ester (167) by Hegedus [80, 81], intramolecular aminopalladation of 164 was accomplished by a Pd(n)-catalyzed process lo give the tricyclic azepinoindole 16S. 

The Heck reaction has been widely used for the synthesis of many natural and unnatural products. The Heck reaction catalyzed by palladium acetate in water using a water-soluble ligand has been employed for the synthesis of clavicipitic acid (Scheme 5.24). 

Clavicipitic acid (1) is an unusual ergot alkaloid biosynthesis derailment product and occurs in nature as a mixture of cis- and ran -diasteromers (la/lb). The synthesis of the N-acetyl)methylesters of la and lb has been achieved by the following route starting with 2-bromo-6-nitrotoluene (X) ... 

Scheme 53 Synthesis of diastereomeric clavicipitic acids (281) by Yokoyama and co-workers [207] and of rac-aurantioclavin (285) by Ishikura and co-workers [208]...

Acid catalysed cyclisation of the substituted furans 20 led to formation of the spiro-systems 21 and 22, the latter being formed preferably <97TL7641>. Other syntheses involving the intermediacy of an oxonium ion include the preparation of thieno[2]azepines <97JHC1494>, l,2,3,4-tetrahydro-5//-l-benzazepine-6,9-quinones <97H(45)1703> and a new synthesis of ( )-cis- and ( )-/ra 8-clavicipitic acid <97T51 >. 

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... 

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