Clavicipitic acid total synthesis

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... 

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

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). 

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-... 

By using a related synthesis strategy, Jia and co-workers could accomplish the total syntheses of (-)-trans- and (+)-c s-clavicipitic acid as well as the syntheses of both aurantioclavine enantiomers (189). Thereby, misassignments regarding the relative configuration of trans- and c s-clavicipitic acid could be corrected. 

Yokoyama Y, Hikawa H, Mitsuhashi M, Uyama A, Hiroki Y, Murakami Y (2004) Total Synthesis Without Protection Three-Step Synthesis of Optically Active Clavicipitic Acids by a Biomimetic Route. Eur J Org Chem 1244... 

Yokoyama, Y, Matsumoto, T. and Murakami, Y. (1995) Optically active total synthesis of clavicipitic acid. J. Org. Chem., 60, 1486-7. 

Yokoyama, Y, Hikawa, H. and Murakami, Y. (1997) Organic S5mthesis without protecting group total synthesis of optically active clavicipitic acid in aqueous media. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, 39, 325-30 Chem. Abstr., 131, 73829 (1999). 

A related sequence was used by Kozikowski and Greco for a total synthesis of ( )-clavicipitic acid (107) (1984JOC2310). On heating azide 104 at 190 °C, the initially formed triazoHne intermediate 105 underwent loss... 

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. ... 

Palladium catalysts again featured in cyclization reactions to yield ben-zazepines. Palladium and silver species were used to catalyze a ring-closure step in the total synthesis of clavicipitic acid (130L4528) while palladium was used to catalyze the annulation of an aryl amide onto an aryl bromide for the synthesis of a number of dibenzo[l>,e]azepin-6-ones (13CC7623). Annulation of aryl iodides onto aryl aldehydes to form dibenzo[fc,c]azepin-11-ones was also reported (13JOC8136). 

The diester 16 has been shown to undergo decarbonylation to a cis-trans mkture of clavicipitic acids, thus furnishing a formal total synthesis of this alkaloid. 

In the past decade, two Japanese groups, led by Somei and Yokoyama, respectively, have concentrated their synthetic interests and efforts on the ergot alkaloids by exploiting respective methodologies and achieving the total synthesis of clavicipitic acid and many related alkaloids. Originally, they had... 

Recently, Iwao reported (57) the dehydrative cyclization of 119 in the total synthesis of /-clavicipitic acid. Iwao prepared the diester 118, having protected the amino group with a trichloroethoxycarbonyl group, which was then readily cleaved by treatment with zinc dust to recover the free amine 119 in... 

Scheme 12.3 Asymmetric total synthesis of (-)-c/s-clavicipitic acid by a phase-transfer catalytic alkylation.

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