62 FIVE STEP TOTAL SYNTHESIS OF ERGOT ALKALOIDS, (±)-CLAVICIPITIC ACID

Somei Masanori, Hamamoto Shoichi, Nakagawa Kyoko, Yamada Fumio, Ohta Toshiharu

doi:10.24496/tennenyuki.35.0_479

We have now succeeded in achieving five step formal total synthesis of (±)-clavicipitic acid (1) from indole-3-carboxaldehyde (4). It should be stressed that except for the last hydrolysis step, other four steps are our own reactions. Therefore, the originality rate' of the present synthesis of (±)-2 is 86%. The first step is the one pot preparation of 4-(3,3-dimethyl-allyi) indole-3-carboxaldehyde (7) from 4 in 49% yield according to the tin-thall reaction. In the second step, gramine synthetic method from 3-formylindoles was applied. Thus, the treatment of 5 with NaBH_4 in MeOH and aq. 50% Me_2NH produced the desired 7 in 69% yield. As the third step, alkylation method of gramine in the presence of (n-Bu)_3P was applied, and the reaction of 8 with methyl nitroacetate produced 9 in 80% yield. As the fourth step, the reductive amino-cyclisation method of nitro-olefins was applied to 9 with Zn(Hg) in HCl and MeOH, producing 4,6-trans-(14t) and 4,6-cis-clavicipitic acid methyl esters (14c), corresponding N-hydroxycompounds (15t, 15c), together with 16a, b and 17a, b, and the results are summarized in Table 1. Since both compounds (14t and 14c) were hydrolysed to the corresponding (±)-4,6-trans- and cis-clavicipitic acids by M. Natsume and co-workers, formal total synthesis of (±)-2 was completed. Syntheses of 4-methyl- (19c, t) and 4-hydroxymethyl-6-(2-methyl-1-propen-1-yl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indoles (21c,t) were also carried out successfully as shown in Scheme 7.

62 FIVE STEP TOTAL SYNTHESIS OF ERGOT ALKALOIDS, (±)-CLAVICIPITIC ACID

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