| Project/Area Number |
04671314
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | TOHO UNIVERSITY |
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Principal Investigator |
YOKOYAMA Yuusaku Toho University, School of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (10095325)
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| Co-Investigator(Kenkyū-buntansha) |
TANI Masanobu Toho University, School of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (50057733)
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| Project Period (FY) |
1992 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1994: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1993: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1992: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | 4-Bromotryptophan / Palladium / Vinylation / Heck Reaction / Clavicipitic Acid / Lysergic Acid / Total Synthesis / Optically Active / チャノクラビン / ヘック反応 / トリプトファン / 4-ブロムトリプトファン / ビニル化 / 4-ブロムデヒドロトリプトファン |
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| Research Abstract |
We developed the selective vinylation of aromatic bromides (1) with ethtl acrylate (2) using stoichiometric amount of Pd (II) salt ; the vinylation occurred at the most electrophilic position without affecting the carbon-bromine bond which is the reactive position towards Pd-catalyzed vinylation (Heck reaction). This reaction is quite synthetically useful, because the second carbon side chain could be introduced at bromine substituted carbon atom by Heck reaction, hence two different carbon side chain on aromatic ring would be introduced regioselectively.
The first total synthesis of optically active clavicipitic acid (3) was achieved by applying the above vinylation using optically active 4-bromotryptophan (4) as a key intermediate. The palladium-mediated chemoselective vinylation of 4-bromoindole (5) gave 4-bromodehydrotryptophan (6) which was converted to optically active 4 by asymmetric reduction in the presence of DIPAMP-rhodium complex. The compound 4 was vinylated with 2-methyl-3-buten-2-ol (7) at C4-position in the presence of catalytic amount of PdC12 (PPh3) 2 (Heck reaction) to give (S)-N-tert-butoxycarbony1-4-(3-hydroxy-3-methyl-1-buten-1-yl)-1-tosyltryptophan (8). The cyclization occurred simultaneously with the deprotection of tert-butoxycarbonyl group of 8 by treatment with HC1-saturated AcOEt to give the cyclized products, Na-tosylclavicipitic acid methyl ester (9). The detosylation of 9 with Mg/MeOH followed by hydrolysis with KOH/MeOH gave the optically pure clavicipitic acid (trans-3 or cis-3).
This short step synthesis of 3 [6 setp from 4-bromoindole (5)] is the first successful example through optically active tryptophan derivatives. The present investigation shows that this strategy gives an easy access to many optically active indole alkaloids having a tryptophan skeleton, especially to ergot alkaloids in synthetic and biosynthetic fields.
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