New Synthetic Method for Polyalkyl-Substituted Aromatic Bromides using Palladium and its Application

我们开发了使用化学计量量的Pd（II）盐的芳香族溴化物（1）与丙烯酸乙酯（2）的选择性乙烯化;乙烯化发生在最亲电的位置，而不影响碳-溴键，该碳-溴键是Pd催化的乙烯化（Heck反应）的反应位置。利用Heck反应可以在溴取代的碳原子上引入第二个碳侧链，从而区域选择性地在芳环上引入两个不同的碳侧链，利用上述乙烯化反应，以光学活性的4-溴色氨酸（4）为关键中间体，首次实现了光学活性棒酸（3）的全合成。4-溴吲哚（5）经钯催化的化学选择性乙烯化反应得到4-溴去氢色氨酸（6），后者在DIPAMP-铑配合物存在下经不对称还原得到光学活性4。化合物4在催化量的PdCl 2（PPh 3）2存在下与2-甲基-3-丁烯-2-醇（7）在C4-位乙烯基化（Heck反应）得到（S）-N-叔丁氧基羰基-4-（3-羟基-3-甲基-1-丁烯-1-基）-1-甲苯磺酰基色氨酸（8）。环化与8的叔丁氧基羰基的脱保护同时发生，通过用HCl饱和的AcOEt处理，得到环化产物，Na-甲苯磺酰基克拉维酸甲酯（9）。9经Mg/MeOH脱甲苯磺酰化后，再经KOH/MeOH水解，得到光学纯的克拉维酸（反式-3或顺式-3）。3 [6 setp from 4-bromoindole（5）]的这一短步骤合成是第一个通过光学活性色氨酸衍生物成功的例子。本研究表明，这一策略为许多具有色氨酸骨架的光学活性吲哚生物碱，特别是麦角生物碱的合成和生物合成提供了便利。

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.