Vargas Didier F, Larghi Enrique L, Kaufman Teodoro S
Instituto de Química Rosario (IQUIR, CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario Suipacha 531 S2002LRK Rosario Argentina
RSC Adv. 2019 Oct 16;9(57):33096-33106. doi: 10.1039/c9ra06839b. eCollection 2019 Oct 15.
A straightforward and convenient approach toward the first total synthesis of ampullosine, a structurally unique 3-methylisoquinoline alkaloid isolated from , is reported. Access to the related -methyl ampullosine methyl ester from a common intermediate is also disclosed. The synthetic sequence toward the natural product comprised a Kolbe-type carboxylation of 3,5-dihydroxybenzoic acid and further esterification of the diacid, followed by masking of one of the phenols through selective ester reduction and subsequent acetonide formation. Installation of the three-carbon atom required for the 3-methylpyridine ring was performed by triflation of the remaining free phenol and a Pd-catalyzed Suzuki-Miyaura reaction with potassium -propenyltrifluoroborate. Deprotection of the acetonide, followed by partial oxidation of the benzylic alcohol to the salicylaldehyde, -methylation of the free phenol and hydrazonation of the resulting -anisaldehyde derivative gave a hydrazone-based 1-azatriene. This was further subjected to 6π-azaelectrocyclization to afford permethylampullosine (11 steps, 14% overall yield), whereas exhaustive demethylation with AlI generated gave ampullosine (12 steps, 3.2% global yield).
报道了一种直接且简便的方法用于首次全合成从[具体来源未给出]中分离得到的结构独特的3-甲基异喹啉生物碱安普洛辛。还公开了从一个共同中间体获得相关的甲基安普洛辛甲酯的方法。朝向天然产物的合成序列包括3,5-二羟基苯甲酸的科尔贝型羧化反应以及二酸的进一步酯化反应，接着通过选择性酯还原掩蔽其中一个酚羟基并随后形成缩丙酮。通过对剩余的游离酚进行三氟甲磺酸酯化以及与烯丙基三氟硼酸钾进行钯催化的铃木-宫浦反应来构建3-甲基吡啶环所需的三个碳原子。缩丙酮脱保护，接着将苄醇部分氧化为水杨醛，游离酚的甲基化以及所得茴香醛衍生物的腙化反应得到了基于腙的1-氮杂三烯。将其进一步进行6π-氮杂电环化反应得到全甲基安普洛辛（11步，总产率14%），而用碘化铝进行彻底脱甲基反应得到安普洛辛（12步，总产率3.2%）。
