STUDIES ON THE SYNTHESIS OF ANTITUMOR PYRROLOIMINOQUINONE MARINE ALKALOIDS

吡咯亚胺醌类海洋生物碱因其潜在的抗肿瘤活性而受到广泛关注。在本研究项目中，我们主要基于定向锂化策略开发了新的高效的吡咯亚胺醌核的构建和功能化方法。因此，1-三异丙基硅-6-甲氧基草胺在吲哚环的4位通过定向锂化氯化，然后与六氯乙烷反应。用常规方法将氯化谷草胺转化为1-保护-6-甲氧基色胺衍生物。通过芳烃介导的环化，色胺被环化为关键的三环7-甲氧基- 1,3,4,5 -四氢吡咯[4,3,2 - de]喹啉。Fremy's salt或salcomine催化氧化三环化合物生成7-甲氧基吡咯亚胺醌，这些化合物通过与氯化铵或盐酸酪胺的反应转化为吡咯亚胺醌海洋生物碱makaluvamines A， D， 1和K （Tetrahedron, 1998, 54,8999）。接下来，通过n - boc定向锂化，开发了1,3,4,5 -四氢吡咯[4,3,2 -de]喹啉核的6-选择性官能化。用该方法首次合成了C-6位有对羟基苄基取代基的新型吡咯亚胺醌类海洋生物碱维他胺。该方法可用于合成许多6-取代吡罗亚氨基醌海洋生物碱类似物，这对于研究此类潜在抗肿瘤化合物的结构-活性关系至关重要（Tetrahedron Letters, 1999,40,1713）。

Pyrroloiminoquinone marine alkaloids have received considerable attention due to their potential antitumor activity. In this reserch project we have developed new and efficient methods for both construction and functionalization of pyrroloiminoquinone nucleus based mainly upon directed lithiation strategy.Thus, 1-triisopropylsily-6-methoxygramine was chlorinated at 4-position of the indole ring via directed lithiation followed by a reaction with hexachloroethane. The chlorinated gramine was converted to 1-protected-6-methoxytryptamine derivatives by conventional procedure. The tryptamines were cyclized to the key tricyclic 7-methoxy- 1, 3, 4, 5 -tetrahydropyrrolo[4, 3, 2- de] quinolincs by aryne-mediated cyclization. The Fremy's salt or salcomine-catalyzed oxidation of the tricyclic compounds produced the 7-methoxy-pyrroloiminoquinones, which were converted to the pyrroloiminoquinone marine alkaloids makaluvamines A, D, 1, and K by the reactions with ammmonium chloride or tyramine hydrochloride (Tetrahedron, 1998, 54, 8999).Next, the 6-selective functionalization of 1, 3, 4, 5-tetrahydropyrrolo[4, 3, 2-de] quinoline nucleus has been developed via N-Boc-directed lithiation. By using this method, the first total synthesis of veiutamine, a new type of pyrroloiminoquinone marine alkaloid bearing a p-hydroxybenzyl substituent at C-6 position has been achieved. This procedure is useful for the synthesis of a number of 6-substituted pyrroloiminoquinone marine alkaloid analogues, which are essential for structure-activity relationshiip studies of this type of potential antitumor compounds (Tetrahedron Letters, 1999, 40, 1713).