Ishikawa Hayato
Department of Chemistry, Graduate School of Science and Technology, Kumamoto University.
Yakugaku Zasshi. 2015;135(3):383-90. doi: 10.1248/yakushi.14-00240-2.
Many tryptophan-based dimeric diketopiperazine (DKP) alkaloids including WIN 64821 and ditryptophenaline, which exhibit fascinating biological activities, have been isolated from fungi. These alkaloids possess a unique architecture; therefore several total syntheses of these compounds have been accomplished via bio-inspired reactions. Despite these elegant strategies, we were convinced that a more direct bio-inspired solution for the preparation of tryptophan-based DKP alkaloids was possible because in a true biosynthesis, direct dimerization of tryptophan occurs in aqueous media without incorporation of a protecting group on the substrates. Thus we developed direct bio-inspired dimerization reactions in aqueous, acidic media, along with a novel biomimetic pathway, to provide C2-symmetric and non-symmetric dimeric compounds from commercially available amine-free tryptophan derivatives using Mn(OAc)3, VOF3, and V2O5 as one-electron oxidants. In addition, concise two-pot or three-step syntheses of the naturally occurring dimeric DKP alkaloids (+)-WIN 64821, (-)-ditryptophenaline, and (+)-naseseazine B were accomplished with total yields of 20%, 13%, and 20%, respectively. The present synthesis has several noteworthy features: 1) the tryptophan-based C2-symmetric and non-symmetric dimeric key intermediates can be prepared on a multigram scale in one step; 2) the developed oxidation reaction was carried out in aqueous, acidic solution without deactivation of the metal oxidants; 3) protection of the primary amine can be avoided by salt formation in aqueous acid; 4) for the total two-pot operation, the reaction media are environmentally friendly water and ethanol; 5) satisfactory total yields are obtained compared with previously reported syntheses.
许多基于色氨酸的二聚二酮哌嗪（DKP）生物碱，包括具有迷人生物活性的WIN 64821和二色氨酸碱，已从真菌中分离出来。这些生物碱具有独特的结构；因此，通过仿生反应已经完成了这些化合物的几种全合成。尽管有这些精妙的策略，但我们确信，对于制备基于色氨酸的DKP生物碱，可能存在一种更直接的仿生解决方案，因为在真正的生物合成中，色氨酸的直接二聚化发生在水性介质中，而底物上无需引入保护基团。因此，我们开发了在水性酸性介质中的直接仿生二聚化反应，以及一条新颖的仿生途径，以使用醋酸锰（III）、三氟氧钒和五氧化二钒作为单电子氧化剂，从市售的无胺色氨酸衍生物制备C2对称和非对称的二聚化合物。此外，还完成了天然存在的二聚DKP生物碱（+）-WIN 64821、（-）-二色氨酸碱和（+）-纳塞嗪B的简洁两步或三步合成，总产率分别为20%、13%和20%。目前的合成方法有几个值得注意的特点：1）基于色氨酸的C2对称和非对称二聚关键中间体可以一步以多克规模制备；2）所开发的氧化反应在水性酸性溶液中进行，而金属氧化剂不会失活；3）通过在水性酸中形成盐可以避免伯胺的保护；4）对于总的两步操作，反应介质是环境友好的水和乙醇；5）与先前报道的合成方法相比，获得了令人满意的总产率。
