Discovery through total synthesis: A retrospective on the himastatin problem
Discovery through total synthesis: A retrospective on the himastatin problem
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DOI：
10.1002/1521-3765(20010105)7:1
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发表时间：
2001-01-05
影响因子：
4.3
通讯作者：
Danishefsky, SJ
中科院分区：
文献类型：
--
作者：
Kamenecka, TM;Danishefsky, SJ
完成了希马他汀结构的全合成。由于全合成材料与组胺抑制素的不同一性，需要对指定结构进行修订。随后通过全合成证实了修正的立体结构。在这一努力期间的成就包括i）反顺式和顺式吡咯吲哚啉亚结构的立体特异性途径; ii）对映体纯形式的5-羟基哌嗪酸的实际合成; iii）导致复杂的双吲哚部分的Stille偶联，以及iv）在整个进化的缩肽结构域中的有效保护基团管理。生物药效团的轮廓已被描绘。6-mer中的交替的D-和L-取代基以及连接两个相同亚基的联芳基键对于维持生物活性至关重要。这种模式在另一种抗生素中模拟，并表明未来SAR研究的可能结构趋势。
A total synthesis of a structure proposed for himastatin was accomplished. The non-identity of the fully synthetic material with himastatin necessitated a revision of the assigned structure. Confirmation of the revised stereostructure was subsequently confirmed through total synthesis. Among the achievements during this effort were i) stereospecific routes to both anti-cis and syn-cis pyrrolindoline substructures; ii) a practical synthesis to 5-hydroxypiperazic acid in enantiomerically pure form; iii) a Stille coupling leading to a complex bi-indole moiety, and iv) efficient protecting group management throughout the evolving depsipeptide domain. The outlines for a biological pharmacophore have been delineated. The alternating D- and L-substituents in the 6-mer as well as the biaryl linkage connecting the two identical subunits are critical for maintaining biological activity. This pattern is simulated in another antibiotic, and suggests a possible structural trend for future SAR investigations.