Synthesis of Biselyngbyaside and Biselyngbyolide A

本项目的目标是全合成两个相关的18元大环内酯双倍半苷(1)或其配基，以及双倍半内酯A(2)。大内酯环含有几个二次羟基和双键，其中两个是共轭体系的一部分。具有六个碳原子长度的侧链包含两个被亚甲基(跳过的二烯)隔开的双键。生物学研究表明，两个目标分子都具有生长抑制活性，其中双烯内酯A(2)的活性最强，其IC50值为12 nM(HL60细胞株)。在前期工作中，我们已经合成了二倍半乳糖苷(1)的C1-C13部分。计划通过Stille偶联反应将以末端碘乙烯为特征的这一片段与C14-C23构建块偶联，以获得Seco酸并最终与大内酯结合。我们的初步研究还表明，在合成过程中用更稳定的双键异构化的烯丙醇取代侧链的末端丙烯基部分可能是有利的。对于双龙内酯A(2)的C1-C13部分，我们可以使用来自双龙内酯合成的高级构筑块。计划通过二硫杂环丙烷策略或乙醇化羟醛基法建立双倍半内酯A(2)的多元醇亚单位。为了引入结构修饰，C19和C23的侧链位置似乎是合适的。如果这一区域的修饰应该被容忍，将制备一些用于化学生物学研究的衍生品。可替换地，3-OH基团可用于连接连接型片段，因为在双键(1)中，该OH基团是糖基化的，并且该化合物仍然是活性的。

Aim of the project is the total synthesis of the two related 18-membered macrolides biselyngbyaside (1) or its aglycon, respectively, and of biselyngbyolide A (2). The macrolactone rings contain several secondary hydroxyl functions and double bonds, with two of them being part of a conjugated system. The side chain having a length of six carbon atoms contains two double bonds, separated by a methylene group (skipped diene). Biological studies showed that both of the target molecules have growth inhibition activity, whereby biselyngbyolide A (2) was the most active with an IC50 value of 12 nM (HL60 cell line). In preliminary work we already developed a synthesis for the C1-C13 part of biselyngbyaside (1). It is planned to couple this fragment, featuring a terminal vinyl iodide, with a C14-C23 building block via a Stille coupling reaction to obtain the seco acid and ultimately to the macrolactone. Our preliminary studies also showed that it might be advantageous to replace the terminal propenyl part of the side chain during the synthesis with a corresponding allylic alcohol which is more stable towards double bond isomerization. For the C1-C13 part of biselyngbyolide A (2) we can use an advanced building block from the biselyngbyaside synthesis. It is planned to establish the polyol subunit of biselyngbyolide A (2) through a dithiane strategy or a vinylogous aldol approach. In order to introduce structural modifications, the side chain positions at C19 and C23 appear suitable. If modifications in this region should be tolerated, some derivatives for use in chemical biology studies will be prepared. Alternatively, the 3-OH group might be used for attaching linker type fragments since in biselyngbyaside (1) this OH group is glycosylated and the compound is still active.