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biselyngbyaside（1）或其苷元，以及biselyngbyatrium A（2）。大环内酯环含有几个仲羟基官能团和双键，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含有两个双键，由亚甲基（跳过的二烯）分开。生物学研究表明，这两种靶分子都具有生长抑制活性，其中biselyngbyteA（2）的活性最高，IC 50值为12 nM（HL 60细胞系）。在前期工作中，我们已经开发了biselyngbyaside（1）的C1-C13部分的合成方法。计划通过Stille偶联反应将具有末端乙烯基碘的该片段与C14-C23结构单元偶联，以获得开环酸并最终获得大环内酯。我们的初步研究还表明，在合成过程中用对双键异构化更稳定的相应烯丙醇取代侧链的末端丙烯基部分可能是有利的。对于双黄连苷A（2）的C1-C13部分，我们可以使用来自双黄连苷合成的高级结构单元。计划通过二噻烷策略或乙烯基羟醛方法建立biselyngbydolamine A（2）的多元醇亚基。为了引入结构修饰，C19和C23处的侧链位置似乎是合适的。如果该区域的修饰是可以容忍的，将制备一些用于化学生物学研究的衍生物。或者，3-OH基团可用于连接接头型片段，因为在biselyngbyaside（1）中，该OH基团被糖基化，并且化合物仍然具有活性。

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.