The synthesis of angiolam A

血管生成素A的合成

• 批准号: 226515476
• 负责人: Professor Dr. Markus Kalesse
• 金额: --
• 依托单位: Institut für Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226515476?language=en
• 关键词: synthesis; angiolam

Angiolam was discovered at the Helmholtz Center for Infection Research in 1985 by Kohl et al. from the fermentation broth of the myxobacterium Angiococcus disciformis, strain An d30. This isolation was part of the general program at the HZI to search for antibiotics produced by myxobacteria. The configurational assignment was done with the aid of NMR and X-ray spectroscopy and provided the constitution as well as the configuration of angiolam. This natural product contains a 19-membered lacton and a functionalized side chain with overall eight chiral centers. First biological investigation unraveled activities against membrane deficient Escherichia coli mutants, Bacillus subtilis and Candida albicansHere we propose the synthesis of this natural product by taking advantage of a highly convergent and efficient strategy. The ultimate goal is to provide sufficient quantities for detailed biological studies and SAR investigations. In the course of this project we will additionally, investigate and further develop two concepts for rapid and practical natural products synthesis. These two concepts are the vinylogus Mukaiyama aldol reaction of aldehyde derived enol ethers and the conjugate reduction of such unsaturated aldehydes with concomitant asymmetric protonation. Finally, the biological properties of angiolam A will be optimized through derivatization. The biological properties will be performed in collaboration with the HZI in Braunschweig. In synthetic direction we divided angiolam into two equally complex subunits. First, a peptide linkage and second a macro lactonization should be employed in order to join both segments. The macro lactonization should be established between the hydroxyl group at C18 and the corresponding free acid. Removal of all protecting groups should provide angiolam A.We will use a sequence of asymmetric Mukaiyama aldol reaction followed by 1,4-reduction and asymmetric protonation for the rapid assembly of the southern hemisphere. This strategy allows a two-step access to natural products containing an anti-configured 1,4 functional group distance between the hydroxyl and methyl groups. This strategy will be employed twice to establish four chiral centers during this synthesis.

Angiolam是由Kohl等人于1985年在Helmholtz Center for Infection Research发现的，来自粘细菌Angiococcus angioformis菌株An d30的发酵液。这种分离是HZI寻找粘细菌产生的抗生素的一般计划的一部分。借助核磁共振和X-射线光谱进行了构型归属，并提供了angiolam的组成和构型。该天然产物含有一个19元内酯和一个官能化的侧链，共有8个手性中心。第一个生物学研究揭示了对膜缺陷大肠杆菌突变体，枯草芽孢杆菌和白色念珠菌的活性在这里，我们提出了利用高度收敛和有效的策略合成这种天然产物。最终目标是为详细的生物学研究和SAR调查提供足够的数量。在这个项目的过程中，我们还将研究和进一步开发两个快速实用的天然产物合成概念。这两个概念是醛衍生的烯醇醚的乙烯基向山羟醛缩合反应和伴随不对称质子化的这种不饱和醛的共轭还原。最后，通过衍生化作用优化了angiolam A的生物学性质。生物学特性将与布伦瑞克的HZI合作进行。在合成方向上，我们将angiolam分为两个同样复杂的亚基。首先，应当采用肽连接和第二大内酯化以连接两个片段。大分子内酯化应在C18位的羟基和相应的游离酸之间建立。去除所有保护基团应提供angiolam A。我们将使用一系列的不对称Mukaiyama羟醛缩合反应，然后是1，4-还原和不对称质子化，用于南半球的快速组装。该策略允许两步获得在羟基和甲基之间含有反构型1，4官能团距离的天然产物。在该合成过程中，该策略将被采用两次以建立四个手性中心。