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.

1985年，Kohl等人在Helmholtz感染研究中心发现了Angiolam。从盘状血管球菌发酵液中筛选出一株AND30菌株。这种分离是HZI寻找粘性细菌产生的抗生素的一般程序的一部分。通过核磁共振和X-射线光谱分析对其结构进行了指认，确定了该化合物的结构和构型。该天然产物含有一个19元内酯和一个带有8个手性中心的官能化侧链。首次生物学研究揭示了抗膜缺陷型大肠杆菌、枯草芽孢杆菌和白色念珠菌的活性。在此，我们建议利用高度收敛和高效的策略来合成这一天然产物。最终目标是为详细的生物学研究和搜救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发展两个概念，以快速和实用的天然产物合成。这两个概念是醛衍生的烯醇醚的Venylogus Mukaiyama Aldol反应和这种不饱和醛的共轭还原伴随着不对称质子化。最后，通过衍生化对血管紧张素A的生物学性质进行优化。生物特性将与布伦斯韦格的HZI合作进行。在合成方向上，我们将Angiolam分成两个同样复杂的亚基。首先，为了连接这两个片段，应该使用多肽连接和第二大内酯连接。在C18位的羟基和相应的游离酸之间应建立大分子内酯化反应。所有保护基团的移除应提供血管紧张素A。我们将使用一系列不对称Mukaiyama Aldol反应，然后是1，4-还原和不对称质子化，以快速组装南半球。这一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品。在此合成过程中，将使用该策略两次建立四个手性中心。