From synthesis to function via iterative assembly of N-methyliminodiacetic acid boronate building blocks.
From synthesis to function via iterative assembly of N-methyliminodiacetic acid boronate building blocks.
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DOI：
10.1021/acs.accounts.5b00128
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发表时间：
2015-08-18
影响因子：
18.3
通讯作者：
Burke MD
中科院分区：
文献类型：
--
作者：
Li J;Grillo AS;Burke MD
小分子可以极大地造福社会，但其功能的研究和优化往往受到通常用于制造它们的时间密集型和专业人员依赖型过程的阻碍。相比之下，已经开发了用于肽、寡核苷酸和越来越多的寡糖合成的通用和自动化平台，从而即使对于非专业人员也可以按需获得这些分子。一种更普遍和自动化的制造小分子的方法同样可以帮助将小分子科学中的限速步骤从合成转移到功能。为了实现这一目标，我们开发了一个全自动且日益通用的平台，用于硼酸盐构建模块的迭代偶联。类似于肽合成，该过程涉及作为相应的N-甲基亚氨基二乙酸（MIDA）硼酸盐保护的卤代硼酸的迭代偶联。这个平台使我们和其他团体能够获得许多多烯天然产品，包括超过75%的多烯天然产品中的多烯基序。它进一步使我们能够衍生化，从而了解强大的，但也是高毒性的抗真菌天然产物阿替霉素B，这导致了目前正在评估的药物候选人毒性较低的衍生物的发展。我们还发现了立体控制进入手性非外消旋α-硼基醛，其是合成许多Csp 3硼酸酯结构单元的通用中间体，这些结构单元在其他方面难以获得。我们还扩大了平台的范围，包括使用线性到环化策略的富含Csp 3的多环分子，其中Csp 3硼酸酯构建块迭代组装成线性前体，然后环化成在许多天然产物和天然产物样结构中发现的环状框架。通过偶然发现的捕获和释放协议，一般纯化MIDA硼酸盐中间体，该平台已经自动化。使用这种新的合成机器已经实现了14种不同类别的小分子的合成，包括药物，材料和多环天然产物。预计该平台可访问的小分子范围将通过构建块合成、Csp 3交叉偶联方法和环化策略的进一步发展而继续扩大。
Small molecules can powerfully benefit society, but the study and optimization of their function is too often impeded by the time-intensive and specialist-dependent process that is typically used to make them. In contrast, general and automated platforms have been developed for peptide, oligonucleotide, and increasingly oligosaccharide synthesis, resulting in on-demand access to these molecules, even for non-specialists. A more generalized and automated approach for making small molecules could similarly help shift the rate limiting step in small molecule science from synthesis to function. Targeting this goal, we have developed a fully automated and increasingly general platform for iterative coupling of boronate building blocks. Analogous to peptide synthesis, the process involves iterative coupling of haloboronic acids protected as the corresponding N-methyliminodiacetic acid (MIDA) boronates. This platform has enabled us and other groups to access many polyene natural products, including the polyene motifs in >75% of all polyene natural products. It further allowed us to derivatize and thereby understand the powerful but also highly toxic antifungal natural product amphotericin B, which has led to the development of less toxic derivatives currently under evaluation as drug candidates. We also discovered a stereocontrolled entry into chiral, non-racemic α-boryl aldehydes, which are versatile intermediates for the synthesis of many Csp3 boronate building blocks that are otherwise difficult to access. We have also expanded the scope of the platform to include Csp3-rich, polycyclic molecules using a linear-to-cyclized strategy, in which Csp3 boronate building blocks are iteratively assembled into linear precursors that are then cyclized into the cyclic frameworks found in many natural products and natural product-like structures. Enabled by the serendipitous discovery of a catch-and-release protocol for generally purifying MIDA boronate intermediates, the platform has been automated. The synthesis of 14 distinct classes of small molecules, including pharmaceuticals, materials, and polycyclic natural products has been achieved using this new synthesis machine. It is anticipated that the scope of small molecules accessible by this platform will continue to expand via further developments in building block synthesis, Csp3 cross-coupling methodologies, and cyclization strategies.