Banerjee Ankush, Brisco Tiffany A, Ray Sneha, Datta Arani, Zhang Xiaoyu, Zhang Zhen, Busse Alexander A, Niederstrasser Hanspeter, Sumida Krissty, Posner Bruce A, Wetzel Dawn M, Phillips Margaret A, Smith Myles W
Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
Org Biomol Chem. 2024 Dec 11;22(48):9413-9425. doi: 10.1039/d4ob01552e.
We describe the development of a unified synthetic strategy for the preparation of all known 5/5-spirocyclic spiroindimicin (SPM) alkaloids, namely spiroindimicins B-G. The present synthetic route relies on four fundamental transformations: Grignard-based fragment coupling between halogenated pyrrolemetal and isatin partners, Suzuki coupling to generate a triaryl scaffold encompassing all requisite skeletal atoms of the natural products, Lewis acid-mediated spirocyclization to construct the 5/5-spirocyclic core, and chemoselective lactam reduction. The developed syntheses are step-economic (6-7 steps from commercial materials), scalable, and amenable to analogue synthesis. Preliminary investigations into a catalytic asymmetric spirocyclization towards an enantioselective SPM synthesis are also described. Further studies of the antiparasitic properties of this class have revealed promising activity against for certain congeners. Together with our prior approach to the 6/5-family members, our work constitutes a synthetic solution to all known spiroindimicin natural products.
我们描述了一种统一的合成策略的开发，用于制备所有已知的5/5-螺环螺吲哚霉素（SPM）生物碱，即螺吲哚霉素B-G。目前的合成路线依赖于四个基本转化：卤代吡咯金属与异吲哚酮底物之间基于格氏试剂的片段偶联、用于生成包含天然产物所有必需骨架原子的三芳基支架的铃木偶联、路易斯酸介导的螺环化反应以构建5/5-螺环核心以及化学选择性内酰胺还原。所开发的合成方法步骤经济（从市售原料开始6-7步）、可扩展且适用于类似物合成。还描述了对催化不对称螺环化反应以实现对映选择性SPM合成的初步研究。对该类化合物抗寄生虫特性的进一步研究表明，某些同系物具有有前景的活性。连同我们之前制备6/5-家族成员的方法，我们的工作构成了所有已知螺吲哚霉素天然产物的合成解决方案。
