This study involved the development of a new and scalable procedure for the stereoselective total synthesis of unnatural N -methyl tubulysin. The procedure encompasses linear sequence of 30 steps with an overall yield of 1.2%. The Tuv unit was prepared by diastereoselective synthesis from l -valine following MacMillan α-hydroxylation and an improved thiazole formation strategy. The stereocenters of the Tup unit were generated by using an Evans asymmetric aldol reaction initiated by l -phenylalanine. Notably, epimerization was completely avoided during all amide-forming reactions. The procedure that forms the basis of this sequence can be reliably performed on a gram scale and represents a significant improvement over previously reported syntheses of these and related tubulysin analogues. The scalability, associated yields, excellent stereoselectivity, and mild reaction conditions are the advantageous features of this approach.

中文翻译：

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非天然 N-甲基微管溶素的高度立体选择性全合成

该研究涉及开发一种用于非天然 N-甲基微管溶素的立体选择性全合成的新的可扩展程序。该程序包括 30 个步骤的线性序列，总产率为 1.2%。在 MacMillan α-羟基化和改进的噻唑形成策略之后，Tuv 单元是通过从 l-缬氨酸非对映选择性合成制备的。Tup 单元的立体中心是通过使用由 l-苯丙氨酸引发的 Evans 不对称醛醇反应生成的。值得注意的是，在所有酰胺形成反应中完全避免了差向异构化。形成该序列基础的程序可以在克级规模上可靠地进行，并且比以前报道的这些和相关微管溶素类似物的合成有了显着的改进。可扩展性、相关收益率、