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Gram-scale synthesis of iejimalide B

机译：依杰麦利德B的克级合成

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IejimalideB (2) is the most promising member of a small family of marine polyene macrolides endowed with remarkably selective activity against human cancer cell lines. As this product, however, is hardly available from the natural sources, a detailed evaluation requires the development of an efficient and practical synthetic approach. This challenge has now been met by adapting the first total synthesis of 2 previously reported by our group to the needs of high material throughput. Redesigning the access routes to the five required building blocks in combination with a careful optimization of the fragment coupling processes provided gram amounts of this valuable compound in a sequence of no more than 16 linear steps with an overall yield of about 7 %. Key elements of the successful strategy include: i) three hydrostannylation processes of elaborate terminal alkynes with "lower order" stannyl cuprates, ii) a Brown allylation, a Noyori transfer hydrogenation, and a Marshall propargylation to set the chiral centers at C9, C17, C22 and C23, and iii) a modified Takai-Utimoto olefination for the preparation of the very labile skipped 1,4-diene flanking the ester group. The assembly process benefited from a particularly mild protocol for the Stille cross-coupling previously developed in this laboratory, which clearly outperformed the alternative Suzuki reaction in terms of yield and scalability. The 24-membered macrocyclic frame was forged by a remarkably selective ring-closing metathesis reaction (RCM), in which two out of the ten double bonds present in the cyclization precursor were selectively activated with the aid of a second-generation Grubbs catalyst.
机译：IejimalideB（2）是一类海洋多烯大环内酯类化合物中最有前途的成员，该化合物具有针对人类癌细胞系的显着选择性活性。但是，由于几乎无法从天然来源获得该产品，因此详细评估需要开发一种有效且实用的合成方法。现在，通过将我们小组先前报告的2的第一个全合成方法适应高物料通过量的需求，已经解决了这一难题。重新设计通往五个所需构件的通道，并仔细优化了片段偶联过程，以不超过16个线性步骤的顺序提供了克量的这种有价值的化合物，总产率约为7％。成功策略的关键要素包括：i）精制的末端炔烃与“低级”锡烷基铜的三个氢化锡烷基化工艺; ii）布朗烯丙基化，诺赖转移氢化和马歇尔炔丙基化，将手性中心设置在C9，C17， C22和C23，以及iii）用于制备酯基侧翼的非常不稳定的跳过的1，4-二烯的改性的Takai-Utimoto烯烃化。组装过程得益于该实验室先前开发的Stille交叉偶联方案，该方案特别温和，在产率和可扩展性方面明显优于替代Suzuki反应。通过显着选择性的闭环复分解反应（RCM）锻造24元大环骨架，其中借助第二代Grubbs催化剂选择性活化环化前体中存在的十个双键中的两个。

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