Stereocontrolled Synthesis of C20S-C26 and C20R-C26 Fragments of Amphidinolide L,The Journal of Organic Chemistry

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Stereocontrolled Synthesis of C20S-C26 and C20R-C26 Fragments of Amphidinolide L
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2022-08-10 , DOI: 10.1021/acs.joc.2c01497
Jun Koizumi ₁ , Kaoru Tanaka ₁ , Keisuke Fukaya ₁ , Daisuke Urabe ₁

Affiliation

Amphidinolide L is a cytotoxic macrolide isolated from marine symbiotic dinoflagellates of the genus Amphidinium. While its planar structure and the absolute stereochemistry of the C21–C26 part have been determined, six stereocenters have remained unassigned. Aiming at structure determination, we have developed a synthetic route to the C20S-C26 and C20R-C26 fragments via the Li-mediated stereocontrolled aldol reaction. Two aldehydes, 16 with the C22-hydroxy group and 19 with the C22-TES ether, were synthesized from lactone 4. The aldol reactions using the Li-enolate of 4-methyl-2-pentanone in THF provided the C20S-C26 fragment 20 from 16 and a 1:3.5 mixture of the C20–C26 fragment 22 favoring the C20R-isomer. Mechanistic studies based on an extensive search of transition states in explicit solvents indicated that the C20S-isomer would be generated via a tri-solvated transition state, while the C20R-isomer would be formed via a di-solvated transition state. The calculation emphasizes the importance of the coordination network as a higher-order complex composed of solvent molecules, aldehyde, enolate, and Li atoms in the reaction of 16 to minimize steric interactions but maximize the stabilizing effect by the coordination of solvents. The presence of the rotationally free aldehyde in the reaction of 19 results in moderate diastereoselectivity.

中文翻译：

Amphidinolide L C20S-C26 和 C20R-C26 片段的立体控制合成

Amphidinolide L 是一种从Amphidinium属海洋共生甲藻中分离出来的细胞毒性大环内酯。虽然其平面结构和 C21-C26 部分的绝对立体化学已确定，但六个立体中心仍未确定。针对结构确定，我们开发了一种通过Li介导的立体控制羟醛反应合成C20 S -C26和C20 R -C26片段的路线。由内酯4合成了两种醛，其中 16 个具有 C22-羟基， 19 个具有 C22-TES 醚。使用THF中4-甲基-2-戊酮的Li-烯醇化物的羟醛反应提供了来自16的C20S -C26片段20和有利于C20R异构体的C20-C26片段22的1:3.5混合物。基于对显式溶剂中过渡态的广泛搜索的机理研究表明，C20 S异构体将通过三溶剂化过渡态生成，而 C20 R异构体将通过二溶剂化过渡态形成。该计算强调了配位网络作为由溶剂分子、醛、烯醇化物和Li原子组成的高阶络合物在16的反应中的重要性，以最小化空间相互作用，但最大化溶剂配位的稳定效果。 19的反应中旋转游离醛的存在导致中等的非对映选择性。

更新日期：2022-08-10

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