Catalysis-Based and Protecting-Group-Free Total Syntheses of the Marine Oxylipins Hybridalactone and the Ecklonialactones A, B, and C

Concise and protecting-group-free total syntheses of the marine oxylipins hybridalactone (1) and three members of the ecklonialactone family (2–4) were developed. They deliver these targets in optically pure form in 14 or 13 steps, respectively, in the longest linear sequence; five of these steps are metal-catalyzed and four others are metal-mediated. The route to either 1 or 2–4 diverges from the common building block 22, which is accessible in 7 steps from 2[5H]furanone by recourse to a rhodium-catalyzed asymmetric 1,4-addition reaction controlled by the carvone-derived diene ligand 35 and a ring-closing alkene metathesis (RCM) catalyzed by the ruthenium indenylidene complex 17 as the key operations. Alternatively, 22 can be made in 10 steps from furfural via a diastereoselective three-component coupling process. The further elaboration of 22 into hybridalactone as the structurally most complex target with seven contiguous chiral centers was based upon a sequence of cyclopropanation followed by a vanadium-catalyzed epoxidation, both of which were directed by the same free hydroxy group at C15. The macrocyclic scaffold was annulated to the headgroup by means of a ring-closing alkyne metathesis reaction (RCAM). In response to the unusually high propensity of the oxirane of the targeted oxylipins for ring opening, this transformation had to be performed with complexes of the type [(Ar3SiO)4MoCPh][K·OEt2] (43), which represent a new generation of exceedingly tolerant yet remarkably efficient catalysts. Their ancillary triarylsilanolate ligands temper the Lewis acidity of the molybdenum center but are not sufficiently nucleophilic to engage in the opening of the fragile epoxide ring. A final semireduction of the cycloalkyne formed in the RCAM step to the required (Z)-alkene completed the total synthesis of (−)-1. The fact that the route from the common fragment 22 to the ecklonialactones could follow a similar logic showcased the flexibility inherent to the chosen approach.

本研究成功实现了海洋类氧脂类化合物杂交内酯（1）以及三种拟埃克洛诺酮家族成员（2-4）的简洁且无保护基团的完全合成。这些目标产物分别以14步和13步的纯光学形式产出，其中最长线性序列；五步采用金属催化，其余四步则通过金属介导完成。通往1或2-4的合成路径均源自于通用构建模块22，该模块可通过从2[5H]呋喃酮出发，经过7步合成，利用由香茅醇衍生的二烯配体35和由钌 indenylidene 复合物17催化的环闭烯烃迁移反应（RCM）作为关键操作来获得。或者，22也可以通过10步从糠醛出发，通过立体选择性的三组分偶联反应制得。将22进一步转化为结构上最为复杂的杂交内酯，作为具有七个连续手性中心的靶标，其合成基于环丙烷化反应序列，随后是钒催化的环氧化反应，这两个步骤均由位于C15的自由羟基所引导。通过环闭炔烃迁移反应（RCAM）将大环骨架连接到头部集团。鉴于目标氧脂类化合物的环氧烷基具有异常高的开环倾向，这一转化必须使用如[(Ar3SiO)4MoCPh][K·OEt2]（43）之类的复合物进行，这些复合物代表着新一代极具容忍度且效率显著的催化剂。它们辅助的三芳基硅氮醇配体缓和了钼中心的路易斯酸性，但不足以表现出足够的亲核性，以参与脆弱的环氧环的开环反应。将RCAM步骤中形成的环状炔烃进行半还原，得到所需的(Z)-烯烃，从而完成了(−)-1的完全合成。从通用片段22到埃克洛诺酮的合成路径能够遵循类似的逻辑，这展示了所选方法固有的灵活性。