Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany.
J Am Chem Soc. 2011 Aug 31;133(34):13471-80. doi: 10.1021/ja204027a. Epub 2011 Aug 5.
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 [(Ar(3)SiO)(4)Mo≡CPh][K·OEt(2)] (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.
简洁且无保护基团的海洋氧化脂类杂种内酯（1）和 ecklonialactone 家族的三个成员（2-4）的全合成已被开发出来。通过最长线性序列，分别在 14 步或 13 步内以光学纯形式提供这些目标；其中五个步骤是金属催化的，另外四个步骤是金属介导的。1 或 2-4 的路线与常见的构建块 22 不同，22 可以通过 2[5H]呋喃酮的七个步骤来获得，通过求助于由莰烯衍生的二烯配体 35 控制的铑催化不对称 1,4-加成反应和由钌茚基二烯配合物 17 催化的环闭烯烃复分解（RCM）作为关键操作。或者，22 可以通过立体选择性三组分偶联过程从糠醛以 10 步合成。22 进一步细化为杂种内酯，作为结构上最复杂的目标，具有七个连续的手性中心，基于一系列环丙烷化反应，随后进行钒催化环氧化反应，这两个反应都由 C15 上的相同游离羟基指导。大环支架通过闭环炔烃复分解反应（RCAM）连接到头基团。针对目标氧化脂中环氧化物异常倾向于开环的情况，此转化必须使用（Ar(3)SiO)(4)Mo≡CPh][K·OEt(2)]（43）类型的配合物进行，该配合物代表了新一代极其耐受但非常有效的催化剂。它们的辅助三芳基硅烷醇盐配体调节钼中心的路易斯酸度，但不够亲核，无法参与易碎环氧化物环的开环。RCAM 步骤中形成的环炔烃的最终半还原完成了（-）-1 的全合成。从常见片段 22 到 ecklonialactones 的路线可以遵循类似逻辑的事实，展示了所选择方法固有的灵活性。
