Evolution of the Total Synthesis of (−)-Okilactomycin Exploiting a Tandem Oxy-Cope Rearrangement/Oxidation, a Petasis−Ferrier Union/Rearrangement, and Ring-Closing Metathesis

An effective, asymmetric total synthesis of the antitumor antibiotic (−)-okilactomycin (1), as well as assignment of the absolute configuration, has been achieved exploiting a convergent strategy. Highlights of the synthesis include a diastereoselective oxy-Cope rearrangement/oxidation sequence to install the C(1) and C(13) stereogenic centers, a Petasis−Ferrier union/rearrangement to construct the highly functionalized tetrahydropyranone inscribed within the 13-membered macrocycle ring, employing for the first time a sterically demanding acetal, an intramolecular chemoselective acylation to access an embedded bicyclic lactone, and an efficient ring-closing metathesis (RCM) reaction to generate the macrocyclic ring.

本研究采用汇聚式合成策略，成功实现了抗肿瘤抗生素(-)-okilactomycin (1)的高效不对称全合成，并完成了其绝对构型的归属。该合成路线的核心亮点如下：通过非对映选择性oxy-Cope重排（oxy-Cope rearrangement）/氧化串联反应构建C(1)与C(13)位手性中心；采用Petasis-Ferrier偶联-重排反应构建13元大环骨架内的高度官能化四氢吡喃酮（tetrahydropyranone）环系，该反应首次使用了位阻较大的缩醛；通过分子内化学选择性酰化反应得到内嵌双环内酯（bicyclic lactone）；并通过高效的关环复分解（ring-closing metathesis, RCM）反应生成目标大环结构。