Castoldi Damiano, Caggiano Lorenzo, Panigada Laura, Sharon Ofer, Costa Anna M, Gennari Cesare
Dipartimento di Chimica Organica e Industriale, Centro di Eccellenza C.I.S.I. Università degli Studi di Milano, Istituto di Scienze e Tecnologie Molecolari (ISTM) del CNR, Via G. Venezian, 21, 20133 Milano, Italy.
Chemistry. 2005 Dec 16;12(1):51-62. doi: 10.1002/chem.200500749.
Asymmetric oxyallylation reactions and ring-closing metathesis have been used to synthesize compound 3, a key advanced intermediate used in the total synthesis of eleutherobin reported by Danishefsky and co-workers. The aldehyde 6, which is readily prepared from commercially available R-(-)-carvone in six steps in 30 % overall yield on multigram quantities, was converted into the diene 5 utilizing two stereoselective titanium-mediated Hafner-Duthaler oxyallylation reactions. The reactions gave the desired products (8 and 12) in high yields (73 and 83 %, respectively) as single diastereoisomers, with the allylic alcohol already protected as the p-methoxyphenyl (PMP) ether, which previous work has demonstrated actually aids ring-closing metathesis compared to other protective groups and the corresponding free alcohol. Cyclization under forcing conditions, using Grubbs' second-generation catalyst 13, gave the ten-membered carbocycle (E)-14 in 64 % yield. This result is in sharp contrast to similar, but less functionalized, dienes, which have all undergone cyclization to give the Z stereoisomers exclusively. A detailed investigation of this unusual cyclization stereochemistry by computational methods has shown that the E isomer of the ten-membered carbocycle is indeed less thermodynamically stable than the corresponding Z isomer. In fact, the selectivity is believed to be due to the dense functionality around the ruthenacyclobutane intermediate that favors the trans-ruthenacycle, which ultimately leads to the less stable E isomer of the ten-membered carbocycle under kinetic control. During the final synthetic manipulations the double bond of enedione (E)-16 isomerized to the more thermodynamically stable enedione (Z)-4, giving access to the advanced key-intermediate 3, which was spectroscopically and analytically identical to the data reported by Danishefsky and co-workers, and thereby completing the formal synthesis of eleutherobin.
不对称氧代烯丙基化反应和关环复分解反应已被用于合成化合物3，它是Danishefsky及其同事报道的在红珊瑚醇全合成中使用的关键高级中间体。醛6可由市售的R-(-)-香芹酮经六步反应轻松制备，总收率为30%，可制备多克量，利用两个立体选择性钛介导的哈夫纳-杜泰勒氧代烯丙基化反应将其转化为二烯5。反应以高产率（分别为73%和83%）得到所需产物（8和12），为单一非对映异构体，烯丙醇已被保护为对甲氧基苯基（PMP）醚，先前的工作表明，与其他保护基团和相应的游离醇相比，该醚实际上有助于关环复分解反应。在强制条件下，使用格拉布第二代催化剂13进行环化反应，以64%的产率得到十元碳环（E）-14。该结果与类似但官能团较少的二烯形成鲜明对比，这些二烯均发生环化反应，仅生成Z立体异构体。通过计算方法对这种不寻常的环化立体化学进行的详细研究表明，十元碳环的E异构体在热力学上确实不如相应的Z异构体稳定。事实上，这种选择性被认为是由于钌杂环丁烷中间体周围的密集官能团有利于反式钌杂环，最终在动力学控制下导致十元碳环的较不稳定E异构体。在最后的合成操作中，烯二酮（E）-16的双键异构化为热力学上更稳定的烯二酮（Z）-4，从而得到高级关键中间体3，其光谱和分析数据与Danishefsky及其同事报道的数据一致，从而完成了红珊瑚醇的形式合成。
