Total Synthesis of Palmerolide A

描述（由申请人提供）：Palmerolide A是从南极被囊动物滑膜中分离出来的一种海洋天然产物，据报道具有显著的细胞毒活性。Palmerolide A在美国国家癌症研究所（NCI）的60个细胞系中进行了筛选，显示出对黑色素瘤（例如，UACC-62, LC50= 6.5 nM）的有效活性，相对于其他细胞系的敏感性高3个数量级。黑色素瘤是最不常见但最致命的皮肤癌。传统的治疗方案包括手术、化疗、放疗和生物疗法。棕榈内酯的选择性指数表明，它是抗黑色素瘤治疗的首选候选药物。由于从天然来源获得天然产物的途径有限，化学合成仍然是获得大量棕榈内酯用于各种生物学研究的唯一可行选择。我们对棕榈内酯全合成的建议主要是利用高度非对映选择性的双烯丙基硼化反应来构建C(1)-C（15）片段，以安装C(7)-C（11）三醇单元。我们预计，如果中间的烯丙基硼酸酯（在第一次烯丙基化之后）在末端的烯烃上被硅基或硼酸基修饰，那么作为新的烯丙基硼酸化反应的直接结果，可以得到三醇单元。硅基或硼基取代烯烃经烯丙基硼化反应后，生成的含1,5-二醇的硅和/或硼将通过金属-碳键的氧化转化为三醇。一种互补方法涉及使用手性锡烷烯丙基硼化物序列。在采用这两种策略后，棕榈内酯的C(1)-C（15）段的所有四个非对映体都可以得到。在生成C(1)-C（15）片段的各种立体异构体后，我们将采用非对映选择性手性丙烯硼烷或锡烷加成和铜催化的酰胺化反应，通过简洁的路线合成酰胺侧链。C(1)-C（15）片段与酰胺侧链的偶联将通过交叉偶联和大内酯化序列进行，以获得天然产物。我们对棕榈内酯的合成建议应该提供各种立体和结构异构体，这些异构体可以用于生物学评价，以最大限度地提高细胞毒性母体化合物(-)-棕榈内酯a的选择性和效力。公共卫生相关性：在本研究中产生的(-)-棕榈内酯的数量将提交给正在进行的生物学研究。将评价棕榈内酯的立体和结构异构体作为抗黑色素瘤药物的生物活性。

DESCRIPTION (provided by applicant): Palmerolide A is a marine natural product isolated from the Antarctic tunicate Synoicum adareanum, and has been reported to exhibit significant cytotoxic activity. Palmerolide A was screened against the National Cancer Institute's (NCI) 60 cell line panel, and demonstrates potent activity against melanoma (e.g., UACC-62, LC50= 6.5 nM) with three orders of magnitude greater sensitivity relative to other cell lines. Melanoma is the least common, but most deadly skin cancer. Traditional treatment options include surgery, chemotherapy, radiation and biologic therapy. The selectivity index demonstrated by palmerolide identifies it as a premiere candidate for anti-melanoma treatment. With limited access to the natural product from natural sources, chemical synthesis remains the only viable option to acquire quantities of palmerolide to be used in various biological studies. Our proposal for the total synthesis of palmerolide focuses on the construction of the C(1)-C(15) fragment using a highly diastereoselective double allylboration reaction to install the C(7)-C(11) triol unit. We anticipate that access to the triol unit as a direct result of the new allylboration reaction would be conceivable if the intermediate allylboronate (following the first allylation) is modified with a silyl or boronate group at the terminal olefin. Following the allylboration of this silyl or boryl substituted olefin, the resultant silicon and/or boron containing-1,5-diol would be converted to the triol by oxidation of the metal-carbon bond. A complimentary approach involves use of a chiral stannane allylboration sequence. Upon employing both strategies all four diastereomers of the C(1)-C(15) segment of palmerolide will be accessible. Upon generating various stereoisomers of the C(1)-C(15) fragment, we will then synthesize the enamide side chain by a concise route employing a diastereoselective chiral allenylborane or stannane addition and copper catalyzed amidation reaction. Coupling of the C(1)-C(15) fragment with the enamide side chain will then proceed by a cross-coupling andmacrolactonization sequence to access the natural product. Our synthetic proposal to palmerolide should provide access to various stereo and structural isomers that could be used for biological evaluation in an effort to maximize selectivity and potency of the cytotoxic parent compound (-)-palmerolide A. Public Health Relevance: Quantities of (-)-palmerolide generated during this study will be submitted for ongoing biological studies. Stereo and structural isomers of palmerolide will be evaluated for their biological activity in regard to therapuetic potential as anti-melanoma agents.