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首页> 外文学位 >I. Total synthesis, stereochemical reassignment, and biological evaluation of (+)-neopeltolide and related stereoisomers. II. Development of chiral benzylsilanes: Reagents for stereoselective, silicon-mediated oxa-Pictet-Spengler reactions.
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I. Total synthesis, stereochemical reassignment, and biological evaluation of (+)-neopeltolide and related stereoisomers. II. Development of chiral benzylsilanes: Reagents for stereoselective, silicon-mediated oxa-Pictet-Spengler reactions.

机译：I.（+）-neopeltolide和相关立体异构体的全合成，立体化学重新分配和生物学评估。二。手性苄基硅烷的开发：用于立体选择性硅介导的oxa-Pictet-Spengler反应的试剂。

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摘要

(+)-Neopeltolide is a biologically active marine natural product that was recently isolated from a previously unknown species of deep-sea sponge. Preliminary bioactivity assays indicated (+)-neopeltolide possessed anti-cancer properties with a potency rivaling the known chemotherapeutic agent Taxol RTM. The promising pharmaceutical potential and intriguing architecture of this natural product prompted us to initiate synthetic studies towards its preparation. Two of six stereogenic centers were procured from chiral pool reagents, while a third was installed via highly stereoselective Evans-Tishchenko reduction. An organosilane-based [4+2]-annulation was critical in the asymmetric assembly of the tetrahydropyran segment while simultaneously establishing two additional stereocenters at C3 and C7. Union of the 14-membered lactone with the oxazole side chain occurred under Mitsunobu conditions to give the compound originally identified as (+)-neopeltolide. Comparison of the natural and synthetic material revealed that the two compounds were not identical. Re-evaluation of the natural material led to the supposition that the original structure was a related stereoisomer and subsequent preparation of a select subset of neopeltolide diastereomers successfully identified the correct relative and absolute stereochemistry of (+)-neopeltolide. (+)-Neopeltolide and four additional stereoisomers were evaluated for biological activity where the natural product demonstrated a remarkable tolerance for stereochemical modification.;Substituted isochromans (1H-3,4-dihydro-2-benzopyrans) are common structural archetypes in biologically active compounds. A common approach to these templates is the oxa-Pictet Spengler condensation of a carbonyl with a phenylethyl alcohol. While successfully applied towards natural product syntheses, the general reaction suffers from several constraints, including limited substrate scope and preferential formation of cis-pyrans. Incorporation of a substituted silicon group within the phenylethyl alcohol may circumvent these restrictions. To explore this possibility, several novel benzylsilane reagents were obtained from silyl glycidate openings utilizing various aryl metal nucleophiles. These new silane reagents were then evaluated in a kinetically-controlled oxa-Pictet Spengler reaction wherein they displayed exceptional cis-diastereoselectivity and yields in isochroman formation. The annulation of electron-deficient aromatic systems, as well as trans-selective pyran assembly, proved more difficult but could be achieved under alternative conditions.
机译：（+）-新萘乙酸是一种具有生物活性的海洋天然产物，最近从以前未知的深海海绵物种中分离出来。初步的生物活性测定表明，（+）-新邻苯二酚具有抗癌特性，其功效可与已知的化学治疗剂Taxol RTM媲美。这种天然产物的有前途的药物潜力和令人着迷的结构促使我们开始进行合成研究以制备其。六个立体定位中心中的两个是从手性池试剂中获得的，而另一个则是通过高度立体选择性Evans-Tishchenko还原而安装的。在四氢吡喃链段的不对称组装中，同时基于C3和C7建立两个额外的立体中心时，基于有机硅烷的[4 + 2]环状结构至关重要。 14位内酯与恶唑侧链的结合在Mitsunobu条件下发生，得到的化合物最初鉴定为（+）-neopeltolide。天然和合成材料的比较表明，两种化合物不相同。对天然物质的重新评估导致了这样的假设，即原始结构是相关的立体异构体，随后制备新的新内酯类非对映异构体的选择子集成功地确定了（+）-新的内酯类的正确相对和绝对立体化学。 （+）-新邻苯二酚和四种其他立体异构体的生物活性得到了评估，其中天然产物表现出对立体化学修饰的显着耐受性；取代的异色满（1H-3,4-二氢-2-苯并吡喃）是生物活性化合物中的常见结构原型。这些模板的常用方法是羰基与苯乙醇的氧杂-Pictet Spengler缩合反应。虽然成功应用于天然产物合成中，但一般反应仍受到一些限制，包括有限的底物范围和顺式吡喃的优先形成。在苯乙醇中引入取代的硅基团可以规避这些限制。为了探索这种可能性，利用各种芳基金属亲核试剂从缩水甘油基甲硅烷基酯开口中获得了几种新颖的苄基硅烷试剂。这些新的硅烷试剂随后在动力学控制的oxa-Pictet Spengler反应中进行了评估，其中它们表现出出色的顺-非对映选择性和异色满形成的产率。缺乏电子的芳族体系以及反式选择性吡喃组装的环化被证明更加困难，但可以在替代条件下实现。

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  • 作者

    Youngsaye, Willmen Wing-Menn.;

  • 作者单位

    Boston University.;

  • 授予单位 Boston University.;
  • 学科 Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 409 p.
  • 总页数 409
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
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