Synthesis of a Bridged Bicyclic Natural Product Using Allenyl Esters

描述(由申请人提供)：本提案提出了一项研究计划，旨在开发新的有机反应，以便于合成与医学相关的天然产品(维替比索D)。合成计划将涉及在有机化学(手性烯丙基酯)中应用相对较新的未被充分利用的构筑块，利用存在的高度不饱和度和独特的官能团并置。因此，使用这些新的构建块和新的环化序列(还原羟醛)，将(首次)在14个步骤中合成维的松D，这是一种抑制血液凝固的天然产物。重要的是，计划中的合成将提供足够数量的维的松D，以便进行生化研究，以确定这种结构独特、几乎无法获得的天然产品的作用机制。该项目还将扩大制备更复杂的烯丙基酯作为单一异构体(非外消旋)的方法。这些方法需要开发独特的催化剂，以提供对导致烯丙基酯产品的键形成的高度控制。有了这些丙二烯积木，一系列维的松D衍生物将 高效合成(3-5步)。通过与附近的Torrey Pines分子研究所合作，将研究维的松酚D及其衍生物抗凝血的活性。这些生物学研究是由作为该项目一部分开发的合成方法实现的，目的是确定维的松D的酶靶标，最终作为未来凝血疾病药物化学研究的起点。

DESCRIPTION (provided by applicant): This proposal sets forth a research program for the development of new organic reactions for the facilitated synthesis of a medicinally-relevant natural product (vitisinol D). The synthesis plan will involve the application of relatively new an underutilized building blocks in organic chemistry (chiral allenyl esters) exploiting the high degree of unsaturation and unique juxtaposition of functional groups present. Thus vitisinol D, a natural product that inhibits blood clotting, will be synthesized (for the first time) in 14 steps using these new building blocks and a new cyclization sequence (reductive aldol). Importantly, the planned synthesis will make available sufficient quantities of vitisinol D to allow for biochemical studies to determine the mechanism of action for this structurally unique, and virtually inaccessible, natural product. The project will also expand methods to prepare more complex allenyl esters as single isomers (non-racemic). These methods entail the development of unique catalysts to afford a high degree of control in bond formation leading to the allenyl ester products. With these allene building blocks in hand, a series of vitisinol D derivatives will be efficiently synthesized (3-5 steps). Through collaboration with nearby Torrey Pines Institute for Molecular Studies, the activity of vitisinol D and its derivatives against blood clotting will e examined. These biological studies, enabled by the synthesis methods developed as part of this project, are aimed at determining the enzymatic target of vitisinol D ultimately serving as a starting point for future medicinal chemistry investigations of blood clotting diseases.