Synthesis of a Bridged Bicyclic Natural Product Using Allenyl Esters

描述（由申请人提供）：本提案提出了一个研究计划，用于开发新的有机反应，以促进合成与医学相关的天然产物（vitisinol D）。合成计划将涉及应用相对较新的有机化学中未被充分利用的构建块（手性烯丙基酯），利用存在的高度不饱和和独特的并置官能团。因此，vitisinol D，一种抑制血液凝固的天然产物，将使用这些新的构建模块和一个新的环化序列（还原性醛醇），通过14步合成（首次）。重要的是，计划中的合成将提供足够数量的vitisinol D，以便进行生化研究，以确定这种结构独特且几乎无法获得的天然产物的作用机制。该项目还将扩大方法，以制备更复杂的烯基酯作为单异构体（非外消旋）。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物的键形成的高度控制。有了这些烯基化合物，一系列的菌素醇D衍生物将会

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.