Synthesis of a Bridged Bicyclic Natural Product Using Allenyl Esters

使用烯丙酯合成桥联双环天然产物

• 批准号: 8687285
• 负责人: SALVATORE D LEPORE
• 金额: $ 31.13万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687285
• 关键词: 3-hydroxybutanal; Aldehydes; Area; BINOL; Bicycling; Bicyclo Compounds; Biochemical; Biological; Biological Assay; Biological Factors; Blood coagulation; Chemicals; Chemistry; Collaborations; Complex; Cyclization; Development; Disease; Doctor' s Degree; Eligibility Determination; Engineering; Esters; Exhibits; Factor Xa; Future; Goals; Grant; Hand; Health; Institutes; Institution; Investigation; Isomerism; Methanol; Methods; Minor; Molecular; Natural Products Chemistry; Organic Chemistry; Pharmaceutical Chemistry; Platelet aggregation; Positioning Attribute; Preparation; Program Development; Reaction; Recording of previous events; Reporting; Research; Route; Series; Staging; Structure; Thrombin; Time; analog; base; catalyst; design; functional group; improved; in vitro testing; inhibitor/antagonist; marine natural product; pi bond; programs; propadiene; stereochemistry; undergraduate research

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.

描述（由申请人提供）：该提案提出了一项研究计划，旨在开发新的有机反应，以促进医学相关天然产物（葡萄醇 D）的合成。该合成计划将涉及在有机化学中应用相对较新且未充分利用的结构单元（手性烯基酯），利用存在的高度不饱和度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新的环化序列（还原醛醇）分 14 个步骤合成（首次）。重要的是，计划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。该项目还将扩展制备更复杂的联烯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，以对形成丙二烯基酯产物的键形成提供高度控制。有了这些丙二烯结构单元，一系列维生素醇 D 衍生物将 有效合成（3-5步）。通过与附近的多利松分子研究所合作，我们将检查维生素醇 D 及其衍生物的抗凝血活性。这些生物学研究通过作为该项目一部分开发的合成方法实现，旨在确定 vitisinol D 的酶靶标，最终作为未来凝血疾病药物化学研究的起点。