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）：该提案阐明了一项研究计划，以开发新的有机反应，以促进与药物相关的自然产品（Vitasinol D）的合成。合成计划将涉及在有机化学（手性艾烯基酯）中应用相对较新的构建块，以利用存在的高度不饱和度和官能团的独特并置。因此，使用这些新的构建块和新的环化序列（还原性醛醇），将（首次）在14个步骤中（首次将抑制血液凝结的天然产物）（首次抑制血液凝结的天然产物）合成。重要的是，计划的合成将使足够数量的静脉醇D可以允许生化研究确定这种结构独特且几乎无法访问的天然产物的作用机理。该项目还将扩展方法，以准备更复杂的艾烯基酯作为单个异构体（非流行病）。这些方法需要开发独特的催化剂，以在形成键形成的键形成中获得高度控制。借助这些Allene构建块，一系列静脉醇D衍生物将 有效合成（3-5步）。通过与附近的Torrey Pines分子研究研究所合作，将检查静脉醇D及其对血液凝结的衍生物的活性。这些生物学研究是由作为该项目的一部分开发的合成方法启用的，旨在确定静脉醇D的酶促靶标最终是对血液凝血疾病的未来药物化学研究的起点。