Expeditious Synthesis of Complexity and Diversity

复杂性和多样性的快速综合

• 批准号: 6858826
• 负责人: STEVEN D. BURKE
• 金额: $ 22.94万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858826
• 关键词: antineoplastics; bryostatin; chemical genetics; chemical synthesis; combinatorial chemistry; cyclization; drug design /synthesis /production; ketal; molecular asymmetry; oxazoles; palladium; pyrans

DESCRIPTION (provided by applicant): Specific Aim I. Total Synthesis of Bryostatin 2. We propose to expand the utility of our recently developed method for the rapid construction of the 6,8-dioxabicyclo[3.2.1]octane ring system in the total synthesis of bryostatin 2, a clinically promising anticancer agent. In this context, we will: 1. Further develop our intermolecular ketalization/intramolecular ring-closing metathesis bond construction strategy to access the 6,9-dioxabicyclo[3.3.1]nonane ring system. 2. Use this desymmetrization strategy to accomplish efficient assembly of the C1-C16 and C17-C27 fragments of the bryostatins using (R,R)-1,6-heptadiene-3,5-diol as a common starting material for both fragments. Specific Aim II. Total Synthesis of Phorboxazoles A and B. Based upon new preliminary results in Pd[0]- mediated desymmetrization, we will focus on these goals: 1. To develop and apply symmetry and novel strategies for symmetry-breaking to simplify a complex target and to provide a short, efficient synthesis. In this context we will investigate palladium-mediated, ligand-controlled double cyclization as a desymmetrization tactic. 2. To develop a regioselective differentiation of two vinyl appendages on the C5-C15 bis-pyran for converging subunits through the C 16-C 18 oxazole. Specific Aim III. 6,8-Dioxabicyclo[3.2.1loctane and 1,7-Dioxaspiro[5.5]undecane Pharmacophore Libraries. Based upon our powerful ketalization/ring-closing metathesis route to bicyclic acetals and their demonstrated rearrangement to spiroketals, we intend: 1. To further demonstrate the utility of the intermolecular ketalization/intramolecular ring-closing metathesis protocol in a short synthesis of the didemniserinolipids. 2. To employ the 6,8-dioxabicyclo[3.2.1]octane skeleton as a scaffold for diversity-oriented synthesis. 3. To effect skeletal diversification via partitioning between 6,8-dioxabicyclo[3.2.1]octane and 1,7- dioxaspiro[5.5]undecane structures upon cleavage from solid support. 4. To prepare a pilot library of 2,600 pure compounds with these natural product-like scaffolds with three side-chain diversity elements and screen for a broad range of biological activities in the Keck Center for Chemical Genomics in our Department, and with collaborators on the campus of the UWMadison.

描述（由申请人提供）：特定目的I。苔藓抑素的全合成我们建议扩大我们最近开发的方法的效用，用于快速构建6，8-二氧杂双环[3.2.1]辛烷环系统的全合成苔藓抑素2，一种临床上有前途的抗癌剂。在这方面，我们将： 1.进一步发展我们的分子间缩酮化/分子内闭环复分解键构建策略，以获得6，9-二氧杂双环[3.3.1]壬烷环系统。 2. 使用这种去对称化策略，使用（R，R）-1，6-庚二烯-3，5-二醇作为两个片段的共同起始材料，实现苔藓抑制素C1-C1, 6和C17-C27片段的有效组装。 具体目标二。恶唑A和B的全合成。基于Pd[0]介导的去对称化的新的初步结果，我们将专注于这些目标： 1. 发展和应用对称性和新的策略来简化复杂的目标，并提供一个简短，有效的合成。在这种情况下，我们将研究钯介导的，配体控制的双环化作为去对称化策略。 2.发展C5-C15双吡喃上的两个乙烯基附件的区域选择性分化，以通过C16-C18恶唑会聚亚基。 具体目标三。6，8-二氧杂双环[3.2.1]辛烷和1，7-二氧杂螺[5.5]十一烷药效团文库。基于我们强大的双环缩醛缩酮化/闭环复分解路线及其证明的螺缩酮重排，我们打算： 1.进一步证明分子间缩酮化/分子内闭环复分解方案在双烯色林脂短合成中的实用性。 2.以6，8-二氧杂双环[3.2.1]辛烷骨架为骨架进行多样性导向合成。 3.通过在从固体载体上裂解时在6，8-二氧杂双环[3.2.1]辛烷和1，7-二氧杂螺[5.5]十一烷结构之间分配来实现骨架多样化。 4. 准备一个2，600纯化合物的试点库，这些天然产物样支架具有三个侧链多样性元素，并在我们部门的Keck中心化学基因组学中筛选广泛的生物活性，并与UWMadison校园的合作者合作。