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; 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. Bryostatin 2的总合成。我们建议扩大我们最近开发的方法，用于快速构建6,8-二甲状腺素[3.2.1]辛烷环系统在Bryostatin 2的总合成中，这是一种临床上有希望的抗癌药。在这种情况下，我们将： 1。进一步开发我们的分子间的酮化/分子内环的闭合元置键构建策略，以访问6,9-二比克利克[3.3.1] nonane环系统。 2。使用这种去对称策略，使用（R，R）-1,6-饱和体3,5-二醇作为两个片段的常见起始材料，以实现Bryostatins的C1-C16和C17-C27片段的有效组装。 具体目标II。基于PD [0]的新初步结果 - 介导的降压化，我们将重点关注这些目标： 1。开发和应用对称性和新型策略以进行对称性破坏，以简化复杂的目标并提供短而有效的合成。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一种​​对称策略。 2。在C5-C15 Bis-Pyran上开发两个乙烯基附属物的区域选择性分化，用于通过C 16-C 18恶唑融合亚基。 特定目标III。 6,8-Dioxabicyclo [3.2.1 loctane和1,7-Dioxaspiro [5.5] Undecane Pharmacocolore库。基于我们强大的开talization/cling圈的元看途径，及其表现为螺旋体的重新排列，我们打算： 1。进一步证明了分子间的酮化/分子内环闭合分解方案的实用性，该方案在简短的didemniserinolipids中。 2。采用6,8-二甲状腺素[3.2.1]辛烷骨骼作为面向多样性的合成的支架。 3。通过在6,8-二甲苯[3.2.1]和1,7- Dioxaspiro [5.5]之间分配骨骼多样化时，在从固体支撑上切割时，骨骼多样化。 4.为了准备一个由这些类似天然产品的脚手架的试点库，其中包括三个侧链多样性元素，并在我们部门的凯克化学基因组学中心以及在Uwmadison校园内与合作者在凯克化学基因组学中心进行了广泛的生物活动。