Expeditious Synthesis of Complexity and Diversity

描述(申请人提供)：特定目的I.Bryostatin 2的全合成。我们建议扩大我们最近开发的快速构建6，8-二恶二环[3.2.1]辛烷环体系的方法在全合成Bryostatin 2中的应用，Bryostatin 2是一种临床上有前途的抗癌药物。在这方面，我们将： 1.进一步发展我们的分子间酮化/分子内开环复分解键构建策略，以获得6，9-二氧双环[3.3.1]正庚烷环系。 2.采用这种去对称化策略，以(R，R)-1，6-庚二烯-3，5-二醇为起始原料，实现了苔藓他汀类化合物的C1-C16和C17-C27片段的高效组装。 具体目标II.Phorboxazoles A和Phorboxazoles B的全合成基于Pd[0]介导的去对称化的新的初步结果，我们将重点关注以下目标： 1.开发和应用对称性和新的对称性破缺策略，以简化复杂的目标并提供简短、有效的合成。在此背景下，我们将研究钯介导的、配体控制的双环化作为一种去对称化策略。 2.对C5-C15双吡喃上的两个乙烯基附属物进行区域选择性区分，以通过C16-C18恶唑聚合亚基。 具体目标三.6，8-二氧双环[3.2.1十一烷和1，7-二氧螺[5.5]十一烷药效团文库。基于我们对双环缩醛的强大的酮化/闭环歧化反应路线以及它们向螺酮的重排，我们打算： 1.进一步论证了分子间酮化/分子内开环复分解反应在短时间内合成二异甘油酸脂中的应用。 2.以6，8-二氧双环[3.2.1]辛烷骨架为骨架进行多样性合成。 3.通过6，8-二氧二环[3.2.1]辛烷和1，7-二氧杂螺[5.5]十一烷结构之间的分配实现骨架多样化。 4.利用这些具有三个侧链多样性元素的天然产物状支架，准备一个包含2600个纯化合物的中试文库，并在我司凯克化学基因组学中心以及华盛顿大学麦迪逊分校与合作者一起筛选广泛的生物活性。

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.