Expeditious Synthesis of Complexity and Diversity

描述（由申请人提供）：具体目的1 .苔藓虫素2的全合成。我们建议将我们最近开发的方法扩展到快速构建6,8-二恶比环[3.2.1]辛烷环体系在苔藓虫素2全合成中的应用，苔藓虫素2是一种临床上很有前景的抗癌药物。在这方面，我们将：

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.