Stereoselective Synthesis through Allylic Alcohol Transposition and Trapping

 描述(申请人提供)：本意见书的目的是促进最近开发的立体化学随机烯丙醇转位和捕获过程在合成医学相关结构中的应用。复杂分子的合成仍然是一项费力的工作，而且通常是建立生物活性分子的结构和活性关系的限制因素。在立体化学定义的成键反应之前，明智地使用立体化学上不可靠的工艺可以缩短合成序列的长度，从而实现更快和更经济的先导优化。这一强大议定书的新进展为扩大该方法的范围创造了许多机会。这一建议在这一领域追求五个新的研究方向。第一个目标是开发基于底物、试剂或催化剂的立体诱导合成密集官能化四氢吡喃的新方案，用于天然产物和构象探针的合成。第二个目标是将该方法应用于药物相关的含氮杂环的合成。第三和第四个目标将导致 控制导致天然产物和刚性支架的多环化反应的立体化学结果的新方法。最终目标是在片段偶联步骤之后采用立体化学编辑步骤，作为促进复杂分子收敛合成的一种手段。更多地获得对映体纯的药物先导可以提供关于配体在其生物靶标中的结合构象的重要信息，而手性药物的对映选择性合成是非常可取的。

 DESCRIPTION (provided by applicant): The objective of this submission is to advance the applications of a recently developed stereochemically random allylic alcohol transposition and trapping process to the synthesis of medicinally relevant structures. Complex molecule synthesis remains a laborious effort, and is often a limiting factor in establishing structure activity relationships for biologically active molecules. The judicious use of stereochemically unfaithful processes that precede stereochemically defined bond formation reactions can reduce the length of synthetic sequences, allowing for faster and more economical lead optimization. New advances in this powerful protocol create many opportunities to enhance the scope of the method. This proposal pursues five new research directions in this area. The first objective is to develop new protocols for substrate-, reagent-, or catalyst-based stereoinduction in the synthesis of densely functionalized tetrahydropyrans for use in natural product and conformational probe synthesis. The second objective is to apply the method to the synthesis of medicinally relevant nitrogen-containing heterocycles. The third and fourth objectives will lead to new approaches to control the stereochemical outcomes protocols for polycyclization reactions that lead to natural products and rigid scaffolds. The final objective is to employ a stereochemistry-editing step following a fragment-coupling step as a means to facilitate convergent syntheses of complex molecules. Increased access to enantiomerically pure medicinal leads can provide important information regarding the binding conformation of ligands in their biological targets, and enantioselective synthesis is highly desirable for chiral drugs tobe approved for use.