Organocatalytic Asymmetric Cascade Reactions

描述(由申请人提供)：对映体选择性亚胺和烯胺催化的途径已被证明是构建不对称键的高效手段。由于烯胺中间体的伴随形成，亚胺介导的过程为在单一合成步骤中构建多个键提供了独特的机会。尽管文献中广泛记载了亚胺和烯胺过程的例子，但在多米诺骨牌序列中将这两种途径结合在一起的报道很少。这项建议的目的是发展由单一手性胺有机催化剂催化的最小催化不对称胺共轭加成/碳环化反应。重要的碳环化反应有烷基化、羟醛、曼尼希和迈克尔加成反应。这一方法将为构建具有光学活性的密集官能化的吡咯烷和哌啶杂环提供一种高度收敛的方法。作为这项提案的最终目标，所开发的方法学将应用于全功能化的吡咯烷类化合物Plakoridine A和B的全合成。Plakoridine A因其对小鼠淋巴瘤L1210细胞的细胞毒性而引起特别关注。

DESCRIPTION (provided by applicant): Enantioselective imminium and enamine catalyzed pathways have proven to be highly effective means for asymmetric bond constructions. Imminium mediated processes provide unique opportunities for multiple bond constructions in a single synthetic step because of concomitant formation of enamine intermediates. Though examples of both imminium and enamine processes have been extensively documented in the literature, reported cases uniting the two pathways in a domino sequence are rare. It is the intent of this proposal to develop imminium catalzyed asymmetric amine conjugate addition/carbocyclization reactions catalyzed by a single chiral amine organocatalyst. The carbocyclizations of interest are alkylation, aldol, Mannich, and Michael addition processes. This methodology would provide a highly convergent method for the construction of optically active densely functionalized pyrrolidine and piperidine heterocycles. As a final goal of this proposal, the methodology developed will be applied to the total syntheses of the fully- functionalized pyrrolidines plakoridines A and B. Plakoridine A is of particular interest due to its documented cytotoxicity towards murine lymphoma L1210 cells.