Concise Total Synthesis of (+)-Croomine

( )-Croomine 的简明全合成

• 批准号: 6551093
• 负责人: TEHSHIK P YOON
• 金额: $ 3.66万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6551093
• 关键词: Diels Alder reaction; Schiff bases; acylation; alkaloids; alkylation; biological products; butyrolactone; catalyst; chemical addition; chemical structure; chemical synthesis; combinatorial chemistry; furans; high throughput technology; postdoctoral investigator; protonation; pyrrolidines; stereochemistry

DESCRIPTION (provided by applicant): Croomine is a representative member of the Stemona class of alkaloids. These novel polycyclic natural products were isolated from medicinal plants used extensively in traditional East Asian medicine as antitussive and antituburcular agents. In addition to their medicinal uses, the Stemona alkaloids have recently attracted attention for their potent insecticidal activity. Notably, the structures of most members of this class of natural products are characterized by a common pyrrolidinyl butyrolactone core. An enantioselective method of accessing this structural motif via a catalytic vinylogous Mannich reaction has been proposed. This research plan relies on the ability of Jacobsen's recently developed non-metal catalyst for the Strecker reaction to activate imines towards nucleophilic attack. The addition of electron-rich 2-silyloxyfurans to the imine-catalyst complex is expected to occur with high levels of enantio- and diastereoselectivity. Optimization of the catalyst structure for this transformation will be performed by combinatorial synthesis of a small, "focused" library of catalyst analogs. After exploring the substrate scope of this new reaction, the synthetic utility of the enantioselective vinylogous Mannich will be demonstrated in a concise total synthesis of (+)-croomine (7 steps, best case).

描述（由申请人提供）：Croomine 是百部生物碱类的代表成员。这些新型多环天然产物是从药用植物中分离出来的，在传统东亚医学中广泛用作镇咳剂和抗结核剂。除了药用用途外，百部生物碱最近还因其强大的杀虫活性而引起人们的关注。值得注意的是，此类天然产物的大多数成员的结构都以共同的吡咯烷基丁内酯核心为特征。已经提出了一种通过催化插烯曼尼希反应获得该结构基序的对映选择性方法。该研究计划依赖于雅各布森最近开发的 Strecker 反应非金属催化剂激活亚胺进行亲核攻击的能力。富电子的 2-甲硅烷基氧基呋喃添加到亚胺催化剂复合物中预计会产生高水平的对映选择性和非对映选择性。这种转化的催化剂结构的优化将通过组合合成小型、“集中”的催化剂类似物库来进行。在探索了这一新反应的底物范围后，对映选择性插烯曼尼希的合成效用将在 (+)-色鲁明的简明全合成中得到证明（7 个步骤，最佳情况）。