ENANTIOSELECTIVE (4+2) REACTIONS IN TOTAL SYNTHESIS

全合成中的对映选择性 (4 2) 反应

• 批准号: 2392184
• 负责人: RICHARD H SCHLESSINGER
• 金额: $ 19.71万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2392184
• 关键词: Diels Alder reaction; aminosugar; antihypercholesterolemic agent; antineoplastics; carbohydrate analog; chemical bond; chemical synthesis; enolate; furans; lactams; mannose; stereochemistry; urethan

This proposal has three themes, each associated with a different asymmetric method for the formation of carbon-carbon bonds in the highly functionalized environments of biologically interesting compounds. The first outlines current and anticipated developments and applications of both chiral 4-amino and chiral 3-amino furans as applied to the Diels- Alder reaction. This constitutes a continuation of the research sponsored under grant R01-GM49496. The second examines applications of newly developed vinylogous urea lactam enolates as four carbon synthons for the synthesis of amino sugars--in particular neuraminidase inhibitors. The third explored new applications of vinylogous urethane enolate methodology to the side chain sub-structures of zaragozic acid A. We intend to continue the development of Diels-Alder reactions of chiral 4-amino furans. In addition, we wish to further explore our recently developed Diels-Alder reaction that employs chiral 3-amino furans. Developments will include the formulation of methods for asymmetric carbon-carbon bond formation from chiral amino furans in either absolute topicity using the same optical antipode of the auxiliary. Further, we hope to take advantage of the oxa-bicyclo-heptane adducts obtained from these Diels-Alder reactions to develop new and novel stereochemical and chemospecific transformations directed towards efficient synthesis of the core of the hypocholesterolemic agent zaragozic acid, the antineoplastic agents ovalicin, fumagillol, fumagillin, the carbosugar analogs of NANA and p-amino-mannose, and the aglycone of the antineoplastic agent esperamicin. The reader will see in later sections of this proposal that the synthesis of compounds, such as ovalicin, are conducted using the oxa-bicyclic skeleton until the final step. This last step involves fluoride mediated ring opening of the oxa-bicyclic system to reveal the natural product. It occurred to us that the entire synthesis of the natural product could be conducted on a solid phase support using the silyl ketal as the connecting anchor. This could allow an enantio and chemo selective synthetic exercise to be carried out in such a fashion as to require no standard work-up procedures or chromatographic purification of intermediates. We feel that development of this type of technology and comparison of it to a comparable solution phase synthesis with respect to overall yield, reagent usage, and ease would be of great interest. We emphasize that solid phase syntheses of this type are not to be confused with combinatorial regimes. However, it should noted that the oxa-bicyclic- heptane ring systems derived from either a chiral 4 amino or 3 amino furan in combination with an electron deficient olefin could provide a multiply reactive molecular scaffold for combinatorial syntheses.

该提案有三个主题，每个主题都与不同的 用于在高分子中形成碳-碳键的不对称方法 生物感兴趣的化合物的功能化环境。 的 首先概述了目前和预期的发展和应用， 手性4-氨基呋喃和手性3-氨基呋喃都适用于第尔斯- 桤木反应。 这构成了赞助研究的延续 根据R01-GM49496号授权。 第二部分审查了新的 开发了乙烯基脲内酰胺烯醇化物作为四碳二酮， 合成氨基糖--特别是神经氨酸酶抑制剂。 的 三是探索乙烯基氨基甲酸酯烯醇化物的新应用方法 萨拉戈萨酸A的侧链亚结构。 我们打算继续发展手性化合物的Diels-Alder反应， 4-氨基呋喃。 此外，我们希望进一步探讨我们最近 开发了使用手性3-氨基呋喃的Diels-Alder反应。 发展将包括制定不对称 从手性氨基呋喃以绝对或非绝对形式形成碳-碳键 使用助剂的相同光学对映体的拓扑性。 我们还 我希望利用从以下得到的氧杂-双环-庚烷加合物 这些Diels-Alder反应开发新的和新颖的立体化学和 化学特异性转化，旨在有效合成 核心的降胆固醇剂萨拉戈萨酸， 药剂卵蒜素、烟曲霉醇、烟曲霉素、NANA的碳糖类似物 和p-氨基-甘露糖，以及抗肿瘤剂的糖苷配基， 埃斯帕霉素。 读者将在本建议的后面部分看到， 化合物，如卵蒜素，使用氧杂双环 直到最后一步。 这最后一步涉及氟化物介导 氧杂-双环体系开环以显示天然产物。 它 我们突然想到，天然产物的整个合成过程可能是 在固相载体上进行，使用甲硅烷基缩酮作为连接， 锚。 这可以允许对映体和化学选择性合成 以不需要标准的方式进行的练习 后处理程序或中间体的色谱纯化。 我们 感受到这种技术发展以及它与 相对于总产率的可比较的溶液相合成， 试剂的使用和容易性将是非常感兴趣的。 我们强调 这种类型的固相合成不应与 组合制度 然而，应注意，氧杂-双环- 衍生自手性4氨基或3氨基呋喃的庚烷环系统 与缺电子烯烃组合可以提供倍增器 用于组合合成的反应性分子支架。