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主题相关 高度不对称碳-碳键形成方法 具有生物学意义的化合物的功能化环境。 这 首先概述了当前和预期的发展和应用 应用于狄尔斯-的手性4-氨基和手性3-氨基呋喃 桤木反应。 这是赞助研究的延续 根据拨款 R01-GM49496。 第二项审查新的应用 开发了插烯尿素内酰胺烯醇化物作为四种碳合成子 氨基糖的合成——特别是神经氨酸酶抑制剂。 这 第三探索了插烯聚氨酯烯醇化物方法的新应用 萨拉哥酸 A 的侧链亚结构。 我们打算继续发展手性的狄尔斯-阿尔德反应 4-氨基呋喃。 此外，我们希望进一步探讨我们最近的 开发了采用手性 3-氨基呋喃的 Diels-Alder 反应。 发展将包括制定不对称方法 手性氨基呋喃以绝对形式形成碳-碳键 topicity使用相同光学对映体的辅助。 此外，我们 希望利用获得的氧杂双环庚烷加合物 这些狄尔斯-阿尔德反应开发出新的立体化学和 化学特异性转化旨在有效合成 降胆固醇药萨拉戈酸的核心，抗肿瘤药物 卵酸素、烟曲霉醇、夫马洁林、NANA 的碳糖类似物 和对氨基甘露糖，以及抗肿瘤剂的糖苷配基 埃斯帕霉素。 读者将在本提案的后面部分中看到综合 化合物，例如卵磷脂，是使用氧杂双环进行的 骨架直到最后一步。 最后一步涉及氟化物介导的 氧杂双环系统的开环以揭示天然产物。 它 我们想到天然产物的整个合成可以是 使用甲硅烷基缩酮作为连接剂在固相载体上进行 锚。 这可以实现对映体和化学选择性合成 练习以不需要任何标准的方式进行 中间体的后处理程序或色谱纯化。 我们 感觉此类技术的发展及其与 就总产率而言，可比较的溶液相合成， 试剂的使用和易用性将引起人们极大的兴趣。 我们强调 这种类型的固相合成不应与 组合制度。 然而，应该指出的是，氧杂双环 源自手性 4 氨基或 3 氨基呋喃的庚烷环系统 与缺电子烯烃结合可以提供多种 用于组合合成的反应性分子支架。