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 高密度碳-碳键形成的不对称方法 具有生物意义的化合物的功能化环境。这个 首先概述了当前和预期的发展和应用 手性4-氨基和手性3-氨基呋喃都适用于Diels- 阿尔德反应。这是受赞助研究的继续。 在授予R01-GM49496项下。第二部分考察了新技术的应用 开发的乙烯基脲内酰胺烯醇酸酯作为四个碳合成子用于 氨基糖的合成--特别是神经氨酸酶抑制剂。这个 第三，探索了乙烯基氨基甲酸酯烯醇化方法的新应用 对萨拉戈齐酸A的侧链亚结构进行了研究。 我们打算继续手性Diels-Alder反应的发展 4-氨基呋喃。此外，我们还希望进一步探索我们最近 发展了使用手性3-氨基呋喃的Diels-Alder反应。 发展将包括制定不对称的方法 由手性氨基呋喃在两种绝对值中形成碳-碳键 使用相同光学对极的辅助剂。此外，我们 希望利用从以下途径获得的氧杂双环庚烷加合物 这些Diels-Alder反应开发新的和新的立体化学和 指向高效合成的化学专一性转化 降胆固醇药扎拉戈齐酸的核心，抗肿瘤 Ovalicin，Fumagillol，Fumagylin，Nana的碳糖类似物 和对氨基甘露糖，以及抗肿瘤药物的苷元 埃司帕米星。 读者将在本提案的后面几节中看到，综合 使用氧-双环进行化合物的合成，例如卵黄素 骨架，直到最后一步。最后一步涉及氟化物介导的 氧杂双环体系的开环，揭示天然产物。它 我们想到，天然产物的整个合成可能是 以硅酮为连接物的固相载体 抛锚。这可能会使对映体和化疗选择性合成 以不需要标准的方式进行练习 中间体的加工程序或层析提纯。我们 感受这类技术的发展，并将其与 相对于总收率而言的可比较的溶液相合成， 试剂的使用和易用性将引起极大的兴趣。我们强调， 这种类型的固相合成不能与 组合政体。然而，应该指出的是，氧-双环- 手性4氨基或3氨基呋喃衍生的庚烷环系 与缺电子的烯烃结合可以提供倍增 用于组合合成的活性分子支架。