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.

该提议有三个主题，每个主题都与不同 高度形成碳碳键的非对称方法 生物学有趣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 手性4-氨基和手性3-氨基呋喃都适用于Diels- alder反应。 这构成了赞助的研究的延续 根据Grant R01-GM49496。 第二个检查了新的应用 开发的乙烯基尿素lactam作为四个碳合成子的烯醇 氨基糖的合成 - 特别是神经氨酸酶抑制剂。 这 第三探索了乙烯基氨基烷酸酯方法的新应用 到Zaragozic A的侧链子结构。 我们打算继续发展手性的Diels-Alder反应 4-Amino Furans。 此外，我们希望进一步探索我们的最近 开发的Diels-Alder反应采用了手性3-氨基呋喃。 发展将包括制定不对称方法 来自手性氨基呋喃的碳碳键形成任一绝对 主题使用辅助的相同的光学反模具。 此外，我们 希望利用从 这些Diels-Alder反应，以发展新的和新颖的立体化学化学和 针对有效合成的化学特异性转化 降胆固醇剂Zaragozic，抗肿瘤的核心 特工椭圆形，富马吉略，富马吉林，娜娜的碳糖类似物 和p-氨基甘露糖，以及抗肿瘤剂的aglycone 杂草素。 读者将在本提案的后面部分看到合成 使用Oxa-Bicyclic进行化合物，例如椭圆形 骨骼直到最后一步。 最后一步涉及氟化物介导 Oxa-Bicyclic系统的环开口揭示天然产物。 它 我们发生的是，天然产品的整个合成可能是 使用Silyl ketal在固相支撑上进行 锚。 这可以允许对映体和化学选择性合成 锻炼要以不需要标准的方式进行 中间体的锻炼程序或色谱纯化。 我们 认为这种技术的发展及其比较 相对于整体产率的可比溶液相合成 试剂的用法和轻松的使用将引起极大的兴趣。 我们强调了这一点 这种类型的固相合成不应与 组合制度。 但是，应该注意的是Oxa-Bicyclic- 源自手性4氨基或3个氨基呋喃的项内环系统 与电子不足的烯烃结合使用可以提供多重 组合合成的反应性分子支架。