SYNTHESIS OF NOVEL BIOLOGICALLY ACTIVE NATURAL PRODUCTS

新型生物活性天然产物的合成

• 批准号: 6342785
• 负责人: ROBERT K BOECKMAN
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-15 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342785
• 关键词: antimetabolites; biological products; chemical addition; cyclization; drug design /synthesis /production; hypoglycemic agents; molecular rearrangement; stereochemistry; titanium; vinyl ether

The studies to be conducted under this grant fall in three major areas: 1) complete work on the total synthesis of the hypoglycemic agent Saudin (1); test 1 and its precursors to identify the pharmacophore, and determine if possible the mechanism by which the hypoglycemic effects are elicited (in collaboration with Sandoz Research Institute); prepare appropriate analogues as warranted by the preceding studies; 2) continue work directed at the application of Lewis acid catalyzed asymmetric [2+2] cycloaddition reactions and asymmetric SN2' substitutions as general methods to access the chiral vinylcyclobutane precursors for (+)-Laurencin (2) and (+)-Laurenyne (3). To employ the novel retro-Claisen rearrangement to create the required oxocene ring system in enantiomerically pure form. 3) investigate the mechanism, scope, and limitations of the novel TiC14 catalyzed Claisen rearrangement of endocyclic vinyl allyl ethers. This process permits modification of the stereochemical outcome of the process relative to the thermal rearrangement. The hypothesis that an internal chelate of suitably disposed oxygen functions permits the modification of the ring conformation from half-chair to half-boat will be tested.

根据这笔赠款将进行的研究分为三个主要领域：1)完成降糖剂Sandin(1)的全合成工作；测试1及其前体以鉴定药效团，并在可能的情况下确定产生降血糖作用的机制(与Sandoz研究所合作)；根据先前研究的保证制备适当的类似物；2)继续针对Lewis酸催化的不对称[2+2]环加成反应和不对称SN2‘取代作为获得(+)-Laurencin(2)和(+)-Laurenyne(3)的手性乙烯基环丁烷前体的通用方法进行的工作。利用新颖的逆克莱森重排反应，以对映体纯净的形式生成所需的六茂环体系。3)研究了新型TiC14催化内环乙烯基烯丙基醚Claisen重排反应的机理、范围和局限性。该过程允许相对于热重排改变该过程的立体化学结果。适当配置的氧官能团的内部络合物允许将环的构象从半椅子修改为半船的假设将得到测试。