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.

该基金资助的研究主要集中在三个方面：1）完成降糖药Saudin（1）的全合成工作;测试1及其前体以鉴定药效团，并确定是否可能引起降糖作用的机制（与山德士研究所合作）;根据先前研究的需要制备适当的类似物; 2）继续开展刘易斯酸催化的不对称[2+2]环加成反应和不对称SN 2 '取代反应作为获得（+）-Laurencin（2）和（+）-Laurenyne（3）的手性乙烯基环丁烷前体的一般方法的工作。 采用新型逆克莱森重排来产生对映体纯形式的所需氧茂环系统。3)研究了新型TiC 14催化的乙烯基烯丙基醚的Claisen重排的机理、范围和局限性。 该方法允许相对于热重排改变该方法的立体化学结果。 将测试适当配置的氧功能的内部螯合物允许从半椅到半船的环构象的修改的假设。