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.

在该赠款下进行的研究属于三个主要领域：1）完成降血糖剂沙特（1）的全面合成的全部工作；测试1及其识别药效团的前体，并确定是否可能引起降血糖作用的机制（与Sandoz Research Institute合作）；按照上述研究保证，准备适当的类似物； 2）继续致力于应用刘易斯酸的不对称[2+2]环加成反应和不对称的SN2替代物作为通用方法，以访问（+） - laurencin（2）和（+） - laurenyne（3）的手性乙烯基环丁烷前体。 采用新型的恢复重排来创建所需的氧化环系统，以对映体纯形形式。 3）研究新型TIC14的机理，范围和局限性催化了内吞乙烯基烯丙基醚的重排。 该过程允许修改该过程相对于热重排的立体化学结果。 可以测试环内晶状体的螯合物的假说，可以测试环形构象从半椅子到半船的修饰。