Synthesis of structurally unique natural products having glutamate receptor agonist and antagonist activities

具有谷氨酸受体激动剂和拮抗剂活性的结构独特的天然产物的合成

• 批准号: 13470471
• 负责人: HATAKEYAMA Susumi
• 金额: $ 10.11万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470471/
• 关键词: dysiherbeine; kaitocephalin; glutamate receptor agonist; glutamate receptor antagonist; amino acid; total synthesis; クロスカップリング; アレニルメチルスタナン

The compounds that interact with glutamate receptors are in high demand in order to investigate the relationship between glutamate receptors and brain diseases. These compounds are also useful for designing a new type of glutamate receptor antagonist which may have therapeutic value as a neuroprotective agent. In this research, we focused on dysiherbaine, a glutamate receptor agonist isolated from Dysidea herbacea, and kaitocephalin, a glutamate receptor antagonist isolated from Eupenicillium shearii PF1191 strain, and aimed to develop efficient methods for the syntheses of these compounds.For dysiherbaine, we have developed an efficient method for the preparation of the key intermediate starting with D-glucose based on highly stereoselective Hosomi-Sakurai reaction to attach the side chain to the pyrane ring and palladium catalyzed cross-coupling reaction of the functionalized enol triflate and the organozinc reagent derived from L-iodoalanine to install the glutamic acid moiety.For kaitocephalin, we examined 1, 3-butadienylation of the Garner aldehyde derived from L-serine. When the Garner aldehyde was reacted with 2, 3-butadienyltrichlorostannane, prepared in site from 1, 3-butadien-2-yltributylstananne and SnCl_4, the addition reaction proceeded with perfect anti-selectivity to give the compound convertible to kaitocephalin.

与谷氨酸受体相互作用的化合物的需求量很大，以研究谷氨酸受体和脑疾病之间的关系。这些化合物还可用于设计新型谷氨酸受体拮抗剂，其可作为神经保护剂具有治疗价值。本研究以从草本植物中分离得到的谷氨酸受体激动剂dysiherbacea和谷氨酸受体拮抗剂kaitocephalin为研究对象，旨在开发合成这两种化合物的有效方法。我们已经开发了一种基于高度立体选择性的Hosomi的从D-葡萄糖开始制备关键中间体的有效方法，通过Sakurai反应将侧链连接到吡喃环上，通过钯催化的烯醇三氟甲磺酸酯与衍生自L-碘丙氨酸的有机锌试剂的交叉偶联反应将谷氨酸部分连接到吡喃环上;对于kaitocephalin，我们研究了衍生自L-丝氨酸的Garner醛的1，3-丁二烯化。由1，3-丁二烯-2-基三丁基锡烷与SnCl_4原位合成2，3-丁二烯基三氯锡烷，再与Garner醛反应，以完全的反选择性进行加成反应，得到可转化为Kaitocephalin的化合物。