NEW METHODS FOR ALKALOID SYNTHESIS

本文提出的研究的主要目标是 开发了一种新的和通用的合成方案， 制备多种具有生物医学意义的生物碱。 许多看似无关的化合物具有共同的结构 子特征;即，与另一个稠合的吡咯烷或3-吡咯啉 在桥头位置与氮气形成环。 示例 包括Castanospemine（糖蛋白加工抑制剂 目前正在作为艾滋病药物进行测试）， (an抗肿瘤剂），斯拉明（刺激毒蕈碱 胆碱能受体）和gephyrotoxin（一种神经毒素， 毒蕈碱拮抗剂活性）。 一种灵活的普通合成材料 这些和许多其他生物碱的方法将是有用的。 等 在上一个供资期间制定了一种方法， 现在将实际应用于化合物的合成 上面提到的。 双环3-吡咯啉可以组装成一个 通过将叠氮化物分子内环加成到 杂二烯 作为并发症，提供了制备这些药物的方法， 正在开发光学纯形式的材料。 许多 这些靶标具有几个邻近的手性中心，每个手性中心带有 杂原子（氧、）氮或硫）。 的方法 用正确的立体化学组合这些单元 在上一个供资期间建立了关系， 现在将扩展到上述实际目标。 的 方法涉及某些杂环（1，3-二氧戊环- 4-酮; 1，3-恶唑烷-5-酮;咪唑烷-3-酮; 1，3- 氧杂噻唑烷-4-酮）与手性助剂以刚性键连接， 立体化学信息可以有效地传递给 在使用烯醇化物化学形成碳-碳键的过程中。 在 这样，α-杂和α，β-脱杂酸及其 可以制备衍生物。 这些可用作手性化合物。 用于上述生物碱合成的起始材料，或将用于 其他生物医学重要材料的合成。 实例是碳水化合物，例如KDO（关键结构蛋白质）。 革兰氏（-）细菌细胞壁中的组分）、L-葡萄糖（一种L- 来自抗肿瘤抗生素博来霉素的糖）和材料 如抗肿瘤剂bestatin和赤霉素bestatin LL-P880beta.

The principle objective of the research proposed herein is the development of a new and general synthetic protocol for the preparation of a variety of biomedically significant alkaloids. Many seemingly unrelated compounds have a common structural subfeature; namely, a pyrrolidine or 3-pyrroline fused to another ring with the nitrogen at the bridgehead position. Examples include castanospemine (an inhibitor of glycoprotein processing which is currently being tested as an AIDS drug), indicine-N-oxide (an antitumor agent), slaframine (stimulates muscarinic cholinergic receptors), and gephyrotoxin (a neurotoxin exhibiting muscarinic antagonist activity). A flexible, common synthetic approach to these and many other alkaloids would be useful. Such a method has been developed during the previously funded period and will now be actually applied to the synthesis of the compounds mentioned above. Bicyclic 3-pyrrolines can be assembled in one step by the intramolecular cycloaddition of an azide onto a heterodiene. As a concurrent gaol, a method for the preparation of these materials in optically pure form is being developed. Many of these targets have several vicinal chiral centers, each bearing a heteroatom (oxygen,) nitrogen, or sulfur). A method for assembling these units with the correct stereochemical relationship was developed during the previously funded period, and will now be extended to the actual targets above. The method involves the fusion of certain heterocycles (1,3-dioxolan- 4-ones; 1,3-oxazolidin-5-ones; imidazolidin 3-ones; 1,3- oxathiazolidin-4-ones) to chiral auxiliaries in a rigid fshion, so that stereochemical information can be effectively transferred during carbon-carbon bond formations using enolate chemistry. In this way, alpha-hetero and alpha,beta-dehetero acids and their derivatives may be prepared. These may be used as chiral starting materials for alkaloid synthesis above, or will be used in the synthesis of other biomedically significant materials. Examples are carbohydrates such as KDO (a key structural component in the cell walls of Gram(-) bacteria), L-glucose (an L- sugar from the antitumor antibiotic bleomycin), and materials such as the antitumor agent bestatin and the gibberellin synergist LL-P880beta.