NEW METHODS FOR ALKALOID SYNTHESIS

在此提出的研究的主要目标是 开发一种新的、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都有一个共同的结构 子特征；即，一种吡咯烷或3-吡咯烷与另一种 在桥头位置用氮气打圈。示例 包括卡司他明(一种糖蛋白加工抑制剂 目前正在作为艾滋病药物进行测试)，吲哚-N-氧化物 (一种抗肿瘤药物)，斯拉夫拉明(刺激毒鼠强) 胆碱能受体)和地藻毒素(一种神经毒素，表现为 M受体拮抗剂活性)。一种灵活的、普通的合成材料 研究这些生物碱和许多其他生物碱的方法将是有用的。是这样的 在以前的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 如上所述。双环3-吡咯烷可以组装成一个 通过叠氮化合物在分子内的环加成反应 杂二烯。 作为一种并发的GOL，一种用于制备这些 光学纯形式的材料正在开发中。许多. 这些靶标有几个邻近的手性中心，每个中心都带有一个 杂原子(氧、氮或硫)。一种方法，该方法 用正确的立体化学物质组装这些单元 在上一次供资期间发展了关系， 现在将扩展到上面的实际目标。这个 该方法涉及某些杂环(1，3-二氧杂环戊烷- 4-酮；1，3-恶唑烷-5-酮；咪唑烷3-酮；1，3- 恶硫唑烷-4-酮)转化为刚性基团中的手性助剂，因此 立体化学信息可以有效地传递 在使用烯醇化学形成碳-碳键的过程中。在……里面 这样，α-异构酸和α，β-去异构酸及其 可以准备衍生品。这些化合物可用作手性物质。 上述生物碱合成的起始原料，或将用于 其他具有生物医学意义的材料的合成。 例如碳水化合物，如KDO(一种关键的结构 革兰氏(-)菌细胞壁成分)、L-葡萄糖(安L- 来自抗肿瘤抗生素博莱霉素的糖)和材料 如抗肿瘤药物贝斯汀和赤霉素增效剂 LL-P880测试版。

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.