Methods for Bioactive Compound Synthesis

描述（由申请方提供）：本提案的目的是实施磷酸三酯系链方法，用于合成复杂的生物相关天然产物。我们提供了经验证据，反驳了与磷酸盐在合成中的利用相关的历史和传统观点。实施磷酸盐系链的逻辑是基于磷固有的一些显著特征，包括：（i）容易的多价偶联途径（ii）在磷上的手性，（iii）通过磷酸酯系链内的先天离去基团能力对相应甲醇中心的多价活化，（iv）赋予保护基特征的正交稳定性/反应性特征，和（v）侧链磷酸酯/酸中固有的亲核特性，其能够实现碘膦酰化方案。所提出的方法将作为（1）细胞抑制素的不对称合成的基础，已知细胞抑制素通过选择性抑制蛋白磷酸酶2A来抑制细胞粘附到细胞外基质，并且已经显示在某些细胞系中防止转移、抑制肿瘤细胞生长、抑制细胞粘附和引起细胞凋亡;（2）leustroducsin B（LSN-B），它具有抗肿瘤活性，并有可能作为一种新的造血生长因子（HGF）应用于许多造血系统疾病;（3）fostriecin，一种有效的磷酸酶抑制剂，其显示出针对广泛范围的癌细胞系（包括肺癌、乳腺癌和卵巢癌）的体外活性以及体内抗肿瘤活性;（4）dolabelides A和B，它们是最近分离的22-和24-元大环内酯家族，其对HeLaSa细胞显示出有希望的细胞毒性性质，和（5）Iso-migrastatin，一种分离自Streptomycesplatens的天然产物和migrastatin家族的成员。偏头痛抑制素是异偏头痛抑制素的分流代谢产物，已被发现是一种有效的肿瘤细胞迁移抑制剂。这种创新方法的开发代表了一个集成平台，用于出现一种新的强大的小分子合成系链。总体而言，磷酸酯系链将起到多方面的作用，作为偶联剂、保护基、潜在离去基团和侧接亲核试剂，提供多价活化并最终决定几种双环和单环磷酸酯三酯内的选择性裂解反应。

DESCRIPTION (provided by applicant): The purpose of this proposal is to implement phosphate triester tether methods for the synthesis of complex biologically relevant natural products. We have provided empirical evidence that counters historical and traditional views associated with the utilization of phosphates in synthesis. The logic of implementing phosphate-tethers is predicated in a number of salient features inherent to phosphorus, including: (i) facile multivalent coupling pathways (ii) chirality at phosphorus, (iii) multivalent activation to corresponding carbinol centers via innate leaving group ability within the phosphate tether, (iv) an orthogonal stability/reactivity profile that imparts protecting group features, and (v) inherent nucleophilic characteristics in pendant phosphate esters/acids that enable iodophosphonylation protocols. The proposed method will serve as the cornerstone in the asymmetric synthesis of (1) cytostatin, which is known to inhibit cell adhesion to the extra-cellular matrix by selectively inhibiting protein phosphatase 2A and has been shown to prevent metastasis, inhibit tumor cell growth, inhibit cell adhesion and cause apoptosis in certain cell lines; (2) leustroducsin B (LSN-B), which has shown antitumor activity and has potential as a novel hematopoietic growth factor (HGF) with application to a number of hematopoietic diseases; (3) fostriecin, a potent phosphatase inhibitor that displays in vitro activity against a broad range of cancerous cell lines including lung cancer, breast cancer, and ovarian cancer, as well as in vivo antitumor activity; (4) dolabelides A and B which are a family of recently isolated 22- and 24-membered macrolides that exhibit promising cytotoxicity properties against HeLaSa cells and (5) Iso-migrastatin, a natural product isolated from Streptomyces platens is and a member of the migrastatin family. Migrastatin is a shunt metabolite of iso-migrastatin and has been found to be a potent tumor cell migration inhibitor. The development of this innovative approach represents an integrated platform for the emergence of a new and powerful tether for small molecule synthesis. Overall, the phosphate tether will serve a multi- faceted role as a coupling agent, protecting group, latent leaving group and pendant nucleophile providing multivalent activation and ultimately dictating selective cleavage reactions within several bicyclic and monocyclic phosphate triesters.