Methods for Bioactive Compound Synthesis

描述(申请人提供)：本建议的目的是实施磷酸三酯系链法来合成复杂的生物相关天然产品。我们已经提供了经验证据，反驳了与合成中使用磷酸盐相关的历史和传统观点。实现磷酸链系的逻辑是建立在磷固有的许多显著特征上的，包括：(I)简单的多价偶联途径(Ii)在磷上的手性，(Iii)通过磷酸系链中固有的离开基团的能力对相应的甲醇中心进行多价激活，(Iv)赋予保护基团特征的正交稳定性/反应性轮廓，以及(V)能够进行碘膦酰化反应的悬挂磷酸酯/酸中固有的亲核特性。所提出的方法将作为不对称合成的基石：(1)细胞抑素，它通过选择性地抑制蛋白磷酸酶2A而抑制细胞与细胞外基质的黏附，已被证明能防止转移，抑制肿瘤细胞生长，抑制细胞黏附，并导致某些细胞系的凋亡；(2)亮氨酸B(LSN-B)，它已显示出抗肿瘤活性，并有可能成为一种新的造血生长因子(HGF)，应用于多种血液系统疾病；(3)fostriecin是一种有效的磷酸酶抑制剂，在体外对包括肺癌、乳腺癌和卵巢癌在内的多种癌症细胞株具有抑制活性，同时在体内也具有抗肿瘤活性；(4)dolabeldes A和B，这是一种最近分离的22和24元大环内酯家族，具有良好的细胞毒活性；(5)异米曲菌素，这是从白链霉菌中分离出来的天然产物，也是偏头痛素家族的成员。米格雷他汀是异米曲他汀的分流代谢物，已被发现是一种有效的肿瘤细胞迁移抑制因子。这一创新方法的发展为出现一种新的、强大的小分子合成系链提供了一个集成的平台。总体而言，磷酸根将作为偶联剂、保护基团、潜在离开基团和侧链亲核剂发挥多方面的作用，提供多价激活，并最终决定几个双环和单环磷酸三酯中的选择性裂解反应。

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.