The Continuous Flow Total Synthesis of a Series of Analogs of the Cephalotaxus Esters for the Development of Novel Antileukemia Therapies

 描述(申请人提供)：三尖杉生物碱作为合成靶标已被广泛研究，这是由于某些酯类衍生物的抗白血病活性和 综合挑战核心结构。高三尖杉酯碱，也被称为甲基丁二酸奥马西汀，最近已被批准用于治疗慢性髓细胞白血病。然而，尽管有这些研究，只对活性天然产物进行了极小的修饰来研究活性，而且合成变异只在酯侧链上进行。 这项建议描述了一种详细的合成核心头孢菌素支架的策略，分7-9步进行，与已知的合成方法相比，这是一个相当大的减少。通过对合成一步反应的改进，使该路线具有不对称合成天然产物的选择性。使用流动化学可以快速合成核心支架，并能够安全地使用活性试剂和有毒试剂。在线制备活性中间体允许迅速引入复杂性，而这在大规模是不可行的。该战略旨在以模块化方法合成结构类似物，用于结构-活性关系研究和改进疗法的开发。

 DESCRIPTION (provided by applicant): The Cephalotaxus alkaloids have been extensively studied as synthetic targets, due to the antileukemic activity of certain ester derivatives and the synthetically challenging core structure. Homoharringtonine, also known as omacetaxin mepesuccinate, has recently been approved as a treatment for chronic myeloid leukemia. However, despite these studies, only minimal modifications of the active natural product have been studied for activity, and synthetic variation has only been performed on the ester side chain. This proposal describes a detailed strategy for the synthesis of the core cephalotaxine scaffold in 7-9 steps, a sizable reduction over known syntheses. Through the modification of one step in the synthesis, the route can be made enantioselective to synthesize the natural product. The use of flow chemistry allows for the rapid synthesis of the core scaffold, and enables the safe use of reactive and toxic reagents. In-line preparation of reactive intermediates allows for the rapid introduction of complexity that would be infeasible on large scale. The strategy is designed to enable a modular approach to the synthesis of structural analogs for the purposes of structure-activity relationship studies and the development of improved therapeutics.