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

 描述（由申请人提供）：由于某些酯衍生物的抗白血病活性和紫杉醇的抗白血病活性， 综合挑战核心结构。高三尖杉酯碱，也称为omacetaxin mepesuccinate，最近已被批准用于治疗慢性粒细胞白血病。然而，尽管进行了这些研究，但仅对活性天然产物的最小修饰进行了活性研究，并且仅在酯侧链上进行了合成变化。 该提案描述了在7-9个步骤中合成核心三尖杉碱支架的详细策略，这比已知的合成方法大大减少。通过对合成步骤的改进，使该路线具有对映选择性，可用于天然产物的合成。流动化学的使用允许核心支架的快速合成，并且使得能够安全使用反应性和毒性试剂。反应性中间体的在线制备允许快速引入大规模不可行的复杂性。该策略旨在实现结构类似物合成的模块化方法，用于结构-活性关系研究和开发改进的治疗方法。

 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.