The Synthesis of Leucascandrolide A

本研究项目的主要目的是开发一种实用的合成方法，合成一种由Pietra于1996年分离出的新型海洋大环内酯-亮子糖内酯a(1)。在初步的体外研究中，亮色木糖内酯A显示出强大的细胞毒性，并对白色念珠菌有很强的抑制作用。由于亚芥子油内酯A的分离困难，加上目前未知的生物成因，一种有效的化学合成方法是唯一可行的方法来获得这种罕见的天然产物。在完成了该天然产物C(1)-C（15）片段的合成后，我们提出了一种收敛的、完全立体控制的合成方法来合成亮色木糖内酯a，适合于生产足够数量的该天然产物进行全面的生物学评价。此外，我们将开发新的合成方法，包括不对称普林斯反对称，串联和催化不对称硅氢化反应，旨在提供各种有价值的合成中间体的途径。从有机和有机金属合成的基础研究水平出发，为新型抗癌药物的开发提供新的方向是我们的最终目标。

The primary objective of this research program is to develop a practical synthesis of leucascandrolide A (1), a novel marine macrolide isolated by Pietra in 1996. In preliminary in vitro studies, leucascandrolide A deisplayed a potent cytotoxicity, and strong inhibition of the pathogenic yeast Candida albicans. Due to the difficulty of isolation of leucascandrolide A, combined with the presently unknown biogenetic origin, an efficient chemical synthesis represents the only viable approach to this rare natural product. Having completed the synthesis of the C(1)-C(15) fragment of this natural product, we propose a convergent, fully stereocontrolled synthetic approach to leucascandrolide A, suitable for the production of sufficient amount of this natural product for a comprehensive biological evaluation. In addition, we will develop the new synthetic methods including asymmetric Prins desymmetrization, tandem and catalytic asymmetric hydrosilylations, designed to provide an access to a variety of valuable synthetic intermediates. Starting at the level of basic research in organic and organometallic synthesis, it is our ultimate objective to provide new directions for the development of new anticancer therapeutic agents.