The Synthesis of Leucascandrolide A

本研究计划的主要目的是开发一种实用的合成方法，leucascandrolide A（1），一种由Pietra于1996年分离的新型海洋大环内酯。 在初步的体外研究中，白念珠菌内酯A表现出了很强的细胞毒性，并对致病性酵母菌白色念珠菌有很强的抑制作用。 由于分离无色Candrolide A的困难，结合目前未知的生物起源，有效的化学合成代表了这种稀有天然产物的唯一可行方法。 在完成了该天然产物的C（1）-C（15）片段的合成后，我们提出了一种收敛的、完全立体控制的白木香内酯A的合成方法，该方法适合于生产足够量的该天然产物用于全面的生物学评价。 此外，我们将开发新的合成方法，包括不对称Prins去对称化，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。 从有机和有机金属合成的基础研究水平开始，我们的最终目标是为开发新的抗癌治疗药物提供新的方向。

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.