Stereoselective Synthesis of Isochromanones by an Asymmetric Ortho-Lithiation Strategy: Synthetic Access to the Isochromanone Core of the Ajudazols

Full details on the design, development, and application of a highly stereoselective strategy for the synthesis of isochromanones are reported. The method is based on an asymmetric ortho lithiation with aldehyde electrophiles and utilizes the chiral memory of a preoriented atropisomeric amide axis for stereocontrol. For direct transformation of sterically hindered amides to isochromanones, efficient and mild one-pot protocols involving either O-alkylation or acidic microwave activation were developed. The procedures may be applied also to highly functionalized as well as stereochemically complex and sensitive substrates and demonstrate a high protective group tolerance. Furthermore, asymmetric crotylborations of axially chiral amides were studied in detail. These methodologies enable a general access to all possible stereoisomers of hydroxyl-isochromanones with up to three contiguous stereocenters. The true applicability of our approach was finally demonstrated by synthesis of the authentic anti,anti-configured isochromanone core of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain from myxobacteria.本文报道了一种用于合成异色满酮（isochromanones）的高立体选择性策略的完整设计、开发及应用细节。该方法以醛亲电试剂参与的不对称邻位锂化为基础，借助预取向阻转异构酰胺轴的手性记忆效应实现立体调控。针对将位阻较大的酰胺直接转化为异色满酮的需求，我们开发了两种高效温和的一锅法方案，分别通过O-烷基化或酸性微波活化实现转化。该方法同样适用于高官能化、立体化学结构复杂且敏感的底物，且展现出优异的保护基耐受性。此外，我们还对轴手性酰胺的不对称巴豆基硼化反应进行了详尽研究。上述策略可通用合成最多含三个连续手性中心的羟基异色满酮的所有立体异构体。最后，我们通过合成阿久达唑（ajudazols）的真实反,反-构型异色满酮核心结构，验证了本方法的实际适用性——阿久达唑是一类源自黏细菌的强效线粒体呼吸链抑制剂。