Directed C–H Bond Oxidation of (+)-Pleuromutilin

Antibiotics derived from the diterpene fungal metabolite (+)-pleuromutilin (1) are useful agents for the treatment Gram-positive infections in humans and farm animals. Pleuromutilins elicit slow rates of resistance development and minimal cross-resistance with existing antibiotics. Despite efforts aimed at producing new derivatives by semisynthesis, modification of the tricyclic core is underexplored, in part due to a limited number of functional group handles. Herein, we report methods to selectively functionalize the methyl groups of (+)-pleuromutilin (1) by hydroxyl-directed iridium-catalyzed C–H silylation, followed by Tamao–Fleming oxidation. These reactions provided access to C16, C17, and C18 monooxidized products, as well as C15/C16 and C17/C18 dioxidized products. Four new functionalized derivatives were prepared from the protected C17 oxidation product. C6 carboxylic acid, aldehyde, and normethyl derivatives were prepared from the C16 oxidation product. Many of these sequences were executed on gram scales. The efficiency and practicality of these routes provides an easy method to rapidly interrogate structure–activity relationships that were previously beyond reach. This study will inform the design of fully synthetic approaches to novel pleuromutilins and underscores the power of the hydroxyl-directed iridium-catalyzed C–H silylation reaction.源自二萜类真菌代谢产物(+)-截短侧耳素（(+)-pleuromutilin，编号1）的抗生素，可用于治疗人类与畜禽的革兰氏阳性菌（Gram-positive）感染。截短侧耳素类化合物具有耐药性发展速率缓慢、与现有抗生素交叉耐药性极弱的优势。尽管已有诸多通过半合成（semisynthesis）策略开发新型衍生物的研究尝试，但截短侧耳素的三环母核修饰仍未得到充分探索，部分原因在于其可利用的官能团修饰位点有限。本文报道了一种通过羟基导向的铱催化（iridium-catalyzed）C-H硅基化反应，结合后续Tamao–Fleming氧化（Tamao–Fleming oxidation）反应，实现(+)-截短侧耳素（1）上甲基位点选择性官能团化的方法。通过该反应策略，可获得C16、C17及C18位单氧化产物，以及C15/C16、C17/C18位双氧化产物。以保护后的C17位氧化产物为原料，可合成4种新型官能化衍生物；以C16位氧化产物为原料，则可制备得到C6位羧酸、醛基及去甲基衍生物。该系列反应中的多数步骤均可在克级规模下完成。该合成路线的高效性与实用性，为快速探究此前难以实现的构效关系（structure–activity relationships）提供了简便可行的手段。本研究可为新型截短侧耳素类化合物的全合成路线设计提供参考，同时凸显了羟基导向铱催化C-H硅基化反应的应用价值。