Total Synthesis of (−)-Glionitrin A and B Enabled by an Asymmetric Oxidative Sulfenylation of Triketopiperazines

Abstract

Asymmetric construction of dithiodiketopiperazines on otherwise achiral scaffolds remains a pivotal synthetic challenge encountered in many biologically significant natural products. Herein, we report the first total syntheses of (−)-glionitrin A/B and revise the absolute configurations. Emerging from the study is a novel oxidative sulfenylation of triketopiperazines that enables asymmetric formation of dithiodiketopiperazines on sensitive substrates. The concise route paves the way for further studies on the potent antimicrobial and antitumor activities of glionitrin A and the intriguing ability of glionitrin B to inhibit invasive ability of cancer cells.

Research Progress in Synthesis and Application of Thiosulfonates

“…22). 机理研 究表明, 该反应可能是铜卡宾先与硫代磺酸酯反应得到 硫叶立德中间体, 其再发生 [1,2] 光照条件下, 芳基重氮化合物可作为自由基前体与 硫代磺酸酯发生取代反应, 生成芳基硫醚, 其中芳基是 前者提供的, 烷硫基来自于硫代磺酸酯 [98] . 通常, 芳基 重氮四氟硼酸盐是芳基自由基前体(Eq.…”

“…In the future, among the researches on the construction of new sulfides with thiosulfonates, various difunctionalization reactions are still promising directions. Keywords thiosulfonate; green chemistry; C-S bond formation; photocatalysis; radical reaction; difunctionalization reaction 含硫有机化合物广泛出现在天然产物 [1] 、合成药 物 [2] 、 荧光探针 [3] 等分子中, 在诸多领域都有着十分广泛 的应用 [4] . 硫代磺酸酯是一种特殊的硫化物, 它包含一 个氧化态为 II 的硫原子和另一个氧化态为 VI 的硫原子, 这使它们能够与亲核试剂和亲电试剂反应 [5] .…”

A C–H Activation Approach to the Tricyclic Core of Glionitrin A and B

“…S 8 was recrystallized from benzene. 1 H and 13 C ( 1 H decoupled) NMR spectroscopy data were collected on a Bruker AVANCE II 400 MHz ( 1 H 400 MHz; 13 denoted by (br). IR spectra were recorded on a Bruker ALPHA II spectrometer and peaks denoted as strong (s), medium (m), weak (w), and broad (br).…”

“…Purification by column chromatography was performed using Merck 60 Å (40−63 μm particle size) silica or using the Biotage Isolera One system. (13). To a stirred suspension of serine 14 (7.61 g, 37.1 mmol) and nitrophenyl alanine 15 .…”

“…12 The first syntheses of (−)-glionitrin A and B were recently reported by our group. 13 In this study, the DTDKP motif was constructed in a stepwise manner outgoing from a triketopiperazine precursor. Still, a more direct approach would be to form the disulfide bridge on a DKP scaffold.…”