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(?)-Pleurotin (1) 和 (+)-dihydropleurotinic acid (2) 是從真菌中分離得到的苯醌類雜萜，具有強(qiáng)效廣譜的抗腫瘤和抗菌活性，尤其表現(xiàn)為硫氧還蛋白還原酶 (TrxR) 的強(qiáng)效抑制劑。然而，由于可修飾的官能團(tuán)位點(diǎn)有限，其半合成衍生物的開發(fā)幾乎尚未開展。為了解決這一難題，蘇州大學(xué)龍亞秋教授/黃斌副教授團(tuán)隊(duì)開發(fā)了灰側(cè)耳菌素類天然產(chǎn)物的不對(duì)稱合成中用于F 環(huán)內(nèi)酯構(gòu)建的收尾策略，由此獲得了此前未能實(shí)現(xiàn)的C7-及軸向C8官能化的灰側(cè)耳菌素衍生物。具體而言，利用選擇性烯丙位氧化實(shí)現(xiàn)了C7官能化，并通過Tebbe烯化/硼氫化氧化，成功制備了前所未有的C8-軸向取代衍生物，這些轉(zhuǎn)化均源自可規(guī)模制備的五環(huán)骨架中間體7。新獲得的衍生物對(duì)TrxR過表達(dá)的腫瘤細(xì)胞具有顯著的殺傷作用，其中C8-軸向取代的化合物23對(duì)TrxR的抑制活性分別較灰側(cè)耳菌素(1)和陽性對(duì)照藥物金諾芬提升了9倍和16.7倍。該迂回的收尾策略為此前無法獲得的多樣化衍生物提供了合成途徑，拓展了灰側(cè)耳菌素類天然產(chǎn)物的化學(xué)與生物學(xué)空間，并為轉(zhuǎn)化醫(yī)學(xué)應(yīng)用奠定了良好基礎(chǔ)。

Figure 1. Representative examples of pleurotin natural products, and our devised C7-/C8-axially accessible analogs based on late-stage functionalization strategy.

Scheme 1. Alternative endgame strategies to construct the F ring in the synthesis of pleurotin natural products enabling late-stage functionalization.

Scheme 2. Synthesis and C14 selective oxidation exploration of 7 (Strategy A).

Scheme 3. The detoured endgame strategies (Strategy B) to the total synthesis of dihydropleurotinic acid (2) and pleurotin (1), providing C8-axial functionalizable intermediate.

Scheme 4. Synthesis of previously unavailable C7/C8-functionalized pleurotin analogs, harnessing the corresponding pentacyclic scaffold intermediates resulting from the alternative endgame strategy.

Table 1. The antiproliferative activities (IC₅₀ values, Mean ± SD [μM], 72 h) of 21a, 21b, 22, 23, and 1 against MDA-MB-231 and HepG2 cell lines, and their inhibitory potency against the isolated TrxR1 enzyme. 

Diversifiable total synthesis of pleurotin natural products through alternative endgame strategies enabling unprecedented C7-/C8 axial-functionalization.

Jing Pang^#, Nan Cao^#, Ya-Shuang Dai^#, Xiaolei Huang, Yanli Liu, Bin Huang^?, Ya-Qiu Long^?.

原文鏈接：https://doi.org/10.1021/acs.orglett.5c03701