(?)-Pleurotin (1) 和 (+)-dihydropleurotinic acid (2) 是從真菌中分離得到的苯醌類雜萜，具有強效廣譜的抗腫瘤和抗菌活性，尤其表現為硫氧還蛋白還原酶 (TrxR) 的強效抑制劑。然而，由于可修飾的官能團位點有限，其半合成衍生物的開發幾乎尚未開展。為了解決這一難題，蘇州大學龍亞秋教授/黃斌副教授團隊開發了灰側耳菌素類天然產物的不對稱合成中用于F 環內酯構建的收尾策略，由此獲得了此前未能實現的C7-及軸向C8官能化的灰側耳菌素衍生物。具體而言，利用選擇性烯丙位氧化實現了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，這些轉化均源自可規模制備的五環骨架中間體7。新獲得的衍生物對TrxR過表達的腫瘤細胞具有顯著的殺傷作用，其中C8-軸向取代的化合物23對TrxR的抑制活性分別較灰側耳菌素(1)和陽性對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，拓展了灰側耳菌素類天然產物的化學與生物學空間，并為轉化醫學應用奠定了良好基礎。

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