Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States.
J Am Chem Soc. 2022 Jul 20;144(28):12970-12978. doi: 10.1021/jacs.2c05366. Epub 2022 Jul 6.
3,5-Dimethylorsellinic acid (DMOA)-derived spiromeroterpenoids are a unique natural product family with attractive structures, unconventional stereochemistry, and potent biological activities. Herein, we report the first asymmetric total syntheses of the asnovolins, DMOA-derived spiromeroterpenoids. The spirocyclic skeleton was efficiently assembled through a sterically hindered bis-neopentyl 1,2-addition coupling/oxidative Michael addition sequence. The unusual axial C12-methyl stereochemistry was established metal hydrogen atom transfer (MHAT) reduction involving a chair-to-boat conformational change. The mechanism of the HAT process was studied through both deuterium labeling and computational studies. Attempted late-stage alkene isomerization of an exocyclic enone proved to be challenging and resulted in hetero-Diels-Alder dimerization, which ultimately led to development of an alternative desaturation/coupling sequence. Endgame core modifications including orthogonal desaturation, Sc(III)-promoted regioselective Baeyer-Villiger oxidation, and Meerwein-Ponndorf-Verley reduction enabled collective syntheses of five asnovolin-related natural products. This study demonstrates the utility of anionic fragment coupling to assemble a sterically congested molecular framework and provides a foundation for the synthesis of spiromeroterpenoid congeners with higher oxidation states for biological studies.
3,5-二甲基奥尔酸（DMOA）衍生的螺旋美罗萜类化合物是一类具有独特结构、非常规立体化学和强大生物活性的天然产物。本文首次报道了 DMOA 衍生的螺旋美罗萜类化合物 asnovolins 的不对称全合成。通过立体位阻的双新戊基 1,2-加成偶联/氧化迈克尔加成序列有效地组装了螺环骨架。通过涉及椅式到船式构象变化的金属氢原子转移（MHAT）还原，确定了不寻常的轴向 C12-甲基立体化学。通过氘标记和计算研究研究了 HAT 过程的机制。尝试对外环烯酮进行晚期烯键异构化证明具有挑战性，导致了杂 Diels-Alder 二聚化，最终开发了另一种去饱和/偶联序列。最终的核心修饰包括正交去饱和、Sc(III)促进的区域选择性 Baeyer-Villiger 氧化和 Meerwein-Ponndorf-Verley 还原，使五种 asnovolin 相关天然产物的集体合成成为可能。该研究展示了阴离子片段偶联在组装空间拥挤的分子骨架中的应用，并为合成具有更高氧化态的螺旋美罗萜类化合物以进行生物研究提供了基础。
