Unified, Asymmetric Total Synthesis of the Asnovolins and Related Spiromeroterpenoids: A Fragment Coupling Approach.
Unified, Asymmetric Total Synthesis of the Asnovolins and Related Spiromeroterpenoids: A Fragment Coupling Approach.
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DOI：
10.1021/jacs.2c05366
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发表时间：
2022-07-20
影响因子：
15
通讯作者：
Porc, John A. o, Jr.
中科院分区：
文献类型：
--
作者：
Yang, Feng;Porc, John A. o, Jr.
DMOA衍生的螺萜类化合物是一类独特的天然产物，具有独特的结构、非常规的立体化学和生物活性。在此，我们报告了第一个不对称全合成的asnovolins，DMOA衍生的spiromerotenoids。螺环骨架通过位阻双新戊基1，2-加成偶联/氧化Michael加成序列有效组装。不寻常的轴向C12-甲基立体化学建立通过金属氢原子转移（MHAT）还原涉及椅子到船的构象变化。HAT过程的机制进行了研究，通过氘标记和计算研究。尝试环外烯酮的后期烯烃异构化被证明是具有挑战性的，并导致杂-Diels-桤木二聚化，这最终导致开发替代的去饱和/偶联序列。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还原在内的末端核心修饰使得能够集体合成五种asnovolin相关的天然产物。本研究证明了阴离子片段偶联组装空间拥挤的分子框架的效用，并为后续生物学研究提供了合成具有更高氧化态的螺萜同系物的基础。
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 via 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 subsequent biological studies.
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影响因子：
3.2
作者：
Ding C;Wang L;Chen H;Wild C;Ye N;Ding Y;Wang T;White MA;Shen Q;Zhou J
通讯作者：
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影响因子：
5.2
作者：
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影响因子：
5.2
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影响因子：
15
作者：
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通讯作者：
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影响因子：
5.1
作者：
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通讯作者：
Kamat, SP