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Lithiation of a Silyl Ether; Formation on an ortho-Fries Hydroxyketone

Angew. Chem. Int. Ed. 2014, Early View Article. ( Angew. Chem. Int. Ed. 2014, 53, 1-5)
DOI: 10.1002/anie.201404495R1 and 10.1002/ange.201404495R1

Hong-Jay Lo, Chin-Yin Lin, Mei-Chun Tseng, and Rong-Jie Chein*

藉由苯環鄰位定向基團的導引,二異丙基氨基鋰可選擇性鋰化烷基矽氧上的 a-質子,繼以發生分子內親核取代反應達成 "矽→碳" 烷基轉移的效果。這個方法突破了長久以來矽醚保護基的單一用途,並開啟矽醚類化合物在有機合成上的新發展。在本研究中,我們進一步拓展此反應的應用性,開發出陰離子性 Snieckus-Fries 重排的延伸反應。此官能基轉換包含了三個重要概念:(1) 利用錯合物引導的概念進行去質子化步驟;(2) a-矽基碳陰離子和醯胺基間進行分子內 Peterson 類型反應;(3) β-含氧矽化物中間體的快速降解。此方法更可進一步應用在天然物合成中,縮短合成路徑以提升合成效率,如 PI3K 抑制劑 LY294002 的合成 (以鄰苯基苯酚為起始物經四步得到 LY294002,總產率 68%)。

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The hydroxy-directed nucleophilic acyl alkylation of hydroxyarylamides and salicylic acid through an anionic Si→C alkyl migration was developed using a simple reagent combination of LDA and chlorosilane. The transformation involves (1) a complex-induced proximity effect (CIPE) in the deprotonation step, (2) an intramolecular Peterson type reaction of the resulting a-silyl carbanion with the amide group, and (3) fission of the final β-oxygenated silyl intermediate. This reaction giving silyl ether a new role in organic synthesis was further developed for application to an extended anionic Snieckus-Fries rearrangement. The exceptional functional group transformations achievable using a simple reagent combination of LDA and chlorosilane renders these reactions highly valuable for the synthesis of natural products and medicinally important compounds, such as the PI3K inhibitor LY294002.

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Plausible reaction mechanism of the ortho-directed nucleophilic acyl methylation of a hydroxyarylamide (arrows may be considered equilibria) and the D2O quenching experiment.


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