溫和條件水解酯基“三板斧”

酯在堿性條件下水解為羧酸在有機合成化學中非常常見（主要為甲酯或乙酯，而叔丁酯則通常采用酸性水解，芐基酯采用氫化條件），常用的堿性條件是LiOH/THF/MeOH/H2O。但當底物中含有對堿敏感的基團（如氰基）時，使用LiOH水解酯的過程中則容易引入雜質（氰基水解等），那么該如何解決呢？本期小編將給大家介紹堿性敏感基團下溫和水解酯基的“三板斧”，趕緊收藏吧。

方法一：TMSOK體系

TMSOK體系也是一個溫和水解酯基的條件，下圖原料1在NaOH條件下水解甲酯時，會生成氰基也被水解成甲酰胺的副產物。

鑒于氰基的因素，后期采用TMSOK進行水解，反應的選擇性就非常好，在選擇性水解甲酯的同時很好地保護氰基，僅用乙腈作溶劑，水解后的產物直接以鉀鹽晶體的形式從反應液中析出，經測定，該鉀鹽晶體的純度超過了98%。(Org. Process Res. Dev. 2018,

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久置的TMSOK會有不同程度的吸水，生成KOH，繼而影響反應的官能團相容性，可以通過將TMSOK溶解在乙腈里，再加入中性氧化鋁攪拌4h后，過濾，母液便可直接使用。其實TMSOK在有機溶劑中的溶解度比大多數無機堿都要好很多，它在促進（加速）Suzuki偶聯反應中也是非常給力。TMSOK除了能水解甲酯以外，其它的乙酯，異丙酯，正戊酯，芐酯等也能非常高效的水解（2 eq TMSOK，THF作溶劑，室溫反應即可）。

方法二：Me3SnOH體系

2005年，Scripps研究所K. C. Nicolaou（KCN大牛）小組在ACIE上發表了三甲基氫氧化錫（Me3SnOH）水解甲酯的方法，Me3SnOH作為一種溫和的堿，反應選擇性非常不錯，底物中的手性中心能夠得到最大程度的保留，并且可以很好地保護對強堿敏感的基團不被破壞；當底物中同時存在多種類型的酯基（甲酯、乙酯、異丙酯等）時，Me3SnOH還可實現選擇性水解甲酯（下圖 entry 9-12）。（

Angew. Chem. Int. Ed.

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在水解氨基酸衍生物方面，與其它水解甲酯的方法相比，Me3SnOH的條件能夠最大程度上保留手性中心。即使在上述介紹的方法一（TMSOK體系）下，產物的dr值也有頗大的變化。

實驗操作:The carboxylic ester (0.01–0.15 mmol) was dissolved in 1,2-dichloroethane and after addition of trimethyltin hydroxide (1–10 equiv), the mixture was heated at 60–80℃ until TLC analysis indicated a complete reaction. After completion of the reaction, the mixture was concentrated in vacuo, and the residue was taken up in ethyl acetate (15 mL). The organic layer was washed with aqueous KHSO4 (0.01n) or HCl (5%) (3 5–15 mL). The organic layer was then washed with brine (5–15 mL) and dried over sodium sulfate. Removal of the solvent in vacuo afforded the carboxylic acid, often in >98% purity (by 1H NMR spectroscopy).

方法三：LiBr/Et3N/H2O-CH3CN體系

該體系本質上與LiOH水解酯基一樣，只不過采用LiBr/Et3N/H2O-CH3CN體系是在原位生成低濃度的LiOH，從而提高水解酯基的選擇性，底物中的酰胺鍵也能得到保留。（

Tetrahedron Letters.

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實驗操作：the ester (typically 0.5–1 g) was dissolved in CH3CN (10 ml/g of ester) containing 2 vol % of water. Triethylamine (3 equiv) was added followed by the addition of LiBr (10 equiv). The mixture was stirred vigorously at room temperature, except in one case, in which the reaction was performed at reflux (compound 3!4). When full conversion was achieved, as judged by LC analysis of the crude mixtures, the acids (or alcohol 10) were isolated after a simple work-up procedure. Alternatively, the acids were isolated after purification by preparative HPLC.
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