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硅醚保护基是一种非常重要的羟基保护基【常见的羟基保护方法】，此类保护基引入条件温和，脱保护条件多样化，应用非常广泛。对于一些小位阻的有机硅保护基（如TMS), 稳定性相对较差，在酸性或碱性条件下都很容易脱保护，但是位阻较大的TBDPS保护基，就需要用氟离子类试剂脱保护【氟离子对Si-O键和Si-C键的断裂】。常见硅醚保护基稳定性顺序：在酸中的稳定性为TMS(1)<TES(64)<TBDMS(20,000)<TIPS(700,000)<TBDPS (5,000,000)；在碱中稳定性为TMS (1)<TES (10-100)<TBDMS~TBDPS (20,000)< TIPS (100,000)。TBAF是一种非常高效的脱硅基试剂，但是TBAF后处理通常需要水洗才能除去，小编曾专门介绍过TBAF的除去方法【反应后处理，如何去除TBAF?】。但是对于一些大极性水溶性好的产物，后处理就很棘手。

早在2007年，哈佛大学Kishi课题组就报道了一种利用50WX8离子交换树脂和碳酸钙高效除去TBAF的方法，后处理过程无需水洗，纯化效率极高，并成功应用于Halichondrin B的全合成【Org. Lett. 2007, 9, 723–726】。

此方法对于多醇类底物脱保护去除TBAF无需水洗, 即可除去，已应用于各种糖类及各种天然产物的脱保护后处理。需要注意的是，阳离子交换树脂使用前需要预处理。【陶氏阳离子交换树脂预处理操作】

作用机理
首先，四正丁铵正离子和离子交换树脂的质子进行交换生成HF，此交换平衡的驱动力来自于碳酸钙会和交换产生的HF反应生成CaF2沉淀，二氧化碳和水。在反应体系中加入离子交换树脂和碳酸钙充分搅拌后，只需要过滤即可除去TBAF。
反应操作
近期，加州大学Neil K. Garg课题组发表了一篇《Org. Synth. ：A Convenient Method for the Removal of Tetrabutylammonium Salts from Desilylation Reactions》专门介绍此方法【Org. Synth. 2022, 99, 53-67】，下面小编将具体操作分享给大家。
4-Bromophenol (2). A single-necked (24/40 joint) 250 mL round-bottomed flask is equipped with a Teflon-coated magnetic stir bar (3.0 x 1.5 cm, footballshaped). The apparatus is flame-dried under reduced pressure and cooled to 23 °C under an atmosphere of nitrogen. The flask is then equipped with a rubber septum and then placed under positive pressure of nitrogen using a nitrogen inlet. To the flask is then added (4-bromophenol)(tertbutyl) dimethylsilane (1) (4.5 g, 3.8 mL, 16 mmol, 1.0 equiv) (Note 2) via syringe. Then, dry THF (30 mL) (Note 3) is added at 23 °C to the flask via syringe and stirring is started (300 rpm). After one min of stirring, tetrabutylammonium fluoride solution (19 mL, 1.0 M in THF, 19 mmol, 1.2 equiv) (Note 4) is added via syringe dropwise over five min (Figure 1A). The reaction mixture is then allowed to stir (300 rpm) at 23 °C for 30 min (Note 5). Then, the rubber septum is removed, and calcium carbonate (8.2 g, 82 mmol, 5.3 equiv) (Note 6) is added in one portion followed by Dowex 50WX8, 200–400 mesh, ion exchange resin (24 g) (Note 7) in two equal portions using a funnel to assist with the addition. To the reaction mixture is then added methanol (60 mL) (Figure 1B) (Note 8), the rubber septum is replaced, including the nitrogen inlet, and the suspension is stirred for 1 h at 23 °C (900 rpm).
The resulting mixture is then filtered through a wetted celite pad (28 g, wetted with methanol (100 mL)) (Note 9) (7 x 4 cm) in a 150 mL medium porosity fritted Büchner funnel into a 1 L round-bottomed flask (24/40 joint) (Figure 2) using methanol (300 mL) as the eluent (Note 10).

The filtrate is then concentrated by rotary evaporation (30 °C, 150 mmHg to 15 mmHg) under reduced pressure to yield a biphasic mixture of a colorless liquid and a yellow liquid. The 1 L round-bottomed flask is then charged with silica gel (10.0 g) (Note 11). The crude material and silica gel are suspended in methylene chloride (60 mL) (Note 12) and concentrated under reduced pressure (30 °C, 375 mmHg to 22 mmHg) until a fine powder results. The product-adsorbed silica is then added to a column (7 cm OD x 20 cm tall) which is prepared using silica gel (165 g) that is wetted with pentane (500 mL) (Notes 13 and 14) (Figure 3A, 3B). The column is then eluted with 19:1 pentane:diethyl ether (2 L) (Note 15), followed by 9:1 pentane:diethyl ether (1 L), followed by 4:1 pentane:diethyl ether (1 L).

The product is collected in 55 mL culture tubes, and the desired product elutes in fractions 35–66 (Note 16). These fractions are pooled and concentrated under reduced pressure (30 °C, 300 mmHg to 22 mmHg). The resulting yellow oil is then transferred to an 8-dram vial using diethyl ether and concentrated under reduced pressure (30 °C, 300 mmHg to 22 mmHg).Then, the resulting oil is dried under high vacuum at 23 °C for 18 h (Note 17) to yield a crystalline white solid (2.44 g, 88% yield, 98% purity) (Notes 18, 19, 20, and 21).

【Org. Synth.】阳离子交换树脂除TBAF！过滤就行？赶紧收藏备用！

参考资料

一、Org. Lett. 2007, 9, 4, 723–726；https:///10.1021/ol063113h

二、Org. Synth. 2022, 99, 53-67；DOI: 10.15227/57 orgsyn.099.0053

相关文章：陶氏阳离子交换树脂预处理操作

有关离子交换树脂

阳离子交换树脂分为以下两类：1. 强酸型阳离子交换树脂：主要含有强酸性的反应基如磺酸基（－SO3H），此离子交换树脂可以交换所有的阳离子。2.弱酸型阳离子交换树脂：具有较弱的反应基如羧基（－COOH基），此离子交换树脂仅可交换弱碱中的阳离子如Ca2+、Mg2+，对于强碱中的离子如Na+、K+等无法进行交换。

阴离子交换树脂，指分子中含有碱性基团的离子交换树脂。在溶液中具有碱性，能以其羟离子交换溶液中的阴离子。可分为强碱性和碱性。1.强碱型阴离子交换树脂：这类树脂含有强碱性基团，如季铵基（亦称四级胺基）－NR3OH（R为烷基），能在水中离解出OH－而呈强碱性。这种树脂的正电基团能与溶液中的阴离子吸附结合，从而产生阴离子交换作用。这种树脂的离解性很强，在不同pH下都能正常工作。它用强碱（如NaOH）进行再生。2.弱碱型阴离子交换树脂：这类树脂含有弱碱性基团，如伯胺基（亦称一级胺基）-NH2、仲胺基（二级胺基）-NHR、或叔胺基（三级胺基）-NR2，它们在水中能离解出OH－而呈弱碱性。这种树脂在多数情况下是将溶液中的整个其他酸分子吸附。它只能在中性或酸性条件（如pH1～9）下工作。它可用Na2CO3、NH4OH进行再生。