大极性产物中的TBAF如何除去?

chem 有机方法 8.0K+ 0

硅醚保护基是一种非常重要的羟基保护基,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,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】。

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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。

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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。

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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。

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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).

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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).

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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).


参考资料

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

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


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