由于微信更改了訂閱號的推送規(guī)則,很多朋友不能快速找到我們,其實(shí)我們每天都在推送!您可以將有機(jī)合成設(shè)置為星標(biāo)(點(diǎn)擊右上方“...", 設(shè)為星標(biāo)),就能在微信訂閱號中快速找到我們,查看每天內(nèi)容。叔丁酯因?qū)τH核試劑和還原劑的高穩(wěn)定性及酸性條件下的易脫保護(hù)等特點(diǎn),被廣泛用作羧酸保護(hù)基, 小編往期曾總結(jié)過其常見的上保護(hù)方法,可點(diǎn)擊查看【通過叔丁酯保護(hù)羧基】。傳統(tǒng)方法(如高氯酸/t-BuOAc體系)存在安全隱患(高氯酸易爆炸)且反應(yīng)效率低。游離氨基酸因在有機(jī)溶劑中溶解性差,進(jìn)一步限制了傳統(tǒng)方法的適用性。近期,Chie Ogasa等人開發(fā)了一種簡單且安全的叔丁基化反應(yīng)。將多種游離氨基酸與1.1當(dāng)量的雙(三氟甲磺酰)亞胺在叔丁基乙酸酯中于0°C反應(yīng),可直接快速獲得游離氨基的叔丁酯,產(chǎn)率良好(例:HABA,2-hydroxy-4-aminobutyric acid,產(chǎn)率86%)。此外,不含氨基的羧酸(如氫化肉桂酸,76%產(chǎn)率)和醇類(如癸醇,94%產(chǎn)率)在少量Tf?NH(1-10 mol%)催化下,高效轉(zhuǎn)化為叔丁酯/醚。與傳統(tǒng)方法相比,所有反應(yīng)速度顯著提升(例:L-蘋果酸衍生物反應(yīng)時(shí)間從7天縮短至3小時(shí)),產(chǎn)率更高。【Synlett 2024, 35, 235–239】反應(yīng)關(guān)鍵試劑----雙(三氟甲磺酰)亞胺(Tf?NH)在反應(yīng)中起到以下兩種作用:(1)與氨基酸氨基形成可溶性鹽;(2)強(qiáng)酸性(pKa ≈ -12)促進(jìn)t-BuOAc釋放叔丁基正離子。溶劑:叔丁基乙酸酯(t-BuOAc)作為溶劑和叔丁基供體。最優(yōu)反應(yīng)條件:1.1當(dāng)量Tf?NH,2.5小時(shí)反應(yīng),產(chǎn)率提升至86%(驗(yàn)證:正文“典型步驟”及表1條目5)。失敗案例:TFA(50當(dāng)量)僅7%產(chǎn)率;H?SO?、HNO?等強(qiáng)酸無產(chǎn)物。多種游離氨基酸均可以高效叔丁酯化。單羧酸氨基酸,D-纈氨酸,產(chǎn)率81%;L-苯丙氨酸,產(chǎn)率86%,經(jīng)Mosher酰胺驗(yàn)證無外消旋。多官能團(tuán)氨基酸,L-絲氨酸雙叔丁基化(羧酸+羥基),定量產(chǎn)率;L-酪氨酸,僅羧酸叔丁酯化(產(chǎn)率68%),酚羥基部分保護(hù)為次要產(chǎn)物(產(chǎn)率33%)。特殊案例:L-甲硫氨酸因硫醚基團(tuán)淬滅Tf?NH,產(chǎn)率僅7%。羧酸催化條件(2-10 mol% Tf?NH)即可以順利叔丁酯化:氫化肉桂酸 (76%產(chǎn)率,2 mol% Tf?NH);含酮基羧酸19 (79%產(chǎn)率,5 mol% Tf?NH);N-Cbz保護(hù)氨基酸(如N-Cbz-L-絲氨酸)(89%產(chǎn)率,5 mol% Tf?NH)。醇類也在催化條件下(1-2 mol% Tf?NH)即可順利叔丁酯化:正癸醇 (94%產(chǎn)率,2 mol% Tf?NH);1,6-己二醇 雙叔丁醚化(93%產(chǎn)率,2 mol% Tf?NH)。傳統(tǒng)方法對比實(shí)驗(yàn):以L-蘋果酸衍生物(32→34)為例,傳統(tǒng)方法(H?SO?/異丁烯氣體),反應(yīng)需6天,產(chǎn)率59%;Tf?NH催化法只需要6小時(shí),產(chǎn)率78%。 tert-Butyl 4-Amino-2-tert-butoxybutanoate (6) Typical Procedure:A suspension of 2-hydroxy-4-aminobutyric acid (HABA; 5; 2.15g, 18.0 mmol) in t-BuOAc (180 mL, 0.1 M) was cooled to 0 °C.and a solution of Tf2NH (5.58 g, 19.8 mmol) in CH2Cl2 (27 mL) at 0 °C was added to the suspension. The resulting mixture was stirred at 0 °C for 2.5 h and then slowly added to sat. aq NaHCO3 (350 mL) at 0 °C (reverse addition). The mixture was extracted with CH2Cl2 (3 × 500 mL), and the combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel, hexane–EtOAc (5:1, 2:1, to 0:1)] to give a white deliquescent Tf2NH salt; yield: 8.1 g (86%). 本研究開發(fā)了一種基于雙(三氟甲磺酰)亞胺(Tf?NH)的叔丁基化策略。Tf?NH通過形成可溶性氨基酸鹽并作為強(qiáng)酸催化劑,在乙酸叔丁酯中實(shí)現(xiàn)了游離氨基酸的直接高效保護(hù)(例:HABA產(chǎn)率86%)。對于羧酸和醇類,催化量Tf?NH(1-10 mol%)即可驅(qū)動(dòng)反應(yīng),產(chǎn)率顯著優(yōu)于傳統(tǒng)方法(例:氫化肉桂酸酯化76%,而傳統(tǒng)方法不足50%)。該方法避免了高危試劑(如高氯酸)和氣體操作(如異丁烯),為合成化學(xué)提供了更安全、高效的選擇,尤其適用于復(fù)雜分子(如天然產(chǎn)物mugineic酸類似物)的規(guī)模化制備。參考文獻(xiàn):A Simple and Powerful tert-Butylation of Carboxylic Acids and Alcohols, C. Ogasa et al.; Synlett 2024, 35, 235–239; DOI: 10.1055/a-2161-9689.
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