游離氨基在用NaOH 或NaHCO3 控制的堿性條件下用二氧六環(huán)和水的混合溶劑中很容易同Boc2O反應(yīng)得到N-叔丁氧羰基氨基化合物。這是引入Boc常用方法之一，它的優(yōu)點(diǎn)是其副產(chǎn)物無多大干擾并容易除去。有時(shí)對(duì)一些親核性較大的胺，一般可在甲醇中和Boc酸酐直接反應(yīng)即可，無須其他的堿，其處理也方便。

對(duì)水較為敏感的氨基衍生物，采用Boc2O/TEA/MeOHor DMF 在40-50℃下進(jìn)行較好，因?yàn)檫@些無水條件下用于保護(hù)O17標(biāo)記的氨基酸而不會(huì)由于與水交換使O17丟失。有空間位阻的氨基酸而言，用Boc2O/Me4NOH.5H2O/CH3CN是十分有利的。

芳香胺由于其親核性較弱，一般反應(yīng)需要加入催化劑，另外對(duì)于伯胺，通過DMAP的使用可以上兩個(gè)Boc.

對(duì)于有酚羥基存在的胺，酚羥基上接Boc的速度也是相當(dāng)快的，因而一般沒太大的選擇性。對(duì)于有醇羥基存在的，若用DMAP做催化劑，時(shí)間長了以后醇羥基也能上Boc，因此反應(yīng)盡量不要過夜。

由于氰酸酯的生成，有位阻的胺往往會(huì)與Boc2O生成脲。這個(gè)問題可通過該胺NaH或NaHMDS反應(yīng)，然后再與Boc2O反應(yīng)來加以避免。

有時(shí)在反應(yīng)中有可能多加了Boc酸酐，當(dāng)分子中無游離酸堿時(shí)很難出去，若一定要除去，一般在體系中加入一些N,N-二甲基乙二胺或N,N-二甲基丙二胺，而后將上了Boc的N,N-二甲基乙二胺或N,N-二甲基丙二胺用稀酸除去。

由于Boc對(duì)酸敏感，因此在合成過程中用到酸洗或酸溶解等操作時(shí)，為了保險(xiǎn)起見，盡量不用鹽酸，而用10%檸檬酸（0.5M）或在低溫條件進(jìn)行。

反應(yīng)實(shí)例

一、氨基酸Boc保護(hù)示例

Oskar Keller,Walter E. Keller, Gert van Look et al., Org. Syn., 63, 160

A 4-L, four-necked, round-bottomed flask, equipped with anefficient stirrer, a droppingfunnel, reflux condenser, and thermometer is charged with a solution of 44 g (1.1 mol) of sodium hydroxidein 1.1 L of water. Stirring isinitiated and 165.2 g (1 mol) of L-phenylalanine is added at ambienttemperature, and then diluted with 750 mL of tert-butyl alcohol. To the well-stirred, clearsolution is added dropwise within 1 hr, 223 g(1 mol) of di-tert-butyl dicarbonate.A white precipitate appears during addition of the di-tert-butyldicarbonate. After a short induction period, the temperature rises toabout 30–35°C. Thereaction is brought to completion by further stirring overnight at roomtemperature. At this time, the clear solution will have reached a pH of7.5–8.5. The reaction mixture is extracted two times with 250mL of pentane, and the organic phase isextracted three times with 100 mL of saturated aqueous sodium bicarbonate solution. The combined aqueous layersare acidified to pH 1–1.5 by careful addition of a solution of 224 g (1.65 mol) of potassium hydrogensulfate in 1.5 L ofwater. The acidification is accompanied by copious evolution of carbon dioxide. The turbid reaction mixture is thenextracted with four 400-mL portions of ethyl ether. The combined organic layers are washed twotimes with 200 mL of water, dried over anhydrous sodiumsulfate or magnesium sulfate, and filtered.The solvent is removed under reduced pressure using a rotaryevaporator at a bath temperature not exceeding 30°C. The yellowish oil that remains istreated with 150 mL of hexaneand allowed to stand overnight. Within 1 day the following portions of hexane are added with stirring tothe partially crystallized product: 2 × 50 mL, 4 × 100 mL, and 1 × 200 mL.The solution is placed in a refrigeratorovernight; the white precipitate is collected on a Büchnerfunnel and washed with cold pentane. Thesolid is dried under reduced pressure at ambient temperature to constant weightto give a first crop. The mother liquor is evaporated to dryness leaving ayellowish oil, which is treated in the same manner as described above, giving asecond crop. The total yield of pure white N-tert-butoxycarbonyl-L-phenylalanine is 207–230 g(78–87%), mp 86–88°C, [α]D20 + 25.5° (ethanol c 1.0).

二、 Boc酸酐在甲醇中與胺直接反應(yīng)

Boc2O (262 g, 1.2 mol) in MeOH (250 ml) was added toa soluton of compound 1 (157.2 g,1.0 mol) in MeOH (350 ml) at 10°C,and the resulting mixture was stirred at room temperature for 2 h. N1,N1-dimethylethane-1,2-diamine (26 g, 0.3 mol) was added and the mixture was stirredat room temperature for 15 min. The solvent was removed in vacuo, and theresidue was dissolved with ethyl acetate (750 ml). The combined organics werewashed with 1 N HCl (2 x 250 ml) and brine (2 x 250 ml), dried over sodiumsulfate and filtered. The solvent was removed to give compound 2 (250 g, 96%), which was used directly in thenext step.

三、芳胺的單Boc保護(hù)示例

Luo, Qun-Li;Liu, Zhi-Ying et al., J. Med. Chem., 2003, 46(13), 2631-2640

3-Aminopyridine-2-carboxylic acid(5.02 g, 36 mmol) was suspendedin 60 mL of dry DMF, and Et3N (15.2 mL, 108 mmol) was added dropwise at roomtemperature. To the resulting brown solution was added Boc2O (11.80 g, 54 mmol). After being stirred for 10min, the mixture was heated at 40-50 °Covernight. The reaction mixture was poured into water and was then extractedwith EtOAc (2 X 50 mL). The aqueous phase was acidified to pH 4-5 with 2 M aqueous HCl and then extracted with CH2Cl2(3 X 50 mL). The combined organic phases were thenprocessed in the usual way and chromatographed (13:1 CHCl3/MeOH) to yieldthe desired product(4.2 g,49%).

四、 芳胺的雙Boc保護(hù)示例

Macleod, Calim;Mckieman, Gordon J et al., J. Org. Chem., 2003, 68(2),387-401

A solution of NaHMDS (22.0 mL, 22.0 mmol, 1 M in THF) was added to a solution of the amine (2.11 g, 10.0 mmol) and (Boc)2O (5.46 g, 25.0 mmol) in THF (50 mL) at 0°C under nitrogen. The reaction was allowedto warm to rt and stirred for 16 h. After this time, the reaction was poured intowater, extracted into CH2Cl2(2 X 25 mL),washed with water (2 X 25 mL), dried over Na2SO4, and concentrated to yield a white-yellowsolid. Recrystalization from petroleum ether (40-60 °C) gave the imide as needles (3.21 g, 7.80 mmol, 78%). Rf (hexane/ CH2Cl2 1:9, SiO2): 0.10. Mp:106-109 °C.

五、 酰胺的Boc保護(hù)示例

Lars G. J. Hammarstr?m, Yanwen Fu et al., Org. Syn., 81, 213

A 2000-mL, three-necked, round-bottomed flask equippedwith an argon inlet adapter, glass stopper, and an overheadmechanical stirrer is charged with a suspension of the hydantoin 1 (26.0 g,154 mmol) in 1000 mL of 1,2-dimethoxyethane. Triethylamine (15.7 g, 154mmol) is added in one portion, and the resulting white suspension isstirred for 30 min. Di-tert-butyl dicarbonate (168.0 g, 770mmol) is then added by pipette, followed by4-dimethylaminopyridine (DMAP)(0.2 g, 1.5 mmol). Six additional 0.2 g-portionsof DMAP are added at 12 hr intervals during the course of the reaction.The reaction mixture is stirred vigorously for a total of 72 hr, and the resultinglight yellow solid is then collected in a Büchner funnelusing suction filtration. The filtrate is concentrated to a volume of 60 mL byrotary evaporation, and the resulting solution is cooled to 15°C. The precipitate which appears iscollected using suction filtration, added to the first crop, and the combinedsolids are dissolved in 500 mL of chloroform. This solution is washed with three 200-mL portions of 1.0N HCl, and the combinedaqueous phases are extracted with 100 mL of chloroform. The combined organic layers are washed with 100 mL of saturated aq NaHCO3solution and 100 mL of brine,dried over anhydrous MgSO4,filtered, and concentrated by rotary evaporation. The resulting solid is driedat room temperature at 0.01 mmfor 24 hr. The resulting finely ground light yellow solid is suspended in 400 mL of diethyl ether in a 1000-mL, round-bottomed flask equipped with a magnetic stirbar, stirred for 2 hr, and filtered on aBüchner funnel washing with four 50-mL portions of diethyl ether. The product is dried under vacuum (85°C; 0.5 mm) for 24 hr to give 60.0–65.3 g (83-90%)of 2 as a ivory-colored solid.

六、吲哚Boc保護(hù)示例

G. Tong; P. Ruiyan et al., J. Org.Chem., 1997, 26, 9298

To a solution of6-methoxy-3-methylindole (5.0 g,31 mmol) in distilled acetonitrile (150 mL) were added di-tertbutyl dicarbonate(7.44 g, 34.1 mmol) andDMAP (0.195 g, 1.6 mmol).The reaction mixture was stirred at rt for 12 h. The solvent was removed underreduced pressure. The residue was dissolved in CH2Cl2(100 mL) and washed with an aqueous solution of 1 N HCl (2 x 50 mL). Theaqueous layer was extracted with CH2Cl2(3 x 30 mL). The combined organic ayers were dried (K2CO3). Afterremoval of solvent under reduced pressure, the residue was solidified to affordthe product (8.12 g, 99%) as a yellow solid: mp 45-46 °C.

Boc去保護(hù)

Boc比Cbz對(duì)酸敏感，酸解產(chǎn)物為異丁烯和CO2（見下式）。在液相肽的合成中，Boc的脫除一般可用TFA或50%TFA（TFA:CH2Cl2= 1:1,v/v）。而在固相肽合成中，由于TFA會(huì)帶來一些副反應(yīng)（如在得到的胺上上一個(gè)三氟乙?；龋?，因此多采用1-2MHCl/有機(jī)溶劑。一般而言用HCl/二氧六環(huán)，比較多見。

用甲醇作溶劑，HCl/EtOAc的組合使TBDMS和TBDPS酯[1]以及叔丁酯和非酚類酯在Boc脫除時(shí)不被斷裂，而S-Boc除外[2]。但當(dāng)同時(shí)脫除分子中Boc和叔丁酯, 或分子中有游離羧酸基，千萬記住不能用HCl/MeOH,其可將羧酸變?yōu)榧柞ァＭ瑫r(shí)AcCl/MeOH，則是一個(gè)在甲醇中產(chǎn)生無水HCl的便利方法。這些條件也可用來從羧酸制備酯以及形成胺的鹽酸鹽[3]。

在中性的無水條件下Me3SiI在CHCl3或CH3CN中除了能脫除Boc外，也能斷裂氨基甲酸酯、酯、醚和縮酮。通過控制條件可以得到一定的選擇性[4]。

當(dāng)分子中存在一些官能團(tuán)其可與副產(chǎn)物叔丁基碳正離子在酸性下反應(yīng)時(shí)，需要添加硫酚(如苯硫酚)來清除叔丁基碳正離子，如此舉可防止蛋氨酸和色氨酸的脫Boc時(shí)的烷基化[5]。也可使用其它的清除劑，如苯甲醚、苯硫基甲醚、甲苯硫酚、甲苯酚及二甲硫醚[6]。在Boc脫去過程中TBDPS[7]和TBDMS[8]基對(duì)CF3COOH是穩(wěn)定的（在TBS存在，用相對(duì)稀一些的10－20％TFA）。伯胺衍生物存在下，ZnBr2/CH2Cl2可以選擇性的脫除仲胺上的Boc[9]

1. F. Cavelier, C.Enjabal., Tetrahedron Lett., 1996, 37, 5131

2. F. S. Gibson,S. C. Bergmeier, H. Rapoport., J. Org. Chem., 1994, 59, 3216

3. A.Nudelman, Y.Bechor et al., Synth. Commun., 1998, 28, 471

4. R. S. Lott, V.S. Chauhan et al., J. Chem. Soc. Chem. Commun., 1979, 495; G. A.Olah, S. C. Narang., Tetrahedron., 1982, 38, 2225

5. R. A. T. M. vanBenthem, H. Hiemstra et al., I J. P. P. Res,12,258(1978) 7, 6083

6. M. Bodanszky,A. Bodanszky., Int. J. Pept. Protein Res., 1984, 23, 565;Y. Masui, N. Chino et al., Bull. Chem. Soc. Jpn., 1980, 53,464

7. P. A. Jacobi,S. Murphree et al., J. Org. Chem., 1996, 61, 2413

8. J. Deng, Y.Hamada et al., J. Am. Chem. Soc., 1995, 117, 7824

9. S. C. Nigam, A. Mann et al., Synth. Commun.,1989, 19, 3139

反應(yīng)實(shí)例

一、TMSOTf中性條件下脫Boc示例

Gilbertson, Scott R; Chang, Cheng-Wei et al., J.Org. Chem., 1998, 63(23), 8424-8431

To a solution containing 2 (1.0 g, 3.9 mmol) in 30 mL of dry CH2Cl2was slowly added TBDMSOTf (0.9 mL, 4.1 mmol). After stirring the reactionmixture for 6 h, the solvent was evaporated, and the crude product (0.8 g, 75%) was obtaineded, which was used directly inthe next step.

二、 TMSOTf-2,6-lutidine中性條件下脫Boc示例

Kemp, Scott J; Bao, Jiaming et al J. Org.Chem., 1996, 61(20), 7162-7167

To a stirring solution of compound 1 (800 mg, 2.0 mmol) and2,6-lutidine (0.4463 ml, 4.0 mmol) in CH2Cl2(6 mL) was added tert-butyldimethylsilyl triflate (0.690 ml, 3.0mmol) dropwise over 5 min. After 20 min, saturated NH4Cl (10 mL) wasadded. The mixture was stirred and separated, and the aqueous layer wasextracted with Et2O (3 x 15 mL). The combined organic layers were washedwith water (2 x 10 mL) and saturated NaCl (10 mL), dried (MgSO4), andconcentrated to give the crude silyl carbamate, which was dissolved inTHF (10 mL) and cooled to 0°C.A 1.0 M solution of TBAF in THF(2 mL, 2 mmol) was added over 5 min, and then the solution was stirred at 0°C for 1 h. The solution was concentratedand chromatographed (95:5 CH2Cl2-methanol) through a small plug of silica to give compound2 (882 mg, 75%) as a clear oil.

三、TFA脫Boc示例

M. Alberto; A. Eduardo et al., J. Org. Chem., 2004, 21,7004

To a solution ofthe β-aminoester (0.2 mmol) in CH2Cl2 (3 mL), cooled to 0°C was added TFA (1mL). After the consumption of the starting material (45 min, monitored by TLC), the mixture was evaporated and thensaturated aqueous NaHCO3 was added. The aqueous layer was extractedtwice with CH2Cl2 (15 mL), and the organic layer washedwith brine and dried over anhydrous Na2SO4. The solventwas removered under vacuum, to afford the amine, which were employed without further purification to prepare the Mosher’s diastereoisomeric amides.

四、HCl-THF脫Boc示例

J.Wehbe et al., Tetrahedron: Asymmetry, 2004, 15, 851

Tothe Boc protected amine (0.06 g,0.17 mmol) dissolved in THF (1mL) was added 2M HCl (1mL, 2 mmol) and the mixture stirred 2 h atroom temperature. After evaporation of the solvent, the product was extractedinto EtOAc (3.5mL).The organic layer was dried and evaporated under vacuum to afford 17b in 95% yield as a whitesolid.

五、叔丁酯存在下的脫Boc示例1

US5610144

1.77 ml of Me3SiIare added dropwise at room temperature in the vicinity of 25°Cto a soution of 3.8 gof compound 1 in50 ml of CHCl3. Stirring is contiuned for 30 min, then 20 ml f waterare addede. The aqueous phase is separated, then extracted with CHCl3(2x 20 ml). The organic phases are combined, washed successively with a saturatedaqueous Na2CO3(30 ml) and water(2 x 30 ml), then driedover MgSO4 and concentrated to dryness under reduced pressure at 40°C. The mixture of the two diastereoisomersobtained is separated by chromatography on silica (eluent: ethylacetate/cyclohexane = 1/4). The fractions containing the expected product arecombined and concentrated to dryness under reduced pressure at 40°C to give compound 2 (0.5 g), as a yellow-orange oil, used as it isin subsequent syntheses.

六、叔丁酯存在下的脫Boc示例2

WO20040106286

To a solution of compound 1(149 mg, 0.33 mmol) in CH2Cl2 (2 ml), TFA (1 ml) as addedat 0°C and the mixture was stirred for 1 h at 0°C. Saturated aqueous Na2CO3was added and the mixture was etracted with CHCl3. The etract waspurified by silica gel column chromatography to obtained compound 2 (92mg, 79%).

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