氨基的保护及脱保护.doc

1、药明康德内部保密资料经典化学合成反应标准操作氨基的保护及脱保护策略编者： 彭宪药明康德新药开发有限公司化学合成部经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 1 of 79目 录1氨基的保护及脱保护概要22烷氧羰基类2-1. 苄氧羰基（Cbz） 42-2. 叔丁氧羰基（Boc） 162-3. 笏甲氧羰基（Fmoc） 282-4. 烯丙氧羰基（Alloc） 342-5. 三甲基硅乙氧羰基（Teoc） 362-6. 甲（或乙）氧羰基 403酰基类3-1. 邻苯二甲酰基（Pht） 433-2. 对甲苯磺酰基（Tos） 493-3. 三氟乙酰基（Tfa

2、） 534烷基类4-1. 三苯甲基（Trt ） 574-2. 2,4-二甲氧基苄基（Dmb ） 634-3. 对甲氧基苄基（PMB） 65经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 2 of 794-4. 苄基（Bn） 70经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 3 of 791氨基的保护及脱保护概要选择一个氨基保护基时，必须仔细考虑到所有的反应物，反应条件及所设计的反应过程中会涉及的所有官能团。首先，要对所有的反应官能团作出评估，确定哪些在所设定的反应条件下是不稳定并需要加以保护的，并

3、在充分考虑保护基的性质的基础上，选择能和反应条件相匹配的氨基保护基。其次，当几个保护基需要同时被除去时，用相同的保护基来保护不同的官能团是非常有效（如苄基可保护羟基为醚，保护羧酸为酯，保护氨基为氨基甲酸酯） 。要选择性去除保护基时，就只能采用不同种类的保护基（如一个 Cbz 保护的氨基可氢解除去，但对另一个 Boc 保护的氨基则是稳定的） 。此外，还要从电子和立体的因素去考虑对保护的生成和去除速率的影响（如羧酸叔醇酯远比伯醇酯难以生成或除去） 。最后，如果难以找到合适的保护基，要么适当调整反应路线使官能团不再需要保护或使原来在反应中会起反应的保护基成为稳定的；要么重新设计路线，看是否有可能应用

4、前体官能团（如硝基，亚胺等） ；或者设计出新的不需要保护基的合成路线。在合成反应中，伯胺、仲氨、咪唑、吡咯、吲哚和其他芳香氮杂环中的氨基往往是需要进行保护的。已经使用过的氨基保护基很多，但归纳起来，可以分为烷氧羰基、酰基和烷基三大类。烷氧羰基使用最多，因为 N-烷氧羰基保护的氨基酸在接肽时不易发生消旋化。伯胺、仲氨、咪唑、吡咯、吲哚和其他芳香氮氢都可以选择合适的保护基进行保护。下表列举了几种代表性的常用的氨基保护基。经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 4 of 79几种代表性的常用的氨基保护基结构 缩写 应用 引入条件 脱去条件OXO

5、 Cbz 伯胺、仲氨、咪唑、 吡咯、吲哚等 Cbz-Cl/Na2CO3/CHCl3/H2OH2/Pd-C，供氢体/Pd-C，BBr 3/CH2Cl2 or TFA， HBr/HOAc 等OXO Boc 伯胺、仲氨、咪唑、 吡咯、吲哚等Boc2O/NaOH/diox/H2O, Boc2O/ /MeOH, Boc2O/Me4NOH/CH3CN3MHCl/EtOAc, HCl/MeOH or diox, TosOH/THF-CH2Cl2, Me3SiI/CHCl3orCH3CNOXO Fmoc 伯胺、仲氨等 Fmoc-Cl/NaHCO3,/diox/H2O20%哌啶 /DMF，50%哌啶 /CH2C

6、l2 等OXO Alloc 伯胺、仲氨、咪唑、 吡咯、吲哚等 Aloc-Cl/Py Ni(CO)4/DMF/H2O;Pd(PPh3)4/Bu3SnH;Cl OOTMSTeoc 伯胺、仲氨、咪唑、 吡咯、吲哚等 Teoc-Cl/碱/diox/H 2O TBAF；TEAFMe( or Et)OXO - 伯胺、仲氨、咪唑、吡咯、吲哚等ROCOCl/NaHCO3,/diox/H2OHBr/HOAc;Me3SiI;KOH/H2O/乙二醇NOOX Pht 伯胺邻苯二甲酸酐/CHCl3/70;邻苯二甲酰亚胺-NCO 2Et/aq. Na2CO3H2NNH2/EtOH，NaBH 4/i-PrOH-H2O（6：

7、1）SOXTos 伯胺、仲氨、咪唑、 吡咯、吲哚等 Tos-Cl/Et3N HBr/HOAc, 48%HBr/苯酚（cat）XOCF3 Tfa 伯胺、仲氨、咪唑、 吡咯、吲哚等 TFAA/Py; 苯二甲酰亚胺-NCO2CF3/CH2Cl2K2CO3/MeOH/H2O;NH3/MeOH;HCl/MeOHXTrt 伯胺、仲氨、咪唑、 吡咯、吲哚等 Trt-Cl/Et3NHCl/MeOH, H2/Pd/EtOH, TFA/CH2Cl2XMeO OMeDmb 伯胺、仲氨、咪唑、 吡咯、吲哚等 ArCHO/NaCNBH3/MeOHX OMe PMB 伯胺、仲氨、咪唑、 吡咯、吲哚等PMB-Br/ K2C

8、O3/CH3CN;PhCHO/NaCNBH3/MeOHHCO2H/Pd-C/MeOH; H2/Pd(OH)2/EtOH; TFA; CAN/ CH3CNXBn 伯胺、仲氨、咪唑、 吡咯、吲哚等Bn-Br/Et3N or K2CO3/CH3CN;PhCHO/NaCNBH3/MeOHHCO2H/Pd-C/MeOH; H2/Pd(OH)2/EtOH; CCl3CH2OCOCl/CH3CN经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 5 of 792烷氧羰基类保护基烷氧羰基类保护基可用于氨基酸，以在肽合成中减少外消旋化的程度。外消旋化发生在碱催化的 N

9、-保护的羧基活化的氨基酸的偶联反应中，也发生在易由 N-酰基保护的氨基酸形成的中间体恶唑酮中。要使外消旋化程度减到最小，需使用非极性溶剂、最弱的碱、低的反应温度，并使用烷氧羰基类保护的氨基酸是有效的。其中常用的有易通过酸性水解去保护的 Boc基、由催化氢解去保护的 Cbz 基、用碱经 -消除去保护的 Fmoc 基和易由钯催化异构化去保护的 Alloc 基。2.1 苄氧羰基（Cbz）苄氧羰基（Cbz）是 1932 年 Bergmann 发现的一个很老的氨基保护基，但一直到今天还在应用。其优点在于：试剂的制备和保护基的导入都比较容易；N-苄氧羰基氨基酸和肽易于结晶而且比较稳定；苄氧羰基氨基酸在活化

10、时不易消旋；能用多种温和的方法选择性地脱去。2.1.1 苄氧羰基的导入 苄氧羰基的导入，一般都是用 Cbz-Cl。游离氨基在用 NaOH 或 NaHCO3 控制的碱性条件下可以很容易同 Cbz-Cl 反应得到 N-苄氧羰基氨基化合物。,-二胺可用该试剂在 pH= 3.5-4.5 稍有选择性地被保护，其选择性随碳链地增长而减弱，如 H2N(CH2)nNH2, n=2 时 71%被单保护; n=7 时 29%被单保护 1。 氨基酸酯同 Cbz-Cl 的反应则是在有机溶剂中进行，并用碳酸氢盐或三乙胺来中和反应所产生的 HCl。此外，Cbz-ONB（ 4-O2NC6H4OCOOBn）等苄氧羰基活化酯也

11、可用来作为苄氧羰基的导入试剂，该试剂使伯胺比仲胺易被保护，但苯胺由于亲核性不足，与该试剂不反应 2。HNR1 R2 Cbz-ClBase NR1R2CbzNH2R1R2OOC Cbz-ClBaseNHCbzR1R2OC1G. J. Atwell, W. A. Denny., Synthesis, 1984, 10322D. R. Kelly, M. Gingell, Chem. Ind.(London) , 1991, 888经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 6 of 79Cbz-Cl 很容易用苯甲醇同光气的反应来制备（见下式） ，

12、在低温下可以保存半年以上而不发生显著的分解。CH2OH COCl2 CH2OCOCl + HCl除 Cbz-Leu 为油状物外，绝大多数氨基酸的苄氧羰基衍生物都可以得到结晶。有的 N-苄氧羰基氨基酸能同它的钠盐按一定比例形成共晶，共晶产物的熔点较高，并难溶于有机溶剂。例如，苯丙氨酸经苄氧羰基化后再加酸析出 Cbz-Phe 时往往得到共晶产物（熔点 144） ，此共晶产物用乙酸乙酯和 1M HCl 一道震摇时可完全转化为 Cbz-Phe 而溶于乙酸乙酯中。因此。除 Cbz-Gly 以外，一般都是采用酸化后用有机溶剂提取的方法来得到纯的 N-苄氧羰基氨基酸。2.1.1.1 游离氨基酸的 Cbz 保

13、护示例Konda-Yamada, Yaeko; Okada, Chiharu et al., Tetrahedrom; 2002, 58(39), 7851-7865 Cbz-Cl (18.5 l, 0.155 mmol) in diethyl ether (0.2 ml) was dropped to a solution of (R)-1 (36.4 mg, 0.129 mmol) in 10% aqueous Na2CO3 (1.8 ml) at 0C, and stirred for 5 h. The reaction mixture was acidified with 10% ci

14、tric acid, extracted with CHCl3 (10 mlX3). The organic layer was washed with water, dried over Na2SO4, evaporated to give light yellow gels, which were purified by preparative TLC (CHCl3/MeOH=5:1) to afford (R)-6 (25.7 mg, 47.1%) as yellow amorphous solid. Rf = 0.87 (n-BuOH/AcOH/H2O=4:1:5); aD23 = -

15、27.270 (c = 0.99, CHCl3);经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 7 of 792.1.1.2 氨基酸酯的 Cbz 保护示例S ONH2.Cl Cbz-lK2CO3 S ONHCbz1 2M. Carrasco, R. J. Jones, S. Kamel et a1., Org. Syn., 70, 29A 3-L, three-necked, Morton flask equipped with an efficient mechanical stirrer, thermometer, and a droppi

16、ng funnel is charged with L-methionine methyl ester hydrochloride 1 (117.6 g, 0.56 mol), potassium bicarbonate (282.3 g, 2.82 mol, 5 eq.), water (750 mL), and ether(750 mL), and the solution is cooled to 0C. Benzyl chloroformate (105 g, 88.6 mL, 0.62 mol, 1.1 eq.) is added dropwise over 1 hr, the co

17、oling bath is removed, and the solution is stirred for 5 hr. Glycine (8.5 g, 0.11 mol, 0.2 eq.) is added (to scavenge excess chloroformate) and the solution is stirred for an additional 18 hr. The organic layer is separated, and the aqueous layer is extracted with ether (2 200 mL). The combined orga

18、nic layers are washed with 0.01 M hydrochloric acid (2 500 mL), water (2 500 mL), and saturated brine (500 mL), and then dried (Na2SO4), filtered, and evaporated on a rotary evaporator. The resulting oil is further dried in a Kugelrohr oven (50C, 0.1 mm, 12 hr) to leave product 2 as a clear oil that

19、 solidifies upon cooling: 165166 g (9899%), mp 4243C.2.1.1.3 氨基醇的 Cbz 保护示例(1) Cbz-ClNa2CO3THF, 2CbzHNOHH2NOHClariana, Jaume; Santiago, G. G. et al Tetrahedron: Asymmetry, 2000, 11(22), 4549-4558Benzyl chloroformate (0.95 ml, 6.7 mmol) was added via syringe into a stirred mixture of aminoalcohol 7 (0

20、.989 g, 5.1 mmol) and sodium carbonate (0.683 g, 6.4 mmol) in the solvent system water (10 ml)THF (3 ml) maintained at 0C. The mixture was stirred at room temperature for 18 h (TLC monitoring) and then partitioned between dichloromethane and 经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 8 of 79wat

21、er. The organic phase was dried and evaporated to afford a white solid which was passed through a column of silica gel with hexanesethyl acetate (v:v 2:1) to afford the desired product (1.198 g, 72%), mp 125127C.2.1.1.4 氨基醇的 Cbz 保护示例(2) Cbz-ClK2CO3Tol, H2H2NOOOH CbzHNOOOHInaba, Takashi; Yamada, Yasu

22、ki et al J. Org. Chem., 2000, 65(6), 1623-1628To a mixture of toluene (3.85 L), water (3.85 L), and K2CO3 (470 g, 3.40 mol) were successively added 1a (770 g, 2.72 mol) and CbzCl (488 g, 2.72 mol) with vigorous stirring at a temperature below 25 C. After stirring at room temperature for 3 h, triethy

23、lamine (27.5 g, 270 mmol) and NaCl (578 g) were successively added, and the mixture was stirred for a further 30 min. The organic layer was separated and concentrated to give the desired product as oil, which was used for the next reaction without purification. The analytical sample was prepared by

24、column chromatography;2.1.2 苄氧羰基的脱去 苄氧羰基的脱除主要有以下几种方法：1). 催化氢解；2). 酸解裂解；3). Na/NH3（液）还原。 一般而言目前实验室常用简洁的方法就是催化氢解， 但当分子中存在对催化氢解敏感或钝化的基团时，我们就必须采用化学方法如酸解裂解或Na/NH3（液）还原等。 催化氢解如下式所示。催化氢解的供氢体可以是 H2、环己二烯 1, 2、1，4-环己二烯 2、甲酸铵 3和甲酸 4-6等，以后四个为供氢体的反应又叫催化转氢反应，通常这比催化氢化反应更迅速。NR1 CbzR2 CH3 +CO2 + HNR1 R2H2 CH3 + NR1

25、COHR2经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 9 of 79催化剂主要用 5-10%的钯-碳、10-20% 的氢氧化钯 -碳或钯- 聚乙烯亚胺，钯-聚乙烯亚胺/ 甲酸对于除去 Cbz 要比前两者要好 7。当 HBr/HOAc 脱去 Cbz 保护基时，产物往往带又一点颜色，而且分解产生的溴化苄会产生一些副反应并难以除尽，而催化氢解多数能得到无色得产物。由于硫能使催化剂中毒，因此，含有胱氨酸、半胱氨酸等含硫的肽等 N-苄氧羰基氨基衍生物一般不用催化氢解法脱除。一般溶剂可以用甲醇，乙醇，乙酸乙酯， 四氢呋喃等，在醇类质子溶剂中反应速度要快的

26、多。1. G. Briefer, T. T. Nesftrick., Chem. Rew., 1974, 74, 5672. A. E. Jackson, R. A. Johnstone., Synthesis., 1976, 685; G. M. Anantharamaiah, K. M. Sivanandaiah., J. Chem. Soc., Perkin Trans. 1, 1977, 4903. M. Makowski, B. Rzeszotarska, L. Smelka et al., Liebigs Ann. Chem., 1985, 14574. D. R. Coleman

27、, G. P. Royer., J. Org. Chem., 1980, 45, 22685. B. Eiamin, G. M. Anantharamaiah, G. P. Royer et al., J. Org. Chem., 1979, 44, 34426. M, J. O. Anteunis, C. Becu, F. Becu et al., Bull. Soc. Chim. Belg., 1987, 96, 7757. D. R. Coleman, G. P. Royer., J. Org. Chem., 1980, 45, 2268 D. R. Coleman, G. P. Roy

28、er., J. Org. Chem., 1980, 45, 2268如果在 Boc2O 存在下用 Pd/C 进行氢化，则释放出的胺直接转变成 Boc 衍生物 1。而且这类反应往往要比不加 Boc2O 来的快，其主要由于氢解出来的胺往往会与贵金属有一定的络合，使催化剂的活性降低，和 Boc2O 反应为酰胺后则去除了这一效果。另外有时在氢解时加入适当的酸促进反应也是一样的道理，避免了生成的胺降低反应的活性。1. M. Sakaitani, K. Hori, Y. Ohfune., Tetrahedron Lett., 1988, 29, 2983另外当分子中有卤原子(Cl, Br, I)存在时，一

29、般直接用 Pd/C 会造成脱卤的发生，一般这种情况下，使用 PdCl2 为催化剂，以乙酸乙酯或二氯甲烷为溶剂可较好的避免脱卤的发生。用 MeOH/DMF 为溶剂时，在 Cbz-赖氨酸衍生物氢化的过程中会生成 N-甲基化的赖氨酸 1。使用氨为溶剂时，H 2/Pd-C 在-33下氢化，肽中的半胱氨酸或蛋氨酸单元不使催化剂毒化，此外，氨还会阻止 BnO 醚的还原，所以对 Cbz 可得到一些选择性 2-3。经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 10 of 791. D. R. Coleman, G. P. Royer., J. Org. Che

30、m., 1980, 45, 22682. J. P. Mazaleyrat, J. Xie, M. Wakselman., Tetrahedron Lett., 1992, 33, 43013. N. L. Benoiton., Int. J. Pept. Petein Res., 1993, 41, 6112.1.2.1 5-10%的钯-碳催化氢解示例 H2NOHCbzHNOHH215%Pd/CMeOHC. Jaume; G. G. Santiago et al., Tetrahedron: Asymmetry, 2000, 11(22), 4549-4458A solution of (R

31、)-8 (0.170 g, 0.52 mmol) in absolute methanol (3 ml) was hydrogenated in the presence of 15% Pd/C (0.026 g) at room temperature for 12 h. The mixture was filtered (Celite) and washed with methanol. Then, perchloric acid (0.050 ml, 0.83 mmol) was added and the mixture was stirred for 5 min. The solve

32、nt was evaporated to afford (R)-7HClO4, mp 233235C; aD23=15.6 (c=0.68, methanol).2.1.2.2 5-10%的钯-碳催化氢解示例 H220%Pd(O)2/CMeHF NHCbzOHH F NH2OHHB. Pierfrancesco; C. silvia et al., Tetrahedron, 1999, 55(10), 3025A solution of N-Cbz arylglycinol (17) (1.02 mmol) in MeOH (10 mL) was stirred for 15 min in t

33、he presence of an excess of Pd(OH)2/C under a dihydrogen atmosphere. The solution was then filtered on a Celite pad and the solvent removed in vaccuo. Purification of the crude afforded the desired free 2-arylglycinols (S)-21 in 87% yield, white solid; aD20=+47.0 (c=0.78, CHCl3); mp 94-96C (AcOEt)。2

34、.1.2.3 Pd/C-甲酸铵催化氢解示例 OHNO OOHNHCbzOHCONH410%Pd-C OHNO OOHNH2O1 2Alargov, D. K; Naydenova, Z; Monatsh. Chem., 1997, 128(6-7), 725-732经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 11 of 79576.6 mg of compound 1 (1 mmol) was dissolved in 20 ml of methanol. Then 150 mg of ammonium formate (3 mmol) an

35、d 75 mg of 10% Pd-C was added and the reaction mixture was stirred at room temperature 10 min and then heated to reflux for 45 min. The mixture was filtered through celite and the filtrate was evaporate to dryness to give 430 mg of compound 2 (98%). This compound was used without further purificatio

36、n in the subsequent step.2.1.2.4 Pd/C-甲酸催化氢解示例OHNOOO10%Pd-CHOH ONH2O1 2Fyles, T. M.; Zeng, B.; J. Org. Chem., 1998, 63(23), 8337-8345Compound 1 (0.6 g, 0.8 mmol) was dissolved in 1:1 formic acid/methanol (60 mL) and added to a round-bottom flask (100 mL) containing 1 equiv of palladium catalyst (10%

37、 Pd/C, 1.0 g, 0.9 mmol). The mixture was continuously stirred under reflux temperature for 24 h. The catalyst was removed by filtration and washed with an additional 10 mL of methanol. The combined solvents were removed by evaporation under reduced pressure to give Compound 2 (0.34 g, 81%, a white s

38、olid, mp 96-98 C). This compound was used without further purification in the subsequent step.2.1.2.5 Pd/C 催化氢解脱 Cbz 上 Boc 示例 OBocHNNHH2/10%Pd-C(Boc)2OOHNNH1 2WO200409216610%Pd-C was addede to a solution of compound 1 (596 mg , 1.77 mmol) and (Boc)2O (773 mg, 3.54 mmol) in etnyl acetate (30 ml). The

39、 reation vessel was evacuated and back-filled 经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 12 of 79with nitrogen (three times), then back-filled with hydrogen (1 atm). After 2 h, the mixture was filtered and concentrated. Purification by silica gel chromatography (30% ethyl acetate/ hexanes - 50%

40、 ethyl acetate/ hexanes) gave compound 2 (289 mg, 54%).2.1.2.6 PdCl2 催化氢解脱除带卤原子分子上的 Cbz 示例ClNHNONHClPdCl2Et3SiHClNHNONOCl 1 2US20030144297To a solution o compound 1 (900 mg) in methylene chloride (16.5 ml) was addede PdCl2 (30 mg) and triethylamine (0.229 ml). Triethyl silane was added (2 x 0.395 ml

41、) over 2 h. The reaction mixture stirred 1 h and 2 ml of trifluoroacetic acid was added. After 30 min the reaction was basified with 2 N NaOH, extracted with methylene chloride, dried over MgSO4, filtered and concentrated. Chromatography was run on a biotage 40S column with 3-5% MeOH/CH2Cl2 with 0.5

42、% NH4OH to provide compound 2 as a oil (501 mg, 74%).2.1.2.7 Pd 黑催化氢解，用氨为溶剂,半胱氨酸的 Cbz 脱除示例 S OHNH2H2PdS OHNHCbz 43Arthur M. Felix, Manuel H. Jimenz et a1., Org. Syn., 59, 159经典合成反应标准操作氨基的保护及脱保护 药明康德新药开发有限公司药明康德内部保密资料 Page 13 of 79A dry 1-L three-necked, round-bottomed flask is equipped with a dry ic

43、e reflux condenser, a gas-inlet tube, and a magnetic stirring bar as illustrated in the figure. The reaction vessel is immersed in an acetonedry ice bath, and a total of 300 mL of ammonia is passed through a drying tower containing potassium hydroxide pellets and collected in the flask. The bath is

44、removed to permit the reaction to proceed at the boiling point of ammonia (33), and a gentle stream of dry nitrogen is bubbled into the flask. A solution of 0.708 g (0.80250 mole) of N-benzyloxycarbonyl-L-methionine in 10 ml. of N,N-dimethylacetamide 1.02 g (1.40 ml., 0.0101 mole) of triethylamine a

45、nd 1.25 g of freshly prepared palladium black are added. The nitrogen stream is discontinued and replaced by a stream of hydrogen that has been passed through a concentrated sulfuric acid scrubber. The mixture is stirred under reflux for 5.5 hours to effect hydrogenolysis. The hydrogen stream is dis

46、continued, a flow of nitrogen is resumed, and the dry ice is removed from the reflux condenser, permitting rapid evaporation of ammonia. The flask is attached to a rotary evaporator, and the mixture is evaporated to dryness under reduced pressure. The residue is dissolved in water and filtered throu

47、gh a sintered funnel of medium porosity to remove the catalyst. The filtrate is evaporated to dryness, and the residue (354 mg, 95%) is crystallized from waterethanol. The white crystalline product, after drying under reduced pressure at 25, weighs 272305 mg. (7382%), m.p. 280282 (dec.), 25D +23.1 (c = 1, aqueous 5 N hydrochloric acid). 酸解脱除 氨基甲酸苄酯在强酸性条件下容易去保护。HBr/HOA