2.6 甲（或乙）氧羰基
甲（或乙）氧羰基同前面提到的各种烷氧羰基不同，它对一般的酸、碱和氢解等都很稳定，在它的存在下，Cbz、Boc和苄基等可选择性去保护。 2.6.1 甲（或乙）氧羰基的引入
同Cbz、Fmoc 和Alloc的引入方法类似，用甲（或乙）氧羰酰氯在有机溶剂/Na2CO3、NaHCO3或有机碱同氨基化合物反应则可得到甲（或乙）氧羰基保护的氨基衍生物[1]。
1. E. J. Corey, M. G. Bock et al., Tetrahedron Lett. 1978, 1051
2.6.1.1 甲（或乙）氧羰基的引入示例
SNHCOOHSClCOOEtNEt3NCOOHCOOEt
E. F. B. Mara; S. B. Hugo et al., Synthesis, 1999, 6, 943
To a suspension of 2b (5 mmol, 1.05 g) in acetone (10 mL) cooled to 0 °C (ice-salt bath) was added TEA (9.56 mmol, 1.74 mL). The mixture was stirred at r.t. for 15 min. To this mixture at 0 °C was added dropwise ethyl chloroformate (12.9 mmol, 1.16 mL). The solution was stirred at r.t. for 2 h and the solvent was removed in vacuo. The residue was treated with H2O (25mL) and then with HCl 10% until pH 3 and extracted with EtOAc. The organic layer was washed with H2O, dried (Na2SO4) and the solvent was removed in vacuo yielded 4b (76%) as thick oil.
NH2COOHO1ClCOOMeNaHCO3O2NHCOOMeCOOH甲（或乙）氧羰基的引入示例
M. Dawei; D. Ke et al., Tetrahedron: Asymmetry, 2002, 13, 961
A suspension of compound 1 (20 g, 77.8 mmol), NaHCO3 (13.0 g, 155.6 mmol) in water (120 mL) and chloroform (20 mL) was treated with methyl chloroformate (12.0 mL, 155.6 mmol) in a dropwise manner. The solution was stirred for 24 h and 1N aq. HCl was added to adjust
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the pH to 4. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over MgSO4, and concentrated to yield compound 2 (23.3 g, 94%) as a crude solid.
2.5.2 甲（或乙）氧羰基的脱去
因为甲（或乙）氧羰基较强的稳定性，它们通常只用较剧烈的条件去保护，如HBr/HOAc处理[1]、KOH/MeOH、6 N HCl 和TMSI等。
1. M. C. Wani, H. F. Campbell et al., J. Am. Chem. Soc., 1972, 94, 3631; P. Magnus, J. Rodrigues-Lopez et al., J. Am. Chem. Soc., 1992, 114, 382; J. Patjens; G. T. Ramin et al., Helv. Chim. Acta. 1986, 69(4), 905-607
2.6.2.1 HBr-AcOH脱除甲（或乙）氧羰基示例
COOEtN33% HBr-AcOHNN2 HBrH2HNHNN1
J. Patjens; G. T. Ramin et al., Helv. Chim. Acta. 1986, 69(4), 905-607
Compound 1 (18.1 g, 0.1 mol) was added to 33 % HBr (in AcOH, 100 mL, 0.52 mol) at room temperature. The mixture was stirred and heated to 70℃for 12 h. The excess HBr and AcOH were removed in vacuo. The residue was washed with dry ether (3 x 50 ml) to give compound 2 (23 g, 85 %) as a orange solid
2.6.2.2 KOH-MeOH脱除甲（或乙）氧羰基示例
AcOHO5 N KOHNHCOOMe1MeOHH2NH2H
A. R. Hergueta; C. Lopez et al., Tetrahedron: Asymmetry, 2003, 23, 3773
A mixture of compound 1(3.60 g, 14.0 mmol) and 5N KOH (25 mL) in MeOH (50 mL) was refluxed for 18 h and brought to pH 3 with 2N H2SO4. Removal of the solvents at low pressure afforded a white solid (10 g) that was extracted with MeOH, the extract was passed
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through basic ion exchange resin (Amberlite IRA-400(OH), 100 mL), and the eluate was concentrated under reduced pressure to a brown oil (2.81 g) that upon flash chromatography (1:1 EtOAc/MeOH) afforded a colourless oil that 1H NMR spectroscopy showed to be virtually pure compound 2 (1.87 g, 85%). [α]D25 = +22.6 (c=0.52, MeOH).
2.6.2.3 6NHCl脱除甲（或乙）氧羰基示例
COOMeNHMeO1COOMe6 N HClrefluxHHO2NH.HClCOOH
F. Liu; Z. Huiyan et al., J. Org. Chem., 2003, 17, 6679
Compound 1 (44 mg, 0.14 mmol) was refluxed with HCl (6 N, 10 mL) for 4 days. The mixture was concentrated in vacuo to give compound 2 as a white solid (38 mg, 100%). [α] D
20
= +33.2 (c =1.20, H2O).
2.6.2.3 TMSI脱除甲（或乙）氧羰基示例
CF3CF3ONHTMSINHCOOMeCH3CNONHNH2
G. M. Ksander; J. Reynalda de et al., J. Med. Chem., 2001, 26, 4677
A mixture of 8aR (1.53 g, 3.27 mmol), 75 mL of acetonitrile, and trimethylsilyliodide (1.86 mL, 13 mmol) was stirred overnight at room temperature. Methanol was added, and the mixture was concentrated, cold 1 N NaOH added, and the mixture was extracted with EtOAc. The organic layer was washed with aqueous Na2S2O3 and brine, dried, filtered, concentrated and recrystallized from ether to give 1.19 g (89%) of 9aR as a white solid melting at 109-112 °C.
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3．酰基类
3.1 邻苯二甲酰基（Pht）
同一般的酰基氨基酸比较，Pht-氨基酸在接肽时不易消旋，但它对碱不稳定，在碱皂化的条件下发生邻苯二甲酰亚胺环的开环生成邻羧基苯甲酰基衍生物[1]。因此，当选用Pht作氨基保护基时，肽链的羧基末端则不能用甲酯（或乙酯）保护，而只能用苄酯或叔丁酯保护，以避免将来用皂化去酯的步骤。Pht对催化氢解、HBr/HOAc处理以及Na/NH3（液）还原（后处理的碱性条件需要避免）等均稳定，但很容易用肼处理脱去。 3.1.1 邻苯二甲酰基的引入
最先导入Pht基的方法是将邻苯二甲酸酐同氨基酸在145-150℃进行熔融反应，但这个方法对有的氨基酸会引起部分消旋作用，因而后来又进行了一些改进，如邻苯二甲酸酐/CHCl3/70℃下反应[2]。然而最成功的是Nefkens提出的用N-乙氧羰基邻苯二甲酰亚胺为试剂的方法（见下式）[3]，即N-乙氧羰基邻苯二甲酰亚胺与氨基酸在Na2CO3水溶液仲于25℃反应10-15分钟，就可以得到85-95%的Pht-氨基衍生物[4]。这个试剂可在仲胺的存在的情况下选择性地保护伯胺[5]。
OEtOCOClNKONOOOOEtRCOOHNH2CONHCOOEtCONHCHRCOONaNa2CO3ORNCOONaO+H2NCOOEt+NaHCO3HClORNCOOHO
1. S. J. Leach, H. Lindley., Australian, J. Chem., 1954, 7, 173 2. T. Sasaki, K. Minamoto et al., J. Org. Chem., 1978, 43, 2320
3. G. H. I. Nefkens, G. I. Tesser et al., Rec. Trav. Chim., 1960, 79, 688; Soai, Kenso; Ookawa,
Atsuhiro et al., Bull. Chem. Soc. Jpn., 1982, 55(5), 1671-1672; N. Aguilar; A. Moyano et al., J. Org. Chem., 1998, 11, 3560; Santaniello, Enzo; Ponti, Fedegco et al., Synth. Commun., 1980, 10(8), 611-614; Siedlecka, Renata; Skarzewski, Jacek et al., Synth. Commun., 1997, 27(12), 281-2086
4. C. R. McArthur, P. M. Worster et al., Synth. Commun., 1983, 13, 311 5. G. Sosnovsky, J. Lukszo., Z. Naturforsch. B., 1986, 41B, 122
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