【精品】氨基的保護及脫保護策略

1、經(jīng)典化學(xué)合成反應(yīng)標準操作1. 氨基的保護及脫保護概要22. 烷氧撥基類2- 1.節(jié)氧撥基（cbz） 42- 2.叔丁氧撥基（boc） 162- 3.笏甲氧撥基（fmoc） 282-4.烯丙氧撥基（alloc） 342- 5.三甲基硅乙氧撥基（teoc ） 3626甲（或乙）氧撥基 403. ?；?- 1.鄰苯二甲?；╬ht） 433- 2.對甲苯磺?；╰os） 493- 3.三氟乙酰基（tfg 534. 烷基類4- 1.三苯甲基（trt） 574-2. 2,4二甲氧基節(jié)基（dmb ） 634- 3.對甲氧基節(jié)基（pmb） 654- 4.節(jié)基（bn） 701. 氨基的保護及脫保護概要選擇一

2、個氨基保護基時，必須仔細考慮到所冇的反應(yīng)物，反應(yīng)條件及所設(shè)計的反應(yīng) 過程中會涉及的所有官能團。首先，要對所有的反應(yīng)官能團作出評估，確定哪些在所設(shè) 定的反應(yīng)條件下是不穩(wěn)定并需要加以保護的，并在充分考慮保護基的性質(zhì)的基礎(chǔ)上，選 擇能和反應(yīng)條件相匹配的氨基保護基。其次，當(dāng)幾個保護基需要同吋被除去吋，用相同 的保護基來保護不同的官能團是非常有效（如節(jié)基可保護疑基為瞇，保護竣酸為酯，保 護氨基為氨基甲酸酯）。要選擇性去除保護基時，就只能采用不同種類的保護基（如一 個cbz保護的氨基可氫解除去，但對另一個boc保護的氨基則是穩(wěn)定的）。此外，還要 從屯子和立體的因索去考慮對保護的生成和去除速率的影響（如竣酸

3、叔醇酣遠比伯醇酣 難以生成或除去）。最后，如果難以找到合適的保護基，要么適當(dāng)調(diào)整反應(yīng)路線使官能 團不再需要保護或使原來在反應(yīng)中會起反應(yīng)的保護基成為穩(wěn)定的；要么重新設(shè)計路線， 看是否冇可能應(yīng)用前體官能團（如硝基，亞胺等）；或者設(shè)計出新的不需要保護基的合 成路線。在合成反應(yīng)中，伯胺、仲氨、咪呼、毗咯、町i味和其他芳香氮雜環(huán)中的氨基往往是 需要進行保護的。已經(jīng)使用過的氨基保護基很多，但歸納起來，可以分為烷氧撥基、酰 基和烷基三大類。烷氧撥基使用最多，因為n烷氧撥基保護的氨基酸在接肽時不易發(fā) 生消旋化。伯胺、仲氨、咪墜毗咯、卩引喙和其他芳香氮氫都可以選擇合適的保護基進 行保護。卜表列舉了幾種代表性的常

4、用的氨基保護基。幾種代表性的常用的氨基保護基縮寫應(yīng)用引入條件脫公條件msf3coaxemcbzbocfmocallocteocphttfadmbpmbbn伯胺、仲氨、咪哇、毗咯、ii引味等伯胺、仲氨、咪畔、毗咯、眄際等們胺、仲氨等伯胺、仲氨、咪哇、毗咯、口引味等伯胺、仲氨、咪呼、毗咯、眄i味等伯胺、仲氨、咪呼、毗咯、呵味等們胺伯胺、仲氨、咪昵、毗咯、眄際等伯胺、仲氨、咪喘、ii比咯、ii引喙等們胺、仲氨、咪呼、毗咯、眄i味等伯胺、仲氨、咪哇、ii比咯、ii引味等伯胺、仲氨、咪昵、毗咯、眄i味等伯胺、仲氨、咪畔、毗咯、口引味等cbz-ci/na2co3/chcl3/h°oboc2o/n

5、aoh/diox/h2o, b0c2o/ /meoh,boc2o/mc4noh/ch3cnfmoc-cl/nahcoj/diox/h2oaloc-cl/pyteoc-ci/堿/diox/h?。rococl/nahco3,/diox/h2o鄰苯二卩酸阡/chch/70°c;鄰苯二甲酰亞胺-nco2et/aq.nagcostos-cl/et3ntfaa/py;苯二卩酰亞胺-nco2cf3/ch2c12trt-cl/et3narcho/nacnbhs/meohpmb-br/k2co3/ch3cn;phcho/nacnbh3/meohbn-br/etsn ork2co3/ch3cn;phch

6、o/nacnbh3/meohh2/pd-c,供氫體/pd-c, bbr3/ch2cl2 or tfa, hbr/hoac 等3mhcl/etoac,hcl/mcoh or diox,tosoh/thf-ch2c12,me3siuchcl3orch3cn20%哌唳/dmf, 50%哌®/ch2cl2 等ni(co)4/dmf/h2o;pd(pph3)4/bu3snh;tbaf； teafhbr/hoac;me3sii;koh/h2o/ 乙二醇h2nnh2/etoh,nabh4/i-proh-h2o (6：1)hbr/hoac, 48%hbr/苯酚(cat)k2co3/meoh/h2o;

7、nh3/meoh;hcl/mcohhcl/meoh,h2/pd/etoh,tfa/ch2ci2hco2h/pd-c/mcoh;h2/pd(oh)2/etoh; tfa;can/ ch3cnhco2h/pd-c/meoh;h2/pd(oh)2/etoh;cci3ch2ococi/ch3cn2. 烷氧撥基類保護基烷氧嫌基類保護基可用于氨基酸，以在肽合成屮減少外消旋化的程度。外消旋化發(fā) 生在堿催化的n保護的竣基活化的氨基酸的偶聯(lián)反應(yīng)中，也發(fā)生在易由n?；Ｗo的 氨基酸形成的中間體惡卩坐酮中。要使外消旋化程度減到最小，需使用非極性溶劑、最弱的堿、低的反應(yīng)溫度，并使 用烷氧撥基類保護的氨基酸是有效的。其

8、中常用的有易通過酸性水解去保護的boc基、 由催化氫解去保護的cbz基、用堿經(jīng)0 消除去保護的fmoc基和易由耙催化異構(gòu)化去保 護的alloc基。2.1節(jié)氧撥基(cbz)節(jié)氧按基(cbz)是1932年bergmann發(fā)現(xiàn)的一個很老的氨基保護基，但一直到今 天還在應(yīng)用。其優(yōu)點在于：試劑的制備和保護基的導(dǎo)入都比較容易；n節(jié)氧撥基氨基酸 和肽易丁結(jié)品而且比較穩(wěn)定；節(jié)氧離基氨基酸在活化時不易消旋；能用多種溫和的方法 選擇性地脫去。2.1.1節(jié)氧按基的導(dǎo)入節(jié)氧按基的導(dǎo)入，一般都是用cbz-clo游離氨基在用naoh或nahco3控制的堿 性條件下可以很容易同cbz-cl反應(yīng)得到n節(jié)氧撥基氨基化合物。a

9、, b 二胺可用該試劑 在ph=3.54.5稍冇選擇性地被保護，其選擇性隨碳鏈地增長而減弱，如h2n(ch2)nnh2, n=2時71%被單保護;n=7時29%被單保護。氨基酸酯同cbz-cl的反應(yīng)則是在有機溶 劑中進行，并用碳酸氫鹽或三乙胺來中和反應(yīng)所產(chǎn)生的hc1。此外，cbz-onb (4-o2nc6h4ocoob11)等節(jié)氧撥基活化酯也可用來作為節(jié)氧按基的導(dǎo)入試劑，該試劑 使伯胺比仲胺易被保護，但苯胺由于親核性不足，與該試劑不反應(yīng)役cbz-clbasern'cbzr2ooccbz-clbaser2oocnhcbza1. g. j. atwell, w. a. denny., sy

10、nthesis, 1984, 10322. d. r. kelly, m. gingcll, chem. ind.(london), 1991, 888cbz-cl很容易用苯甲醇同光氣的反應(yīng)來制備（見下式），在低溫下口j以保存半年以上而不發(fā)生顯著的分解。coci2ch2ococi+ hci除cbz-leu為油狀物外，絕大多數(shù)氨基酸的節(jié)氧撥基衍生物都可以得到結(jié)品。冇的 n節(jié)氧琰基氨基酸能同它的鈉鹽按一定比例形成共晶，共晶產(chǎn)物的熔點較高，并難溶于 冇機溶劑。例如，苯丙氨酸經(jīng)茉氧碳基化后再加酸析出cbz-phe吋往往得到共晶產(chǎn)物（熔 點144°c）,此共晶產(chǎn)物用乙酸乙酯和1mhc1 -道農(nóng)

11、搖吋可完全轉(zhuǎn)化為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機溶劑提取的方法來得 到純的n節(jié)氧璇基氨基酸。2.1.1.1游離氨基酸的cbz保護示例konda-yamada, yaeko; okada, chiharu et al., tetrahedrom 2002, 58(39), 7851-7865cbz-cl (18.5(11, 0.155 mmol) in diethyl ether (0.2 ml) was dropped to a solution of (r)-l (36.4 mg, 0.129 mmol) in 10% aqueous n

12、a?co3 (1.8 ml) at 0°c, and stirred for 5 h. the reaction mixture was acidified with 10% citric acid, extracted with chci3 (10 mlx3). the organic layer was washed with water, dried over nazsoq, evaporated to give light yellow gels, which were purified by preparative tlc (chc13/meoh=5:1) to affor

13、d (r)-6 (25.7 mg, 47.1%) as yellow amorphous solid. rf = 0.87 (n-buoh/acoh/h2o=4:l:5); ao23 = -27.27° (c =0.99, chci3)；2.1.1.2氨基酸酯的cbz保護示例1cbz-cik2co32m. carrasco, r. j. jones, s. kamel et al., org. syn., 70, 29a 3-l, three-necked, morton flask equipped with an efficient mechanical stirrer, the

14、rmometer, and a dropping funnel is charged with l-methionine methyl ester hydrochloride 1 (117.6 g5 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 0°c. benzyl chloroformate (105 g, 8&6 ml, 0.62 mol, 1.1 eq.) is ad

15、ded dropwise over 1 hr, the cooling bath is removed, and the solution is stirred for 5 hr. glycine (&5 g, 01 mol, 0.2 eq.) is added (to scavenge excess chlorofbrmate) and the solution is stirred for an additional 18 hr. the organic layer is separated, and the aqueous layer is extracted with ethe

16、r (2 x 200 ml). the combined organic layers are washed with 0.01 m hydrochloric acid (2 x 500 ml), water (2 x 500 ml), and saturated brine (500 ml), and then dried (na2sc)4), filtered, and evaporated on a rotary evaporator. the resulting oil is further dried in a kugelrohr oven (50°c, 0j mm, 12

17、 hr) to leave product 2 as a clear oil that solidifies upon cooling: 165-166 g (98-99%), mp 42-43°c.2.1.1.3氨基醇的cbz保護示例cbz-cinazcogthf, h2oclariana, 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 s

18、tirred mixture of aminoalcohol 7 (0.989 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 0°c. the mixture was stirred at room temperature for 18 h (tlc monitoring) and then partitioned between dichloromethane andwater. the organi

19、c phase was dried and evaporated to afford a white solid which was passed through a column of silica gel with hexanes-ethyl acetate (v:v 2:1) to afford the desired product (1.198 g, 72%), mp 125-127°c.2.1.1.4氨基醇的cbz保護示例(2)inaba, takashi; yamada, yasuki et al j. org. chem., 2000, 65(6), 1623-162

20、8to a mixture of toluene (3.85 l), water (3.85 l), and k2co3 (470 g, 3.40 mol) were successively added la (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 h5 triethylamine (27.5 g, 270 mmol) and nacl (578

21、 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 column chromatography;2.1.2 氧按基的脫去節(jié)氧撥基的

22、脫除主要有以下幾種方法：1)催化氫解；2).酸解裂解；3). na/nh3 (液) 還原。一般而言目前實驗室常用簡潔的方法就是催化氫解，但當(dāng)分子中存在對催化氫 解敏感或鈍化的基團時，我們就必須采用化學(xué)方法如酸解裂解或na/nhs (液)述原等。催化氫解如卜式所示。催化氫解的供氫體可以是比、環(huán)己二烯山2】、1, 4環(huán)己二烯 2】、甲酸鞍卩和甲酸4®等，以后四個為供氫體的反應(yīng)又叫催化轉(zhuǎn)氫反應(yīng)，通常這比催化 氫化反應(yīng)更迅速。+催化劑主耍用5-10%的鋰碳、10-20%的氫氧化耙碳或耙聚乙烯亞胺，鋰聚乙烯亞胺/甲酸對于除去cbz要比詢兩者要好。當(dāng)hbr/hoac脫去cbz保護基時，產(chǎn)物往往

23、帶又-點顏色，而且分解產(chǎn)生的澡化節(jié)會產(chǎn)生一些副反應(yīng)并難以除盡，而催化氫解多數(shù) 能得到無色得產(chǎn)物。由于硫能使催化劑中毒，因此，含有胱氨酸、半胱氨酸等含硫的肽 等n節(jié)氧撥基氨基衍生物一般不用催化氫解法脫除。一般溶劑可以用甲醇，乙醇，乙 酸乙酯，四氫咲喃等，在醇類質(zhì)了溶劑中反應(yīng)速度要快的多。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.

24、, j. chem. soc., perkin trans. 1, 1977, 4903. m. makowski, b. rzeszotarska, l. smelka et al., liebigs ann. chem.f 1985, 14574. d. r. coleman, 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,

25、 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. royer., j. org. chem.f 1980, 45, 2268如果在boc2o存在下用pd/c進行氫化，則釋放出的胺直接轉(zhuǎn)變成boc衍主物。而月這類反應(yīng)往往要比不加boc2o來的快，其主要由于氫解出來的胺往往會與貴金屈冇 一定的絡(luò)合，使催化劑的活性降低，和boc?。反應(yīng)為酰胺后則去除了這一效果。另外有 時在氫解時

26、加入適當(dāng)?shù)乃岽龠M反應(yīng)也是一樣的道理，避免了生成的胺降低反應(yīng)的活性。1. m. sakaitani, k. hori, y. ohfune., tetrahedron lett., 1988, 29, 2983另外當(dāng)分子中有鹵原子(cl, br, i)存在時，一般直接用pd/c會造成脫鹵的發(fā)生，一般 這種情況下，使用pdcb為催化劑，以乙酸乙酯或二氯卬烷為溶劑可較好的避免脫鹵的 發(fā)生。用meoh/dmf為溶劑時，在cbz賴氨酸衍生物氣化的過程中會生成n甲基化的賴 氨酸。使用氨為溶劑吋，h2/pdc在33°c下氫化，肽小的半胱氨酸或蛋氨酸單元不使 催化劑毒化，此外，氨還會阻止bno &#

27、171;的還原，所以對cbz可得到一些選擇性3。1. d. r. coleman, g. p. royer., j. org. chem., 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%的耙碳催化氫解示例c. jaume; g. g. santiago et al., tetrahedron: asymmetiy,

28、 2000, 11(22), 4549-4458a solution of (/?)-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

29、 mixture was stirred for 5 min. the solvent was evaporated to afford (/?)7 hc1c)4, mp 233-235°c; ad23=-15.6 (c=0.6& methanol).2.1.2.2 5-10%的耙碳催化氫解示例20%pd(oh)2/cmeoh/ohnh2 ab. pierfrancesco; c. silvia et al., tetrahedron, 1999, 55(10), 3025a solution of n-cbz arylglycinol (17) (1.02 mmol) in

30、 meoh (10 ml) was stirred for 15 min in the 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; ad2()=

31、+47.0 (c=0.78, chci3)； mp 94-96°c (acoet)oa largo v5 d. k; naydenova, z; monatsh. chem., 1997, 128(6-7), 725-732576.6 mg of compound 1 (1 mmol) was dissolved in 20 ml of methanol. then 150 mg of ammonium formate (3 mmol) and 75 mg of 10% pd-c was added and the reaction mixture was stirred at ro

32、om temperature 10 min and then heated to reflux for 45 min. the mixture wasfiltered through celite and the filtrate was evaporate to dryness to give 430 mg of compound 2 (98%). this compound was used without further purification in the subsequent step.2.1.2.4 pd/c甲酸催化氫解示例10%pd-chcooh2fyles, t. m.; z

33、eng, b.; z org. chern., 199& 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% pd/c, 1.0 g, 0.9 mmol). the mixture was continuously stirred under reflux temperat

34、ure 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 g5 81%, a white solid, mp 96-98 °c). this compound was used without further purification in the

35、 subsequent step.2.1.2.5 pd/c催化氫解脫cbz上boc示例w0200409216610%pd-c was addede to a solution of compound 1 (596 mg , 1.77 mmol) and (boc)?。(773 mg, 3.54 mmol) in etnyl acetate (30 ml). the reation vessel was evacuated and back-filled with nitrogen (three times), then back-filled with hydrogen (1 atm). af

36、ter 2 h, the mixture was filtered and concentrated purification by silica gel chromatography (30% ethyl acetate/ hexanes 50% ethyl acetate/ hexanes) gave compound 2 (289 mg, 54%).2.1.2.6 pdcb催化氫解脫除帶鹵原子分子上的cbz示例nhus20030144297to a solution o compound 1 (900 mg) in methylene chloride (16.5 ml) was add

37、ede pdch (30 mg) and triethylamine (0.229 ml). triethyl silane was added (2 x 0.395 ml) over 2 h. the reaction mixture stirred 1 h and 2 ml of tri fluoroacetic acid was added. after 30 min the reaction was basified with 2 n naoh, extracted with methylene chloride, dried over mgso4, filtered and conc

38、entrated. chromatography was run on a biotage 40s column with 3-5%meoh/ch2c12 with 0.5% nh4oh to provide compound 2 as a oil (501 mg, 74%).2.1.2.7 pd黑催化氫解，用氨為溶劑，半胱氨酸的cbz脫除示例pdarthur m. felix, manuel h. jimenz et al., org. syn., 59y 159a dry 1l three-necked, round-bottomed flask is equipped with a dr

39、y ice reflux condenser, a gas-inlet tube, and a magnetic stirring bar as illustrated in the figure. the reaction vessel isimmersed in an acetone-dry 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

40、 is removed to permit the reaction to proceed at the boiling point of ammonia (-33°c), and a gentle stream of dry nitrogen is bubbled into the flask. a solution of 0.708 g (0.80250 mole) of ?/-benzyloxycarbonyl-lmethionine in 10 ml. of /-dimethylacetamide 1.02 g (1.40 ml.9 0.0101 mole) of triet

41、hylamine and 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 scrubbe匚 the mixture is stirred under reflux for 5.5 hours to effect hydrogenolysis. the hydrogen stre

42、am is discontinued, 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 filte

43、red through 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 water-ethanol the white crystalline product, after drying under reduced pressure at 25°, weighs 272-305 mg. (73-82%), m.p. 280-282&#

44、176; (dec.), a25d +23.1° (c = 1, aqueous 5 n hydrochloric acid).酸解脫除 氨基甲酸茉酯在強酸性條件下容易去保護。hbr/hoac是酸解脫除茉氧 按基的最常用的試劑。脫除反應(yīng)主要按下式進行2。反應(yīng)需要消耗2分子的hbr, cbz 的脫除速度隨hbr濃度的增大而增大，因此實際上都是采用高濃度的過量hbr/hoac 溶液(1.2m3.3m)以保證反應(yīng)的完全。r<nxcbzbr*h+ hbr+ co2h.hbr/n、11. d. ben-ishai, a. berger., j. org. chem., 1952,17,

45、1564; r. a. boissonnas, j. biodinger, a. d. welcher., j. am. chem. soc., 1952, 74、53092. r. a. boissonnas, j. biodinger, a. d. welcher., j. am. chem. soc., 1952, 74, 5309; j. meienhofer, e. schnabel., z. natiirforsch., 1965, 20b, 661含有絲氨酸和蘇氨酸的肽或其它含疑基的氨基衍生物用hbr/hoac脫除cbz時 會發(fā)生疑基的o乙?；磻?yīng)。雖然o乙?；苡脡A皂化或氨解脫

46、去，但為了避免這個 副反應(yīng)，可以改用hbr/二氧六環(huán)或hbr/三氟乙酸來代替hbr/hoac。由于hb1在三 氟乙酸屮的溶解度較小，因此不能預(yù)先制成hbr/三氟乙酸溶液，而只能將保護的肽或氨 基衍主物溶于無水三氟乙酸中，先于0°c下通入干燥的hbr,待cbz大部分脫除后，再 室溫通短時間以求完全脫除變化基。cbz被hbr分解產(chǎn)生的浪化茉能同肽中的某種氨基 酸反應(yīng)，也是需要加以注意的。如，甲硫氨酸的硫原了能同浪化節(jié)反應(yīng)生成s節(jié)基甲硫 氨酸，防止的辦法是加入硫瞇（ch3sc2h5）為捕捉劑。色氨酸被hbr/hoac分解產(chǎn) 生有色物質(zhì)，防止的辦法是加入亞磷酸二乙酯。硝基精氨酸會發(fā)生硝基的部

47、分脫落，改 用液體hbr于67°c處理可以避免。1. g. d. fasman, e. r. blout., j. am. chern. soc., 1960, 82, 22622. s. fujiwara, s. moerinaga, k. narita., bull. chem. soc. japan., 1962, 35, 4383. j. meienhofer, e. schnabel., z. naturforsch., 1965, 20b, 661;黃惟德等，生物化學(xué)與生 物物理學(xué)報,1961, 984. n. f. albertson, f. c. mckay., j.

48、 am. chem. soc.f 1953, 73, 53235. s. guttmann, r. a. boissonnas, helv. chim. acta., 1959, 42, 1257用液體hf在0°c處理1030分鐘即可將cbz完全脫去。fso3h2> ch3so3h2>3 cf3so3h33和c6h5sch3-tfa也是較好的試劑。messil在氯仿、乙臘中能于幾分鐘內(nèi) 選擇性脫去cbz和boc保護基。對于bbr3/ch2cl2而言，較大分子的肽的cbz衍生物 可在tfa中去除，因為肽在酸中的溶解度比在ch2ci2中大。從肽中脫去cbz,可在 tfa中添加

49、0.5 m 4-（甲硫基）苯酚或使用hf/me2s/對甲苯酚刃（25:65:10,v/v）來抑 制bn+對芳香氨基酸的加成。1. s. sakakibara et al., bull. chem. soc. japan., 1967, 40, 2164; s. matsuura, c. h. niu, j. s.cohen., j. chem. soc. chem. cormnun., 1976,4512. h. yajima, h. ogawa, h. sakurai., j. chem. soc. chem. commun., 1977, 9093. h. yajima et al., j

50、. chem. soc. chem. commun., 1974, 1074. h. yajima et al., chem. pharm. bull., 1975, 23, 11645. y. kiso, k. ukawa, t. akita., j. chem. soc. chem. commun., 1980, 1016. r. s.lott, v. s. chauham, c. h. stammer., j. chem. soc. chem. commun., 1979, 4957. j. pless, w. bauer., angew chem, int. ed. engl., 19

51、73, 72, 147; a. m. felix., j. org.chem., 1974, 39, 14278. m. bodanszky, a. bodanszky., int. j. pept. protein res., 1984, 23, 2879. j. p. tam, w. f. heath, r. b. merrifield., j. am. chem. soc., 1983, 105, 6442此外，已經(jīng)報道過的還有以下的一些不常用的方法。如hcl/chcb、hc1/h0ac2、 hbr/so23> 液體 hbr4 tosoh、hi/hoac、碘化磷、et3sih8 沸

52、騰的 tfa、 8m hc1的乙醇液或6 m hc1回流1小時或濃鹽酸于25-75°c加熱處理11.5小時 等。1. g. d. fasman, m. idelson, e. r. blout., j. am. chem. soc, 1961, 83, 7092. r. b. merrifield., j. am. chem. soc., 1963, 85, 21493. m. idelson, e. r. blout., j. am. chem. soc.f 195& 80, 46314. m. brenner, h. c. curtius., helv. chim. ac

53、ta., 1963, 46, 21265 e. taschner, b. liberek, abstr. int. cong. biochemistry, vienna 19586. e. waldschmidt-leitz, k. kuhn., chem. ber.f 1951,3817. e. brand, b. f. erlanger, h. sachs., j. am. chem. soc., 1952, 74, 18498. birkofer et al., angew. chem., int. ed., 1965, 4, 4179. f. weygand, w. steglich.

54、, z. naturforsch., 1959, 14b, 47210. a.e. barkdoll, w. f. ross., j. am. chem. soc., 1944, 66, 567; g. chelucci, m. falorni, g.giacomelli., synthesis., 1990, 112111. j. white., j. biol. chem., 1934,106, 1412.1.2.8 hbr-acoh 脫除 cbz 示例etooc33% hbracoh, 91%etoochbrb. anna; p. gerald., heterocycles, 2002,

55、 5& 521a solution of the amine cbz compund (208 mg, 0.44 mmol) in 33 % hydrobromic acid in acetic acid (1 ml) and glacial acetic acid (0.6 ml) was stirred at rt for 3 h under an atmosphere of nitrogen. the volatiles were removed in vacuo to leave the free aminehydrobromide (168 mg, 91 %) as a br

56、own, highly hygroscopic powder; ap 18.0° (c = 0.4,etoh);2.1.2.9 tmsi 脫除 cbz 示例 1us20040204397messil (0.73 ml, 0.73 mmol) was added to a soluton of compound 1 (146 mg, 0.33 mmol) in acetonitrile (10 ml) at room temperature, and the resulting mixture was stirred at room temperature for 2 h. etsn

57、(0.12 ml) was added and the mixture was stirred at room temperature for 15 min. the solvents were removed in vacuo, and the residue was extracted with ethyl acetate. the combined organics were washed with sodium bicarbonate and brine,dried over sodium sulfateand filtered solvents were removed and the residue was useddirectly in the next step.1me3silet3n, ch3cnus200502030782.1 g (4.45 mmol) of compound 1 in 30 ml of ch