常見的羥基的保護(hù)與脫保護(hù)方法

1、目 錄1. 簡(jiǎn)介22. 硅醚22.1 三甲基硅醚 (TMS-OR) 32.2 叔丁基二甲基硅醚 (TBDMS-OR) 42.3叔丁基二苯基硅醚(TBDPS-OR) 43. 芐醚64. 取代芐醚75. 取代甲基醚86. 四氫吡喃醚97. 烯丙基醚101. 前言羥基廣泛存在于許多在生理上和合成上有意義的化合物中，如核苷，碳水化合物、甾族化合物、大環(huán)內(nèi)酯類化合物、聚醚、某些氨基酸的側(cè)鏈。另外，羥基也是有機(jī)合成中一個(gè)很重要的官能基，其可轉(zhuǎn)變?yōu)辂u素、氨基、羰基、酸基等多種官能團(tuán)。在化合物的氧化、酰基化、用鹵代磷或鹵化氫的鹵化、脫水的反應(yīng)或許多官能團(tuán)的轉(zhuǎn)化過程中，我們常常需要將羥基保護(hù)起來。 在含有多官能

2、團(tuán)復(fù)雜分子的合成中，如何選擇性保護(hù)羥基和脫保護(hù)往往是許多新化合物開發(fā)時(shí)的關(guān)鍵所在，如紫杉醇的全合成。羥基保護(hù)主要將其轉(zhuǎn)變?yōu)橄鄳?yīng)的醚或酯，以醚更為常見。一般用于羥基保護(hù)醚主要有硅醚、甲基醚、烯丙基醚、芐基醚、烷氧甲基醚、烷巰基甲基醚、三甲基硅乙基甲基醚等等。羥基的酯保護(hù)一般用的不多，但在糖及核糖化學(xué)中較為多見。2. 羥基硅醚保護(hù)及脫除 硅醚是最常見的保護(hù)羥基的方法之一。隨著硅原子上的取代基的不同，保護(hù)和去保護(hù)的反應(yīng)活性均有較大的變化。當(dāng)分子中有多官能團(tuán)時(shí)，空間效應(yīng)及電子效應(yīng)是影響反應(yīng)的主要因素。在進(jìn)行選擇性去保護(hù)反應(yīng)時(shí)，硅原子周圍的空間效應(yīng)，以及被保護(hù)分子的結(jié)構(gòu)環(huán)境均需考慮。例如，一般情況下，在

3、TBDMS基團(tuán)存在時(shí)，斷裂DEIPS( 二乙基異丙基硅基) 基團(tuán)是較容易的，但實(shí)際得出的一些結(jié)果是相反的。在這些例子中，分子結(jié)構(gòu)中空間阻礙是產(chǎn)生相反選擇性的原因。電子效應(yīng)的不同也會(huì)影響反應(yīng)的選擇性。對(duì)于兩種空間結(jié)構(gòu)相似的醇來說，電子云密度不同造成酸催化去保護(hù)速率不同，因此可以選擇性去保護(hù)。這一點(diǎn)對(duì)酚基和烷基硅醚特別有效：烷基硅醚在酸中容易去保護(hù)，而酚基醚在堿性條件下更容易去保護(hù)。降低硅的堿性還可以用于改變Lewis酸催化反應(yīng)的結(jié)果，并且有助于選擇性去保護(hù)。在硅原子上引入吸電子取代基可以提高堿性條下水解反應(yīng)的靈敏性，而對(duì)酸的敏感性降低。對(duì)大多數(shù)醚來說，在酸中的穩(wěn)定性為TMS (1)<TES

4、 (64)<TBDMS (20,000)<TIPS (700,000)<TBDPS (5,000,000)；在堿中穩(wěn)定性為TMS (1)<TES (10-100)<TBDMSTBDPS (20,000)< TIPS (100,000)。一般而言，對(duì)于沒有什么位阻的伯醇和仲醇，盡量不要選用TMS作為保護(hù)基團(tuán)，因?yàn)榈玫降漠a(chǎn)物一般在硅膠這樣弱的酸性條件下也會(huì)被裂解掉。任何羥基硅醚的都可以通過四烷基氟化胺如TBAF脫除，其主要硅原子對(duì)氟原子的親和性遠(yuǎn)遠(yuǎn)大于硅-氧之間的親和性。在用TBAF裂解硅醚后，分解產(chǎn)生的四丁銨離子有時(shí)通過柱層析或HPLC很難除干凈，而季銨鹽的質(zhì)

5、譜豐度(Bu4N+: 242)又特別的強(qiáng)有時(shí)會(huì)干擾質(zhì)譜，因此這時(shí)需要使用四甲基氟化銨或四乙基氟化銨來脫除。使用硅醚保護(hù)的另一個(gè)好處是可以在分子中游離伯胺或仲胺基的存在下，對(duì)羥基進(jìn)行保護(hù)，其主要由于硅-氮鍵的結(jié)合遠(yuǎn)比硅-氧鍵來的弱，硅原子優(yōu)先與羥基上的氧原子結(jié)合，這正是與其他保護(hù)基不同之處。順便提一句，一般而言，決大部分的硅-氮鍵的結(jié)合是不穩(wěn)定的，其很容易被水解掉。2.1 三甲基硅醚的保護(hù) (TMS-OR)許多硅基化試劑均可用于在各種醇中引入三甲基硅基。一般來說，空間位阻較小的醇最容易硅基化，但同時(shí)在酸或堿中也非常不穩(wěn)定易水解,三甲基硅基化廣泛用于多官能團(tuán)化合物，生成的衍生物具有較高的揮發(fā)度而利

6、于其相色譜和質(zhì)譜分析。2.1.1 三甲基硅醚羥基保護(hù)示例 (J. Org.Chem. 1996, 61, 2065)Compound 1 (3.00g, 4.286mmol) was dissolved in dry DMF (17 mL). To this solution at 0oC was added imidazole (874.3 mg, 12.86mmol), followed by TMSCl (1.63 mL, 12.86 mmol). After stirring at 0oC for 1.5 h, the reaction mixture was diluted with

7、 EtOAc (300 mL) and washed with water (3 ´ 20 mL) and then brine (30 mL). The organic layer was dried and concentrated in vacuo. The resulting material was then dissolved in dry DMF (20 mL) and treated at 0oC with imidazole (816 mg, 12.00 mmol), followed by chlorodimethylsilane (1.135g, 12.00mm

8、ol). The reaction mixture was stirred for 1h at 0oC and then diluted with EtOAc (200mL). The organic layer was washed with water and brine. Upon silica gel chromatography (10% ethyl acetate in hexane), 3.197 g (90%) of the desired product 2 was obtained.Cleavage (J. Org.Chem. 1996, 61, 2065)Hydrolys

9、is was carried out under aprotic condition-anhydrous tetrabutylammonium fluoride in THF solution.2.2 t-Butyldimethylsilyl ether (TBDMS-OR)在化學(xué)合成中，采用硅基化進(jìn)行羥基保護(hù)生成叔丁基甲基硅基醚是應(yīng)用較多的方法之一。一般來說，在分子中羥基位阻不大時(shí)主要通過TBSCl對(duì)羥基進(jìn)行保護(hù)。 但當(dāng)羥基位阻較大時(shí)則采用較強(qiáng)的硅醚化試劑TBSOTf來實(shí)現(xiàn)。生成的叔丁基二甲基醚在多種有機(jī)反應(yīng)中是相當(dāng)穩(wěn)定的，在一定條件下去保護(hù)時(shí)一般不會(huì)影響其他官能團(tuán)。它在堿性水解時(shí)的穩(wěn)定性約

10、為三甲基硅醚的104倍。它對(duì)堿穩(wěn)定。相對(duì)來說對(duì)酸敏感些。TBS醚的生成和斷裂的難易取決于空間因素，因此常常用于對(duì)多官能團(tuán)，位阻不同的分子進(jìn)行選擇性保護(hù)。在伯、仲醇中，TBS基相對(duì)來說較易于與伯醇反應(yīng)。TBS醚的斷裂除了常用的四烷基氟化胺外，許多情況下也可用酸來斷。當(dāng)分子內(nèi)沒有對(duì)強(qiáng)酸敏感的官能基存在時(shí)，可用 HCl-MeOH, HCl-Dioxane 體系去除TBS，若有對(duì)強(qiáng)酸敏感的官能基存在時(shí)，則可選用AcOH-THF體系去除。2.2.1 通過TBSCl進(jìn)行羥基的叔丁基二甲基硅醚保護(hù)示例 (J. Am. Chem. Soc. 1972, 94, 6190)The hydroxyl lacton

11、e 1, upon treatment with TBDMSCl (1.2 equiv) and imidazole (2.5 equiv.) in DMF (2 mL/g of 1) at 35oC for 10 h, produced the silyl ether-lactone 2 in 96% yield. 2.2.2 通過TBSOTf進(jìn)行羥基的叔丁基二甲基硅醚保護(hù)示例(J.Org.Chem. 1987, 52, 622)To an ice-cold solution of 4.8 g of pyridine (2.0 equiv) and 4.20 g of 1 in 30 mL

12、of dry acetonitrile was added slowly 9.6 g of tert-butyldimethylsilyl triflate (36.2 mmol, 1.2 equiv). The reaction mixture was stirred for 5 h at room temperature and then poured into 200 mL of saturated sodium bicarbonate solution at 0oC. The solution was extracted thoroughly with hexane, and the

13、organic extracts were dried over anhydrous potassium carbonate and filtered. Removal of the solvent under reduced pressure followed by distillation of the residue gave 6.29 g (82% yield). 2.2.3 通過TBAF脫TBDPS示例 (Can. J. Chem. 1975, 53, 2975)To a solution of THP ether 1 (1.7 g, 3.3 mmol) in THF (10 mL)

14、 was added a 1 M solution of tetrabutylammonium fluoride in THF (5 mL, 5 mmol) at 22-24oC. The solution was stirred for 2 h and diluted with 100 mL (1:1) of Et2O/EtOAc solution. The organic layer was separated and washed with H2O (3 ´ 100 mL). The water extract was washed with 2:1 Et2O/EtOAc so

15、lution (2 ´ 50 mL), and the organic layers were combined and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was chromatographed over silica gel using (5:1) hexanes/ethyl acetate solution to give 2 (0.75 g, 82%). 2.2.4 通過AcOH-THF脫TBS示例(Tetrahedron Lett. 1988, 29, 6331)Sel

16、ective removal of one of the TBDMS groups of 1 was accomplished by treatment with acetic acid-water-THF (13:7:3) (30°C, 15h) to give the monohydroxy compound 2 in 79% yield.2.3 t-Butyldiphenylsilyl ether (TBDPS-OR)在酸性水解條件下TBDPS保護(hù)基比TBDMS更加穩(wěn)定（約100倍），而TBDPS保護(hù)基對(duì)堿的穩(wěn)定性比TBDMS要差。 另外，由于該保護(hù)基的分子量較大，容易使底物固

17、化而易于分離。 TBDPS保護(hù)基對(duì)許多與TBDMS保護(hù)基不相容的試劑顯出比TBDMS基團(tuán)更好的穩(wěn)定性。TBDMS基團(tuán)在酸性條件下不易遷移。TBDPS醚對(duì)K2CO3 /CH3OH，對(duì)9M氨水、60、2h；對(duì)MeONa（cat.）/CH3OH、25、24h均穩(wěn)定。該醚對(duì)80%乙酸穩(wěn)定，后者可用于脫除醚中TBDMS，三苯甲基，四氫吡喃保護(hù)基也對(duì)HBr /AcOH，12，2min；對(duì)25%75%甲酸，25，2h6h；以及50%三氟乙酸，25，15min穩(wěn)定。2.3.1 通過TBDPSCl進(jìn)行羥基的叔丁基二甲基硅醚保護(hù)示例(J.Org. Chem, 1992, 57, 1722)To a solutio

18、n of 1,4-butanediol (5 g, 55 mmol) in CH2Cl2 (10 mL) containing i-Pr2NEt (10 mL) was added t-BDPSiCl (5 mL, 18 mmol) dropwise under N2 at 22-24oC. The solution was stirred at 22-24oC for 2 h, concentrated in vacuo and chromatographed, eluting with hexanes/ethyl acetate (10:1) to 2 (clear oil, 5.6 g,

19、 95%). 2.4 三異丙基硅醚保護(hù) (TIPS-OR)酸性水解時(shí)，有較大體積的TIPS醚比叔丁基二甲基硅醚要更穩(wěn)定些。但穩(wěn)定性比叔丁基二苯基硅基差。TIPS基堿性水解時(shí)比TBDMS基或TBDPS基穩(wěn)定。相對(duì)于仲羥基，TIPS基對(duì)伯羥基有更好的選擇性。2.4.1通過TIPSCl進(jìn)行羥基的三異丙基硅醚保護(hù)示例(J. Org. Chem. 1995, 60, 7796)To a stirred solution of (1)(1.5 g) in CH2Cl2 (53 mL) cooled to 0oC were successively added 2,6-lutidine (6.2 mL, 5

20、3.3 mmol) and triisopropylsilyl triflate (7.90 mL, 29.5mmol). The mixture was allowed to warm to room temperature (30 min). Then excess triflate was consumed by addition of methanol (10 mL) and a saturated aqueous NH4Cl solution (60 mL). The phase was separated and the aqueous layer was extracted wi

21、th CH2Cl2 (4 ´ 50 Ml). The combined organic phases were washed with a saturated NaHCO3 (100 mL) a, 1M NaHSO4 (3 ´ 50 mL), and brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography (10% ethyl acetate in hexane) afforded silyl ether (2) (6.90 g, 8

22、9%). 3. 羥基芐醚保護(hù)及脫除 一般羥基的芐醚保護(hù)主要有芐基，對(duì)甲氧芐基及三苯甲基醚。3.1芐基醚保護(hù)羥基 (Bn-OR)一般烷基上的羥基在用芐基醚保護(hù)時(shí)需要用強(qiáng)堿，但酚羥基的芐基醚保護(hù)一般只要用碳酸鉀在乙腈或丙酮中回流即可，回流情況下，這類烷基化在乙腈中速度比丙酮中要快四倍左右，因此一般用乙腈做溶劑居多。若反應(yīng)速度慢可用DMF做溶劑，提高反應(yīng)溫度，或加NaI,KI催化反應(yīng)。芐基醚的裂解主要是通過催化加氫的方法，Pd是理想的催化劑，用Pt時(shí)會(huì)產(chǎn)生芳環(huán)上的氫化作用。在含色氨酸的肽中氫解蘇氨酸常導(dǎo)致色氨酸還原成2，3-二氫衍生物。非芳性的胺可以使催化劑活性降低，阻礙O-脫芐；在氫化體系中加入N

23、a2CO3可以防止芐基被裂解，但可使雙鍵發(fā)生還原。孤立烯烴有可能影響芐基醚鍵的裂解（H2，5% Pd-C，97%產(chǎn)率）。一般而言選擇性的大小取決于取代的類型及空間位阻的情況。與酯共扼的三取代的烯烴存在時(shí)，芐基的水解也有相當(dāng)好的選擇性。對(duì)甲氧芐基基團(tuán)存在時(shí)，芐基的水解（Pd-C，EtOAc，室溫，18小時(shí)）有非常好的選擇性。在反應(yīng)體系中加入Pyridine 可使對(duì)甲氧芐基和芐基氫解產(chǎn)生區(qū)別。 芐基的氫解有溶劑的作用，如下列表：Effect of solvent on the hydrogenlysis of benzyl etherSolventReaction rate(mm H2 / min

24、 /0.1g cat)THF40Hexanol25Methanol5Toluene2Hexane63.1.1烷基羥基的芐基醚保護(hù)示例(Bull. Chem. Soc. Jpn. 1987, 60, 1529)Compound 1 (12.1 g) in DMF (200 mL) was treated with 60% NaH (1.32 g), benzyl bromide (6.44 g) and tetrabutylammonium iodide (0.11 g). The reaction mixture was stirred at room temperature for 1.5

25、h. The product was purified by chromatography on silica gel with toluene-ethanol (20:1) to give 2 (14.0 g, 99%).3.1.2 酚羥基的芐基醚保護(hù)示例 To a solution of 1 (37.65 g, 277 mmol) in EtOH (135 mL) was added benzyl chloride (36.5 g, 289 mmol), KI (1.75 g, 10 mmol) and K2CO3 (24.6 g, 178 mmol) with stirring. The

26、 resulting mixture was refluxed for 5 h. The mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was added water (100 mL) and extracted with Et2O (80 mL ´ 3). The extract was washed with saturated NaHCO3, water and brine successively. The organic la

27、yer was dried over Na2SO4 and concentrated in vacuo to give the crude product, which was distilled to afford 2 (49.1 g, 79%).3.1.3芐基醚氫解脫保護(hù)示例(J. Am. Chem. Soc. 1971, 93, 1746)Compound 3 (105 mg) was hydrogenated in ethanol (10 mL) containing 1M hydrochloric acid (0.5 mL) in the presence of 10% pallad

28、ium on charcoal (50 mg) in an initial hydrogen pressure of 3.4 MPa overnight. The product was purified by chromatography on silica gel with toluene-ethanol (3:1) to give 4 (90 mg, quant.)3.2對(duì)甲氧基芐基醚保護(hù)羥基 (PMB-OR)各種甲氧基芐醚已經(jīng)合成得到并被用作保護(hù)基。實(shí)際上甲氧基取代的芐基醚較未取代的芐基醚更容易通過氧化去保護(hù)。下表給出了用二氯二氰苯醌去保護(hù)時(shí)的相對(duì)速率。Cleavage of MPM,

29、 DMPM, and TMPM ethers with DDQ in CH2Cl2/H2O at 20oCProtective GroupTime (h)Yield(%)ii iiiProtectiveGroupTime (h)Yield(%)( ii 3,4-DMPM<0.3386842-MPM3.593704-MPM0.3389863,5-DMPM873922,3,4-TMPM0.560752,3-DMPM12.575733,4,5-TMPM189893-MPM2480942,5-DMPM2.595162,6-DMPM27.58095一般而言，對(duì)甲氧基芐醚在合成中更為常用，羥基上對(duì)甲

30、氧基芐基的方法和芐基類似，但脫除除了氫解的方法外，還可以氧化除去。3.2.1對(duì)甲氧基芐基醚保護(hù)示例(Tetrahedron Lett. 1988, 29, 2459)To a stirred suspension of NaH (26 mg 1.09 mmol) in DMSO (1 mL) was added dropwise a THF solution (3 mL) of 1 (250 mg, 0.78 mmol) under Ar. After 45 min. at room temperature MPM chloride (158 mg, 1.01mmol) was added,

31、and the stirring was continued for 3 h. the mixture was poured into sat. NH4Cl aq. And then extracted with ether. The extract was washed with sat. NaCl aq., dried over MgSO4, and concentrated in vacuo to leave an oil, which was chromatographed on a short silica gel column elution with EtOAc-n-hexane

32、 (1:1) gave a colorless oil of 2 296 mg, 86%.3.2.2 在芐氧基存在下選擇性脫去對(duì)甲氧基芐基示例(Tetrahedron Lett. 1988, 29, 2459)To a stirred solution of 2 (92 mg, 0.286 mmol) in CH2Cl2 (2.9 mL) and water (0.17 mL) was added DDQ (97 mg, 0.427 mmol) at room temp. After 2.5 h precipitated DDQH was removed by decantation and

33、washed with a small amount of CH2Cl2. The combined CH2Cl2 solution was washed with sat. NaHCO3 aq. And sat. NaCl aq. And dried over Na2SO4. Evaporated of the solvent in vacuo gave an oil, which was chromatographed on a silica gel column with EtOAc-n-hexane (1:1) as eluant gave a colorless solid of 1

34、 43.8 mg, 84%.4. 烷氧基甲基醚或烷氧基取代甲基醚烷氧基甲基醚或烷氧基取代甲基醚在羥基保護(hù)中也是較為多用的一類，常用的有THP (2-四氫吡喃)，MOM（甲氧基甲機(jī)基），EE（2-乙氧基乙基），這類保護(hù)基都對(duì)酸不穩(wěn)定，因此一般都是脫保護(hù)。它們對(duì)酸的穩(wěn)定性是MOM>EE>THP。4.1 THP (2-四氫吡喃)保護(hù)羥基 THP醚引入到一個(gè)手性分子的結(jié)果是形成了一個(gè)非對(duì)映體，因?yàn)樵谒臍溥拎h(huán)上新增了一個(gè)手性中心。（有時(shí)它會(huì)使NMR譜的表達(dá)有點(diǎn)困難）。盡管如此， 它仍是有機(jī)合成中一個(gè)非常有用的保護(hù)基團(tuán)，它的成本低，易于分離，對(duì)大多數(shù)非質(zhì)子酸試劑有一定的穩(wěn)定性，易于被出去。通

35、常，幾乎任何酸性試劑或任何可以在原位產(chǎn)生酸的試劑都可被用來引入THP基團(tuán)。4.1.1 THP (2-四氫吡喃)保護(hù)羥基示例(J.Org.Chem.1977,42,3772) To a solution of 1 (1.5 g, 3.5mmol) in CH2Cl2 (10 mL) at 22-24oC was added 3,4- dihydro-2H-pyran (0.479 mL, 0.442 g, 5.25mmol) and PPTs (20 mg, 0.08mmol). The solution was stirred at 22-24oC for 1 h and diluted wi

36、th a 100-mL solution of (1:1) diethyl ether and ethyl acetate. The organic layer was separated, washed with H2O (3 ´ 100mL), and the residue was chromatographed, eluting with hexane/ethyl acetate (20:1) to give the THP ether 2 as clear oil (1.75 g, 97%).4.1.2 THP (2-四氫吡喃)脫保護(hù)示例(J.Org.Chem.1977,4

37、2,3772)To an ethanol solution (30 mL) of THP ether 1 (1.87 g, 5mmol) was added PPTS (20 mg, 0.08mmol) in one portion. The solution was refluxed for 1 h, cooled to 22-24oC, and diluted with a mixture of diethyl ether (100 mL) and H2O (200 mL). The organic layer was washed with H2O (2 ´ 100mL), d

38、ried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (3:1) to give 2 (1.36 g, 94%) as clear oil.4.2 MOM保護(hù)羥基MOM是一般是通過MOMCl-DIEA 引入；其對(duì)酸還是較為穩(wěn)定的，一般它的脫除需要在強(qiáng)酸條件下進(jìn)行。4.2.1 MOM (CH3OCH2-OR)羥基保護(hù)示例(J. Org. Chem. 1995,60,7796)To

39、a stirred solution of (1) (51.0 g, 99 mmol) in CH2Cl2 (1.0 L) at room temperature were successively added DIEA (51.5 mL, 0.297 mol) and MOMCl (15.0 mL, 0.198 mol) over a 10 min period. The solution was stirred 11 h at room temperature after which a saturated aqueous NH4Cl solution (200 mL) was added

40、. The aqueous phase was segregated, and the organic one was washed with water (100 mL), brine (100 mL0, dried with anhydrous MgSO4, filtered, and concentrated to give pure MOM ether (2) (55.3 g, 100%) (slightly yellowish oil).4.2.2 MOM脫保護(hù)示例(ibid)To a stirred solution (1) (1.00 g, 1.45 mmol) in dry i

41、sopropyl alcohol (10.0 mL) were added two drops (0.06 mL) of concentrated aqueous hydrochloric acid. The solution was stirred at 55oC for 10 h and although incomplete as indicated by TLC analysis, was allowed to cool to room temperature (prolonged reaction times tend to give substantial decompositio

42、n). A saturated aqueous NaHCO3 (20 mL) and diethyl ether (50 mL) were added to the mixture. The phase was separated and the aqueous layer was extracted with diethyl ether (5 ´ 50 mL). The combined organic layer was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated. The cru

43、de product was purified by flash chromatography to give (2) (0.63 g, 65%). 4.3 EE（CH3 CH2OCH3CH-OR）保護(hù)羥基EE的性質(zhì)和THP差的不是很多。4.3.1 EE（CH3 CH2OCH3CH-OR）羥基保護(hù)示例(J.Am.Chem.Soc. 1981,103,2427)Selective reaction of the primary hydroxyl group in 1 with ethyl vinyl ether at 22oC by using pyridinium tosylate as ca

44、talyst in CH2C12 was followed by formation of the methanesulfonate ester at C-6, to produce EE脫保護(hù)示例(J.Am.Chem.Soc. 1986,108,1035)A solution of 19 mg (0.043 mmol) of ester 20 in 0.2 mL ether was treated at 0oC with 100 mL of a 1 M solution of LAH in ether. After 5 min the solution was quenche

45、d with water and was extracted with ether. The solvent was evaporated and the residue was dissolved in 0.5 mL of methanol containing a few crystals of PPTS. The solution was stirred at 25oC for 2 h. The methanol was evaporated and the residue was dissolved in ether. The combined organic extract was

46、washed with saturated aqueous sodium bicarbonate and the aqueous phase was back extracted with ether. The ether extracts were combined, washed with brine, dried (Na2SO4,), and concentrated. The solid product was purified by HPLC (p-Porasil) to furnish 13 mg (90% overall) of desepoxyasperdiol as an o

47、il.4.4 SEM-Cl(TMSCH2CH2OCH2-)保護(hù)羥基SEM-作為羥基的保護(hù)基，其主要特點(diǎn)為最后脫保護(hù)可以通過四烷基氟化胺來脫去。SEM醚對(duì)分解四氫吡喃基(THP) 和叔丁基二甲基硅醚（TBS）的酸性條件（AcOH-H2O, THF, 45oC, 7小時(shí)）是穩(wěn)定的。4.4.1 SEM-Cl(TMSCH2CH2OCH2-)保護(hù)羥基示例(TL, 1980,3343)Exposure of an alcohol 1 in CH2Cl2 (ca, 2M) under an inert atmosphere containing 4-5 eq. of DIEA, to SEMCl (ca,

48、3 eq) at 25-40oC,affords the SEM ether in high yield. 在二氯甲烷中的酒精1曝光（CA，2m）在含有4-5平衡狀態(tài)惰性氣體下，以semcl（CA，3eq）在25-40，提供高產(chǎn)SEM醚4.4.2 SEM保護(hù)基脫保護(hù)示例(ibid)Removed of the SEM can be accomplished via reaction with Bu4NF (at concentration > 2M) in dry THF at 45oC. Standard extractive workup followed by rough SiO2

49、 filtration give the desired product. 移除的SEM可以通過反應(yīng)bu4nf完成（在濃度大于2m）在無(wú)水THF45條件下。標(biāo)準(zhǔn)的萃取處理后粗糙的二氧化硅過濾得到所需的產(chǎn)品。5. 其他保護(hù)基5.1 烯丙基保護(hù)羥基 有關(guān)碳水化合物的文獻(xiàn)中，烯丙醚用來保護(hù)醇是很常見的，原因在于烯丙醚通常可用各種方法形成糖苷。顯然，烯丙醚不能與強(qiáng)的的親電試劑共存，如溴、催化氫化的試劑。但它在中等強(qiáng)度的酸性條件（1N HCl，回流，10小時(shí)）下穩(wěn)定。易于生成，在大量其它保護(hù)基存在下有許多溫和的脫保護(hù)方法，及其總體上的穩(wěn)定性，使得烯丙醚成為許多反應(yīng)系列中的主干。已有關(guān)于全氘代烯丙溴的合成

50、及將它用作碳水化合物保護(hù)基方面的報(bào)道，全氘化合物的優(yōu)點(diǎn)在于：烯丙基的NMR中的共振不再掩蔽其它可供鑒定的共振吸收峰，如糖苷的導(dǎo)頭碳的吸收峰。5.1.1 烯丙基保護(hù)羥基示例(J.Org.Chem.C 1969, 2367)A mixture of 1 (50 g), powdered NaOH (50 g), benzene (500 mL), and allyl bromide (12 mL) was heated under reflux and the progress of the reaction was followed by TLC (ether: petroleum, 1:1).

51、 After 80 min. some starting material (Rf 0.15) remained and some diallyl derivatives present, but the major product was the monoallyl derivatives (Rf 0.56), the benzene solution was washed with water, dried (K2CO3) and evaporated. The syrupy product was chromatographed on alumina, elution with benz

52、ene:ether removed the diallyl derivative (9 g) and elution with ether-methanol (25:1) gave the monoallyl derivatives (35 g ). Further elution with methanol gave unchanged starting material (8 g).混合物1（50克）、NaOH（50克）、苯（500毫升），與烯丙基溴（12毫升）加熱回流反應(yīng)的進(jìn)展是薄層色譜（乙醚：石油，1:1）。80分鐘后，一些原料（RF 0.15）保持和二烯丙基衍生物的存在，但主要的產(chǎn)品

53、是單烯丙基衍生物（RF 0.56）的苯溶液，用水洗滌，干燥（K2CO3）和蒸發(fā)。糖漿產(chǎn)品以氧化鋁、洗脫苯醚的進(jìn)程去除：二烯丙基衍生物（9 g）和乙醚甲醇洗脫（25:1）給單烯丙基衍生物（35克）。甲醇進(jìn)一步洗脫與不變起始原料（8克）。5.1.2 烯丙基脫保護(hù)示例(J.Chem.Soc. Perkins Trans 1, 1980,738)A solution of menthyl allyl ether (0.114 g, 0.58 mmol) (prepared from menthol, sodium hydride, and allyl bromide), RhCl(PPh3)3 (0.

54、037 g, 0.040 mmol) and diazabicyclo2,2,2octane (0.013 g, 0.120 mmol) (added to inhibit premature hydrolysis of the intermediate enol ether. Free propionaldehyde reacts with RhCl(PPh3)3 to form the catalytically much less active RhCl(PPh3)2CO.) in 10% aqueous ethanol was heated at reflux for 3 h. An

55、aliquot was injected into 1 N HCl and after a few minutes was assayed by vpc analysis which showed only menthol and menthyl allyl ether in 93% and 7% yield, respectively. Work up of a parallel reaction (by poured into water, extracting with ether, washing the ether with brine acidified to pH 2, dryi

56、ng over MgSO4, concentrated, and separation on silica gel) gave menthol in 93% yield. 一份基烯丙基醚的溶液（0.114克，0.58毫摩爾）（由薄荷腦、氫化鈉、烯丙基溴）RhCl（PPh3），3（0.037克，0.040毫摩爾）和二氮雜雙環(huán)2,2,2辛烷（0.013克，0.120毫摩爾）（添加抑制中間體烯醚過早水解。自行RhCl（PPh3）丙醛反應(yīng)3形成的催化活動(dòng)更少RhCl（PPh3）2CO。）在10%乙醇水溶液加熱回流3 h.等分試樣注入1 N HCl和幾分鐘后的VPC分析僅表現(xiàn)在93%和7%薄荷腦和薄荷烯

57、丙基醚產(chǎn)量分別測(cè)定。工作上的平行反應(yīng)（被倒入水中，用乙醚提取，用鹽水酸化至pH 2，洗醚干燥MgSO4、濃縮和硅膠分離）給了薄荷93%產(chǎn)量5.2 ?；Ｗo(hù)醇通過酯的保護(hù)一般用在糖化學(xué)中較為多見，一般主要通過乙酰基、苯甲酰基和特戊?；?。乙?；Ｗo(hù)也常常用于天然產(chǎn)物結(jié)構(gòu)鑒定中羥基衍生化。一般上乙酰基方法較多，其中用乙酸酐在吡啶中引入乙?；顬槌Ｓ茫捎谠摲椒ú荒芤阴；蛔栎^大的叔醇，要想在叔醇引入乙酰基需要加入?；呋瘎―MAP, 4-PPY）等，有時(shí)對(duì)位阻特別大的即使加入酰化催化劑（DMAP, 4-PPY）也無(wú)效時(shí)，可以考慮通過Lewis酸催化，Procopiou P. A.等人報(bào)道利用TM

58、SOTf催化位阻較大的叔醇的乙酰化，效果要比Ac2O/DMAP體系更好（J. Org. Chem. 1998, 2342）。 苯甲?；某Ｓ梅椒ㄊ荁zCl或Bz2O/吡啶。特戊酰化的常用方法是PvCl /吡啶, 0-75。這些?；瘜?duì)伯醇選擇性要大于仲醇，選擇性特戊?；?gt;苯甲酰>乙酰基；有時(shí)特戊?；苫瘜W(xué)選擇性的上在伯醇上。5.2.1 乙?；Ｗo(hù)羥基示例 (DMAP: J. Org. Chem. 1993, 3791)Compound 1 (1.38 g, 10 mmol) and Ac2O (0.95 mL, 10 mmol) in CH2Cl2 (30 mL) were treated