Mitsunobu-反應

1、經(jīng)典合成反響標準操作 Mitsunobu 反響 藥明康德新藥開發(fā)經(jīng)典化學合成反響標準操作Mitsunobu 反響編者： 謝軍藥明康德新藥開發(fā)化學合成部目 錄1 前言22 醇的翻轉(zhuǎn)32.1 Mitsunobu 法醇的構(gòu)型翻轉(zhuǎn)合成方法例如 73 Mitsunobu 醚化反響83.1 Mitsunobu 法醚的合成方法例如 94 Mitsunobu 氨基取代反響104.1 Mitsunobu 法利用苯磺酰胺合成胺方法例如 134.2 Mitsunobu 法利用DPPA合成伯胺方法例如134.3 Mitsunobu 法分子內(nèi)關環(huán)合成相應的環(huán)狀胺方法例如144.4 Mitsunobu 法合成丙二烯方法例

2、如145 Mitsunobu 硫代反響16 5.1 Mitsunobu 法合成硫醚方法例如 166 Mitsunobu 鹵代反響18 6.1 Mitsunobu 法合成鹵代物方法例如 187 其他手性翻轉(zhuǎn)試劑 201. 前言1967年，Oyo Mitsunobu 報導了在三苯膦PPh3和偶氮二甲酸二乙酯DEAD作用下酸和醇縮合成酯的新方法1。當?shù)孜餅橹俅嫉臅r候，與羥基相連的碳原子的構(gòu)型會發(fā)生翻轉(zhuǎn)。 經(jīng)過多年的研究和開展，形成了一大類合成方法，我們稱之為Mitsunobu 反響。這類反響被廣泛應用在有機合成，特別是天然產(chǎn)物的合成中2。2醇的翻轉(zhuǎn) 在Mitsunobu 反響中，DEAD 和三苯膦首

3、先生成一個活性的甜菜堿式中間體betaine intermediate，這個活性中間體奪取作為親核試劑的酸的質(zhì)子并同時活化醇，隨后經(jīng)過SN2取代，得到手性翻轉(zhuǎn)的酯；將得到的酯水解，其凈結(jié)果是醇的構(gòu)型翻轉(zhuǎn)。 反響在很溫和的條件下進行，通常反響溫度是在0oC到室溫，大局部基團都不會影響反響。但親核試劑質(zhì)子的pKa值必須小于甜菜堿式中間體betaine intermediate的pKa 值13，否那么親核試劑的質(zhì)子不能被中間體betaine intermediate奪取，反響不能進行。低極性的溶劑有利于反響，通常用四氫呋喃，乙醚，二氯甲烷和甲苯作為溶劑，有時候乙酸乙酯，乙腈和DMF也用作溶劑。 最早

4、將Mitsunobu 手性翻轉(zhuǎn)用于天然產(chǎn)物的合成的一個例子如下，只需一步就將5-choletan-3-ol 轉(zhuǎn)變?yōu)?-choletan-3-ol，而此前這個轉(zhuǎn)化需要好幾步反響才能實現(xiàn)3。 1991年，Eli Lilly 的化學家 Martin 和 Dodge 發(fā)現(xiàn)用p-硝基苯甲酸PNBA作為親核試劑對立體位阻較大的醇的翻轉(zhuǎn)更有效4。Buszek和Jeong據(jù)此合成了Octalatin A和B的前體5。 p-硝基苯甲酸PNBA還能有效地抑制副反響：醇的消除6。所以，在Mitsunobu 反響中，通常使用p-硝基苯甲酸PNBA。Tsunoda等發(fā)現(xiàn)，對于位阻較大的醇，TMAD(N, N, N, N

5、-tetramethyl- azodicarboxamide) 和三丁基膦的體系效果比擬好7。分子內(nèi)的Mitsunobu反響為內(nèi)酯的合成提供了一個有效的方法。Verderas等利用這個方法合成了一系列的氨基酸8。 磺酸類化合物也能參與Mitsunobu 反響，在生成磺酸酯的同時得到手性翻轉(zhuǎn)的產(chǎn)物9,10。2.1 Mitsunobu 法醇的構(gòu)型翻轉(zhuǎn)合成方法例如Inversion of (-)-menthol 11A 250-mL, three-necked, round-bottomed flask is equipped with a stirring bar, nitrogen inlet,

6、 rubber septum, and thermometer. The flask is charged with 3.00 g of (1R, 2S, 5R)-()-menthol (19.2 mmol), 12.9 g of 4-nitrobenzoic acid (77.2 mmol), 20.1 g of triphenylphosphine (PPh3) (76.6 mmol), and 150 mL of tetrahydrofuran. The flask is immersed in an ice bath, and 12.1 mL of diethyl azodicarbo

7、xylate (77 mmol) is added dropwise at a rate such that the temperature of the reaction mixture is maintained below 10°C. Upon completion of the addition, the flask is removed from the ice bath and the solution is allowed to stir at room temperature overnight (14 hr) and subsequently at 40°

8、C for 3 hr. The reaction mixture is cooled to room temperature, diluted with 150 mL of ether, and washed twice with 100 mL portions of saturated aqueous sodium bicarbonate solution. The aqueous layers are combined and back-extracted with 100 mL of ether. The combined organic layers are dried over so

9、dium sulfate. Excess solvent and other volatile reaction components are completely removed under reduced pressure initially on a rotary evaporator and then under high vacuum (approximately 0.2 mm for 3 hr at 30°C). The resulting semi-solid is suspended in 40 mL of ether and the suspension is al

10、lowed to stand at room temperature overnight. The mixture is stirred while 20 mL of hexanes is slowly added. The resulting white solid is filtered under vacuum and the filter cake is washed with 200 mL of 50% (v/v) ether-hexanes. The solvent is removed from the filtrate on a rotary evaporator under

11、reduced pressure to give a yellow oil that is dissolved in 10 mL of methylene chloride and diluted with 40 mL of 8% ether-hexanes. The solution is applied to a flash chromatography column and eluted with 8% ether-hexanes to give 5.03 g (85.6%) of pure nitrobenzoate ester as a white crystalline solid

12、.3Mitsunobu 醚化反響在Mitsunobu 反響中，羥基也可以作為親核試劑參與SN2取代，結(jié)果是生成醚。但通常只限于酚羥基和pKa<13的羥基，否那么反響不能進行。如下面苯酚的葡糖苷化，兩步收率到達55 12。如果作為親電試劑的羥基活性足夠高，或反響生成穩(wěn)定的環(huán)狀產(chǎn)物，對于較低活性的羥基，Mitsunobu 醚化反響也能進行13。Tsunoda 等發(fā)現(xiàn)TMAD能促進反響進行，從而得到較高的產(chǎn)率14。3.1 Mitsunobu 法醚的合成方法例如A solution of benzyl alcohol (0.200 g, 1.85 mmol), 4-hydroxybenzalde

13、hyde (0.226 g, 1.85 mmol), and PPh3(0.582 g, 2.22 mmol) was stirred in dry THF (20 mL) at 0 °C under a nitrogen atmosphere. To this mixture was added dropwise DIAD (0.44 mL, 2.22 mmol) over a period of 5 min, and the reaction was monitored by TLC. After complete disappearance of starting materi

14、al (1 h), the solvent was evaporated under reduced pressure and the resulting oil purified by flash column chromatography (hexane/AcOEt, 8/2). Phenyl ether (0.297 g, 76%) was finally obtained as a white powder after precipitation from CH2Cl2/petroleum ether. 154Mitsunobu 氨基取代反響氨基化合物也可以作為Mitsunobu 反響

15、中的親核試劑，取代羥基，生成取代的氨基化合物。同樣，參與反響的胺必須有足夠的酸性pKa<13，能被PPh3/DEAD體系奪去質(zhì)子。酰胺，磺酰胺，亞胺和疊氮化合物都可以參與反響。Weinreb 用這種方法，在經(jīng)過連續(xù)兩次的Mitsunobu 反響后，合成了天然產(chǎn)物Sarain A的主環(huán)16。近年來，相繼開展了一些用于Mitsunobu 氨基取代反響的試劑，這些試劑在取代后，再脫去保護基而得到各種氨基化合物。Hart和Campbell報導2-(trimethylsilyl)ethylsulfonylTES保護的Boc酰胺，在Mitsunobu 氨基取代后，可以去保護生成Boc 保護的胺或胺的

16、鹽酸鹽17。Fukuyama報導硝基苯磺酰胺類化合物在經(jīng)過Mitsunobu氨基取代后，能方便地用苯硫酚脫去磺酰基，得到仲胺18。Bach 和Kather 報導Fmoc 保護的磺酰胺在Mitsunobu 氨基取代后，能直接脫去Fmoc 而得到磺酰胺19。 酰胺也能作為Mitsunobu 氨基取代反響的底物。比方下面的分子內(nèi)氨基取代，得到氮雜環(huán)化合物20。一個從Gabriel 氨基合成衍生過來的合成伯胺的方法，在Mitsunobu 氨基取代中用鄰苯二甲酰亞胺作為親核試劑，然后肼解，便得到手性翻轉(zhuǎn)的伯胺21。另一個合成伯胺的方法是在Mitsunobu 反響中用疊氮取代羥基，然后復原，便能得到伯胺2

17、2。由于疊氮酸使用不方便，一個替代方法是用diarylphosphoryl azide (DPPA)作為疊氮基團的來源。Taber 和Decher 通過這個方法得到了相應的疊氮化合物，產(chǎn)率還不錯23。Myers報導磺酰肼與-羥基取代炔經(jīng)過Mitsunobu氨基取代反響，生成的產(chǎn)物不穩(wěn)定，馬上分解為丙二烯化合物，這是一個制備丙二烯化合物的比擬便捷的方法24。有文獻報道游離胺也可分子內(nèi)關環(huán)。4.1 Mitsunobu 法利用苯磺酰胺合成胺方法例如 N-Boc p-toluenesulfonamide (88mg, 0.322 mmol) was dissolved in dry THF (3 mL

18、) and PPh3 (168 mg, 0.645 mmol) was added. The solution was stirred under nitrogen and the alcohol (0.215 mmol) was added followed by DEAD (0.083 mL, 0.53 mmol). The mixture was stirred at room temperature for 3 h, concentrated in vacuo and the residue was purified by flash column chromatography (P:

19、 E 4: 1) to give the product (62%).25 The de-protection was carried out according to the usual procedure.4.2 Mitsunobu 法利用DPPA合成伯胺方法例如 To a cooled solution (-5oC) of DIAD (7.9 g, 93 mmol) in THF (5 mL) was added the substituted alchol (7.06 g, 18.7 mmol) and PPh3 (10.3 g, 39.1 mmol). After 15 min, d

20、iphenyl phosphorazidate (DPPA, 12.86 g, 46.77mmol) was added and the reaction mixture was allowed to warm to room temperature. After stirring overnight, the solvent was removed in vacuo to give a yellow oil. The crude material was purified by flash column chromatograghy (2:1,PE/Tol) to give the desi

21、red product (7.28 g, 91%) as a colorless oil. 26 The de-protection and hydrogenation were routine operations.4.3 Mitsunobu 法分子內(nèi)關環(huán)合成相應的環(huán)狀胺方法例如To a solution of substituted proline (33.6 g, 0.1 mol) and PPh3 (31.5 g, 0.12 mol) in THF (200 mL) was dropped a solution of DEAD (18.8 mL, 0.12 mmol) in dry T

22、HF (50 mL) at ice bath. The reaction mixture was allowed to warm to stirred 20oC for 2 h. The filtrate was evaporated and stirred with EA (100 mL), and the product was collected by filtration (20.66 g, 74%). The solvent was removed under reduced pressure and the crude oil was purified by column chro

23、matograghy to afford the desired product (27.3 g, 86%). 274.4 Mitsunobu 法合成丙二烯方法例如An oven-dried, 500-mL, round-bottomed flask equipped with a large football-shaped Teflon-coated magnetic stirring bar is charged with 15.7 g (60.0 mmol) of triphenylphosphine under an argon atmosphere. The flask is sea

24、led with a rubber septum containing a needle adapter to an argon-filled balloon, and 120 mL of THF is added via cannula. The solution is cooled in a 15°C bath, and 9.02 mL (57.5 mmol) of diethyl azodicarboxylate is added via syringe over 2 min, followed immediately by the addition of a solution

25、 of 8.52 g (50.0 mmol) of 3-(tert-butyldimethyl silyl)-2-propyn-1-ol in 18 mL of THF via cannula over 2 min. After an additional 5 min, a solution of 13.0 g (60.0 mmol) of o-nitrobenzenesulfonyl hydrazide in 65 mL of THF is added to the reaction mixture over 5 min via cannula. The resulting orange-r

26、ed solution is stirred at 15°C for 45 min, after which time the cold mixture is allowed to warm to 23°C and is held at that temperature for 5 hr. During this time, the evolution of dinitrogen is observed. The reaction mixture is poured into a 2-L separatory funnel containing 400 mL of pent

27、ane, and the resulting mixture is washed with four 500-mL portions of ice-cold water. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation at 0°C. The residue is purified by flash chromatography using a short column of 230-400 mesh silica ge

28、l (60 g, packed dry and eluted with pentane. The fractions containing the product are concentrated by rotary evaporation at 0°C to afford 5.38-5.39 g (70%) of (tert-butyldimethylsilyl)allene as a colorless liquid.285Mitsunobu 硫代反響活化的硫親核試劑也能參與Mitsunobu反響，生成手性翻轉(zhuǎn)的硫酯或硫醚。Merck的Volante第一次報導了這種方法29。芳香

29、類硫醇化合物都有足夠的活性參與這種反響。Knutsen等報導了這種類型的應用30。5.1 Mitsunobu 法合成硫醚方法例如 To a solution of 2-(R)N-(tert-butyloxycarbonyl)amino-1-propanol (15 g, 85.6 mmol) in THF (200 mL) was added 2-mercaptobenzothiazole (14.3 g, 85.6 mmol) and PPh3 (24.7 g, 94.2 mmol). After stirring for 0.25 h a solution of DEAD (14.8 mL

30、, 94.2 mmol) in dry THF (100 mL) was added dropwise over 0.5 h. The reaction mixture was stirred for 1 h at 20oC and filtered. The filtrate was evaporated and stirred with EA (100 mL), and the product was collected by filtration (20.66 g, 74%). 306Mitsunobu 鹵代反響 在Mitsunobu 反響中，用鹵原子取代羥基生成鹵代物也有報導，但其應用

31、還不多見。Falck 等報導了通過Mitsunobu 過程合成一系列的鹵代烴，除了氟代的產(chǎn)率不高以外，氯代，溴代和碘代的產(chǎn)率都不錯31。 Joulle 等報導脯胺酸衍生物在經(jīng)過Mitsunobu 過程后得到手性翻轉(zhuǎn)的碘代產(chǎn)物32。反響首先是生成一個甲醚中間體，然后在三苯膦的作用下發(fā)生碘代，同時手性翻轉(zhuǎn)。6.1 Mitsunobu 法合成鹵代物方法例如To a flame-dried round-bottomed flask eguipped with a magnetic stir bar and an addition funnel under N2 was added N-Boc-tran

32、s-4-hydroxy-L-proline methyl ester (19.29 g, 0.079 mol), triphenylphosphine (24.78 g, 0.094 mol) and anhydrous THF (2755 mL). The solution was cooled to 0oC. Diethyl azodicarboxylate (DEAD, 14.9 mL, 0.094 mol) in anhydrous THF (15 mL) was added dropwise, followed by the addition of methyl iodide (5.

33、88 mL, 0.094 mol). Upon addition of MeI, the solution turned from dark brown to bright yellow. The reaction mixture was allowed to warm to ambient temperature and stirred for 10 h. The solvent was removed under reduced pressure and the crude oil was purified by column chromatograghy, eluting with 5%

34、 EA/PE to afford the desired product as a white solid (26.22 g, 93.8%).327. 其他手性翻轉(zhuǎn)試劑（1） Vilsmeier 試劑：(cloromethylene)dimethylammonium chloride 由DMF和草酰氯制，和醇生成亞胺鹽后再經(jīng)過親核取代得到胺33。 （2） DPPA 和DBU Merck的Thompson 和Grabowski 用DPPA和DBU也實現(xiàn)了手性翻轉(zhuǎn)，得到疊氮化合物34。參考文獻：1. Mitsunobu, O; Yamada, M; Mukaiyama, T. Bull.Chem.

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