Mitsunobu 反应应用一览

1. 前言

1967年，Oyo Mitsunobu 报导了在三苯膦（PPh₃）和偶氮二甲酸二乙酯（DEAD）作用下酸和醇缩合成酯的新方法¹。当底物为仲醇的时候，与羟基相连的碳原子的构型会发生翻转。

经过多年的研究和发展，形成了一大类合成方法，我们称之为Mitsunobu 反应。这类反应被广泛应用在有机合成，特别是天然产物的合成中²。

2．醇的翻转

 在Mitsunobu 反应中，DEAD 和三苯膦首先生成一个活性的甜菜碱式中间体（betaine intermediate），这个活性中间体夺取作为亲核试剂的酸的质子并同时活化醇，随后经过S_N2取代，得到手性翻转的酯；将得到的酯水解，其净结果是醇的构型翻转。

反应在很温和的条件下进行，通常反应温度是在0^oC到室温，大部分基团都不会影响反应。但亲核试剂质子的pKa值必须小于甜菜碱式中间体（betaine intermediate）的pKa 值（～13），否则亲核试剂的质子不能被中间体（betaine intermediate）夺取，反应不能进行。低极性的溶剂有利于反应，通常用四氢呋喃，乙醚，二氯甲烷和甲苯作为溶剂，有时候乙酸乙酯，乙腈和DMF也用作溶剂。

最早将Mitsunobu 手性翻转用于天然产物的合成的一个例子如下，只需一步就将5α-choletan-3β-ol 转变为5α-choletan-3α-ol，而此前这个转化需要好几步反应才能实现³。

1991年，Eli Lilly 的化学家 Martin 和 Dodge 发现用p-硝基苯甲酸（PNBA）作为亲核试剂对立体位阻较大的醇的翻转更有效⁴。Buszek和Jeong据此合成了Octalatin A和B的前体⁵。

p-硝基苯甲酸（PNBA）还能有效地抑制副反应：醇的消除⁶。所以，在Mitsunobu 反应中，通常使用p-硝基苯甲酸（PNBA）。

Tsunoda等发现，对于位阻较大的醇，TMAD(N, N, N’, N’-tetramethyl-azodicarboxamide) 和三丁基膦的体系效果比较好⁷。

分子内的Mitsunobu反应为内酯的合成提供了一个有效的方法。Verderas等利用这个方法合成了一系列的氨基酸⁸。

磺酸类化合物也能参与Mitsunobu 反应，在生成磺酸酯的同时得到手性翻转的产物^9,10。

2.1 Mitsunobu 法醇的构型翻转合成方法示例

Inversion of (-)-menthol ¹¹

A250-mL, three-necked, round-bottomed flask isequipped with a stirring bar, nitrogen inlet, 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 azodicarboxylate (77 mmol) is added dropwise at a rate such that thetemperature of the reaction mixture is maintained below 10°C. Upon completionof the addition, the flask is removed from the ice bath and the solution isallowed to stir at room temperature overnight (14 hr) and subsequently at 40°Cfor 3 hr. The reaction mixture is cooled to room temperature, diluted with 150 mL of ether, and washedtwice with 100 mL portions of saturated aqueous sodium bicarbonate solution. The aqueous layers arecombined and back-extracted with 100 mL of ether. The combined organic layers are dried over sodium sulfate. Excess solvent and other volatilereaction components are completely removed under reduced pressure initially ona rotary evaporator and then under high vacuum(approximately 0.2 mm for 3 hr at 30°C). The resulting semi-solid is suspendedin 40 mL of ether andthe suspension is allowed to stand at room temperature overnight. The mixtureis stirred while 20 mL of hexanes is slowly added.The resulting white solid is filtered under vacuum and the filter cake iswashed with 200 mL of 50% (v/v) ether-hexanes.The solvent is removed from the filtrate on a rotary evaporator under reducedpressure to give a yellow oil that is dissolved in 10 mLof methylene chloride and diluted with 40 mL of 8% ether-hexanes. The solution isapplied 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 crystallinesolid.

3．Mitsunobu醚化反应

在Mitsunobu 反应中，羟基也可以作为亲核试剂参与S_N2取代，结果是生成醚。但通常只限于酚羟基和pKa<13的羟基，否则反应不能进行。

如下面苯酚的葡糖苷化，两步收率达到55％ ¹²。

如果作为亲电试剂的羟基活性足够高，或反应生成稳定的环状产物，对于较低活性的羟基，Mitsunobu 醚化反应也能进行¹³。

Tsunoda等发现TMAD能促进反应进行，从而得到较高的产率¹⁴。

3.1 Mitsunobu 法醚的合成方法示例

A solution of benzyl alcohol (0.200 g,1.85 mmol), 4-hydroxybenzaldehyde (0.226 g, 1.85 mmol), and PPh₃(0.582g, 2.22 mmol) was stirred in dry THF (20 mL) at 0 °C under a nitrogenatmosphere. To this mixture was added dropwise DIAD (0.44 mL, 2.22 mmol) over aperiod of 5 min, and the reaction was monitored by TLC. After completedisappearance of starting material (1 h), the solvent was evaporated underreduced pressure and the resulting oil purified by flash column chromatography(hexane/AcOEt, 8/2). Phenyl ether (0.297 g, 76%) was finally obtained as awhite powder after precipitation from CH2Cl2/petroleum ether. ¹⁵

4．Mitsunobu氨基取代反应

氨基化合物也可以作为Mitsunobu 反应中的亲核试剂，取代羟基，生成取代的氨基化合物。同样，参与反应的胺必须有足够的酸性（pKa<13），能被PPh₃/DEAD体系夺去质子。酰胺，磺酰胺，亚胺和叠氮化合物都可以参与反应。

Weinreb 用这种方法，在经过连续两次的Mitsunobu 反应后，合成了天然产物Sarain A的主环¹⁶。

近年来，相继发展了一些用于Mitsunobu 氨基取代反应的试剂，这些试剂在取代后，再脱去保护基而得到各种氨基化合物。

         Hart和Campbell报导2-[(trimethylsilyl)ethyl]sulfonyl（TES）保护的Boc酰胺，在Mitsunobu 氨基取代后，可以去保护生成Boc 保护的胺或胺的盐酸盐¹⁷。

Fukuyama报导硝基苯磺酰胺类化合物在经过Mitsunobu氨基取代后，能方便地用苯硫酚脱去磺酰基，得到仲胺¹⁸。

Bach 和Kather 报导Fmoc 保护的磺酰胺在Mitsunobu 氨基取代后，能直接脱去Fmoc 而得到磺酰胺¹⁹。

酰胺也能作为Mitsunobu 氨基取代反应的底物。比如下面的分子内氨基取代，得到氮杂环化合物²⁰。

一个从Gabriel 氨基合成衍生过来的合成伯胺的方法，在Mitsunobu 氨基取代中用邻苯二甲酰亚胺作为亲核试剂，然后肼解，便得到手性翻转的伯胺²¹。

另一个合成伯胺的方法是在Mitsunobu 反应中用叠氮取代羟基，然后还原，便能得到伯胺²²。

由于叠氮酸使用不方便，一个替代方法是用diarylphosphoryl azide(DPPA)作为叠氮基团的来源。Taber 和Decher 通过这个方法得到了相应的叠氮化合物，产率还不错²³。

Myers报导磺酰肼与α­-羟基取代炔经过Mitsunobu氨基取代反应，生成的产物不稳定，马上分解为丙二烯化合物，这是一个制备丙二烯化合物的比较便捷的方法²⁴。

4.1Mitsunobu 法利用苯磺酰胺合成胺方法示例

N-Boc p-toluenesulfonamide (88mg, 0.322 mmol) was dissolved in dry THF(3 mL) and PPh₃ (168 mg, 0.645 mmol) was added.  The solution was stirred under nitrogen andthe alcohol (0.215 mmol) was added followed by DEAD (0.083 mL, 0.53 mmol).  The mixture was stirred at room temperaturefor 3 h, concentrated in vacuo and the residue was purified by flash columnchromatography (P: E 4: 1) to give the product (62%).²⁵

   The de-protection was carried out according to theusual procedure.

4.2Mitsunobu 法利用DPPA合成伯胺方法示例

To a cooled solution (-5^oC) 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, diphenyl phosphorazidate (DPPA, 12.86 g,46.77mmol) was added and the reaction mixture was allowed to warm to roomtemperature. After stirring overnight, the solvent was removed in vacuo to givea yellow oil. The crude material was purified by flash column chromatograghy(2:1,PE/Tol) to give the desired product (7.28 g, 91%) as a colorless oil. ²⁶

  The de-protection andhydrogenation were routine operations.

4.3Mitsunobu 法分子内关环合成相应的环状胺方法示例

Toa solution of substituted proline (33.6 g, 0.1 mol) and PPh₃ (31.5g, 0.12 mol) in THF (200 mL) was dropped a solution of DEAD (18.8 mL, 0.12mmol) in dry THF (50 mL) at ice bath. The reaction mixture was allowed to warmto stirred 20^oC for 2 h. The filtrate was evaporated and stirredwith 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 purifiedby column chromatograghy to afford the desired product (27.3 g, 86%). ²⁷

4.4Mitsunobu 法合成丙二烯方法示例

An oven-dried, 500-mL, round-bottomed flaskequipped with a large football-shaped Teflon-coated magnetic stirring bar ischarged with 15.7 g (60.0 mmol) of triphenylphosphine under an argonatmosphere. The flask is sealed with a rubber septum containing a needleadapter to an argon-filled balloon, and 120 mL of THFis added via cannula. Thesolution is cooled in a −15°C bath, and 9.02 mL (57.5mmol) of diethyl azodicarboxylate is addedvia syringe over 2 min, followed immediately by the addition of a solution of 8.52 g (50.0 mmol) of 3-(tert-butyldimethylsilyl)-2-propyn-1-ol in 18 mL of THFvia cannula over 2 min.After an additional 5 min, a solution of 13.0 g (60.0mmol) of o-nitrobenzenesulfonyl hydrazide in65 mL of THF is addedto the reaction mixture over 5 min via cannula. The resulting orange-redsolution is stirred at −15°C for 45 min, after which time the cold mixture isallowed to warm to 23°C and is held at that temperature for 5 hr. During thistime, the evolution of dinitrogen is observed. The reaction mixture is pouredinto a 2-L separatory funnel containing 400 mL of pentane, and the resulting mixture is washed with four500-mL portions of ice-cold water. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated by rotaryevaporation at 0°C. The residue is purified by flash chromatography using ashort column of 230-400 mesh silicagel (60 g, packed dry and eluted with pentane. The fractions containing the product areconcentrated by rotary evaporation at 0°C to afford 5.38-5.39g (70%) of (tert-butyldimethylsilyl)alleneas a colorless liquid.²⁸

5．Mitsunobu硫代反应

活化的硫亲核试剂也能参与Mitsunobu反应，生成手性翻转的硫酯或硫醚。Merck的Volante第一次报导了这种方法²⁹。

芳香类硫醇化合物都有足够的活性参与这种反应。Knutsen等报导了这种类型的应用³⁰。

5.1Mitsunobu 法合成硫醚方法示例

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 asolution of DEAD (14.8 mL, 94.2 mmol) in dry THF (100 mL) was added dropwiseover 0.5 h. The reaction mixture was stirred for 1 h at 20oC and filtered. Thefiltrate was evaporated and stirred with EA (100 mL), and the product wascollected by filtration (20.66 g, 74%). ³⁰

6．Mitsunobu卤代反应

    在Mitsunobu 反应中，用卤原子取代羟基生成卤代物也有报导，但其应用还不多见。Falck 等报导了通过Mitsunobu 过程合成一系列的卤代烃，除了氟代的产率不高以外，氯代，溴代和碘代的产率都不错³¹。

 Joulle 等报导脯胺酸衍生物在经过Mitsunobu 过程后得到手性翻转的碘代产物³²。反应首先是生成一个甲醚中间体，然后在三苯膦的作用下发生碘代，同时手性翻转。

6.1Mitsunobu 法合成卤代物方法示例

To a flame-driedround-bottomed flask eguipped with a magnetic stir bar and an addition funnelunder N₂ was added N-Boc-trans-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 0^oC. Diethyl azodicarboxylate(DEAD, 14.9 mL, 0.094 mol) in anhydrous THF (15 mL) was added dropwise,followed by the addition of methyl iodide (5.88 mL, 0.094 mol). Upon additionof MeI, the solution turned from dark brown to bright yellow. The reactionmixture was allowed to warm to ambient temperature and stirred for 10 h. Thesolvent was removed under reduced pressure and the crude oil was purified bycolumn chromatograghy, eluting with 5% EA/PE to afford the desired product as awhite solid (26.22 g, 93.8%).³²

7. 其他手性翻转试剂

（1）  Vilsmeier 试剂：(cloromethylene)dimethylammonium chloride

    由DMF和草酰氯制，和醇生成亚胺盐后再经过亲核取代得到胺³³。

（2）  DPPA 和DBU

Merck的Thompson 和Grabowski 用DPPA和DBU也实现了手性翻转，

得到叠氮化合物34。

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