α-胺基酸的合成
1.3. 羰基α-位氮源引入法
1.3.1 α-溴代酯氨化法
對於非商業化的α-溴代物，一般首先採用Hell-Vollhard-Zelinsky 反應， 在三溴化磷催化，羧酸與溴反應，α-氫被溴取代生成α-溴代物化，然後與氨源反應生成相應的α-胺基酸；或與疊氮化鈉反應生成疊氮化合物，然後還原得到相應的α-胺基酸。如果用手性醇與酸先酯化，然後再氨解，則可以得到手性α-胺基酸。
反應示例：
J. Med. Chem. 2000, 4063-4070
To 3-bromophenylacetic acid (10 g, 47 mmol) under argon was added PBr3 (11.2 mL, 118 mmol) and the suspension stirred at room temperature for 45 min. Bromine (11.1 mL, 216 mmol) was added dropwise over 5 min. The mixture was stirred at 100 oC for 3 h and then cooled. Anhydrous MeOH (35 mL) was added dropwise over 30 min and then the reaction mixture was diluted with Et2O (400 mL), washed with 5% NaHCO3 (800 mL), brine (200 mL), and then dried over MgSO4. The mixture was filtered and concentrated in vacuum to afford 13.9 g of methyl 2-bromo-2-(3-bromophenyl)acetate, which was treated with aqueous ammonia to get 10.2 g (89%) of the desired product methyl 2-amino-2-(3-bromophenyl) acetate.
目前也有人使用NBS在BPO或者AIBN的存在下，在苯乙酸酯類化合物的α位進行溴代，反應示例：
Tetrahedron, 64(22), 5072-5078; 2008
A mixture of ethyl (4-methoxyphenyl) acetate (5g, 0.025 mmol), N-bromosuccinide (4.894g, 0.0275 mmol) and benzoyl peroxide (25 mg) in CCl4 was refluxed for 3h and then allowed to stand overnight to precipitate any dissolved succinimide. The mixture was then filtered and concentrated to give dark yellow oil in quantitative yield. A solution of 15-crown-5 (150 μL, 0.7 mmol) in 60 ml benzene was refluxed for 2h with azeotropic removal of water. On cooling, 3g (10 mmol) of the bromo ethyl ester and 0.71 g (10 mmol) of sodium azide were added. The mixture was stirred at room temperature for 8h and then passed through a silica column eluting with benzene. The filtrate was concentrated and dried to give 82% (2.63 g) of light oil. A mixture of 1.9 g (8.08 mmol) of azide ester, 1.89 g p-toluenesulphonic acid monohydrate (9.94 mmol) and 0.3 g of 10% Pd/C in 100 ml 95% ethanol was hydrogenated at room temperature at 100 psi for 24h. The mixture was filtered through a pad of celite and concentrated to give yellow crystals. These were then washed with saturated NaHCO3 and extracted twice in ether to give the aminoacid ester in 71% yield (1.2 g).
Evans等通過手性亞胺烯醇2的親電疊氮化反應生成了а-疊氮化合物3，再進行還原，生成а-胺基酸，具有較高的立體選擇性，R為CMe3時，e.e.%值達97%.
還有文獻報導，α-溴代醯氯通過與手性醇反應因與一個手性片斷，然後通過分子內手性片斷的自催化作用製備不對稱胺基酸。
反應示例：
Tetrahedron: Asymmetry, 1999, 493-509
A mixture of (R)-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl-2-bromo-2- phenylacetate (401 mg, 1.0 mmol), dibenzylamine (3.0 mmol) and sodium iodide (20 mmol) in anhydrous acetonitrile (60 ml) was heated to reflux in an argon atmosphere for 48 h. The mixture was concentrated in vacuum to the crude product, which was treated with CH2Cl2 (100 ml). The mixture was washed with 5% aqueous citric acid solution (3X30 ml) and saturated aqueous NaHCO3 solution (3X30 ml). The organic layer was dried with anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography [alumina, CH2Cl2] to 450 mg of (R)-(R)-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 2-(dibenzylamino) -2-phenylacetate.
Solid LiOH_H2O (1.5 mmol) was added to a solution of (R)-(R)-4,4-dimethyl -2-oxo-1-phenylpyrrolidin-3-yl 2-(dibenzylamino) -2-phenylacetate (1.0 mmol)in a mixture of THF (20 ml) and water (5 ml). The mixture magnetically stirred at room temperature until completion of the hydrolysis (3 days), following the reaction by thin layer chromatography (TLC). The mixture was concentrated in vacuum, 0.5 N NaOH (30 ml) was added to the residue and then the mixture was extracted with CH2Cl2 (2X10 ml). The combined organic layers were dried with anhydrous Na2SO4 and concentrated in vacuum to give a mixture of (R)-2-(dibenzylamino)-2-phenylacetic acid, which was purified by column chromatography [alumina (7 g)] on elution with a mixture of CH2Cl2/methanol in the ratio of 99.5:0.5 to give 310 mg of the pure desired product.
A mixture of (R)-2-(dibenzylamino)-2-phenylacetic acid (140 mg, 0.42 mmol), conc. HCl (0.2 ml), 10% Pd-C (0.5 g) in a mixture of ethanol/water in the ratio of 1:1 (20 ml) was hydrogenated at 1 atm for 1 h. The mixture was filtered and the filtrate was concentrated in vacuum to give 57 mg of (R)-2-amino-2-phenylacetic acid (89% yield).
1.3.2 KnooD—Oesterlin法（α-位成肟/亞硝化還原法）
KnooD—Oesterlin法一般採用羰基羧酸直接與氨或羥胺反應，生成一個不穩定的亞胺基羧酸離子，以鉑、鈀或Rancy。鎳為催化劑催化還原亞胺基羧酸離子，可得到相應的胺基酸。
反應示例：
Journal of Organic Chemistry 2009 3406-3413
To a 250 mL round bottom flask was added 2-methylallyl 2-oxo-2-(1-tosyl-1H-indol-3-yl) acetate (2.3 g, 6.01 mmol) and dioxane (100 mL). Then hydroxylamine hydrochloride (1.24 g, 18.02 mmol) and pyridine (1.55 mL, 19.23 mmol) were added and the mixture refluxed under nitrogen overnight (enough water to dissolve the hydroxylamine salt was added). The solvent was taken off and the residue was put into solution with EtOAc (100 mL). The organics were washed with 1% HCl (1 x 30 mL) and brine (1 x 30 mL), then dried using anhydrous sodium sulfate and concentrated. The crude residue was purified by column chromatography (silica gel, 30% EtOAc; 70% Hexanes) to afford (E)-2-methylallyl 2-(hydroxyimino)-2-(1-tosyl-1H-indol-3-yl) acetate.
To a 250 mL round bottom flask was added water (55 mL) and AcOH (55 mL). Then (E)-2-methylallyl 2-(hydroxyimino)-2-(1-tosyl-1H-indol-3-yl) acetate (2.12 g, 5.33 mmol) was dissolved in THF (25 mL) and was added to the aqueous acid. The mixture was brought down to 0oC and zinc (3.46 g, 53.3 mmol) was then slowly added in small portions over 20 min. The suspension stirred at 0oC for 2 h. The solid was filtered off and the filtrate was reduced and then brought to a pH of 8 using concentrated ammonium hydroxide. The amine was extracted into ethyl acetate (4 x 50 ml), dried using anhydrous sodium sulfate and concentrated. The crude residue was then put into solution with DCM (5 mL) and TFA (3 mL) was added. The mixture stirred for 10 min and then the solvent and excess TFA was removed. CHCl3 (3 x 15 mL) was added and subsequently taken off to remove any residual TFA. The product was precipitated out of the crude residue using ether/petroleum ether to afford 2-methylallyl 2-amino-2-(1-tosyl-1H-indol-3-yl) acetate as a white solid. Yield (2.25 g, 85%).
早在1909年，德國的科學家就發現芳基乙酸酯類化合物可以在亞硝酸酯的作用下生成苯基α-肟酯，後來在1985年，禮來的科學家使用青黴素催化下，用甲酸/鋅粉的還原得到相應的手性胺基酸衍生物。對於非手性芳甘氨酸的合成，甲酸/鋅粉還原的方法被廣泛應用，反應示例：
Berichte der Deutschen Chemischen Gesellschaft, 42, 1930-40; 1909
J. Med. Chem. 2001, 44, 1158-1176
To a solution phenyl-acetic acid methyl ester (187 g, 1.25 mol) in diethyl ether (2500 mL) were added a solution of isoamyl nitrite (323.5 g, 2.76 mol) in diethyl ether (1400 mL) and then sodium methoxide (108.3 g, 2.0 mol) in methanol (1600 mL). The mixture was stirred at room temperature for 12 h. The solid was filtered, and the filtrate was evaporated to 3000 mL and acidified to pH= 2. The solid was dissolved in water and acidified with HCl to pH= 2. The precipitations of both treatments were combined and re-crystallized from methanol to give 175.9 g (62.5%) of (E)-methyl 2-(hydroxyimino)-2-phenylacetate.
A solution of (E)-methyl 2-(hydroxyimino)-2-phenylacetate (30 g, 133.8 mmol) in methanol (1000 mL) and DMF (250 mL) was hydrogenated over Pd/C (2 g, 10%). The pH value was adjusted between 3 and 4 by addition of HCl in methanol (3.3 mol/L). After 8 h the catalyst was filtered, the filtrate evaporated, and after addition of ethyl acetate the product was precipitated. Re-crystallization from 2-propanol/ethyl acetate gave 24.5 g (84.5%) of methyl 2-amino-2-phenylacetate.
1.3.3 磺醯疊氮作用下羰基α-位疊氮化
磺醯疊氮與羰基α-位的疊氮化反應最初被Dimrothl和Curtius提出。1953年，Doefing和DePuy發展了該反應，從而成為羰基化合物a疊氮化的非常有效的方法。反應過程一般是羰基α-位在鹼的作用下先生成碳負離子，進而碳負離子進攻磺醯疊氮生成三氮烯中間體。
疊氮化反應與重氮轉移反應是一對競爭的反應，用於疊氮化的磺醯疊氮也能用於重氮化反應。疊氮化物在酸性條件下緩慢加熱分解得到了相應的重氮化產物。產物的比例不僅同底物的結構有關，加入的鹼的強弱有關，而且與不同類型的磺醯疊氮關係密切。常用的疊氮化試劑通常有對甲苯磺醯疊氮(TsN3)34a、三氟甲烷磺醯疊氮34b、對硝基苯磺醯疊氮(PNBSA)34c和2,4,6-三異丙基苯磺醯基疊氮(TrisN3)34d。
後來，人們研究了含手性基團的碳基化合物的不對稱疊氮化反應，並分析了各種因素對該反應的影響。他們發現在羰基化合物的一疊氮化反應中，疊氮化產物38的增長是以重氮產物39為代價的。通過研究發現疊氮化產物產率的提高與下列幾個因素有關：
(1)使用強鹼參與反應(Li<na<k)，有利於疊氮化發生。
(2)親電性越弱的磺醯疊氮越有利於疊氮化產物生成(34c<34a<34d)，反之則有利於重氮轉移產物的生成。
(3)用冰醋酸代替活潑的三氟乙酸，TMSCI和1MsOT解滅反應，有利於疊氮化產物生成。
（參考並引用韓耀的博士論文---磺醯疊氮在有機反應中的研究應用/蘭州大學）
反應示例：
Tetrahedron 1996 6409-6420;
To a solution of compound 3 (33 g, 111 mmol) in THF (300 mL) was added KHMDS (222 mL, 222 mmol, 1.0 M sol. in toluene) dropwise at -78 0C under nitrogen. After stirring at -78 0C for 1 hour, the solution of trisyl azide (68.6 g, 222 mmol) in THF (100 mL) cooled to -78 0C was added dropwise. The reaction mixture was stirred at -78 oC for 30 min and then quenched with AcOH (27 mL, 444 mmol), then warmed to room temperature and stirred for 16 hours more, evaporated the solvent, treated with 10 % Na2CO3 (300 mL), extracted with EtOAc (300 mL x 3), washed with brine (300 mL), dried (Na2SO4), concentrated in vacuum. The crude product was purified by silica gel flash column (PE/EA: 20/1 to 5/1) to give the oily product 4 (21.6 g, 58.6 %).
Hruby小組在手性惡唑烷酮衍生物的а-氨基化反應製備胺基酸方面做了大量工作，合成了多種結構的β,γ-內旋轉受阻的а-胺基酸，其合成方法見如下案例， 其目的是研究肽的構象。手性惡唑烷酮衍生物80經由羰基а位疊氮化和催化氫化，終得β取代的а-胺基酸。
1.3.4 羰基化合物和二氮烯（偶氮化合物）反應合成胺基酸
Jorgensen及其合作者對這種方法進行了不少研究，而Duthaler則對該方法進行了總結。Jorgensen小組和List小組先後報導了醛的а-氨基化，後來擴展到酮的а-氨基化及а-酮酯的β-氨基化和β-酮酯的а-氨基化。在手性催化劑或手性片斷的作用下，可選擇性的生成光學純度的胺基酸。
如下例，在L- 脯氨酸的催化下，醛酮的а-位被DIAD氨基化，生成手性化合物72，最後經氧化醛基及氫化還原後，最終得到а-胺基酸(74),
β-酮酯(75)在手性催化劑77的作用下的а-氨基化後，進一步還原最終得β羥基а-胺基酸(79)。 相應的，由а-酮酯的β-氨基化後得到а-羥基β-胺基酸。
反應實例：
Journal of Organic Chemistry, 2012 3191-3196
A mixture of (S)-4-isopropyloxazolidin-2-one (5.00 g, 28.2 mmol) and THF (100 mL) was cooled to −78 oC, and n-butyllithium in hexanes (2.5 M, 11.0 mL, 27.5 mmol) was added. The mixture was stirred at −78 oC for 10 min, and acid chloride 7 (2.50 g, 23.5 mmol) was added. After being stirred at −78 oC for 30 min, the cooling bath was removed, and the reaction was allowed to warm to room temperature. Then saturated aqueous ammonium chloride (100 mL) was added, and the resulting mixture was extracted with ethyl acetate (2 × 200 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by chromatography on silica gel (0−50% ethyl acetate/hexanes) to give cpd 2.
To a solution of cpd 2 (54 mg, 0.164 mmol) in THF (3.0 mL) was added LDA (1 M solution in toluene, 0.307 mmol) at -78 oC under argon. After being stirred at this temperature for 30 min, the mixture was added a pre-cooled (-78 oC) solution of di-tert-butyl azodicarboxylate (40 mg, 0.175 mmol) in CH2Cl2 (1.0 mL). After 3 min, the mixture was quenched with AcOH (100 μL), and a phosphate buffer (pH=7) was added to this mixture and then the mixture was warmed to rt. The whole mixture was extracted with EtOAc (x 2), and the extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, and then concentrated in vacuum. The residue was purified by silica gel column chromatography to give 20 mg of cpd 3.
To a mixture of cpd 3 (890 mg, 2.29 mmol) and LiOH (0.20 g, 4.75 mmol) in THF/H2O (48ml, 3 : 1) was stirred at 0 oC for 1 h. sat. aq. NaHCO3 soln. (10 ml) was added, and the THF was evaporated. Extraction of the aq. residue with CH2Cl2 to remove the auxiliary, acidification with aq. HCl soln. (1_) to pH=2, extraction with AcOEt, and filtration through a plug of SiO2 afforded cpd 4.