其他特定类型的a-氨基酸的合成

2.1. 苯丙氨酸衍生物的合成

2.1.1 Tandem 1,4-加成

2.1.2: Negishi reaction

A three-neck flask was fitted with an addition funnel and charged with Zn turnings (40.0 g, 0.612 mol) and THF (130 mL). Then 1,2-dibromoethane (3.64 mL, 40.0 mmol) was added with stirring. The mixture was refluxed (heat gun) and allowed to cool to room temperature. Then (CH₃)₃SiCl (1.50 mL, 11.6 mmol) was added. After 15 min, a solution of Compound A3 (72.6 g, 0.200 mol) in THF (130 mL) was added drop wise via the addition funnel. The mixture was stirred for 15 min. A separate Schlenk flask was charged with Compound B1 (35 g, 0.175 mol) and 887979-35-9 (1.27 g, 1.8 mmol). The contents of the three-neck flask (estimated as 0.16-0.17 mol of Compound A4) were added by cannula. The orange solution was stirred at 65 ^oC, and after 10 h was cooled to room temperature. The mixture was taken to dryness by rotary evaporation and added to DCM/H2O (1:1, 500 mL). The mixture was filtrated through the Celite, and the cake was washed with DCM, the filtrate was washed with brine (300 mL*2). The organic layer was concentrated and purified by silica-gel column chromatography (PE:EA = 5:1 to 3:1 to 2:1) to give the crude product. The pure product Compound B2 (33 g, 52.9%) was obtained by prep-HPLC further purification.

2.2. 芳甘氨酸类化合物的合成

2.2.1 Petasis Reaction

Petasis反应是构建氨基酸、氨基醇及其相应的衍生物等结构片段的有效方法之一。该反应为多组分反应，以其条件温和、操作简单和官能团兼容性好等优点成为有机合成化学中的重要反应，有时也被称为有机硼酸的Mannich。

反应通式如下：

反应示例：

Tetrahedron 1997 16463-16470

To a stirred solution of glyoxylic acid monohydrate (1.92 g, 20.83 mmol) in DCM (100 mL) was added amine 3 (5.06 g, 20.8 mmol) and cpd 1 (5.0 g, 20.8 mmol). The reaction mixture was stirred at r.t. for 2 mins to form clear solution. The solution was purged with N2 (2 mins) and sealed, the reaction mixture was stirred at r.t. for overnight. The amine and boronic acids consumed >90 % in 4 hrs (TLC / LCMS). The crude mixture was filtered and the solid impurity was washed with DCM (2 * 40 mL). The combined mixture was concentrated to dryness to get the crude product, which was purified by column to afford acid 4 (7.0 g, 84 %).

A mixture of acid 4 (4.5 g, 8.56 mmol) in 70 % aqueous AcOH (20 mL) was heated to reflux (80 ^oC) for 3 hrs. After the reaction was completed, the mixture was evaporated under reduced pressure to give the crude product, which was purified by column chromatography to afford 2-amino-2-(3-methoxythiophen-2-yl)acetic acid

通过手性催化剂或者手性片断的诱导作用，该方法可以选择性的生成相应的手性氨基酸，如下面几个例子所示：

A protocol for Pd(II)-catalyzed asymmetric arylation of N-aryl imino esters affords a practical and direct access to chiral arylglycine derivatives in good yields and with high enantioselectivities.

J. Org. Chem., 2012, 77, 8541-8548.

A new method for the Rh(I)-catalyzed addition of arylboronic acids to chiral N-tert-butanesulfinyl imino esters allows the asymmetric synthesis of arylglycine derivatives in high yields and diastereoselectivities for various functionalized arylboronic acids.
J. Am. Chem. Soc., 2006, 128, 6304-6305.

A cationic palladium-complex catalyzes the addition of arylboronic acids to N-tert-butanesulfinyl iminoacetates to yield optically active arylglycine derivatives with good yield and high diastereoselectivity. This reaction provides a convenient and efficient method for the synthesis of arylglycine derivatives.

2.2.2 双Boc苄胺的α-位插羰反应

2.2.3 甘氨酸席夫碱的Buchwald Reaction

2.3. 脯氨酸类的合成

2.3.1

SYNLETT, 2003,(15),2354-2358

To a solution of 18 (396 mg, 1.11 mmol) in MeCN (12 mL), PdCl₂(MeCN)₂ (29 mg, 0.11 mmol) was added and the reaction mixture was refluxed. Upon completion (TLC), the reaction mixture was concentrated in vacuum and the crude product was purified by chromatography (EtOAc/heptane = 1:3) to afford 24 (192 mg, 0.54 mmol, 48%) as a white solid.

To a solution of 24 (120 mg, 0.34 mmol) in CH₂Cl₂ (6 mL), Et3SiH (0.27 mL, 1.70 mmol), TFAA (0.24 mL, 1.70 mmol) and TFA (0.13 mL, 1.70 mmol) were added at 0 ^oC. The reaction mixture was allowed to reach r.t. and stirred until the reaction had reached completion (TLC). The reaction mixture was concentrated in vacuum and purified by chromatography (EtOAc/heptane = 1:4) to afford a diastereomeric mixture of 26 and the trans-isomer 27 (26/27 = 9:1, 90 mg, 0.25 mmol, 4%). Purification of this mixture by chromatography (EtOAc/heptane = 1:5) followed by crystallisation from Et₂O gave diastereomerically pure 26 as a white solid. Rf = 0.60 (EtOAc/heptane = 1:1).

2.3.2

Small strips of lithium foil (28 mg, 4.0 mmol) were placed in a Schlenk tube containing 4,4_-di-tert-butylbiphenyl (DBB) (1.1 g, 4.0 mmol) and some glass 'anti-bumping' granules. The tube was evacuated and purged with argon several times. The contents were stirred until the lithium foil was completely reduced to powder. Freshly distilled tetrahydrofuran (25 ml) was added (giving a turquoise solution) and the tube was cooled to _78 _C under a positive pressure of argon. The substrate (1.0 mmol) and bis(methoxyethyl)amine (BMEA) (180 μl, 1.2 mmol) in freshly distilled THF (10 ml) were added dropwise over 5 minutes. (The turquoise colour persisted throughout the course of the substrate addition). The reaction mixture was stirred at _78 _C for a further 10 minutes and 1,2-dibromoethane (300 μl, 3.5 mmol) was added. After stirring for 15 minutes, magnesium bromide diethyl etherate (280 mg, 1.1 mmol) was added in one portion and the solution was stirred rapidly for 30 minutes. The aldehyde (2.2 mmol) was then added dropwise and after a further 10 minutes the reaction was quenched with saturated ammonium chloride solution (5 ml). The reaction mixture was warmed to room temperature and poured into dilute hydrochloric acid (1 M, 50 ml) and diethyl ether (50 ml). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 50 ml). The combined organic extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to give a crude product. Purification by chromatography on silica gel, eluting with petrol (to recover DBB) followed by petrol–acetone (4%), gave the aldol products.

2.3.3

2.3.4 Seebach's Self-Reproduction of Chirality

A very interesting example of amino acid synthesis comes from the laboratory of Seebach, in which a chiral amino acid starting material such as L-proline is used. Although the chirality of the original stereogenic center of the amino acid is lost in enolate formation, that stereocenter is directed back to its original conformation.27 In an example of this methodology, Lproline is condensed with pivalaldehyde to yield a single diastereomer of the bicyclic aminal. The stereogenic α-carbon of proline directs the formation of the (S) conformation at the newly formed stereogenic center. The aminal is then deprotonated to form the enolate, thereby rasing the stereochemistry at proline's α-carbon. However, upon nucleophilic attack by the enolate to an electrophlie (such as an alkyl halide or aldehyde), the (S) stereocenter directs the reproduction of the original (S) conformation at the proline's α-carbon. This methodology can be used to synthesize other, non-cyclic amino acid derivatives besides proline.

Angew. Chem. Int. Ed. 2010, 2182-2184

Cis-8-azabicyclo[4.3.0]non-3-ene (1.01 mmol) and TMSCN (2.00 mmol) were dissolved in KPO₄ buffer (5.0 mL, pH 8.0) and demineralized water, and the pH value of the resulting solution was adjusted to pH 8.0 by addition of aqueous HCl. This solution was combined with the cell pellet from E. coli cultures (5.0 g) expressing MAO-N D5. The mixture was homogenized by shaking, transferred to a 500 mL screw cap bottle and the total volume adjusted to 50 mL by addition of demineralized water. The mixture was agitated in a shaking incubator at 378 ^oC/ 250 rpm. Workup was performed after 2 h: the mixture was centrifuged at 48 ^oC for 60 min, and the supernatant was subsequently separated and extracted with tert-butyl methyl ether (3X50 mL). The combined organic extracts were dried with Na₂SO₄ and concentrated by means of a rotary evaporator. The crude a-amino nitrile was treated with HCl aq. solution (6N, 50 mL) to get the desired amino acid, which was purified on on a Dowex 50X8-100 ion exchanged resin (eluted with 1.5 N NH4OH) to afford the desired amino acid.

2.4. 色氨酸类衍生物的合成

2.4.1 焦谷氨酸关环衍生化法

A solution of A1 (100 g, 0.39 mol) in anhydrous THF (1 L) was degassed with N2 for three times, then DIBAL-H (0.86 mol, 1 M/THF) was added drop wise at -78 ^oC. After TLC showed the reaction was complete, 300 mL of Isopropanol was added slowly at -78 ^oC. Then, the mixture was warmed to 0 ^oC and 500 mL of water was added slowly. The mixture was extracted with EtOAc (500 mL*3), and the combined layers was dried over Na₂SO₄ and concentrated to give a residue, which was purified by silica gel column chromatography to give A2 (50 g, yield: 50%), as an oil.

To a solution of A2 (50 g, 0.193 mol) in DMF (500 mL) was added B (45.8 g, 0.193 mol), DABCO (64.8 g, 0.579 mmol) and Pd(OAc)2 (1 g, 4.44 mmol) under N2. The reaction mixture was heated to 85 ^oC overnight. Then, the mixture was diluted with water. The mixture was extracted with EtOAc (500 mL*3), and the combined layers was dried over Na2SO4 and concentrated to give a crude product, which was purified by silica gel column chromatography to give A3 (23 g, yield: 34%), as a white solid.

这一方法同样可以用于高色氨酸的合成，如下图所示：

2.4.3 Larock吲哚合成结合Schollkopf 手性辅基法

Larock吲哚合成是从邻碘苯胺类与二取代炔烃构建吲哚环系。反应一般使用过量的炔烃，在碳酸钯或乙酸钯以及碱存在下进行，并加入计量的氯化锂以提高产率。此反应对苯胺和炔烃上的很多官能团都有耐受性。反应有区域选择性，一般炔烃空间位阻较大的 R 基在反应后成为吲哚的2-位取代基。再用此法合成色氨酸类衍生物一般要用到TES取代的Schollkopf 手性辅基 258，以增加其端位的位阻。如下例所示：

当邻碘苯胺类与端基无取代的Schollkopf 手性辅基反应时，反应将生成异色氨酸类衍生物，该反应被称为Castro 吲哚合成。如下图所示

2.5. 烷基/烯基长链氨基酸的合成

2.5.1 焦谷氨酸衍生化法

该方法中的手性焦谷氨酸原料是由自然界中最便宜的手性氨基酸L-或D-谷氨酸经过简单转化而来。该合成路线简洁，成本低，收率高，可实现放大生产。

该法适合制备六个碳以上手性长链氨基酸，尤其在制备末端烯键长链手性α-氨基酸衍生物时，该法应用广泛常。末端烯键长链手性α-氨基酸衍生物被用来作为药物分子设计的活性片段或药物合成中的重要中间体，如抗HCV新药BILN2061的一关键片段即为总碳数为9的末端烯键长链α-氨基酸。这种方法以手性焦谷氨酸为原料，用末端烯键的长链溴代物的格氏试剂打开焦谷氨酸的环，得到5位含羰基的末端烯键长链手性α-氨基酸，然后试用各种还原剂将羰基脱去，最后证明由TsNHNH_2和NaBH(Ac)3一锅法脱羰基效果最好。

1mol/L 3-Butenylmagnesium bromide in THF (240 mL, 0.24 mol) was added to CUS1 (51.4 g, 0.2 mol) in dry THF (400 mL) at -40℃ under N2 atmosphere by dropwise. After 5 h of stirring, the reaction mixture was quenched with HOAc-MeOH (1:1，100 mL) and diluted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated.silica gel chromatography (PE:EtOAc=100:1 as elution) gave the product CUS2(48.5 g, 77.5 % yield) as an oil.

To a solution of CUS₂ (48 g, 0.15 mol) in acetic acid (450 mL) was added p-toluenesulfonyl hydrazide (33.9 g, 0.18 mol). The mixture was stirred at room temperature for 1 h, then NaBH(OAc)₃ (134.9 g, 0.64 mol).was added and stirred for 20 hours (monitored by TLC). Upon disappearance of the intermediate, the reaction mixture was poured into cold water (2L) and extracted petroleum ether (4×300 mL). The combined organic layers were washed with saturated aqueous Na₂CO₃, brine, dried over Na₂SO₄, filtered, and evaporated under vacuum to afford the crude product, which was chromatographied on silica gel (petroleum ether / ethyl acetate 10:1 to afford CUS3 (30.2 g, yield 65.8%).

2.5.2 丝氨酸衍生化法

英国剑桥大学的Richard F. W. Jackson等人发现丝氨酸锌试剂衍生物4可以与各种亲电试剂反应生产碳链延长的氨基酸。