氨基酸的合成

ambient temperature. The yellow solution was concentrated in vacuo and the resulting residue
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was partitioned between ethyl acetate (EtOAc, 100 mL) and water (100 mL). The aqueous layer was separated and extracted with EtOAc (50 mL). Combined organic extracts were dried over Na2SO4, decanted and concentrated in vacuo to give an oil. Purification by flash chromatography (5% EtOAc/hexanes) gave 1.60 g (47% based on recovered starting material) of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-[2-(tritylsulfanyl)ethyl]-2,5-dihydropyrazine 9. Compound 9: 1H NMR (CDCl3) _ 7.42–7.38 (m, 5H), 7.29–7.12 (m, 10H), 3.96 (ddd, J=7.2, 3.6, 3.6Hz, 1H), 3.81 (dd, J=3.6, 3.6 Hz, 1H), 3.61 (s, 3H), 3.55 (s, 3H), 2.27–2.07 (m, 2H), 1.99–1.88 (m, 1H), 1.78–1.66 (m, 1H), 1.00 (d, J=6.6 Hz, 3H), 0.65 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3) _ 163.67, 163.22, 144.98, 129.60, 127.75, 126.47, 66.51, 60.73, 54.52, 52.36, 33.19, 31.78, 27.75, 18.99, 16.64; ESMS (M+2H)2+ 243.2. Analytical HPLC (2% EtOAc/hexanes): Rt=7.72 min
Synthesis of α-amino acid and its derivant from aziridine 3 ． synthesis of the amino acids from 2-isopropyl-3,6-dimethoxy (or:
diethoxy)-2,5-dihydro-pyrazine4． 4. Synthesis of α-amino acid from Evans Reagent
经典化学合成反应标准操作
Stereoselective Synthesis of Amino acid and its derivant
编者：张治柳
药明康德新药开发有限公司化学合成部
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经典合成反应标准操作— Mitsunobu 反应
目
录
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1. 前言…………………………………………………………………2 2． U.Schollkopf 法---从氨基酸模块开始的合成
Scheme1
O OH
NH2
triphosgene THF, 40℃
H N
O
O
O
EtOOC NH2 .HCl CHCl3,THF, Et3N,-70℃
O N H
NH2
COOEt
toluene reflux
H NO
3Et3O+BF4-
ON H
CH2Cl2, 72h
N OEt EtO N
BuLi RCH2X
triphosgene THF, 40℃
H N
O
O
O
2
EtOOC
3 NH2 .HCl
CHCl3,THF, Et3N,-70℃
O N H
NH2 4
COOEt
toluene reflux
H NO
6 3Et3O+BF4-
ON H
CH2Cl2, 72h
5
N OEt EtO N
7
Ph
Br
Ph 8 S Ph
n-BuLi
2.制备手性氨基酸的常用方法
2．1 U.Schollkopf法---从氨基酸模块开始的合成
U.Schollkopf用L-Val和Gly缩合制得环二肽7,7与Meerwein盐(Me30+BF4-)作用得甲
基醚1，经丁基锂脱质子得甘氨酸负离子8，烷基化生成9，酸水解，得手性a-氨基酸10.
此法所得氨基酸的ee值可达95%以上. 制备反应如Scheme 1所示。
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1．前言
不对称合成 a-氨基酸的工作自 1970 年代后期系统地开展起来，在其后的十余年中， 发现了几十种不对称合成方法。已经报道的 a-氨基酸不对称合成方法可以分为五类，即 酶合成法、αβ-脱氢氨基酸氢化或环加成法、Strecker 型反应、亲电或亲核氨基化法 以及亲电或亲核烷基化法，上述反应都涉及 α-碳的手性控制.就立体选择性的控制方法 而言，手性辅基(chiral auxiliary)方法仍占多数。
mixture became homogeneous, the reaction was stirred at room temperature under N2 for 3
days, after which a solution of NaH2PO4 and Na2HPO4 in water was added to the solution
H N
O
O
O
2
EtOOC
3 NH2 .HCl
CHCl3,THF, Et3N,-70℃
O N H
NH2 4
COOEt
toluene reflux
H NO ON H 5
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A solution of the N-carboxyanhydride 2 (206.37 g, 1.44 mol) in THF (1600 mL) was added dropwise to a vigorously stirred mixture of glycine ethyl ester hydrochloride 3 (201.32 g, 1.44 mol), triethylamine (461 mL, 3.31 mol), and chloroform (2000 mL ) at –70 ℃. After 3 h of stirring at –70 ℃ and 2 h at room temperature, the reaction solution was filtered to remove the triethylamine hydrochloride, the filtrate was concentrate in vacuo to give the residue 4. The residue 4 was added toluene, the suspension which resulted was heated at reflux for 12 h and then cooled to 0 ℃, the bis-lactim which resulted was recovered by vacuum filtration, washed with ether and dried under vacuum at 100 ℃ to provide the pure compound 5.
2.1 U.Schollkopf 法---从氨基酸模块开始的合成示例
2.2 Synthesis of the key intermediate of the novel rennin inhibitor Aliskiren 2.3 Efficient syntheses of biologically important amino acid
用于 不 对 称合成a-氨基酸的手性辅基种类较多，常见的环系模板(cyclic templates)(也叫环系手性辅基)和非环系模板(acyclic templates)（也叫非环系手性 辅基）应用 手 性 辅基的a-氨基酸不对称合成方法
甘氨酸或丙氨酸衍生烯醇盐(enolates)的亲电烷基化是最早发展的a-氨基酸合成 方法，该法变化形式丰富，研究和应用广泛，其中有几种已成为当前制备手性氨基酸的 常规方法. U.Schollkopf法—从氨基酸模块开始的合成, D.Seebach法---手性中心自我 再生”原理的成功应用, Y. N. Belokon法—含甘氨酸席夫碱的金属配位化合物, W.Oppolzer法---方便回收的天然手性源辅基, D.A .E vans法---一种广泛应用的手性 辅基, M.J .O 'Donnell法---基于金鸡纳碱的手性相转移催化。
MeO N
N
OMe S Ph
Ph Ph 9
1. 0.25N HCl (89%) 2. 0.25N LiOH
H2N
S Ph Ph
COOMe Ph
LiOH
10
H2N
S Ph Ph
COOH
Ph
11
Na/NH3