U.Schollkopf用L-Val和Gly缩合制得环二肽，再与Meerwein盐(Et30+BF4-)作用得甲基醚，经丁基锂脱质子得甘氨酸负离子，然后烷基化，酸水解，得手性α -氨基酸. 此法所得氨基酸的ee值可达95%以上. 制备反应如下图。
U.Schollkopf法反应示例（Tetrahedran Asymmetry, 10 (1999), 4151~4156.）
To a stirredsuspension of D-valine 1 (117.15 g, 1.0 mol) in THF (1200 mL) was added phosgene (148.5 g, 0.5mol), the temperature was maintained at 40 ℃ with a heating mantle. After the solid in solutiondisappeared, the solution which resulted was purged with N2 for 2 h,the solvent was removed in vacuo and the residue was flashed with THF twice,the N-carboxyanhydride which formed was dried in the vacuum to provide a rudeproduct 2 (206.37 g, >100%), due to the unstable nature of this anhydride itwas used immediately in the next step without further purification.
A solution of the N-carboxyanhydride 2 (206.37g, 1.44 mol) in THF (1600 mL) was added dropwise to a vigorously stirredmixture 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 roomtemperature, the reaction solution wasfiltered to remove the triethylamine hydrochloride, the filtrate wasconcentrate in vacuo to give the residue 4. The residue 4 was added toluene, thesuspension which resulted was heated at reflux for 12 h and then cooled to 0 ℃, the bis-lactim whichresulted was recovered by vacuum filtration, washed with ether and dried undervacuum at 100 ℃ to provide the purecompound 5.
To a stirred solution of triethyloxoniumtetrafluoroborate 6 (1063.19 g, 5.60 mol) in CH2Cl2was added the bislactim 5 (291 g, 1.86 mol) in portions, after severalhours the reaction mixture became homogeneous, the reaction was stirred at roomtemperature under N2 for 3 days, after which a solution of NaH2PO4and Na2HPO4 in water was added to the solution withstirring, the organic phase was separated and the aqueous phase wasre-extracted with CH2Cl2 twice. The combined organic layers were dried overMgSO4, evaporated to remove the solvent, the residue was vacuumdistilled to provide the pure bis-ethoxy lactim ether 7.
n-BuLi (1.6 M in hexanes, 9.6 mL,15.4 mmol) was added to a −78°C solution of(R)-2,5-dihydro-3,6-diethoxy-2-isopropylpyrazine 7 (3, 2.5 mL, 14 mmol) and 1,3-dimethyl-2-imidazolidinone (DMEU,3.1mL, 28 mmol) in dry THF (140 mL). After 45 min, a solution of 2-bromoethyltriphenylmethylsulfide 8 (6.32 g,16.5 mmol, 1.2 equiv.) in dry THF (30 mL) was added over 25 min. After 20 h at−78°C, the cherry colored reaction mixture was quenched with 5 mL of 100 mmol,pH 7.2 phosphate buffer and warmed to ambient temperature. The yellow solutionwas concentrated in vacuo and the resulting residue was partitioned betweenethyl acetate (EtOAc, 100 mL) and water (100 mL). The aqueous layer wasseparated and extracted with EtOAc (50 mL). Combined organic extracts weredried over Na2SO4, decanted and concentrated in vacuo to give an oil.Purification by flash chromatography (5% EtOAc/hexanes) gave 1.60 g (47% basedon recovered starting material) of(2R,5S)-2-isopropyl-3,6-diethoxy-5-[2-(tritylsulfanyl)ethyl]-2,5-dihydropyrazine9.
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=6.6Hz, 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. AnalyticalHPLC (2% EtOAc/hexanes): Rt=7.72 min
A 0.50 M aqueous solution ofhydrochloric acid (10.1 mL, 5.06 mmol, 2.1 equiv.) was added to a solution of(2R,5S)-2-isopropyl-3,6-diethoxy-5-[2-(tritylsulfanyl)ethyl]-2,5- dihydropyrazine(1.17 g, 2.41 mmol) in dioxane (10.1 mL) and stirred for 6 h at ambienttemperature. The solution was then adjusted to pH 10 with concentrated ammoniumhydroxide and extracted with CHCl3 (340 mL). Combined organic extracts were dried(Na2SO4), decanted and concentrated in vacuo. The residual oil was purified byflash column chromatography (5% MeOH/CH2Cl2; Rf=0.37) toafford methyl (2S)-2-amino-4- (tritylsulfanyl)butanoate 5 as a thick colorlessoil (840 mg, 89%). 1H NMR(CDCl3) 7.43–7.39 (m, 5H), 7.31–7.18 (m, 10H), 3.64 (s, 3H),3.43–3.38 (m, 1H), 2.30 (t, J=7.8 Hz, 2H), 1.80–1.70 (m, 1H), 1.58–1.46 (m,1H); 13C NMR (CDCl3)175.85, 144.79, 129.59, 127.86, 126.62, 66.77, 53.48, 51.96, 33.95, 28.31
The Mosher amide of 10 was prepared by adding triethylamine(10.2 mL, 0.073 mmol) and (R)-(−)-(-)-methoxy-(trifluoromethyl)phenylaceticacid chloride (13.6 mL, 0.073 mmol) in successionto a solution of methyl(2S)-2-amino-4-(tritylsulfanyl)butanoate (5, 19 mg, 0.05 mmol) inanhydrousdichloromethane (1 mL) and stirred for 3 h at ambient temperature thenquenched by addition of water (100 mL). After 15 min of stirring,dichloromethane (20 mL) was added and washed with water (20 mL).The organiclayer was separated, dried (Na2SO4), decanted and concentrated in vacuo toafford an oilwhich was purified by flash chromatography to afford 22 mg (72%)of the Mosher amide of 10. 1HNMR (CDCl3) 7.51–7.42 (m, 2H) 7.35–7.15 (m, 18H), 6.93 (d, J=8.4Hz, 1H), 4.55–4.48 (m, 1H), 3.66 (s,3H), 3.47 (d, J=1.5 Hz, 3H), 2.25–2.15 (m,1H), 2.09–1.98 (m, 1H), 1.83–1.71 (m, 1H), 1.54–1.38 (m,1H); 19F NMR (CDCl3) : −6.15.
A 0.50 M LiOH solution (9.0 mL,4.5 mmol, 2.02 equiv.) was added dropwise to a solution of ester 10 (772 mg, 1.98 mmol) in dioxane (9.0mL) and stirred at room temperature for 3 h. The reaction mixturewasconcentrated in vacuo and the residual solid was suspended in water (20 mL).Careful adjustmentto pH 8 with 1 M aqueous HCl afforded a precipitate. Thewhite solid thus obtained was filtered anddried under high vacuum at 46°C overP2O5 to give (2S)-2-amino-4-(tritylsulfanyl) butanoic acid 11 (, Striphenylmethyl-L-homocysteine, 687 mg, 92%). 1HNMR (DMSO-d6): 7.48–7.18 (m, 15H), 3.02 (t, J=6.3 Hz, 1H), 2.26 (t, J=5.1Hz, 2H), 1.90–1.73 (m, 1H), 1.69–1.53 (m, 1H); 13C NMR (DMSO-d6): 169.17, 144.51, 129.05, 127.93,126.62, 65.90, 53.43, 30.40, 28.11;
Sodium metal (61 mg, 2.65 mmol) was added to a suspensionof S-triphenylmethyl-L- homocysteine (11, 270 mg, 0.72 mmol) in20 mL of liquid ammonia at −33℃. After 1 h, the reaction mixture was warmedtoambient temperature and concentrated in vacuo. (Caution: the product is extremely airsensitive.Exposure to air should be kept to a minimum.) The resulting solid wassuspended in deaerated water (10 mL) and extracted with deaerated ether (10 mL)to remove triphenylmethane. The aqueouslayer was adjusted to pH 6 by careful addition of deaerated 47% aqueous HI.This solution was concentrated invacuo and any remaining HI was removed byazeotroping with deaerated water (3*10 mL). The residue was stirred in deaerated hotethanol for 15 min, cooled to ambient temperature under nitrogen andfiltered. The filtered solid wasisolated and dried under high vacuum for 15 h at 56℃ to afford 51 mg (52%) of L-homocysteine 14. 1HNMR (D2O): 3.73 (dd, J=7.4, 5.7 Hz, 1H), 2.60–2.42 (m,2H), 2.12–1.88 (m, 2H); 13CNMR (D2O): 174.61, 53.97, 34.98, 20.15;
Sodium metal (141 mg, 6.13 mmol) was added to asuspension of 11 (200 mg, 0.53 mmol) in 40 mL of liquid ammonia at −33°Cand stirred for 3.5 h. Unreacted sodium metal was quenched by the addition of afew crystals of NH4Cl. Ammonia was allowed to evaporate by warming to ambienttemperature and any residual ammonia was removed in vacuo. Deaerated water (50 mL) was poured into theflask and the mixture was extracted with deaerated ether (2* 25 mL). Theaqueous layer was adjusted to pH 7 by the careful addition of deaeratedconcentrated HCl, the mixture treated with decolorizing carbon, filteredthrough Celite® and the filter pad washed with deaerated water (15 mL). Theresulting filtrate was flushed with air for 1 h and left sitting open to airfor 12 h. Filtration removed trace suspended solids and the filtrate wasconcentrated in vacuo. The residualsolid was dissolved in water (3 mL) and filtered. Filtrate pH was adjusted from9.8 to 5.5 by careful addition of concentrated HCl and allowed to stand for 30min. The solid thus obtained was washed with water (3* 2 mL) and driedunder high vacuum over P2O5 at 46℃ togive 28 mg (40%) of L-homocystine 13 as an off-white solid. 1HNMR (D2O/NaOD): 3.15 (dd, J=7.4, 5.8 Hz, 2H), 2.58 (t, J=8.0Hz, 4H), 1.90–1.64 (m, 4H); 13CNMR (D2O/NaOD): 183.13, 55.40, 34.78, 34.73;