L-Glutamic acid, 1,5-bis(phenylmethyl) ester, 4-methylbenzenesulfonate (1:1)

10135] 29.4 g (0.2 mol) L-(+)-glutamic acid, 40 g (0.23 mol) p-toluenesulfonic acid, and 80 mE benzyl alcohol were dissolved in 500 mE methylbenzene. 11 mE water was separated out by backflow under the protection of nitrogen gas. The backflow was continued for 3 h, and 150 mE liquid was evaporated and removed. The solution was cooled down to 50° C., and then the reaction solution was poured into a beaker containing 600 mE petroleum ether for stirring 1 h. The precipitation was collected by filtration. The filter cake was dissolved in 280 mE of 95percent ethanol by heating, then the heating was stopped and the solution was cooled overnight. The precipitation was collected by filtration and dried in vacuum to produce 61 g E-(+)-glutamic acid dibenzyl ester p-toluenesulfonate (compound 1).Triethylamine (0.50 cm3, 3.59 mmol) was added dropwise to a solution of dipeptide 5 (0.36 g, 1.12 mmol) and L-glutamic acid dibenzyl ester /?-toluenesulphonate 6 (0.73 g, 1 .46 mmol) in methylene chloride (60 cm3) under nitrogen at room temperature, and the reaction mixture stirred for 10 min. Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BoPCl, 97%) (0.37 g, 1 .41 mmol) was added and the colourless solution stirred for 17 h. The methylene chloride solution was washed successively with 10% aqueous hydrochloric acid (50 cm3) and saturated aqueous sodium hydrogen carbonate (50 cm3), dried (MgSC^), filtered, and evaporated to dryness in vacuo. Purification of the resultant residue by repeated (2x) flash column chromatography (24 g Si02; 30-70% ethyl acetate - hexane; gradient elution) yielded fully protected tripeptide 1 (0.63 g, 89%) as a colourless oil. Tripeptide 7 was shown to be exclusively the trans-orientated conformer by NMR analysis: Rf 0.55 (EtOAc); [alpha]? -41 .9 (c 0.29 in CH2C12); vmax (film)/cm 3583, 3353 br, 2950, 1734, 1660, 1521 , 1499, 1454, 1429, 1257, 1214, 1 1 88, 1 166, 1051 , 91 1 , 737 and 697; ¾ (400 MHz; CDC13; Me4Si) 1 .64 (3H, s, Proa-CH3), 1 .72 (1 H, dt, J 12.8, 7.6 and 7.6, 1 .92 (2H, 5 lines, J 6.7, Proy-H2), 2.04 ( 1 H, 6 lines, J 7.3 Glup-H^He), 2.1 7-2.27 ( 1 H, m, Glup- HAHfi), 2.35-2.51 (3Eta, m, Pro3-HAHfl and GIuy-H2), 3.37-3.57 (2H, m, Pro5-H2), 3.90 ( 1 H, dd, J 17.0 and 3.6, Glya-H^Hu), 4.00 (1 H, dd, J 17.1 and 5.1 , Gly -HAHfl), 4.56 (1 Eta, td, J 7.7 and 4.9, Glua-H), 5.05-5.20 (6H, m, 3 x OCH2Ph), 5.66-5.72 (1 Eta, br m, Gly-NH), 7.26-7.37 ( 15H, m, 3 x Ph) and 7.44 (1 H, d, J 7.2, Glu-NH); Dibenzyl N~benzyloxycarbonyl-glycyl-L-2-methylprolyl-L-glutamate 7 Triethylamine (0.50 cm3, 3.59 mmoi) was added dropwise to a solution of dipeptide 5 (0.36 g, 1.12 mmoi) and L-glutamic acid dibenzyl ester Moluenesulphonate 6 (0.73 g, 1.46 mmoi) in methylene chloride (60 cm3) under nitrogen at room temperature, and the reaction mixture stirred for 10 min. Bis(2-oxo-3-oxazoIidinyl)phosphinic chloride (BoPCl, 97%) (0.37 g, 1.41 mmoi) was added and the colourless solution stirred for 17 h. The methylene chloride solution was washed successively with 10% aqueous hydrochloric acid (50 cm3) and saturated aqueous sodium hydrogen carbonate (50 cm3), dried (MgS0 ), filtered, and evaporated to dryness in vacuo. Purification of the resultant residue by repeated (2x) flash column chromatography (24 g Si02; 30-70% ethyl acetate - hexane; gradient elution) yielded fully protected tripeptide 7 (0.63 g, 89%) as a colourless oil. Tripeptide 7 was shown to be exclusively the irarar-orientated conformer by NMR analysis: Rf 0.55 (EtOAc); [a]D -41.9 (c 0.29 in CH2C12); vroax (film)/cm 3583, 3353 br, 2950, 1734, 1660, 1521, 1499, 1454, 1429, 1257, 1214, 1188, 1 166, 1051, 91 1 , 737 and 697; < (400 MHz; CDC13; Me4Si) 1.64 (3H, s, Proot-CH3), 1.72 (IH, dt, J 12.8, 7.6 and 7.6, Prop-HB), 1.92 (2H, 5 lines, J 6.7, Proy-H2), 2.04 (IH, 6 lines, J 7.3 Glup-HB), 2.17- 2.27 (IH, m, GluP-HA), 2.35-2.51 (3H, m, Prop-HA and Gluy-H2), 3.37-3.57 (2H, m, Pro5- H2), 3.90 (I H, dd, J 17.0 and 3.6, Glya-i^He), 4.00 (IH, dd, J 17.1 and 5.1, Glya-HA), 4.56 (IH, td, J 7.7 and 4.9, Gluex-H), 5.05-5.20 (6H, m, 3 x OCPh), 5.66-5.72 (IH, br m, Gly-NH), 7.26-7.37 (15H, m, 3 x Ph) and 7.44 (IH, d, J 7.2, Glu-NH); < (100 MHz; CDC13) 21.9 (CH3, Proa-C), 23.4 (CH2, Proy-C), 26.6 (CH2, Glup-C), 30.1 (CH2, Gluy-C), 38.3 (CH2, Prop-C), 43.9 (CH2, Glya-C), 47.6 (CH2, Pro5-C), 52.2 (CH, Glua-C), 66.4 (C, OCH2Ph)5 66.8 (CH2, OCH2Ph), 67.1 (CH2, OCH2Ph), 68.2 (quat, Pro -C), 127.9 (CH, Ph), 128.0 (CH, Ph), 128.1, (CH, Ph), 128.2, (CH, Ph), 128.2, (CH, Ph), 128.3, (CH, Ph), 128.4, (CH, Ph), 128.5, (CH, Ph), 128.5, (CH, Ph), 135.2 (quat., Ph), 135.7 (quat., Ph), 136.4 (quat, Ph), 156.1 (quat, NC02), 167.3 (quat., Gly-CO), 171.4 (quat., CO), 172.9 (quat., CO) and 173.4 (quat., CO); m/z (FAB+) 630.2809 (MH+. requires 630.2815).

Molecular Weight:499.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:11
Exact Mass:499.16647344
Monoisotopic Mass:499.16647344
Topological Polar Surface Area:141
Heavy Atom Count:35
Complexity:593
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes