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With dicyclohexyl-carbodiimide In acetonitrile at 0 - 20℃; |
2.a
2 a) Preparation of compound 82,2-Dimethyl-4-aminobutanoic acid (see Chem. Eur. J. 2002, 8, 573-584 for this procedure applied to a similar compound) : 3, 3- Dimethylpyrrolidin-2-one 7 (300 mg, 2.7 mmol) was dissolved in 6 N HCI (20 ml.) and refluxed for 12 hours. After evaporation of the volatile components, the remaining residue was co-evaporated with acetone. The crude hydrochloride of 2, 2-dimethyl-4-aminobutanoic acid (400 mg) was obtained as a slightly yellow solid and introduced directly into the next step. For the following protocol applied to a different compound see J. Am.Chem. Soc. 2004, 126, 16368-16378 :Cbz-Z.-leucine (530 mg, 2 mmol) and N-hydroxysuccinimide (230 mg, 2 mmol) were dissolved in dry acetonitrile (20 mL) and stirred for 15 min at 0 0C. The solution was treated with dicyclohexylcarbodiimide (454 mg, 2.2 mmol) and stirred at room temperature for one night. The urea precipitate was filtered off and the filtrate was concentrated to dryness. The resulting NHS ester of Cbz-Z-leucine (Cbz-/.-Leucine-NHS) was collected and used in the following step without further purification.To a stirred solution of the crude hydrochloride of 2,2-dimethyl-4- aminobutanoic acid (400 mg, excess) in dry CH2CI2ZMeOH 1:1 (20 mL) and at 00C was added a solution of Cbz-Meucine-NHS (2 mmol) in dry CH2CI2 (5 mL). After 10 min, dry triethylamine (200 μL) was added, and stirring was continued overnight at room temperature. The phases were separated, the aqueous phase extracted with CH2CI2 (3 χ30 mL), the combined organic phases dried over anhydrous Na2SO4, before the solvent was removed under reduced pressure. Purification by silicagel column chromatography (CH2CI2/Me0H, 10:1, v/v) gave 8 as a colorless oil (430 mg, 57%). TLC : Rf = 0.46 (CH2CI2/Me0H, 10:1, v/v). 1H NMR (200 MHz, CDCI3) δ 0.90 (d, J = 3.9 Hz, 6H), 1.21 (s, 6H), 1.41-1.78 (m, 5H), 3.25-3.36 (m, 2H), 4.11-4.22 (m, IH), 5.13 (s, IH), 5.47 (br, IH), 6.50 (br s, IH), 7.33 (s, 5H); 13C NMR (50 MHz, CDCI3) δ 21.91, 22.94, 24.74, 36.21, 40.73, 41.33, 53.74, 67.38, 128.10, 128.57, 136.00, 156.92, 172.39, 181.64; MS (ESI, positive mode): m/z 379.2 [M+H]+, 410.2 [M+MeOH]+ |
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With dicyclohexyl-carbodiimide In dichloromethane for 0.166667h; Cooling with ice; |
Preparation of Compound Bisp-(Leu.Z)2 7b
To an ice-cooled solution of Z-Leucine (583 mg, 2.20 mmol) in 70 mL of dry dichloromethane, was added N-hydroxysuccinimide (253 mg, 2.20 mmol) and DCC (454 mg, 2.20 mmol) and stirred for 10 min. Compound 5 (126 mg, 1.00 mmol) and triethylamine (0.306 mL, 2.20 mmol) were added. The reaction mixture was stirred overnight, filtered, washed the filtrate with 2N H2SO4, water and finally with saturated aqueous NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to yield 550 mg of the compound. |