2,5-Piperazinedione, 3,6-bis(2-methylpropyl)-, (3R,6R)- synthesis

Yield:952-43-2 90%

Reaction Conditions:

Stage #1: N-Boc-D-Leuwith dmap;benzotriazol-1-ol;N-ethyl-N,N-diisopropylamine;diisopropyl-carbodiimide in dichloromethane;N,N-dimethyl-formamide at 0 - 20; for 3 h;
Stage #2: with trifluoroacetic acid in dichloromethane; for 0.5 h;
Stage #3: N-Boc-D-LeuFurther stages;

Steps:

6 4.2.1. General procedure

General procedure: 4.2.1.1. Coupling of the first Boc protected α-amino acid on oxime resin. A desired quantity of oxime resin (1.12 mmol/g) was added to a peptide synthesis vessel. The resin was treated three times with CH2Cl2. Amino acid (3.0 equiv) and HOBt (3.0 equiv) were dissolved in DMF in a 100 mL flask and the mixture was stirred for few minutes at 0 °C. DIC (3.0 equiv), DIEA (3.0 equiv) and DMAP (0.1 equiv) were introduced into the peptide synthesis vessel and the mixture was stirred mechanically for 3 h. The mixture was filtered under vacuum and the resin was washed [DMF (3x100 mL), MeOH (3x100 mL), DMF (3x100 mL), MeOH (3x100 mL)] and dried under reduced pressure. 4.2.1.3. Removal of the Boc protecting group. The resin was treated three times with CH2Cl2 (100 mL). A 50% v/v solution of trifluoroacetic acid (TFA) in CH2Cl2 was added to the peptide synthesis vessel, which was stirred for 30 min. Then, the mixture was filtered under vacuum and the resin was washed with DMF (3x100 mL), MeOH (3x100 mL), DMF (3x100 mL), MeOH(3x100 mL) and with a solution of 10% v/v DIEA in CH2Cl2 (100 mL). 4.2.1.4. Coupling of the second Boc protected α-amino acid. The amino acid (3.0 equiv) was dissolved in DMF in a 100 mL flask. The solution was cooled to 0 °C, then HBTU (3.0 equiv) and HOBt (3.0 equiv) were added. The mixture was poured into the peptide synthesis vessel in which the resin has been previously treated with CH2Cl2. DIEA (6.0 equiv) was also added to the vessel and the mixture was stirred for 3 h. After filtration under vacuum, the resin was washed [DMF (3x100 mL), MeOH (3x100 mL), DMF (3x100 mL) and MeOH (3x100 mL)] and dried reduced under pressure. The Kaiser nihydrin test was performed to monitor the efficiency of the coupling, and the coupling procedure was repeated if needed. 4.2.1.5. Cyclization/cleavage from the resin. First, the Boc group was removed using procedure described in (4.2.1.3), but without the 10% v/v DIEA/CH2Cl2 washing step. After drying, CH2Cl2 and DIEA (2.5 equiv) were added to the peptide synthesis vessel and the mixture was stirred for 2 min. Acetic acid (5.0 equiv) was then added and the content was shaken for 24 h. Then the filtrate was collected and the resin was rinsed several times with CH2Cl2 and MeOH. All the filtrates were combined and evaporated, and the resulting solid was dissolved in CH2Cl2. Amberlite IR-120 was introduced to the solution to take off remaining traces of DIEA. The mixture was stirred for a few minutes and filtered. The filtrate was evaporated to give compounds 2 to 19. Trituration in a minimum of cold ether was performed to obtain satisfying purity.

References:

Bérubé, Christopher;Cardinal, Sébastien;Boudreault, Pierre-Luc;Barbeau, Xavier;Delcey, Nicolas;Giguère, Martin;Gleeton, Dave;Voyer, Normand [Tetrahedron,2015,vol. 71,# 42,p. 8077 - 8084]