An Easy and Straight Forward Approach Towards the Synthesis of N-Benzyl-5(S)-Substituted Pyrrolidin-2-ones from N-Benzyl-5(S)-pyroglutaminol through Mitsunobu Reaction

Abstract

Background: Pyroglutamic acid is one of the cheapest chiral synthon for the synthesis of a variety of bioactive molecules ranging from synthetic to natural origin. Derived from glutamic acid by internal cyclization pyroglutamic acid can serve easily as a precursor for prolines or pyroglutaminols by the selective reduction of lactam carbonyl or carboxylic group, respectively. Pyroglutamic acid has two differential carbonyls and a lactam NH group. All these can differentially be modified to get a variety of compounds. These applications coupled with the easy availability of pyroglutamic acid have made it a choice of interest for various research groups in recent years to get a range of bioactive compounds both of natural as well as synthetic origins. In our ongoing research programme, we were interested to develop an easy route for the synthesis of 5-substituted pyrrolidin-2-ones exploiting the chemistry of pyroglutamates, whose synthetic potential is well established. Objective: To develop a simple and efficient methodology for the synthesis of 5-sustituted- pyrrolidin-2-ones as bioactive molecules/intermediate to bioactive molecules. Methods: N-Benzyl-5(S)-pyroglutaminol 1, (0.96 g, 5.0 mmol) was taken in THF (15 mL) and diethylazodicarboxylate (DEAD) (1.21 g, 1.4 eq) and triphenylphosphine (Ph3P) (1.72 g, 1.4 eq), were added to it and the reaction mixture was stirred at RT for 30 min. After 30 min a solution of the substituted pyrazole/imidazole derivative (1.2 eq) in THF (10 mL) was added and the reaction mixture was stirred again at RT for 7 hr. The progress of the reaction was monitored by thin layer chromatography (TLC). At the completion of the reaction, the solvents were evaporated under a vacuum to give a liquid which was poured into water (15 mL) and extracted twice with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine solution (15 mL), dried over sodium sulfate, concentrated and purified by column chromatography on silica gel using 20% EtOAc-hexane as eluent to give pure compounds 2 a-d, 3 and 4, respectively in satisfactory yields. Results: Herein, we wish to describe the synthesis of new 5(S)-substituted pyrrolidin-2- one derivatives through Mitsunobu reaction of N-benzyl-5(S)- pyroglutaminol with substituted pyrazole and imidazole derivatives. Conclusion: An easy and straightforward approach towards the synthesis of enantiomerically pure N-benzyl- (S)-5-substituted pyrrolidin-2-ones from N-benzyl-5(S)- pyroglutaminol through Mitsunobu reaction has been developed. These N-benzyl-(S)-5-substituted pyrrolidin-2-ones could be useful for the synthesis of bioactive natural products requiring pyrazole/imidazole moiety attached at C-5 position of native pyrrolidin-2- one moiety.