Enantioselective Synthesis of Antiepileptic Agent , ( − )-Levetiracetam , through Evans Asymmetric Strategy

A practical and efficient enantioselective synthesis of antiepileptic drug, (−)-Levetiracetam, has been described in �ve steps (33.0% overall yield) and high optical purity (99.0% ee), using Evans asymmetric strategy for αα-alkylation of carbonyl functionality as the key step.e simplicity of the experimental procedures and high stereochemical outcomemake this method synthetically attractive for preparing the target compound on multigram scales.


Introduction
Epilepsy is a chronic neurological disorder that consists of repeated occurrences of spontaneous seizures.Levetiracetam, [(S)-a-ethyl-2-oxopyrrolidine acetamide], (Figure 1) has recently been approved as an add-on therapy for the treatment of refractory epilepsy [1].e (S)-enantiomer of etiracetam (levetiracetam) has shown remarkable pharmacokinetic and pharmacological activity which has led to the quick approval of this antiepileptic drug by the FDA.Levetiracetam offers several advantages over traditional therapy, including twice-daily dosing, a wide margin of safety with no requirements for serum drug concentration monitoring and no interactions with other anticonvulsants, and less adverse effects than traditional treatments [2][3][4].
In this paper, we report a practical and efficient enantio selective synthesis of levetiracetam, 1, in �ve steps with good overall yield using Evans type asymmetric -alkylation of compound 4. e retrosynthetic analysis of 1 is show in (Figure 2).

Experimental Section
All reagents and solvents employed were of commercial grade and were used as such, unless otherwise speci�ed.

Results and Discussion
As shown in (Scheme 1), the synthesis of (−)-levetiracetam, 1, was started from acylation of Evans type auxiliary (S)-4-phenyloxazolidin-2-one, 2, with chloroacetyl chloride in the presence of Et  e alkylation had indeed occurred from the least hindered face of the enolate delivering the required  stereochemistry.

Study of Selectivity during Alkylation with respect to
Auxiliary and Size of Metal Ion.e discrepancy of stereoselectivity during -alkylation with respect to substitution of auxiliary and size of metal ion was studied.e enolate derived from 4a & 4b with NaHMDS was alkylated under same conditions with ethyl iodide and the results are summarized in (Table 1).(S)-phenyl substituted auxiliary showed higher diastereoselectivity (99% ee) as compared to (S)-benzyl auxiliary (<85% ee) with NaHMDS as the base, the diastereomeric ratios during alkylation were determined by chiral HPLC purity of �nal product (−)-Levetiracetam, 1.Whereas LiH-MDS provided similar results with 4a & 4b, but not as well as those with NaHMDS.Removal of the chiral auxiliary in compound 5 was carried out by LiOH/H 2 O 2 in THF to afford the corresponding acid 6 in 85% yield.is is particularly noteworthy in a way that the (S)-4-phenyloxazolidin-2-one could be recovered in 85% yield, aer a simple acid-base workup operation.Acid 6 on treatment with ethyl chloroformate and ammonium hydroxide produced (−)-Levetiracetam, 1, in 86% yield and 99.0% ee (determined by chiral HPLC analysis).e spectral data which were found to be in good agreement with reported values [26].

Conclusion
In conclusion, a practical and efficient enantioselective synthesis of levetiracetam, 1, has been achieved successfully by employing Evans type asymmetric strategy.e merit of the mentioned approach is less number of steps (5 steps), improved overall yield (33.0%) and high enantioselectivity (99.0%ee).is sequence has also been applied to the preparation of the enantiomer of levetiracetam and brivaracetam, and so forth.e simplicity of the experimental procedures and high stereochemical outcome make this method synthetically attractive for preparing the target compound on multigram scales and industrial applications.See Supplementary Material available online at doi:10.1155/2013/176512,including copies of the 1 H, 13 C NMR, Mass, IR spectra of the new compounds.