Enantioselective Synthesis of Antiepileptic Drug : (-)-Levetiracetam — Synthetic Applications of the Versatile New Chiral N-Sul�nimine

We report an asymmetric synthesis of (-)-Levetiracetam (1) in six steps starting from versatile new chiralN-sul�nimine (3).e key step, stereoselective 1,2-addition of ethylmagnesium bromide (EtMgBr) to chiral N-sul�nimine derived from (R)-glyceraldehyde acetonide and (S)-t-BSA, gave the corresponding sulfonamide (2) in high diastereoselectivity. Simultaneous deprotection and deacetylation followed by NaIO4 cleavage and reduction gave ββ-amino alcohol (6). Subsequent reactions yielded the targeted compound levetiracetam (1).


Introduction
Epilepsy is a chronic neurological disorder that consists of repeated occurrences of spontaneous seizures.Levetiracetam, (S)--ethyl-2-oxopyrrolidine acetamide (1), has been approved as an add-on therapy for the treatment of refractory epilepsy [1].e (S)-enantiomer of etiracetam (levetiracetam) has shown outstanding pharmacokinetic and pharmacological activity that has led to the rapid approval of this antiepileptic drug by the FDA (Figure 1).Levetiracetam offers several advantages over traditional therapy, including twice daily dosing, which includes a wide margin of safety with no requirements for serum drug concentration monitoring and no interactions with other anticonvulsants besides having less adverse effects than traditional treatments [2][3][4].
e �eld of asymmetric organocatalysis is rapidly developing and has attracted the attention of an increasing number of research groups around the world.In particular, organo catalytic asymmetric synthesis has provided several new methods for obtaining chiral compounds.In this connection, t-BSA is abundant, inexpensive, and readily available in both enantiomeric forms and has emerged as arguably the most practical and versatile organo catalyst (S)-t-BSA has also been found to be an excellent asymmetric catalyst for -amino alcohol functionalities (Figure 2).
We envisage the new chiral N-sul�nimine amongst the best starting material for functionalized amino alcohols,

Experimental Section
All reagents and solvents employed were of commercial grade and were used as such, unless otherwise speci�ed.
In this context, (R)-glyceraldehyde acetonide is regarded as a common starting material which has previously been synthesized using a new route in our laboratory in four steps and in 31% overall yield starting from commercially available (R)-epichlorohydrin. (R)-Glyceraldehyde acetonide was earlier elaborated in getting (S,E)-N-(((S)-2,2-dimethyl-1,3dioxolan-4-yl) methylene)-2-methyl propane-2-sul�namide 3 by the CuSO 4 catalyzed reaction of (R)-glyceraldehyde acetonide with (S)-t-butylsul�namide ((S)-t-BSA) in dichloromethane at room temperature in 98.94% de (Scheme 1) [37].Among the various methods, nucleophilic 1,2addition of aryl or alkyl carbanion to an imine double bond is a versatile and popular method for the preparation of functionalised amines.However, in this strategy both yield and stereoselectivity are predominantly in�uenced by electrostatic and steric factors of both substrates, that is, imine and the nucleophile.Incorporation of a stereo-directing motif such as chiral sul�nimines is evident for its potential to synthesize chiral amines in stereoselective fashion.
It is apparent that 1,2-addition of EtMgBr to chiral sul�nimine 3 proceeds via transition state (Figure 3).Stereoselectivity resulting from the addition of organometallic reagents to the C-N double bond of sul�nimines can generally be predicted by assuming chelated, chairlike transition states resulting from coordination of the metal ion with the sul�nyl oxygen.e chiral -hydroxy-N-sul�nimines have recently received much attention as important precursors and intermediates for the preparation of a wide variety of natural products and drugs [39].Furthermore, they can be easily converted into chiral -amino alcohols and 2-oxazolidinones.erefore, development of methodologies for the stereoselective synthesis of chiral -Amino alcohols followed by 2-pyrrolidone ring formation to levetiracetam (1) is of considerable interest [40].
Only in diethyl ether as a solvent reaction completion within 5-6 hr was observed and alternate solvents such as THF, toluene, and CH 2 Cl 2 did not enhance the yields and selectivity (Table 1.Entries 2, 3, and 4).e addition of the Grignard reagent to the imines 3 in THF at −78 ∘ C gave good selectivity and observed single diastereomer in reaction monitored by TLC.Same reaction but in different solvents was carried out at the same temperature.However, incomplete reactions were observed.Rising to RT, complete conversion was observed but with low selectivity, and mixture of diastereomeric was observed by TLC.Higher temperatures lead, reaction completion.Deprotection of the t-butylsul�nyl group and 1,3-dimethyl acetal in compound 2 was performed in single step in acidic media (MeOH⋅HCl) to give the corresponding -amino diol 5. Oxidation followed by reduction of amino diol in 5 using NaIO 4 /NaBH 4 gave the corresponding -amino alcohol [41] 6. e compound 6 on reaction with 4-chlorobutyryl chloride [42] gave 2pyrrolidone alcohol 7. e oxidation of 7 with KMnO 4 gave 8, and resultant amidation yielded (Scheme 2) the targeted (-)levetiracetam 1. e spectral data for which were found to be in good agreement with reported values in the literature [38].
In conclusion, an efficient method has been developed for the preparation of levetiracetam 1 starting from chiral N-sul�nimine.e key step comprises a stereoselective 1,2addition of ethylmagnesium bromide (EtMgBr) to chiral N-sul�nimine 3. e synthetic strategy detailed herein is equally applicable to the synthesis of the brivaracetam.Further application of this strategy to a variety of related natural products is currently underway in our laboratories.