合成路线1

Reaction of 2-(1,3-dioxol-5-yl)acetic acid (XXI) with pivaloyl chloride and TEA gives the corresponding anhydride (XXII), which is condensed with the chiral oxazolidinone (XXIII) by means of n-BuLi in THF to yield the amide (XXIV). Condensation of (XXIV) with 2-bromoacetic acid tert-butyl ester (XXV) by means of NaHMDS in THF affords the adduct (XXVI). Elimination of the chiral auxiliary of (XXVI) by means of LiOOH in THF/water provides the chiral succinic acid hemiester (XXVII) (93% ee), which is selectively reduced with BH3­THF complex to give the 4-hydroxysuccinate (XXVIII). Reaction of succinate (XXVIII) with 4-chlorophenylsulfonyl chloride, TEA and DMAP in dichloromethane yields the sulfonate (XXIX), which is condensed with 4-methoxybenzaldoxime (XXX) by means of Cs2CO3 in hot acetonitrile to afford the oxime ether (XXXI). Transesterification of the tert-butyl ester of (XXXI) with trimethyl orthoformate and p-toluenesulfonic acid in hot methanol provides the methyl ester (XXXII), which is cyclized by means of trimethylsilyl triflate and tributylamine in dichloroethane to afford a 9:1 diastereomeric mixture of perhydro-1,2-oxazines (XXXIII) and (XXXIV) which is easily separated. The reductive N-O-bond cleavage of the major oxazine diastereomer (XXXIII) by means of Zn/HOAc or H2 over Pd/C gives the trisubstituted 4-aminobutanol (XXXV), which is cyclized by means of CBr4, PPh3 and TEA to yield chiral pyrrolidine (XXXVI) (4). Finally, pyrrolidine (XXXVI) is alkylated with N,N-dibutyl-2-bromoacetamide (XIII) followed by ester hydrolysis as before.