合成路线1

Silylation of 4(R)-hydroxy-2-pyrrolidone (I) with TBDMS-Cl and imidazole in DMF gives the silyl ether (II), which is protected at the NH group with Boc2O, TEA and DMAP in acetonitrile to yield the protected pyrrolidone derivative (III). Reaction of pyrrolidone (III) with the Grignard reagent (IV) in THF affords the 2-hydroxypyrrolidine adduct (V) in equilibrium with an open-chain form (VI). Reduction of the ketonic group of (VI) with NaBH4 in methanol in the same vessel provides the alcohol (VII), which is cyclized by means of MsCl and TEA in dichloromethane and then treated with TsOH in THF/H2O to furnish the pyrrolidine-benzaldehyde (VIII). The Wittig condensation of the aldehyde group of (VIII) with the phosphonate (IX) by means of NaH in THF gives the cinnamic ester derivative (X), which is desilylated with TBAF in THF to yield the hydroxy pyrrolidine (XI). Stereo-controlled condensation of (XI) with the chiral amine (XII) by means of BuLi in THF affords the N-alkylated b-amino ester (XIII), which is debenzylated with H2 over Pd(OH)2/C in HOAc/methanol to provide the free amino ester (XIV). The protection of the NH2 group of (XIV) with Boc2O and TEA in dioxane/water gives the N-protected amino ester (XV), which is hydrolyzed with NaOH in hot ethanol to afford the carboxylic acid (XVI).