合成路线1

A new and stereoselective synthesis of (3R-trans)-3-ethyl-1-(tert-butyldimethylsilyl)-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XVII), a key intermediate in the synthesis of PS-5 has been developed: The oxidation of 3-benzyloxy-1-propanol (I) with oxalyl chloride in DMSO gives the corresponding aldehyde (II), which is condensed with the phosphonate (III) by means of NaH yielding a mixture of the (Z)- and (E)-isomers of 5-benzyloxy-2-ethyl-2-pentenoic acid ethyl ester (IV) and (V). The undesired (Z)-isomer (IV) is isomerized by treating the mixture with diphenyldisulfide in refluxing THF. The hydrolysis of (V) with LiOH in THF/methanol/water gives the expected free acid (VI), which is treated with SOCl2 in refluxing benzene to afford the acid chloride (VII). The condensation of (VII) with the chiral oxazolidinone (VIII) by means of butyllithium in THF gives the acylated compound (IX), which is treated with benzenethiol and butyllithium in THF to give the addition compound (X) that is purified by medium pressure column chromatography to eliminate the undesired diastereomer. The elimination of the oxazolidinone group of (X) by reaction with trimethylaluminum, benzylthiol and butyllithium in THF yields the thioester (XI), which is treated with silver trfluoroacetate and water to afford the corresponding free acid (XII). The reaction of (XII) with methoxyamine and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDPC) in water affords the methoxyamide (XIII), which is methylated by means of methyl iodide and silver perchlorate to give the sulfonium salt (XIV). The cyclization of (XIV) by means of K2CO3 yields the azetidinone (XV), which is debenzylated by means of calcium in liquid ammonia affording (3R-trans)-3-ethyl-4-(2-hydrxyethyl)azetidin-2-one (XVI). Finally, this compound is silylated with tert-butyldimethylsilyl (TBDMS) trifluoromethanesulfonate affording (3R-trans)-3-ethyl-1-(tert-butyldimethylsilyl)-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XVII), the desired target key intermediate in the synthesis of PS-5.