合成路线1

A new synthesis of orlistat has been described: The ozonolysis of 3(R)-(tetrahydropyranyloxy)-6-heptenoic acid ethyl ester (LV) with O3 gives the corresponding terminal aldehyde (LVI), which is submitted to a Wittig condensation with octyl triphenylphosphonium bromide (LVII) and butyllithium in ether-THF yielding 3(R)-(tetrahydropyranyloxy)-6(Z)-tetradecenoic acid ethyl ester (LVIII). The reduction of (LVIII) with DIBAL in toluene-dichloromethane affords the corresponding aldehyde (LIX), which is condensed with octanoic acid (XXXIV) by means of butyllithium and diisopropylamine in THF to give 2-hexyl-3-hydroxy-5(R)-(tetrahydropyranyloxy)-8(Z)-hexadecenoic acid (LX), which is lactonized with benzenesulfonyl chloride in pyridine to the protected oxetanone (LXI). The deprotection of (LXI) with pyridinium p-toluenesulfonate in hot ethanol affords 3-hexyl-4-[2(R)-hydroxy-5(Z)-tridecenyl]oxetan-2-one (LXII) as a mixture of diastereomers, which are separated by column chromatography yielding the (3S,4S,2'R)-isomer (LXIII). The condensation of (LXIII) with N-formyl-L-leucine (XXIV) as before gives dihydrolipstatin (LXIV), which is finally hydrogenated with H2 over Pd/C in THF.