合成路线1

Esterification of 1,2,3,4-butanetetracarboxylic acid (XXXVI) with EtOH in the presence of H2SO4 in refluxing toluene yields the corresponding tetraethyl ester (XXXVII), which upon treatment with NaOMe in MeOH followed by HCl in refluxing H2O yields trans-4-oxocyclopentane-1,2-dicarboxylic acid (rac-[XXXVIII]). Reduction of intermediate (XXXVIII) with H2 over Rh/C in the presence of NaOH in H2O followed by treatment with H2SO4 in acetone furnishes meso-4-hydroxycyclopentane-1,2-dicarboxylic acid (rac-[XXXIX]), which upon treatment with ethyl chloroformate in the presence of Et3N in THF affords lactone acid (rac-[VI]). Acid rac-(VI) is esterified with benzyl alcohol in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and DMAP in EtOAc. Benzyl ester (rac-[XL]) is treated with Amberlyst-15 or MsOH in MeOH, affording racemic cyclopentanol (rac-[XVIII]). Finally, racemate rac-(XVIII) is resolved by chiral HPLC, yielding the desired (R,R,R)-isomer intermediate (XVIII) .
Intermediate (XV) is prepared from intermediate (XVIII) by hydrogenolysis with H2 over Pd/C in THF or DMF and subsequent amidation of the resulting carboxylic acid (XLI) with N-methylhex-5-enamine (VII) in the presence of DIEA, HATU or O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU) in DMF or acetonitrile, or EDC in the presence or absence of DMAP in THF or CH2Cl2, or EEDQ in refluxing THF .