合成路线1

Protection of 1,5,6,7-tetrahydroindol-4-one (I) with Boc2O by means of t-BuOK in refluxing THF gives the corresponding N-Boc-indolone (II), which is then reduced with H2 over Pt/C in MeOH to yield (3aR*, 4S*,7aR*)-cis-N-Boc-4-hydroxyoctahydroindole (III). Swern oxidation of alcohol (III) using (COCl)2, DMSO and Et3N in THF affords the racemic perhydroindolone (IV), which is resolved using chiral chromatography to the (3aR,7aR)-enantiomer (V). Alternatively, enantioselective acetylation of racemic alcohol (III) with vinyl acetate in the presence of immobilized Candida antarctica lipase (Novozyme 435), followed by flash chromatographic separation of the undesired (3aS,4R,7aS)-acetate provides unreacted (3aR,4S,7aR)-alcohol (VI), which is then oxidized to ketone (V) under Swern conditions. Treatment of 1-ethynyl-3-methylbenzene (VII) with BuLi in THF at –20 °C and subsequent enantioselective condensation with ketone (V) leads to propargylic alcohol (VIII), which is then N-deprotected with HCl in EtOAc to produce the amine (IX). Finally, amine (IX) is acylated with methyl chloroformate (X) in the presence of Et3N in CH2Cl2 .
Alternatively, Michael addition of aziridine (XI) to 2-cyclohexenone (XII) in toluene gives 3-(1-aziridinyl)cyclohexanone (XIII), which is submitted to aziridine ring opening by treatment with methyl chloroformate in toluene to provide methyl N-2-chloroethyl-N-(3-oxocyclohexyl)carba-mate (XIV). Intramolecular cyclization of carbamate (XIV) in the presence of pyrrolidine and Et3N in CH2Cl2 affords racemic methyl 4-oxooctahydroindole-1-carboxylate (XV), which is then subjected to chiral chromatographic separation, resulting in the (3aR,7aR)-enantiomer (XVI). Finally, 1-ethynyl-3-methylbenzene (VII) is stereospecifically added to ketone (XVI) in the presence of n-Hex-Li in THF .