The intermediate ketone (VI) was prepared as follows: 2-Methylcyclopropanecarboxylic acid (I) was converted to the Weinreb amide (III) via activation as the corresponding acid chloride (II) followed by reaction with N,O-dimethylhydroxylamine. The organolithium reagent (V), prepared by metalation of 5-bromo-m-xylene (IV) with n-BuLi, was then added to the methoxy amide (III), producing the target aryl cyclopropyl ketone (VI).

Ethyl 2-(4-nitrophenyl)propionate (VIII), obtained by acid-catalyzed esterification of carboxylic acid (VII), was alkylated by means of iodomethane and NaH to furnish the 2-methylpropionate (IX). Subsequent nitro group hydrogenation over Pd/C gave aniline (X). Diazotization of (X), followed by SnCl2 reduction of the intermediate diazonium salt, afforded the aryl hydrazine (XI). Cyclization between hydrazine (XI) and ketone (VI) under Fischer indolization conditions occurred with concomitant cyclopropyl group rearrangement to generate the racemic beta-methyl tryptamine derivative (XII), which was further separated into the enantiomers.

The (S)-methyl tryptamine (XIII) was protected as the N-Boc derivative (XIV), and its ethyl ester group was then hydrolyzed with KOH to provide acid (XV). Coupling of (XV) with isoquinuclidine (XVI) in the presence of PyBOP gave amide (XVII). Cleavage of the N-Boc group of (XVII) was carried out employing trifluoroacetic acid in anisole. The resultant amine (XVIII) was condensed with 2,4-dinitrobenzenesulfonyl chloride (XIX) under modified Schotten-Baumann conditions to afford the sulfonamide (XX). Mitsunobu coupling of sulfonamide (XX) with 4-(2-hydroxyethyl)pyridine (XXI) gave adduct (XXII). The sulfonyl group of (XXII) was finally removed by treatment with neat propylamine to yield the title secondary amine.

The reaction of 2(R)-methylcyclopropanecarboxylic acid (I) with (COCl)2 gives the corresponding acyl chloride (II), which is treated with N,O-dimethylhydroxylamine (III) and TEA to yield the amide (IV). The condensation of (IV) with 3,5-dimethylphenyl bromide (V) by means of BuLi in THF affords the benzoylcyclopropane (VI), which is cyclized with 2-(4-hydrazinophenyl)-2-methylpropionic acid ethyl ester (VII) in refluxing ethanol to provide the indole derivative (VIII) (1). The reaction of the amino group of (VIII) with 2,4-dinitrophenylsulfonyl chloride (IX) and collidine in dichloromethane gives the corresponding sulfonamide (X), which is condensed with 2-(1,2,3-benzotriazol-5-yl)ethanol (XI) by means of PPh3, DEAD and propylamine in benzene to yield the secondary amine (XII). The hydrolysis of the ester group of (XII) by means of KOH in methanol/THF affords the propionic acid derivative (XIII), which is finally condensed with 2-azabicyclo[2,2,2]octane (XIV) by means of PyBOP and TEA in dichloromethane to provide the target indole derivative.

The (S)-methyl tryptamine (XIII) was protected as the N-Boc derivative (XIV), and its ethyl ester group was then hydrolyzed with KOH to provide acid (XV). Coupling of (XV) with isoquinuclidine (XVI) in the presence of PyBOP gave amide (XVII). Cleavage of the N-Boc group of (XVII) was carried out employing trifluoroacetic acid in anisole. The resultant amine (XVIII) was condensed with 2,4-dinitrobenzenesulfonyl chloride (XIX) under modified Schotten-Baumann conditions to afford the sulfonamide (XX). Mitsunobu coupling of sulfonamide (XX) with 4-(2-hydroxyethyl)pyridine (XXI) gave adduct (XXII). The sulfonyl group of (XXII) was finally removed by treatment with neat propylamine to yield the title secondary amine.

In an alternative procedure, tryptamine (XIII) was acylated with 4-pyridylacetic acid (XXIII) to afford amide (XXIV), which was further reduced to the secondary amine (XXV) with borane in THF. Ester group hydrolysis in (XXV), followed by coupling of the resultant acid (XXVI) with isoquinuclidine (XVI), furnished the target amide.