合成路线1

The intermediate diazonium salt (XIII) has been obtained as follows: the hydrogenation of 3-chloro-4-methoxynitrobenzene (XI) with H2 over Pt/Al2O3 in toluene gives the corresponding aniline (XII), which is diazotized with NaNO2/HCl and treated with sodium tetrafluoroborate to yield the target diazonium salt intermediate (XIII). The reduction of pulegone (I) with H2 over Pd/C gives the menthol (II), which is oxidized with CrO3/H2SO4 to yield 3(R),7-dimethyl-6-oxooctanoic acid (IV), which can also be obtained by direct oxidation of (l)-menthol (III) under the same conditions. The oxidation of (IV) with trifluoroperacetic acid (trifluoroacetic anhydride/H2O2) in dichloromethane yields the 3(R)-methylhexanedioic acid isopropyl monoester (V), which is treated with NaOEt in ethanol to obtain the corresponding ethyl monoester (VI). The reaction of (VI) with diethyl carbonate, EtONa, and "Adogen 464" (a phase transfer catalyst) in ethanol affords 5,5-bis(ethoxycarbonyl)-3(S)-methylpentanoic acid (VII), which is treated with oxalyl chloride to provide the expected acyl chloride (VIII). The reaction of (VIII) with sodium azide and benzyl alcohol gives the intermediate azide that rearranges to the benzyl carbamate (IX). The reductive cyclization of (IX) with H2 over Pd/C in ethanol yields 5(R)-methyl-2-oxopiperidine-3-carboxylic acid ethyl ester (X), which is condensed with the intermediate diazonium salt (XIII) to afford the hydrazono derivative (XIV). The cyclization of (XIV) in hot formic acid provides 7-chloro-6-methoxy-4(R)-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one (XV), which is treated with KOH In refluxing ethanol/water to cleave the lactam ring, yielding 3-(2-amino-1(R)-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid (XVI). The decarboxylation of (XVI) by means of refluxing 3M HCl affords 3-(2-amino-1(R)-methylethyl)-6-chloro-5-methoxy-1H-indole (XVII), which is finally acylated with Ac2O and pyridine in toluene to provide the target 6-chloromelatonin as a pure enantiomer.