Preparation of lycopene metabolites

摘要

Multi-stage preparation of the antitumoral lycopine metabolite 2,6-cyclolycopine-1,5-diol (II) is carried out using a readily available compound, alpha -terpinylacetate, as a starting product. Preparation of the lycopine metabolite 2,6-cyclolycopine-1,5-diol (II) comprises oxidative dihydroxylation of alpha -terpinylacetate (III) to give 4-(1-acetoxy-1-methylethyl)-1-methylcyclohexane-1,2-diol (IV), followed by oxidative cleavage to give 3-(1-acetoxy-1-methylethyl)-6-oxo-heptanal (V). This compound is then subjected to intramolecular aldol condensation to give 3-(1-acetoxy-1-methylethyl)-2-formyl-1-methylcyclopentanol (VI), which is silylated to give 3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-1-trimethylsilyloxycyclo pentane (VII), which is subjected to a chain lengthening reaction with acetone and simultaneous saponification to cleave the acetyl group to give 4-(5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopenty l)-3-buten-2-one (VIII). (VIII) is reacted with vinylmagnesium bromide to give 5-(5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopenty l)-3-methyl-penta-1,4-diene-3-ol (IX). (IX) is converted, with deprotection of the silylated OH group, to give (5-(2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methylcyclopentyl)-3-methy l-penta-2,4-dienyl)triphenylphosphonium salt (X), which is reacted with 2,7-dimethyl-2,4,6-octatriene-1,8-dial (XI) to give 2,7,11-trimethyl-13-(2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methylcyc lopentyl)-trideca-2,4,6,8,10,12-hexaenal (XII), which is reacted with a (3,7,11-trimethyl-dodeca-2,4,6,10-tetraenyl)triphenylphosphonium salt of formula (XIII) to give (II). Ph = phenyl; X<1->, X<2-> = halogenide or hydrogensulfate. Independent claims are also included for the compounds (V), (VI), (VII), (VIII), (IX), 5-(2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methylcyclopentyl)-3-methyl penta-2,4-dien-1-ol (XV), a 5-(5-(1-hydroxy-1-methylethyl)-2-trimethylsilyloxycyclopentyl)-3-methy lpenta-2,4-dienoic acid alkyl ester of formula (XIV), (X) and (XII), which are all claimed as new. Also included is a variation in the method for preparing (II), in which (VIII) is prepared as before, followed by Horner-Emmons olefination with a phosphonoacetic acid trialkyl ester in the presence of a base to give (XIV), which is converted to (XV) and then to (X) and (XII) as before. Alkyl = 1-6C alkyl.