January 1900

Document Type


Degree Name



Dept. of Chemistry


Oregon Graduate Center


Syntheses of daunomycinone and 11-deoxydaunomycinone from a common intermediate were established. In performing this task, a new synthesis of 6-acetyl-4a,5,6,7,8.8a-hexahydro-1(4H)-naphthalenone (I) from (l)-perilaldehyde was developed. Grignard condensation of allylmagnesium bromide with (l)-perilaldehyde gave an alcohol intermediate which was then treated with potassium hydride to effect oxy-Cope rearrangement to 2-(2-propenyl)-4-( 1-methylethenyl)- cyclohexanecarboxaldehyde (II). The aldehyde intermediate was converted to 1-acetyl-4-( 1-methylethenyl)-2-(2-propenyl)cyclohexane (III) by reaction of (II) with methyl lithium followed by Swern oxidation of the resultant alcohol. Ozonolysis of III furnished a diacetyl aldehyde intermediate which was cyclized with hydrogen chloride to give I. 9-Acetyl-5, 12-dihydroxy-4-methoxy-7 ,8,9,10, 10a, 11-hexahydro- 6(6aH)-naphthacenone (IV), which served as a common intermediate for daunomycinone and 11-deoxydaunomycinone, was prepared through condensation of 3-phenylsulfonyl-7 -methoxy-1 (3H)-isobenzofuranone with I. Regiospecific bromination of IV at the C-11 position with N-bromosuccinimide was followed by hydrolysis of the bromide to the C-11 alcohol product. Subsequent oxidation of the alcohol intermediate gave 9-acetyl-4,5, 12-trimethoxy-6a, 7 ,8,9,10,10a-hexahydronaphthacene- 6, 11-dione (V). Selenium dioxide dehydrogenation of V gave 9-acetyl 4,5, 12-trimethoxy-7 ,8.9, 10-tetrahydronaphthacene-6, 11-dione. Regiospecific demethylation of the C-5 and C-12 methyl ethers furnished 7,9-dideoxydaunomycinone. Several approaches to pillaromycinone were examined. Michael condensation of ethyl 2-phenysulfinylmethylbenzoate (VI) with methyl 4-(2-cyclopentenyl)-3-butenoate yielded methyl 3-(2-cyclopentenylmethyl)- 1-hydroxy- 8-methoxynaphthalene-2-carboxylate (VII). Methylation of the phenolic group in VII and conversion of the methyl ester functionality to an aldehyde furnished 3-(2-cyc1opentenylmethyl)- 1,8-dimethoxynapthalene-2-carboxaldehyde (VIII). A variety of Lewis acids were examined in an attempt to catalyze intramolecular ene reaction between the aldehyde and cyclopentene functionalities in VIII to form 5 ,6-dimethoxy-11, 11 a-dihydro-(1 H)-cyclopenta[b ]anthracene. Michael condensation of VI with methyl 4-(3-oxocyclopentyl)-3- butenoate ethylene acetal and then methylation of the phenolic group furnished methyl 1,8-dimethoxy-3-(3-oxocyclopentylmethyl)naphthalene- 2-carboxylate ethylene acetal (IX). Sequential conversion of the ester functionality in IX to an aldehyde, hydrolysis of the ketal group. and then intramolecular aldol cyclization gave 5,6-dimethoxy-2,3,11,11a-tetrahydro- 3(1H)-cyclopenta[b]anthracenone (X). Reduction of the ketone in X to an alcohol was required prior to cis-hydroxylation of the double bond. After hydroxylation, oxidation of the alcohol back to the ketone yielded 3a,4-dihydroxy-5,6-dimethoxy-2,3,3a,4, 11, 11a-hexahydro- 3(1H)-cyclopenta[b]anthracenone which was protected as the acetonide. An efficient general method for the synthesis of 1(H)-2-benzopyran- 1-ones was also developed. Condensation of ortho-carboxybenzaldehydes with various nitroalkanes furnished 3-nitroalkyl substituted 1(3H)-isobenzofuranones. Reductive cleavage of the lactone functionality and Nef conversion of the nitro group to a carbonyl group gave ortho-carboxybenzyl ketones. These were cyclodehydrated to 1(H)-2-benzopyran-1-ones with methyl, ethyl, phenyl, and meta-methoxyphenyl substituents at the C-3 position.





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