A Regioselective Synthesis of (+, -)-Daunomycinone Via Directed Diels-Alder Reactions.

The three most important members of the anthracycline class of antitumor antibiotics are daunorubicin, adriamycin and carminomycin. This work has developed three regioselective syntheses of ((+OR-))-daunomycinone, the linear, tetracyclic aglycone portion of daunorubicin. The necessary regioselectivity was achieved through the use of two successive, selective Diels-Alder reactions starting with either 2,5- (I) or 2,6-dichlorobenzoquinone (II). Diels-Alder reaction of I and 2-trimethylsilyloxy-1,3-butadiene gave a 15:1 mixture of adducts which were converted to pure 7-chloro-5,8-dimethoxy-2(1H)-tetralone by reduction and methylation. This compound was converted to 7-acetyl-2-chloro-7-hydroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone (III) (50% yield from I) via the trimethylsilylcyanohydrin and oxidative demethylation. Parallel experiments starting with II afforded the isomeric 6-acetyl-2-chloro-6-hydroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone (IV) in 60% overall yield. Naphthoquinone III was used in a second Diels-Alder reaction with 1-bromo-6-methoxy-ortho-quinodimethan, generated in situ from 2-bromomethyl-3-dibromomethylanisole. This reaction afforded a 5-6:1 mixture of 2-acetyl-2-hydroxy-7- and 10-methoxy-1,2,3,4-tetrahydro-5,12-naphthacenequinone (V and VI) in 30% yield. Use of 3-methoxy-ortho-quinodimethan (VII), generated in situ from 5-methoxy-2,3-benzoxathin 3-oxide, with naphthoquinone IV afforded a 4:1 mixture of V and VI in 75% yield. Naphthoquinone IV was also used with 1-hydroxy-3-methoxy-ortho- quinodimethan, generated in situ from 6-methoxybenzocyclobuten-1-ol, to afford a 15:1 ratio of V and VI in 60% yield. Reductive acetylation and oxidation of these mixtures afforded ((+OR-))-7-deoxydaunomycinone triacetate and ((+OR-))-7-deoxyisodaunomycinone triacetate. Pure ((+OR-))-7-deoxydaunomycinone was obtained in 6, 15 and 12% overall yields, respectively, from I and II by methanolysis of the above triacetate mixtures and final trituration of the crude products with methanol. The complimentary reaction of III and VII provided a synthesis of pure ((+OR-))-7-deoxyisodaunomycinone. ((+OR-))-7-Deoxydaunomycinone has previously been converted to ((+OR-))-daunomycinone. Since this compound has also been converted to daunorubicin, adriamycin and carminomycin, this work constitutes a formal synthesis of all three of these important drugs.Ph.D.Organic chemistryUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/158560/1/8204573.pd