Synthesis of intermediate (VI): 2) The reaction of 5,8-dimethoxy-2-tetralone (I) with KCN and ammonium carbonate in refluxing ethanol gives 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoic acid (II), which is acetilated with acetic anhydride to give 2-acetylamino-1,2,3,4-tetrahydro-2-naphthoic acid (XV), which is submitted to optical resolution with I-alpha-phenylethylamine yielding the 2(R) isomer (XVI). Esterification of (XVI) with methanol-H2SO4 affords the corresponding methyl ester (XVII), which by reaction first with NaH and DMSO and then with Al-Hg in THF is converted into the acetyl derivative (VI).

Synthesis of intermediate (VI): 1) The reaction of 5,8-dimethoxy-2-tetralone (I) with KCN and ammonium carbonate in refluxing ethanol gives 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoic acid (II), which is esterified with methanol-HCl to the corresponding methyl ester (III). The optical resolution of (III) with D-(-)-mandelic acid affords the 2R isomer (IV), which by reaction first with NaH and DMSO and then with Zn and NaOH in water gives (R)-2-acetyl-2-amino-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (V). The acetylation of (V) with acetic anhydride in pyridine yields (R)-2-acetyl-2-acetamido-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (VI).

(R)-2-acetyl-2-acetamido-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (VI) is submitted to a Friedel-Crafts cyclocondensation with phthalic anhydride (VII) by means of anhydrous AlCl3 at 135 C to afford (R)-9-acetyl-9-acetamido-6,11-dihydroxy-7,8,9,10-tetrahydronaphthacene-5,12-dione (VIII). The protection of the acetyl group of (VIII) with ethylene glycol and p-toluenesulfonic acid gives the corresponding ketal (IX), which by cyclization with 1,3-dibromo-5,5-dimethylhydantoin (DDH) yields the pentacyclic oxazine (X). The hydrolysis of (X) with hot H2SO4 affords 9-amino-4-demethoxy-9-deoxydaunomycinone (XI), which is condensed with 3,4-di-O-acetyl-2-deoxy-beta-D-ribopyranosyl bromide (XII) (obtained from acetyl 3,4-di-O-acetyl-2-deoxy-beta-D-ribopyranoside (XIII) and trimethylsilyl bromide) by means of tetramethylurea in chloroform to give the 3',4'- di-O-acetyl derivative (XIV) of the desired product. Finally, this compound is deprotected by hydrolysis with anhydrous K2CO3 in methanol - dichloroethane.

Synthesis of intermediate (VI): 2) The reaction of 5,8-dimethoxy-2-tetralone (I) with KCN and ammonium carbonate in refluxing ethanol gives 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoic acid (II), which is acetilated with acetic anhydride to give 2-acetylamino-1,2,3,4-tetrahydro-2-naphthoic acid (XV), which is submitted to optical resolution with I-alpha-phenylethylamine yielding the 2(R) isomer (XVI). Esterification of (XVI) with methanol-H2SO4 affords the corresponding methyl ester (XVII), which by reaction first with NaH and DMSO and then with Al-Hg in THF is converted into the acetyl derivative (VI).

Synthesis of intermediate (VI): 1) The reaction of 5,8-dimethoxy-2-tetralone (I) with KCN and ammonium carbonate in refluxing ethanol gives 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoic acid (II), which is esterified with methanol-HCl to the corresponding methyl ester (III). The optical resolution of (III) with D-(-)-mandelic acid affords the 2R isomer (IV), which by reaction first with NaH and DMSO and then with Zn and NaOH in water gives (R)-2-acetyl-2-amino-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (V). The acetylation of (V) with acetic anhydride in pyridine yields (R)-2-acetyl-2-acetamido-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (VI).

(R)-2-acetyl-2-acetamido-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (VI) is submitted to a Friedel-Crafts cyclocondensation with phthalic anhydride (VII) by means of anhydrous AlCl3 at 135 C to afford (R)-9-acetyl-9-acetamido-6,11-dihydroxy-7,8,9,10-tetrahydronaphthacene-5,12-dione (VIII). The protection of the acetyl group of (VIII) with ethylene glycol and p-toluenesulfonic acid gives the corresponding ketal (IX), which by cyclization with 1,3-dibromo-5,5-dimethylhydantoin (DDH) yields the pentacyclic oxazine (X). The hydrolysis of (X) with hot H2SO4 affords 9-amino-4-demethoxy-9-deoxydaunomycinone (XI), which is condensed with 3,4-di-O-acetyl-2-deoxy-beta-D-ribopyranosyl bromide (XII) (obtained from acetyl 3,4-di-O-acetyl-2-deoxy-beta-D-ribopyranoside (XIII) and trimethylsilyl bromide) by means of tetramethylurea in chloroform to give the 3',4'- di-O-acetyl derivative (XIV) of the desired product. Finally, this compound is deprotected by hydrolysis with anhydrous K2CO3 in methanol - dichloroethane.

Synthesis of intermediate (VI): 2) The reaction of 5,8-dimethoxy-2-tetralone (I) with KCN and ammonium carbonate in refluxing ethanol gives 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoic acid (II), which is acetilated with acetic anhydride to give 2-acetylamino-1,2,3,4-tetrahydro-2-naphthoic acid (XV), which is submitted to optical resolution with I-alpha-phenylethylamine yielding the 2(R) isomer (XVI). Esterification of (XVI) with methanol-H2SO4 affords the corresponding methyl ester (XVII), which by reaction first with NaH and DMSO and then with Al-Hg in THF is converted into the acetyl derivative (VI).

Synthesis of intermediate (VI): 1) The reaction of 5,8-dimethoxy-2-tetralone (I) with KCN and ammonium carbonate in refluxing ethanol gives 2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoic acid (II), which is esterified with methanol-HCl to the corresponding methyl ester (III). The optical resolution of (III) with D-(-)-mandelic acid affords the 2R isomer (IV), which by reaction first with NaH and DMSO and then with Zn and NaOH in water gives (R)-2-acetyl-2-amino-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (V). The acetylation of (V) with acetic anhydride in pyridine yields (R)-2-acetyl-2-acetamido-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (VI).

(R)-2-acetyl-2-acetamido-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (VI) is submitted to a Friedel-Crafts cyclocondensation with phthalic anhydride (VII) by means of anhydrous AlCl3 at 135 C to afford (R)-9-acetyl-9-acetamido-6,11-dihydroxy-7,8,9,10-tetrahydronaphthacene-5,12-dione (VIII). The protection of the acetyl group of (VIII) with ethylene glycol and p-toluenesulfonic acid gives the corresponding ketal (IX), which by cyclization with 1,3-dibromo-5,5-dimethylhydantoin (DDH) yields the pentacyclic oxazine (X). The hydrolysis of (X) with hot H2SO4 affords 9-amino-4-demethoxy-9-deoxydaunomycinone (XI), which is condensed with 3,4-di-O-acetyl-2-deoxy-beta-D-ribopyranosyl bromide (XII) (obtained from acetyl 3,4-di-O-acetyl-2-deoxy-beta-D-ribopyranoside (XIII) and trimethylsilyl bromide) by means of tetramethylurea in chloroform to give the 3',4'- di-O-acetyl derivative (XIV) of the desired product. Finally, this compound is deprotected by hydrolysis with anhydrous K2CO3 in methanol - dichloroethane.