Synthetic anthracyclines: regiospecific total synthesis of D-ring thiophene analogues of daunomycin.
The key anhydride 2-acetoxy-[2-carboxy-5-(trimethylsilyl)thiophen-3-yl]acetic acid anhydride (8), prepared from (2-carboxythiophen-3-yl)acetic acid (5), underwent a strong base-induced cycloaddition reaction with the chloroquinone acetal (11) to give the 7,7-ethylenedioxy-2-trimethylsilyl-6,7,8,9- tetrahydroanthra[2,3-b]thiophene-5,10-dione (12) regioselectively. Similarly, the regioisomeric 8,8-ethylenedioxy-2-trimethylsilyl-6,7,8,9-tetrahydroanthra[2,3-b] thiophene- 5,10-dione (30) was obtained by the strong base-induced cycloaddition reaction of 8 with the chloroquinone acetal (29). These cycloadducts (12 and 30) were converted to D-ring thiophene analogues (28 and 38) of daunomycin (1a). Another D-ring thiophene analogue (42) which has a trimethylsilyl substituent in the D-ring was also prepared.
Kita
Y
Y
Faculty of Pharmaceutical Sciences, Osaka University, Japan.
Kirihara
M
M
Sekihachi
J
J
Okunaka
R
R
Sasho
M
M
Mohri
S
S
Honda
T
T
Akai
S
S
Tamura
Y
Y
Shimooka
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D007939:Leukemia L1210 / Q000473:pathology; D013876:Thiophenes / Q000032:analysis / Q000138:chemical synthesis; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D013876:Thiophenes; D003630:Daunorubicin