- Total synthesis of the duocarmycins
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The total synthesis of (+)-duocarmycin A and SA through a common indoline intermediate is described. The key reactions include selective lithiation of a 2,6-dibromoiodobenzene derivative and diastereoselective addition to a chiral nitroalkene, copper-mediated aryl amination, and addition of aryllithium to azlactones. Copyright
- Yamada, Ken,Kurokawa, Toshiki,Tokuyama, Hidetoshi,Fukuyama, Tohru
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p. 6630 - 6631
(2007/10/03)
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- Total synthesis of (+)-duocarmycin A, epi-(+)-duocarmycin A and their unnatural enantiomers: Assessment of chemical and biological properties
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Full details of an enantioselective total synthesis of (+)-duocarmycin A (1) are described in which a solution to the control of the relative and absolute stereochemistry of the remote stereocenters is provided. Catalytic asymmetric dihydroxylation of 15 was employed to introduce the absolute stereochemistry required for the activated cyclopropane, and a diastereoselective Dieckmann-type condensation of 61 was employed to control the absolute stereochemistry of the C6 quaternary center. The complementary diastereoselectivity of a thermodynamic versus kinetic condensation of 61 permitted the divergent synthesis of (+)-duocarmycin A or epi-(+)-duocarmycin A from common intermediates. Final introduction of the reactive cyclopropane was accomplished by transannular spirocyclization of the mesylate 44 upon treatment with base or directly from the corresponding free alcohol itself, duocarmycin D1 (42), upon Mitsunobu activation. Notably, the asymmetric dihydroxylation of 15 employing (DHQD)2-PHAL/(DHQ)2-PHAL was found to proceed with a reverse enantioselectivity than predicted from established models. Employing this approach, the key partial structures (+)-N-BOC-DA (67) and (+)-6-epi-N-BOC-DA (71) and their unnatural enantiomers were also prepared, and a study of their acid-catalyzed solvolysis reactivity, regioselectivity (3:2), and stereochemistry is detailed. Notably, the solvolysis reaction regioselectivity is lower than the characteristic adenine N3 alkylation of duplex DNA, which proceeds with exclusive nucleophilic addition to the least substituted C8 cyclopropane carbon. This may be attributed to the significant destabilizing torsional strain and steric interactions characteristic of the S(N)2 reaction of a large nucleophile that accompany the abnormal addition of adenine when restricted to the minor groove bound orientation of the reactants.
- Boger, Dale L.,McKie, Jeffrey A.,Nishi, Takahide,Ogiku, Tsuyoshi
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p. 311 - 325
(2007/10/03)
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- Duocarmycins, potent antitumor antibiotics produced by Streptomyces sp. structures and chemistry
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Seven novel potent antitumor antibiotics, duocarmycins A (1), C1 (2), C2 (3), D (4), B1 (5), B2 (6) and SA (7), were isolated from three independently collected Streptomyces sp. The complete structures, including absolute stereochemistry, were determined by spectral and chemical studies of those duocarmycins and several derivatives. Duocarmycins A (1) and SA (7) possess a 1,2,7,7a-tetrahydrocycloprop[1,2-c]indol-4-one subunit, a common pharmacophore with that of CC-1065 (10) found from Streptomyces zelensis.
- Yasuzawa,Murol,Ichimura,Takahashi,Ogawa,Takahashi,Sano,Saitoh
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p. 378 - 391
(2007/10/02)
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- Synthetic Studies on Duocarmycin. 1. Total Synthesis of dl-Duocarmycin A and Its 2-Epimer
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The title synthesis was first achieved by employing novel methoxycarbonylation of the C4-position of the 5-aminoindoline by way of the isatin and subsequent Dieckmann cyclization to the methyl 2-methylindoxyl-2-carboxylate as key steps.In vitro cytotoxicity assay against P388 murine leukemia obviously disclosed that cytotoxicities of the synthesized compounds are comparable and almost half of that of natural (+)-duocarmycin A. - Key Words: dl-duocarmycin A, dl-2-epi-duocarmycin A, total synthesis, antitumor antibiotic, cytotoxicity
- Fukuda, Yasumichi,Itoh, Yoshio,Nakatani, Kazuhiko,Terashima, Shiro
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p. 2793 - 2808
(2007/10/02)
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- Synthetic Studies on Duocarmycin. 2. Synthesis and Cytotoxicity of Natural (+)-Duocarmycin A and Its Tree Possible Stereoisomers.
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The title synthesis was achieved by featuring the optical resolution of two types of the tricyclic intermediates and the synthetic scheme established in the synthesis of racemic compounds.In vitro cytotoxicity assay against P388 murine leukemia obviously
- Fukuda, Yasumichi,Nakatani, Kazuhiko,Terashima, Shiro
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p. 2809 - 2820
(2007/10/02)
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- First total synthesis of dl-duocarmycin A
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The title synthesis could be achieved by featuring introduction of a methoxycarbonyl group into the C-4 position of a 5-aminoindoline nucleus by way of an isatin derivative and subsequent ring closure to a methyl 2-methylindoxyl-2-carboxylate system by the Dieckmann cyclization.
- Fukuda, Yasumichi,Nakatani, Kazuhiko,Ito, Yoshio,Terashima, Shiro
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p. 6699 - 6702
(2007/10/02)
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