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戴伟民, Wei-Min Dai, * Jinlong Wu, Kin Chiu Fong, Mavis Yuk Ha Lee, and Chi Wai Lau
J. Org. Chem. 1999, 64, 5062-5082,-0001,():
-1年11月30日
A novel synthesis of acyclic cis-enediynes 2 has been established by an acid-catalyzed rearrangement of 1,2-diyn-2-propen-1-ols 1 possessing a C3-aryl group in the presence of water, alcohols, or thiols. Reactivity of allyl alcohols and regio- and cis/trans diastereoselectivity of the allylic migration were examined. In the presence of (±)-10-camphorsulfonic acid (CSA), the parent allyl alcohol 5 and the C3-methyl-substituted 9 failed to give enediynes, whereas the C3-aryl-substituted 12 and 29 underwent the allylic rearrangement to provide predominantly cis-enediynes 16 and 31 at room temperature or below. Under similar acidic conditions, enediyne alcohol 13 produced 16b and 16d with the same regio- and cis/trans diastereoselectivity observed for 12. Allyl alcohol 30, an isomer of 29, also provided enediynes 31c and 32c after a prolonged reaction (90h) at room temperature in the presence of CSA and EtOH. These results suggested that the same allylic cations were obtained from allyl alcohols 12 and 13 or 29 and 30 even though the ease of ionization differed for each substrate. Involvement of allylic cations in the product-forming step was confirmed by the finding that chiral allyl alcohols (-)-12 and (-)-18c furnished racemic products. In general, the p-MeOPh-substituted allyl alcohol 29 gave a better regioselectivity than the Ph-substituted 12. In the reactions with alcohols, the regioisomeric ratios were 100:0 (31:33) for 29 and ca. 96:4 (16:17) for 12; the ratios decreased to ca. 90:10 (31:33) for 29 and ca. 70:30 (16:17) for 12 when thiols were used. The cis/trans diastereoselectivity is higher for allyl alcohol 12 (100% for 16 at 20℃) compared to that for 29 (31:32) 80:20-94:6 at 0℃). Computational calculations at the RHF/3-21G level, carried out on the model compounds and allylic cations, indicated that nucleophilic trapping takes place preferentially at the C3 carbon to form the thermodynamically much more stable enediynes. Under the best reaction conditions (1 equiv of CSA and 2 equiv of EtOH in CH2Cl2, 20℃), a number of acyclic cis-enediynes can be synthesized in three steps from the commercially available R-bromocinnamaldehyde (10).
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戴伟民, W.-M. Dai, *, C. W. Lau, S. H. Chung, and Y.-D. Wu
J. Org. Chem. 1995, 60, 8128-8129,-0001,():
-1年11月30日
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戴伟民, K. C. Nicolaou, *, †, ‡, W.-M. Dai, Y. P. Hong, S.-C. Tsay, K. K. Baidridge, § and J. S. Siegel‡
J. Am. Chem. Soc. 1993, 115, 7944-7953,-0001,():
-1年11月30日
ica gel in wet benzene. Kinetic studies used to determine the free energies of activation (AG*) for the cycloaromatization of 8 (22.6kcal/mol, 30℃) and 9 (25.7kcal/mol, 37℃) to products 32 and 33, respectively. Ab initio calculations regarding the reactivity of these systems were in agreement with the experimental findings. The isolation of compounds 8, 9, 30, and 31 provide strong support for the postulated intermediates in the dynemicin A reaction cascade. The physical, chemical, and biological profiles of the reported compounds may provide the basis for further applications in mechanistic, biological, and medical studies.
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戴伟民, K. C. Nicolaou, * W.-M. Dai, S.-C. Tsay, V. A. Estevez, W. Wrasidlo
SCIENCE ,-0001,():
-1年11月30日
The rational design and biological actions of a new class of DNA-cleaving molecules with potent and selective anticancer activity are reported. These relatively simple enediyne-type compounds were designed from basic chemical principles to mimic the actions of the rather complex naturally occurring enediyne anticancer antibiotics, particularly dynemicin A. Equipped with locking and triggering devices, these compounds damage DNA in vitro and in vivo on activation by chemical or biological means. Their damaging effects are mani-fested in potent anticancer activity with remarkable selectivities. Their mechanism of action involves intracellular unlocking and triggering of a Bergman reaction, leading to highly reactive benzenoid diradicals that cause severe DNA damage. The results of these studies demonstrate the potential of these de novo designed molecules as biotechnology tools and anticancer agents.
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戴伟民, K. C. Nicolaou*, †, ‡ and W.-M. Dai†, §
J. Am. Chem. Soc. 1992, 114, 8908-8921,-0001,():
-1年11月30日
Continuing the theme of the preceding article, this paper describes the synthesis and chemical properties of designed enediynes related to dynemicin A. These model systems are equipped with triggering devices at C-3 of the aromatic nucleus. The design of these compounds (1 and 2) was based on the hypothesis that a C-3 phenolic group generated in situ would be capable of promoting epoxide opening and subsequent Bergman cycloaromatization according to the dynemicin A cascade. Compound 1 carrying a tert-butyl ester group at C-3 was synthesized from quinoline derivative 28 via the sequence 28 36→45→46→47→48→44→49→50→1. Compound 2 carrying the photoremovable (2-nitrobenzyl)oxy group at C-3 was constructed from quinoline 29 by a similar sequence. Exposure of I and 49 to aqueous LiOH in EtOH led to Bergman cycloaromatization products 58 and 57, respectively. Compounds 2 and 62 bearing the 2-nitrobenzyl group at C-3 were photolytically converted to free phenolic systems 63 and 64, respectively. Reaction of 63 and 64 with the nucleophiles EtOH, EtSH, or nPrNH2 under anaerobic conditions in basic buffer solutions led to aromatized products 66-70. Exposure of 63 and 75, on the other hand, with EtOH under aerobic conditions in basic buffer solutions furnished the novel quinone methide epoxide systems 71 and 76-77, respectively. The chemistry of compounds 63 and 64 combined with their DNA-cleaving capabilities provides support for the quinone methide mechanism of action of dynemicin A.
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