Duocarmycine

Boger et al. prepared Duocarmycin SA via asymmetric epoxidation of a cyclic olefin 54." The stereochemistry set by the epoxidation step was used for subsequent C-C bond forming reactions. Epoxidation of olefin 54 was carried at -78°C to provide... 

Syntheses of duocarmycins and related antibiotics 97CRV787, 98YZ353. 

Shape-dependent catalysis for the CC-1065 and duocarmycin DNA alkylation reaction 99ACR1043. 

Due to the prevalence and diversity of indole alkaloids and the limitations of space, no attempt will be made to describe all of the synthetic efforts in this area. However, noteworthy synthetic achievements include a synthesis of gelsemine <96JA7426>, (+)-duocarmycin by... 

DNA alkylation has the potential to yield a time-dependent spectrum of adducts, in which initially formed kinetically favored lesions give way to the thermodynamically favored adducts over time. Reversible alkylation has been observed at several of the nucleophilic sites in DNA, including N3A (CC-1065,7, Scheme 8.10, duocarmycin, 8)," " NIA (qui-none methide, 9)," N7G (leinamycin, Schane 8.11, aflatoxin Bj epoxide, 10 and quinone methide, 9),57.ii4.ii8 (quinone methide, 9)," and bPG (ecteinascidin 743,11)." The bidentate Nl/ISPG adduct of malondialdehyde also forms reversibly. ... 

Boger, D. L. Johnson, D. S. CC-1065 and the duocarmycins understanding their biological function through mechanistic studies. Angew. Chem. Int. Ed. 1996, 35, 1438-1474. 

Asai, A. Nagamura, S. Saito, H. Takahashi, I. Nakano, H. The reversible DNA-alkylating activity of duocarmycin and its analogue. Nucleic Acids Res. 1994, 22, 88-93. 

The last step of the total synthesis of natural (+)-duocarmycin SA, a potent antitumor antibiotic, was accomplished by forming the amide bond with CDI in 74% yield [60]... 

This inverse correlation has been noted in other instances of biological activity. The cytotoxic activity of a range of duocarmycin analogues behaved similarly. ... 

In a series of papers, rich in chemistry, Natsume has parlayed the intramolecular Heck reaction with 137 and 138 into an elegant construction of (+)-duocarmycin SA and related compounds [96-99],... 

Likewise, Sakamoto has synthesized the CC-1065/duocarmycin pharmacophore 284 via the cyclization of 282 [321]. Silver carbonate prevented unwanted isomerization of the exocyclic double bond in 283. Tietze and co-workers took full advantage of the power of these A-allyl-o-haloaniline Pd-catalyzed cyclizations in developing syntheses of the A-unit of CC-1065 and analogs [322-324]. 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

The crystal structures of the tricyclic ABC-ring fragments of the duocarmycin family of antitumor agents have been reported <1997JA4977>, as has the crystal structure of a diindocarbazole derivative <2000J(P2)2337>. 

The 8-0-trifluoromethanesulfonate substituent on the aromatic B-ring of the duocarmycin derivative DU-86 78 can be replaced in acceptable yields using either palladium(0)-catalyzed reduction or cyanation with tributyltin cyanide (Equation 16) <1996BMC1379>. 

Duocarmycin derivative 99 does not undergo formylation under Vilsmeier conditions at the expected position in the A-ring, but instead is formylated at the amine group of the C-ring although no yields are reported for this transformation <2000BMC1195>. 

Treatment of duocarmycin segment A derivative 99 with hexamethylenetetramine (HMT) in TEA gives the novel ring structure 139 (Equation 38) <2000BMC1195>. 

The tricyclic core of duocarmycin has been produced by a novel copper-mediated aryl amination reaction, which cleanly gives the cyclized product under exceptionally mild conditions <2003JA6630>. Selective /) tw-bromination of indoline with T-bromosuccinimide (NBS) in DMF followed by aryl amination using 2 equiv of copper iodide quantitatively provides the indolinone (Equation 71). 

A novel approach to the construction of the duocarmycin core has involved the formation of the cyclopropane ring and the five-membered C-ring by an intramolecular ring contraction <1998CPB400, 2004OL2953>. Thus, treatment of the dihydroquinoline 210 with potassium carbonate in methanol gives the tetracyclic product 211 (Equation 141). 

Carbenoid additions to y,y-difluoroallylic compounds represent valuable methodology complementary to the difluorocarbene chemistry described in Sect. 2.1. One example was provided by Boger and Jenkins [353] at Scripps during a synthesis of a duocarmycin analogue. Intramolecular rhodium-catalysed carbenoid addition of a p-quinonediazide to a protected difluoroallylic amine formed a key intermediate (Eq. 137). 

Pyrroles, H.M.L. Davies. Synthesis of Porphyrins with Exocy-clic Rings from Cycloalkenopyrroles, T.D. Lash. Palladium-Catalyzed Coupling Reactions of Indoles, A.R. Martin and Q. Zheng. Cycloaddition Reactions of Indole Derivatives, U. Pindur. Transition-Metal Mediated Synthesis of Carbazole Derivatives, H. J. Knoiker. Synthesis of [b]-Annelated Indoles by Thermal Electrocyclic Reactions, S. Hibino and E. Sugi-no. Total Synthesis of (-) and ent (-) Duocarmycin SA, D.L. Boger. Index. I... 

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