Dynemicin synthesis

Lewis-acid-catalyzed Diels-Alder reaction of 3-phenylthio-2- quinolinones with silox-ydiene. Synthesis of the intermediate for dynemicin A core [97]... 

Wender PA, Zercher CK, Beckham S, Haubold EM (1993) A photochemically triggered DNA-cleaving agent - synthesis, mechanistic and DNA cleavage studies on a new analog of the antitumor antibiotic dynemicin. J Org Chem 58 5867-5869... 

Double oxidation reactions of aminophenols (127) to the corresponding quinone-imines (128) using PIDA and PIFA were utilized for total synthesis of an enediyne antibiotic, ( )-dynemicin A (6), by Danishefsky and co-workers... 

Scheme 4. Sonogashira reactions in the synthesis of 6-[2-(2,5-dimethoxyphenyl)ethyl]-4-ethylquinazoline 13, terbinafine 14 and dynemicin A IS.

Both BTI and DIB have been used in key-steps involving phenolic oxidation to quinone imines in the total synthesis of ( )-dynemicin A [12]. 

Substituted benzo[c]furans played a very important role in the quest for natural as well as non-natural molecules. The schemes depicted here are examples showing the use of substituted benzo[f]furans in the synthesis of complex molecules. A short synthesis of ( )-halenaquinone 173 was reported <2001JOC3639>, in which the pivotal step was the Diels-Alder cycloaddition of 4,7-dimethoxybenzo[f]furan 171 to 172, as illustrated in Scheme 62. In a similar manner, the total synthesis of ( )-xestoquinone, ( )-9-methoxyxestoquinone, ( )-10-methoxyxestoquinone <2001T309>, and the naphtho[2,3- ]quinoline portion of dynemicin A <1997JA5591> was also achieved. 

Diels-Alder cycloaddition between l,4,7-tris(trimethylsilyloxy)benzo[f]furan 174 and the dienophile 175 was also the key step in the total synthesis of (+)-dynemicin A 176 reported by Myers <1997JA6072>, as can be seen in Scheme 63. 

During a synthesis of quinone imine precursors to the Dynemicins, Myers and co-workers100 encountered problems with the lability of the dimethyl acetal function in 56,1 [Scheme 1.56] whilst removing the robust phenolic methyl group using sodium ethanethiolate in hot DMF, However prior conversion of the free hydroxy function in the substrate to the magnesium salt 56.2 by reaction with ethylmagnesium bromide afforded protection for the dimethylacetal under the strenuous conditions of nucleophilic demethylation. 

Rather more conventional means were used to remove an alkyl silyl ether in the presence of an ary silyl ether in a synthesis of Dynemicin Here the task was simply accomplished with HF in acetonitrile [Scheme 4.56].92 Acidic conditions also prevailed in a synthesis of Doliculide wherein an alkyl tert-butyl ether, a tert-butyl ester and an N-fert-butoxycarbonyl group were cleaved simultaneously without challenge to the remaining aryl silyl ether [Scheme 4.57] ... 

In a synthesis of a Calicheamicin-Dynemicin hybrid, Nicolaou and co-workers209 removed an Fmoc group in the presence of the base-sensitive 2-(phenylsulfonyl)-... 

Nicolaou, K C, Schreiner, E P, Iwabuchi, Y, Suzuki, T, Total synthesis of calicheamicin dynemicin hybrid molecules, Angew. Chem. Int. Ed. Engl, 31, 340-342, 1992. 

S. L. Schreiber et al. carried out the total synthesis of the potent cytotoxin (+)-tri-0-methyl dynemicin A methyl ester. The key step was a regioselective Friedel-Crafts alkylation of an extremely sensitive aromatic enediyne with 3-bromo-4,7-dimethoxyphthalide. The coupling of these two fragments took place in the presence of silver triflate at 0 °C in 1 minute, and after methylation, gave a 1 1 mixture of diastereomers in 57% yield. 

The total synthesis of (+)-dynemicin A was achieved by S.J. Danishefsky et al. As part of the synthetic studies, highly sensitive enediyne containing quinone imine systems were prepared, and their biological properties were evaluated. The first step in the sequence leading to one such quinone imine began with the oxidation of the nitrogen of the phenanthridine substrate, and the resulting A/-oxide was heated in neat acetic anhydride to induce the Polonovski reaction. 

In the first reported simplified dynemicin analogs a carbamate, which is not easily removable, was present (R = Me, Ph etc), thus requiring a hydride-promoted reduction as the triggering event. However, the employment of a moiety that is easily removed, possibly under physiological conditions, spread rapidly. This substructure is usually introduced at the end of the synthesis, by an exchange reaction on the carbamate best suited... 

A dynemicin A analog resembling also the calicheamicin structure has been synthesized by Magnus et al. In this case the epoxide is not present and the role of safety catch is played by the carbonyl on the shortest bridge. The synthesis of 101 (Scheme 19.27) is achieved exploiting the reaction... 

Guanti, G. Riva, R. Simplified dynemicin analogues diastereoselective synthesis and evaluation of their activity against plasmid DNA. Org. Biomol. Chem. 2003, 1, 3967 3976. 

Banfi, L. Basso, A. Gandolfo, V. Guanti, G. Riva, R. Asymmetric synthesis of a new simplified dynemicin analogue equipped with a handle. Tetrahedron Lett. 2004, 45, 4221 4223. 

Unno, R. Michishita, H. Inagaki. H. Baba. Y. Jomori, T. Nishikawa, T. Isobe, M. Synthesis and biological evaluation of novel cyclic enediyne compounds related to dynemicin A as antitumor agents. Chem. Pharm. Bull. 

Shair, M.D. Yoon, T. Chou, T.-C. Danishefsky, S. J. Enediyne quinone imines truncated biologically active dynemicin congeners. Angew. Chem., Int. Ed. Engl. 1994, 33, 2477-2479 Shair, M.D. Yoon, T.Y. Mosny, K.K. Chou, T.C. Danishefsky, S.J. The total synthesis of dynemicin A leading to development of a fully contained bioreductively activated enediyne prodrug. J. Am. Chem. Soc. 1996. 118, 9509-9525. 

Knowing the structure and the mechanism of action of dynemicin A, and exploiting pre-vous experience in the synthesis of compounds of this class, Nicolaou and co-workers [13] have designed a new series of compounds to mimic but improve on the naturally occurring drug, and succeeded in obtaining powerful anticancer compounds such as 2, that are of much simpler structure and easier to synthesize. 

Once the structures of the first natural enediyne antibiotics had been elucidated, the scientific community was quick to respond. The mechanisms by which these molecules exert their effects continue to be probed ever deeper, with surprising new details still emerging. The hitherto unprecedented and structurally complex molecular architecture of the natural products has required the development of new synthetic methodology in order to synthesize functional models which would shed new light upon the natural enediyne antibiotics. Researchers in the field have pushed the art of organic synthesis to its present limits with total syntheses of calicheamicin yj (2), the most prominent member of the natural enediyne antibiotics, and a derivative of dynemicin A (4) having been achieved. Furthermore, the factors affecting the... 

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