Dynemicin, total synthesis

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... 

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. 

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. 

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. 

Schreiber et al. have been able to apply their enediyne intramolecular Diels-Alder approach to the synthesis of dynemicin model systems [268-270], culminating in the total synthesis of di- and tri-O-methyl dynemicin A methyl esters 388 and 389 (Scheme 7-78) [271], derivatives of the natural product itself. Highlights of this synthetic approach include (a) intramolecular lactonization and concomitant Diels-Alder cyclization (380- 381) (b) allylic hydroxylation followed by an allylic diazene rearrangement in order to regiospecifically isomerize a double bond (381 - 382) (c) a-hydroxylation of the lactone 381 and subsequent conversion to the P-ketoester 383 (d) annelation of the anthraquinone unit (383- 384- 385- 386) (e) mild base-induced P-elimination of the N-protecting group of 386 to give the free amine 387 and (f) a final oxidation to complete the anthraquinone (387 - 388). 

Two recently synthesized oligosaccharide-containing forms of calicheomycin Yi bind strongly to certain duplex DNA sequences. Danishefsky has published a long paper on the details of his total synthesis of this compound and of dynemicin A, including the carbohydrate components. ... 

Scheme 10. Final stages and completion of Myers total synthesis of dynemicin A (1).

Having accomplished the synthesis of both coupling partners, the final steps of the projected total synthesis of dynemicin A (1) were explored immediately, starting, of course, with the merger of the DE subunit with the enediyne-containing tricycle 23. Thus, as shown in Scheme 15, the homophthalic anhydride (95) was treated with... 

Although the Myers and Danishefsky groups were the first to complete total syntheses of dynemicin A (1), the core architecture of the entire natural product had, in fact, been completed several months earher by Professor Stuart L. Schreiber and his group at Yale University (now at Harvard University). All that separated the advanced stracture synthesized by these researchers (107, Scheme 16) from the final target were three phenolic methyl ethers, which, unfortunately, proved resilient to cleavage. As such, the developed route cannot constitute a total synthesis in the strict sense of the definition. However, based on our discussion above, the accomplishment of even this advanced compound is certainly laudable, and, for this reason, this work is included here because it provides an alternative and especially creative solution for the construction of the key architectural elements of dynemicin A. 

Benzyloxypropyl chloroformate 106, a useful reagent in the total synthesis of di-and tri-O-methyl Dynemicin A methyl esters, was prepared by syringe pump addition (over 2 h) of 3-benzyloxypropanol 105 (2.9 equiv.) and pyridine (3.0 equiv.) to a solution of triphosgene in dichloromethane at 0 °C [59]. 

This a-bond insertion reaction with anionic nncleophUes has been nsed in the context of the total synthesis of dynemicin A. The reaction of an aiyne, genraated from the LTMP metalation of a bro-moarene, with lithiated dimethylmalonate leads to homophthaUc ester 78 with a significant 71% yield (Scheme 12.41) [68]. 

SCHEME 2 Key step of a total synthesis of dynemicin A by Danishefsky et al7 It features sequential Stille couplings of the cw-configuied ethene-l,2-distannane cw-10. Its coupling partners are two constitutionally different iodoalkyne moieties of substrate 14. 

Your team is studying the problem of an intramolecular ring closure of enediyne systems important in the total synthesis of dynemicin A, which exhibits potent antitumor activity. 

Even higher selectivity was observed for the addition of (Z)-enediyne 43 to quinoline 42, which proceeds in 89% yield and >25 1 dr (Scheme 11.4) [58]. Myers utilized adduct 44 as a key intermediate in a total synthesis of the enediyne antibiotic dynemicin A (45). 

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... 

---