Fredericamycin antitumor antibiotic

Studies on asymmetric total synthesis of antitumor antibiotic, fredericamycin A 98YGK963. 

The synthesis of both enantiomers of the antitumor-antibiotic fredericamycin A was achieved in the laboratory of D.L. Boger. The DE ring system of the natural product was assembled via a tandem Michael addition-Dieckmann condensation. The highly substituted 4-methylpyridine precursor was treated with excess LDA followed by the addition of the Michaei acceptor cyciopentenone. The Michael adduct underwent an intramolecular acylation with the ester functionaiity in situ to afford the desired DEF tricycie. 

The majority of reported reactions of aryl and heteroaryl substrates with organocopper reagents are examples of Stephens-Castro coupling or the more recent catalytic version of that reaction. The reaction has found recent application in syntheses of C-(6)-substituted pterins and pteridines, substituted pyridines, and the antitumor antibiotic fredericamycin A," to name a few. Aryl iodide can be che-mospecifically displaced in the presence of bromide," and 2,5-dibromopyridine is regioselectively substituted at the 2-position. Substitution of halobenzenes by propargyl alcohol, followed by oxidative cleavage, provides a convenient route to terminal arylalkynes. " Fused heterocycles are formed in reactions of aryl halides bearing nucleophilic ortho substituents. - "... 

This methodology has been elegantly utilized as a key step in a total synthesis of the antitumor antibiotic fredericamycin (Scheme 40) [80]. Thus, 1-azadiene 225 was found to react with olefin 226 to yield adduct 227 as a 1 1 mixture of stereoisomers. This compound could then be aromatized to pyridine 228. In an interesting transformation, 4-methylpyridine 228 reacts with cyclopentenone via an initial Michael addition, followed by a Claisen condensation, to afford tricycle 229. This compound could be aromatized and O-benzylated to produce ketone 230, which was homologated to nitrile ester 231. The ester functionality of 231 could be transformed to ,E-diene 232. It was then possible to utilize this DEF fragment in a sequence leading to fredericamycin. 

Fredericamycin A (18) is a structurally unique and potent antitumor antibiotic isolated from the fermentation broth of a Streptomyces griseus strain. It is active in vitro against fungi. Gram-positive bacteria, and tumor cell lines and shows in-vivo activity against P388 leukemia, CD8F ... 

In a separate communication, Kita and coworkers also reported an enantiodivergent synthesis of an ABODE ring analog of the antitumor antibiotic fredericamycin A via an intramolecular [4 + 2] cycloaddition. Late-stage oxidations were performed on the di-f-butylsilylene for protection of phenolic hydroxyl groups. Syntheses of both (R)- and (5)-enantiomers were reported (eq 18). ... 

Kita Y, Higuchi K, Yoshida Y, lio K, Kitagaki S, Ueda K, Akai S, Fujioka H. Enantioselective total synthesis of a potent antitumor antibiotic, fredericamycin A. J. Am. Chem. Soc. 2001 123 3214-3222. 

Domino reduction/aldol cydization was applied for the synthesis of ( )-fredericamydn A 44, a potent antitumor and antibiotic agent, by Kelly et al. [18] in 1988 (Scheme 9.10). DIBAL-H (diisobutylaluminum hydride) reduction of lactone 45 afforded an intermediate 46 having both enolate and aldehyde. Subsequent cychzation via aldol reaction gave a diastereomeric mixture of spiro hydroxy ketone 47, which was further converted into ( )-fredericamycin A 44 by sequential organic transformations. A similar strategy was employed by Mehta et al. [19] for the synthesis of bicyclo[3.3.1]nonan-9-one core of hyperforin, an antidepressant. 

---