Fredericamycine

The total syntheses of fredericamycin 71 and camptothecin 72 made use of similar strategies. N-Sulfonyl-l-aza-1,3-butadienes in conjunction with electron rich dienophiles participated in the inverse electron demand Diels-Alder reaction to afford pyridines after treatment with base. 

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

Intensive studies towards the total synthesis of fredericamycin A 91 culminated in the enantioselective synthesis of this potent antitumour antibiotic [63]. 

Boger D. L. Azadiene Diels-Alder Reactions Scope and Applications. Total Synthesis of Natural and Ehr-Fredericamycin A J. Heterocycl. Chem. 1996 33 1519-153. 

Benzo[c]furans (isobenzofurans) are reactive molecules usually employed as reactive dienes in the synthesis of more complex molecules. In the synthesis of spiro compounds related to fredericamycin A, Kumar generated the trimethylsiloxytrimethylsilylbenzo[c]furan 125 from phthalide via two consecutive deprotonations and silylations of the resulting anions. Diels-Alder reaction of the isobenzofuran as shown below with a spiroenedione leads to the formation of an endo-exo mixtures that can be smoothly converted to the dihydroxydione <00IJC(B)738>. 

Fig. 2.26. Synthesis of fredericamycin A utilizing a Dotz benzannulation reaction [268].

Despite the many limitations, the Dotz benzannulation remains a powerful tool for the preparation of substituted phenols. One example of the use of a Dotz benzannulation as the key step in a synthesis of the potent natural antibiotic fredericamycin A (as racemate) is sketched in Figure 2.26. 

Fredericamycin has a remarkable structure two aromatic systems join at a chiral spiro centre in a compound with exceptional anticancer activity. The first total synthesis3 drew heavily on directed metallation chemistry for the synthesis of the lower portion of the molecule. 

Fredericamycin is a curious aromatic compound extracted in 1981 from the soil bacterium Streptomyces griseus. It is a powerful antibiotic and antitumour agent, and its structure is shown below. The first time it was made in the laboratory, in 1988, the chemists in Boston started their synthesis with three consecutive lithiation reactions two are ortholithiations, and the third is slightly different. You needn t be concerned about the reagents that react with the organolithiums just look at the lithiation reactions... 

ABCDE-ring analog of fredericamycin A was prepared using an intramolecular [4 - - 2] cycloaddition of a cobalt-complexed alkyne (Scheme 242). 

The preparation of a-selenoketones, esters, nitriles and related compounds can easily be performed via alkylation of the corresponding enolates or stabilized carbanions [21]. These compounds have found many synthetic applications in radical chemistry. In Eq. (9), a typical example involving a ketone is depicted [22]. The stability of a-selenoketones such as 41 is remarkable. Similar reactions with lactones have been performed. For instance, this approach has been applied to the stereoselective synthesis of oxygen-containing rings to either faces of a bicyclic structure [23]. The approach based on a-selenenylation/radical allyla-tion compares favorably with classical enolate allylation procedures, which usually leads to mixture of mono- and diallylated compounds. Furthermore, this strategy is excellent for the preparation of quaternary carbon centers [24] as shown by the conversion of 43 to 45, a key intermediate for the synthesis of fredericamycin A, [Eq. (10)] [25]. Similar reactions with sulfoxides [26] and phosphonates [27] have also been reported. 

W.H. Moser and co-workers developed a new and efficient method for the stereocontrolled construction of spirocyclic compounds, including the spirocyclic core of the antitumor agent fredericamycin The strategy involved a one-pot aldol additioniBrook rearrangement cyclization sequence beginning from arene chromium tricarbonyl complexes and can formally be described as a [3+2] annulation. 

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. 

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