Fredericamycin A, synthesis

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. 

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. 

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. 

During the total synthesis of (+)-fredericamycin A, the spiro 1,3-dione center was introduced by R.D. Bach et al. utilizing a mild mercury-mediated semipinacol rearrangement that involved a [1,2]-acy shift. The indanone dithioacetal was reacted with 1,2-b/s[(trimethylsilyl)oxy]cyclobut-1-ene in the presence of mercuric trifluoroacetate and the rearrangement took place in situ. 

Clive and co-workers employed the 5-exo-dig radical cyclization of a selenide as a key step in their total synthesis of ( )-fredericamycin A (Scheme 4-15) [33]. 

Burgess reagent was found to be the only effective dehydroxylation method during a key intermediate for the total synthesis of fredericamycin A (86-87).26 The dehydration protocol produced the alkene in quantitative yield. However, if compound 86 is exposed to Burgess reagent in refluxing benzene, no reaction occurs. 

Boger DL (1996) Azadiene Diels-Alder reactions scope and applications. Total synthesis of natural and ent-fredericamycin A. J Heterocycl Chem 33 1519-1531... 

Draw the structure of the major enantiomer of the product from reduction of the ketone shown below, used in a synthesis of fredericamycin A. 

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