Fredericamycin 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. 

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... 

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]. 

Homophthalic anhydrides undergo a strong-base induced [4 - - 2] intra- or intermolecular cycloaddition reaction with dienophUes to afford various types of polycyclic peri-hydroxy aromatics in a single step (equation 123). This elegant strategy has been employed in the synthesis of many biologically important compounds such as fredericamycin galtamycinone and dynemycin A. ... 

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. 

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. 

This chapter has attempted to present a thorough overview of alkaloid syntheses in which free-radical cyclizations have played a pivotal role. It is not meant to be a comprehensive review, but focusses on syntheses in which nitrogen plays a clear role in the cyclization process, either as an attenuator of radical reactivity (Sections 4,1.2 and 4.1.3), a tether (Section 4.1.4), or a radical acceptor (Section 4.1.5). Several other notable alkaloids syntheses have been reported in which carbocyclizations play the pivotal role and introduction of nitrogen is secondary, for example Sha s syntheses of (-)-dendrobine [76] and (-t-)-paniculatine [77], and Clive s synthesis of (+)-fredericamycin [78]. Syntheses in which nitrogen-centered radicals play a critical role are also known, such as the Zard synthesis of (—)-dendrobine [79]. My apologies to these authors for not elaborating on their fine contributions, to authors who have nicely used intermolecular radical addition reactions in alkaloid synthesis, and to others whose contributions may have escaped my attention. 

Scheme 25 Synthesis of spiro-compounds related to fredericamycin according to Moser...

Alkoxyoxazoles have also proven to be valuable heterodienes in the synthesis of highly substituted furans and biologically active natural products via oxazole-aUtyne Diels-Alder reactions. Thus the synthesis of a synthon for the DEF ring system of fredericamycin began with the cycloaddition of 5-ethoxy-4-methyl-oxazole 8 with enyne ester 149 (Fig. 3.45). This reaction proceeded in 24 h in refluxing toluene to afford a 65% yield of the 2-ethoxyfuran 150. Furan 150 was then converted to the isoquinoline 151 in six steps. ... 

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

---