Fredericamycin, total 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. 

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]. 

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. 

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

It is pertinent to mention that innumerable approaches for spiro[4,4]-nonane system have been rushed over these years [58-85], a discussion on each of them is not a desirable exercise because of the limitation of space. However, it remains to be seen, how many of these developed strategies could be successfully transformed in the total synthesis of fredericamycin A. 

The first total synthesis of fredericamycin was reported by Kelly s group [84] in 1986. The full details revealing the synthetic approaches were commensurated in... 

In the total synthesis of fredericamycin A reported by Kita et al, the condensation of dimethyl malonate anion with aryne 36 was used to construct the AB-ring system. The intermediate homophthalic esters 37 and 38 were thus obtained in a 58% combined yield with a modest regioselectivity (2 3) (Scheme 12.14) [32]. 

Scheme 1.21 A semipinacol rearrangement strategy as part of the total synthesis of fredericamycin A ri35V a...

Scheme 3.19 Wnlff rearrangement en route to the total synthesis of fredericamycin. Scheme 3.20 A Wolff-mediated Staudinger reaction.

The unprecedented architecture and biological activity of fredericamycin A (18) gave rise to numerous efforts toward the total synthesis of racemic as well as of enantiopure (S)-frederi-camycin A (18). ° i°5 Nevertheless, these synthesis pathways have rarely been used for the generation of fredericamycin A analogs or for SAR studies. We developed a semisynthetic strategy to prepare fredericamycin A derivatives with improved potency and tumor selectivity. " Because we had no initial SAR in hand, the design of the derivatives was maiidy driven by chemical... 

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. 

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. 

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