Total synthesis of calicheamicin

The total synthesis of calicheamicin y/ by the research group of K. C. Nicolaou (The Scripps Research Institute, University of California, San Diego) represents a stunning achievement in synthetic organic chemistry. 

Nicolaou, K C, Schreiner, E P, Iwabuchi, Y, Suzuki, T, Total synthesis of calicheamicin dynemicin hybrid molecules, Angew. Chem. Int. Ed. Engl, 31, 340-342, 1992. 

CH2CI2) and was subsequently proved to be of the same absolute stereochemistry as that in calicheamicin yj (2) by conversion of an advanced intermediate through to the natural product itself [77] (see Section 7.4.2.4). Perhaps the key feature of this synthesis is that it readily yielded the multigram quantities of enantiomerically pure advanced intermediates necessary for the completion of the total synthesis of calicheamicin yf (2). 

Success finally came to the Nicoaou group in September 1992 when they completed the first total synthesis of calicheamicin yf (2) as outlined in Scheme 7-65 [77, 227, 229, 247]. Utiliz-... 

Clive and coworkers have reported a total synthesis of calicheamicinone, the aglycon of the antitumor agent calicheamicin starting from the Diels-Alder reaction of methyl 3-nitro-propenoate with ketene acetal (Eq. 8.32).54 An asymmetric Diels-Alder reaction between ketene acetal presented in Eq. 8.32 and 3-nitropropenoate derived from (-)-8-phenyl-menthol affords the optically pure adduct, which can be converted into either enantiomer of calicheamicinone (Eq. 8.33).55... 

It is noteworthy that Jones and Darby, who pioneered the enediyne rearrangement, now known as the Bergman rearrangement, and Nicolaou, who achieved the first total synthesis of the enediyne antibiotic calicheamicin 7 / were under the joint supervision of Profs. Franz Sondheimer and Peter Garratt. It might seem that all researchers in the enediyne field have been influenced by Sondheimer and Garratt. 

Nicolaou s total synthesis of the enediyne antibiotic, calicheamicin 71 [19], (Scheme 12.15 to Scheme 12.19) involves several new aspects in carbohydrate chemistry. The calicheamicin 71 oligosaccharide synthesis began with the construction of the D-ring intermediate from L-rhamnose. Thus, L-rhamnose 112 was converted into the glycosyl donor, trichloroacetimidate 118, through the... 

Once the structures of the first natural enediyne antibiotics had been elucidated, the scientific community was quick to respond. The mechanisms by which these molecules exert their effects continue to be probed ever deeper, with surprising new details still emerging. The hitherto unprecedented and structurally complex molecular architecture of the natural products has required the development of new synthetic methodology in order to synthesize functional models which would shed new light upon the natural enediyne antibiotics. Researchers in the field have pushed the art of organic synthesis to its present limits with total syntheses of calicheamicin yj (2), the most prominent member of the natural enediyne antibiotics, and a derivative of dynemicin A (4) having been achieved. Furthermore, the factors affecting the... 

The first total synthesis of the calicheamicin aglycone (222, calicheamicinone) was finally achieved in 1990 by Danishefsky and co-workers [217-223]. Their synthesis, shown in Scheme 7-48, was a major achievement in this field. Key steps in the sequence, which begins... 

Total synthesis of the calicheamicin aglycone (Danishefsky and co-workeis). 

Scheme 7-S7 Total synthesis of the calicheamicin y, oligosaccharide as its methyl J...

The completion of the total synthesis only requires a few deprotection steps. It was gratifying to find that the final deprotections could be conducted smoothly and without compromising the newly introduced and potentially labile trisulfide residue. In particular, exposure of intermediate 101 to the action of HF pyridine results in the cleavage of all five triethylsilyl ethers, providing 102 in 90% yield (Scheme 23). Finally, hydrolytic cleavage of the ethylene ketal with aqueous para-toluenesulfonic acid in THF, followed by removal of the FMOC protecting group with diethylamine furnishes calicheamicin y (1) (see Scheme 24). Synthetic calicheami-cin y, produced in this manner, exhibited physical and spectroscopic properties identical to those of an authentic sample. 

In the domain of cancer therapy. Nature has been an especially generous benefactor. The first volume of Classics in Total Synthesis describes two signature events in this regard first, the isolation of Taxol , an agent which induces apoptosis in dividing cells by effecting tubulin polymerization, and second, the discovery of the enediyne class of antitumor antibiotics such as calicheamicin y which effect lethal, double-strand cuts on DNA through the forma-... 

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