Calicheamicin

SCHEME 12.13 Synthesis of elaiophylin by Kinoshita-Toshima-Tatsuta [17]. 

1) MeCHO EtgN, MeOH then NaBH4 Et MeOgC NHa HCI 64% OHC n 

OH AC2O, EtgN DMAP, CH2CI2 V 1) HBr-AcOH. O OAc CH2CI2-AC2O V,. O.. ONB 1) NaOMe MeOH 100% ONB 

MeOH TBSCI, imidazole, CH2CI2 96% form 162 

11) NaOMe, MeOH 2) n-Bu2SnO 3) PMB-Br, CsF, DMF dimethyidioxirane YOs, CH2CI2, acetone 

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Synthesis of calicheamicin oligosaccharide dimers and their duplex DNA recognition 97YGK600. 

The cycloaromatization of enediynes, having a structure like 1, proceeds via formation of a benzenoid 1,4-diradical 2, and is commonly called the Bergman cyclization. It is a relatively recent reaction that has gained importance especially during the last decade. The unusual structural element of enediynes as 1 has been found in natural products (such as calicheamicine and esperamicine) which show a remarkable biological activity... 

The biological activity of calicheamicin 4 (simplified structure) is based on the ability to damage DNA. At the reaction site, initially the distance between the triple bonds is diminished by an addition reaction of a sulfur nucleophile to the enone carbon-carbon double bond, whereupon the Bergman cyclization takes place leading to the benzenoid diradical 5, which is capable of cleaving double-stranded DNA." ... 

Since the syntheses of urea and acetic acid in 1828 and 1845, respectively, synthetic chemists have come a long way in terms of the complexity of the target molecules they can reach. Progress was at first steady, but became rather dramatic in the second half of the 20th century. Vitamin Bi2, ginkgolide B, calicheamicin yi1, taxol, palytoxin, and brevetoxin B (Figure 3) are arguably six of the most impressive molecules to be synthesized to date. 

As impressive as the oligosaccharide domain is, calicheamici-none, the aglycon sector 7 (see Scheme 3) is the most striking substructure of calicheamicin y. The rigid bicyclic framework of 7 accommodates an unusual allylic methyl trisulfide and a novel pattern of unsaturation that had not been encountered in natural products before. 

Another critical stage in the synthesis has been reached. The previous sections have summarized the reactions leading to the synthesis of both domains of calicheamicin y[, each with the correct absolute stereochemistry and in a form suitable for further advance. We are now in a position to describe the union of key intermediates 8 and 9 (see Scheme 21). 

With the free hydroxyl groups in a suitably protected form, the introduction of the reactive allylic trisulfide triggering device can be addressed. When this advanced stage of the synthesis was reached, it was already known from the work of Magnus37 that the calicheamicin-type allylic methyl trisulfide can be formed upon... 

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. 

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