Esperamicins

Esperamicin Ai (2) and related members of this family, originating mainly from chemical hydrolysis or nuclephilic attack inducing the cycloaromatization, were 

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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... 

Scheme 20. Sonogashira couplings in Magnus s calicheamicin/esperamicin model study.

Several novel natural products with an intriguing system containing the cis-endiyne moiety have attracted considerable attention from chemists in recent years. Several derivatives with this characteristic skeleton have now been isolated neocarzinostatin,96 esperamicin,97 calicheamicin y. 9S and dynemicin Ai." The high antitumor activity of these compounds is based on an elegant... 

Bicyclic Core of the Esperamicin/Calichemicin Class of Antitumor Agents... 

The use of vinylallenes as the diene component in Diels-Alder reactions is very common, thus resulting in their ubiquitous use in natural product synthesis. A vinylal-lene has even been proposed by Schreiber and Kiessling [10] as a biogenetic intermediate in the synthesis of the skeleton of esperamicin A (32 —> 33). Their synthetic approach to esperamicin A (34) was modeled after this biogenetic proposal in which a Type II intramolecular Diels-Alder cycloaddition was used to gain access to the highly unsaturated bicyclic core of 34 (Scheme 19.8) [10]. 

The availability of ctetq) advanced synthons that carry the required chirality is an advantage, particularly in projects aimed at industrial total synthesis. Natural products are often used as synthons, ideally fi om a renewable source, such as microbial fermentations. In a few cases, biotechnology has become an ahemative source. The total theses of the antitumor agent esperamicin A and the immunosuppressant FK-506 are exanq>les. In both cases, the synthon was quinic acid (Barco 1997), cheaply obtained by biotechnology (Chapter 14.1.e) rather than fi om the environmentally noxious extraction fi om the bark of Cinchona spp. Used to build up combinatorial libraries, quinic acid has gained further inq)ortance in organic thesis (Phoon 1999). 

In the synthesis of analogues of calicheamicin 71 and esperamicin Ajb, Moutel and Prandi employed the glycosyla-tion of a nitrone with a trichloroacetimidate as a key step - /3-N-O glycosidic bond formation. Preparation of the nitrone begins with the alkylation of the known alcohol 69 <1992CC1494> with 1,4-dibromobutane in the presence of sodium hydride. Subsequent aminoalkylation, amine protection with 9-fluorenylmethoxycarbonyl (Fmoc), and reduction with NaBHsCN were followed by nitrone 70 formation with 4-methoxybenzaldehyde (Scheme 8) <2001J(P1)305>. 

The DNA-binding antibiotics, neocarzinostatin (NCS), dynemicin, calicheami-cin and esperamicin have all in common that they have an enediyne as a structural element, although they are otherwise very different (for a review see Nico-laou and Dai 1991). Their formulae are given in Fig. 12.13. 

H-atoms (Mertens and von Sonntag 1994). In contrast to BLM, where H4 is attacked, it is mainly the H5 that is abstracted by NCS. This points to a highly stereoselective topochemical reaction, since the tertiary HI and H4 would be the thermodynamically, and at equal accessibility, also the kinetically favored targets. This is supported by marked differences between esperamicin A and esperamicin C (Epstein et al. 1997). The former cleaves only at C(5 ) while the latter also cleaves at C(4 ). 

Yu L, Golik J, Harrison R, Dedon P (1994) The deoxyfucose-anthranilate of esperamicin A1 confers intercalative DNA binding and causes a switch in the chemistry of bistranded DNA lesions. J Am Chem Soc 116 9733-9738... 

Figure 11.3 shows the result on the direct observation by NMR of the interaction between duplex DNA and esperamicin. Thus, the planer aglycone group E in esperamicin intercalates between Cl - -G2 and C6 - -G3 of the duplex DNA, and the... 

The following are examples of other generation methods of the same kind of reactive sp2 carbon-centered radicals. Treatment of aromatic diazocarboxylate ester (11) at pH 7.2 forms the phenyl radical, through hydrolysis of the ester, decarboxylation to the phenyldiimide, and finally, reaction with molecular oxygen (eq. 11.9a). Electron transfer reduction of 1,4-diazonium (12) with Cu+ generates the corresponding /7-phenylene biradical (probably step-by-step formation) (eq. 11.9b). These simple sp2 carbon-centered radicals also destroy DNA plasmid at pH 7.6, under living-body conditions, like esperamicin [37-39]. 

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