Enediyne

The coupling reaction has widespread use in the construction of enediyne systems present in naturally occurring anticancer antibiotics[234]. The Pd-Cul catalyzed coupling reaction of the alkenyl bromides 323 and 326 with the... 

Both chlorines of 1,1-dichloroethylene (340) react stepwise with different terminal alkynes to form the unsymmetrical enediyne 341 [250]. The coupling of the dichloroimine 342 with tin acetylide followed by hydrolysis affords the dialkynyl ketone 343[2511. The phenylthioimidoyl chloride 344 undergoes stepwise reactions with two different tin acetylides to give the dialkynylimine 345[252],... 

The cyclization of the enediynes 110 in AcOH gives the cyclohexadiene derivative 114. The reaction starts by the insertion of the triple bond into Pd—H to give 111, followed by tandem insertion of the triple bond and two double bonds to yield the triene system 113, which is cyclized to give the cyclohexadiene system 114. Another possibility is the direct formation of 114 from 112 by endo-rype. insertion of an exo-methylene double bond[53]. The appropriately structured triyne 115 undergoes Pd-catalyzed cyclization to form an aromatic ring 116 in boiling MeCN, by repeating the intramolecular insertion three times. In this cyclization too, addition of AcOH (5 mol%) is essential to start the reaction[54]. 

Beginning in the 1980s research directed toward the isolation of new drugs derived from natural sources identified a family of tumor inhibitory antibiotic substances characterized by novel struc tures containing a C C—C=C—C C unit as part of a nine or ten membered ring With one double bond and two triple bonds (-ene + di- + -yne) these com pounds soon became known as enediyne antibiotics The simplest member of the class is dynemian A most of the other enediynes have even more compli cated structures... 

Enediynes hold substantial promise as anti cancer drugs because of their potency and selectivity Not only do they inhibit cell growth they have a greater tendency to kill cancer cells than they do normal cells The mechanism by which enediynes act involves novel chemistry unique to the C C—C=C—C C unit which leads to a species that cleaves DNA and halts tumor growth... 

Enediyne antibiotics (Section 9 4) A family of tumor inhibit mg substances that is characterized by the presence of a C=C—C=C—C = C unit as part of a nine or ten membered nng... 

In spite of the fact that few cycloalkynes occur naturally, they gained recent attention when it was discovered that some of them hold promise as anticancer drugs. (See the boxed essay Natural and Designed Enediyne Antibiotics following this section.)... 

Design and synthesis of analogs of dynemycin, antitumor antibiotic with an-thraquinone, 10-member enediyne, tetrahydropyridine, and oxirane fragments 99EJ01. 

Enediynes with ethylene carbonate fragment in the synthesis of dienediyne models of the biradical-forming and DNA-cleaving natural neocarzinostatin chromophore 99SL657. 

Bis(alkynyl)-l//-pyrazoles are also obtained by the same procedure. The reaction of (Z)-enediyne sulfones with diazomethane gives bis(alkynyl)-3//-... 

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... 

Upon heating the enediyne la rearranges reversibly to the 1,4-benzenediyl diradical 2a, which in its turn can rearrange to the enediyne lb or—in the presence of a hydrogen donor (e.g. cyclohexa-1,4-diene)—react to the aromatic compound 3a. 

Of great importance for the Bergman cyclization is the distance between the triple bonds. The reaction cannot occur at moderate temperatures if the distance is too large. Optimal reactivity at physiological temperatures is obtained by fitting the enediyne element into a ten-membered ring." ... 

The chemistry of enediynes, enyne allenes and related compounds ... 

With the exocyclic alkylidene at C-13 properly in place, the elaboration of the l,5-diyn-3-ene moiety can now be addressed. Cleavage of both acetate and trimethylsilyl functions in 86 with basic methanol, followed by triethylsilylation of the newly formed tertiary hydroxyl group, efficiently affords alkyne 25 (86 % overall yield). This substance was regarded as a viable candidate for a Pd-catalyzed coupling reaction.12 Indeed, treatment of 25 with (Z)-chloroenyne 26 in the presence of a catalytic amount of Pd(PPh3)4 and Cu1 results in the formation of enediyne 24 in 91 % yield. 

Scheme 20. The intramolecular carbonyl addition reaction used by Danishefsky and coworkers to construct a 10-membered ring enediyne system.

The tightly bound chromophore could be extracted from the protein with methanol [186], and the major component of the extract was determined to have the enediyne structure 116 (Figure 11.21), related to chromophores of other chromoprotein antitumor agents such as neocarzinostatin. Additional minor components were extracted, variously containing an OH group instead of OMe attached to the enediyne core, with Cl instead of OMe when chloride was present in the buffer salt, or with OEt instead of OMe when ethanol was used for the extraction. Another byproduct was isolated in the form of structure 117, consistent with a facile cy-doaromatization reaction as observed for all other enediyne antibiotics. Surprisingly, 117 also displayed antibiotic and antitumor activity, perhaps due to alkylation of DNA or protein by the aziridine. The interpretation of these results was that 116 and the other enediyne byproducts were merely artifacts of the extraction procedure and that the true structure of the maduropeptin chromophore is the aziridine 118. 

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