Enediynes 10-membered

Figure 11.2 Biosynthesis of the nine-membered enediynes. Members of this family share a common biosynthetic pathway for the enediyne core intermediate. Domains are shown in circles with abbreviations (KS, ketosynthase AT, acyltransferase KR, ketoreductase DH, dehydratase TE, thioesterase ACP, acyl carrier protein PPT, phosphopantetheine transferase)...

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... 

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... 

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

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." ... 

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

Enediynes are of interest because of their ability to cleave DNA. The 10-membered oxadiyne (5) cycloaromatises to the isochroman (6) <96TL2433> and a biradical intermediate is proposed to account for the formation of an isochroman from an acyclic enediyne <96TL5397>. 

A similar pre-orientation involving unsaturated carbon chains was operative on generating twelve-membered enediyne 23 and arenediyne lactams 24 [7]. The seco methylesters 21 and 22 were cleaved with LiOH, the corresponding carboxylic acids underwent cyclizations after activation with 2-fluoro-pyridinium tosylate 25 [8]. Dimerization products were found as by-products (<10%). It should be pointed out, that the lactamization succeeded in a single step in about 75% yield by treating the seco-methylesters 21 and 22 with Me3Al in refluxing methylene chloride. Obviously, the latter route was more convenient (Scheme 5). 

In a reaction similar to the (>-alkoxide elimination reactions seen with zir-conocenes, catalytic Rh(OH)(cod)2 and 2 eq. of arylboronic acids gave cyclic products 165 from enynes 166 (Scheme 35) [100]. In this reaction, transmet-allation of Rh - OR with B - Ph gave Rh - Ph species 167, which inserted into the alkyne, cyclized to 168, and finally underwent [>-alkoxidc elimination to provide Rh-OCH3. This reaction is limited to the formation of five-membered rings, but it can also undergo cascade type reactions of enediynes to give multicyclic products [100]. 

Due to the lack of increase in stabilizing re-re interactions at the reaction stage where the destabilizing four-electron repulsive interactions increase steadily, the inward bending of alkyne moieites in unstrained enediynes leads to continuously developing reactant destabilization without any compensation from the increased C1-C6 bonding. Only in the 9-membered enediyne the decrease in the C1-C6 distance results in an immediate increase in the extent of C1-C6 cr-bond formation. 

Interestingly, after reaching the maximum at the 6-membered cycle, the yields drop again. This decrease in efficiency occurs despite the appreciable reduction in the distance between the terminal acetylenic carbons relative to the 6-membered analogue. Here, the efficiency may simply be a function of how photochemical excitation is distributed in the reactive excited state. Calculated enediyne geometries suggest the cyclization is more efficient for those enediynes where the terminal phenyl groups are rotated outside of the enediyne plane (Table 3). 

Figure 9 Structures of representative members of the enediyne family. C-1027 and NCS are two enediynes that require phosphopantetheinylation of proteins for their biosynthesis.

In 2006 the preparation of simplified analogs of natural occurring enediynes, e.g. antitumor antibiotic dynemicin, was reported by Banfi and coworkers. They succeeded in synthesizing two different classes of such compounds where the embedded 10-membered enediyne system is fused either with a (3-lactam ring (lactenediynes) or with an epoxide. Biological tests on these molecules have demonstrated that some representatives are able to cleave the double strand of DNA even at very low concentrations [408]. 

Usuki T, Nakanishi K, Ellestad GA (2006) Spin-Trapping of the p-Benzyne Intermediates from Ten-Membered Enediyne Calicheamicin yi . Org Lett 8 5461... 

Intramolecular Lewis acid-promoted reaction of coordinated propargylic ether with the silyl enol ether in 158 has been applied successfully to the construction of the highly strained 10-membered cyclic enediyne system 159, present in esperamycin and calicheamycin [39,40]. The enediyne system 157 was prepared by the Pd-catalysed Sonogashira coupling of (Z)-l,2-dichloroethylene (154) with two different terminal alkynes 155 and 156. 

Nozaki reaction (12, 137 14, 96 15, 95). An intramolecular version of this reaction can effect cyclization even to a strained nine-membered ring. Thus 1 on treatment with CrCl2 at a low temperature cyclizes mainly to 2, a mixture of epimers in which a cyclononadiyne ring is fused to a cyclopentene ring. After acetylation of the secondary hydroxyl group, the mixture is dehydrated to 3, with a nine-membered enediyne ring. 

Similarly, the 11-membered enediyne systems 455 and 456 were obtained from the nitrone, which was prepared in 10 steps (Equation 71) <2006CC2992>. 

Four TES ethers were cleaved in the final step of an approach to N1999-A2, a member of the highly unstable enediynes.20 After low temperature dehydration of 17.1 via its triflate [Scheme 4.17], deprotection was implemented by treatment with trifluoroacetic acid in aqueous THE at 0 °C to give the target epoxy-dienediyne 17.2 in 45% yield for the two steps. rtrf-Butyldimethytsilyl ethers could not be removed without total destruction of the molecule. 

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