Enediynes cyclizations

Schmittel, M., Kiau, S. Thermal and electron-transfer induced reactions of enediynes and enyne-allenes. Part 9. Electron-transfer versus acid catalysis in enediyne cyclizations. Liebigs Ann. Chem. 1997,1391-1399. 

Scheme 81. The Rh(I)-catalyzed Myers—Saito enediyne cyclization via a metal—vinyUdene-allene-enyne intermediate.

Scheme 83. Reaction scheme for photopromoted, catalytic acyclic enediyne cyclization.

Scheme 16. Enediyne cyclization of strained ring systems...

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]. 

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... 

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 anticancer activity of complex natural products having a cyclodecenediyne system [for a review see <96MI93>] has prompted the synthesis of 54 (X = CH2 and OCH2) <96CC749> and 55 (R = a-OH and p-OH) <95AG(E)2393> on the basis that such compounds are expected to develop anticancer activity as the P-lactam ring opens. This is because cycloaromatization can only occur in the monocyclic enediyne and the diradical intermediate in the cyclization is thought to be the cytotoxic species. 

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). 

Recently, Tour et al. [32] described attempts to prepare PPP derivatives via a Bergman cyclization, starting from substituted enediynes, e.g. poly(2-phenyl-1,4-phenylene) (18) from l-phenyl-hex-3-en-l,5-diyne or the structurally related poly(2-phenyl-1,4-naphthalene) (19) from l-phenylethynyl-2-ethynylbenzene. 

Cationic palladium complex 121 reductively coupled enynes (Eq. 20) using trichlorosilane as the stoichiometric reductant [71]. This combination of catalyst and silane afforded silylated methylenecyclopentanes such as 122 in good yield from enynes such as 123. Attempts to develop an enantioselective version of this reaction were not successful [71]. When enediyne 124 was cyclized in the presence of trichlorosilane, the reaction favored enyne cycli-zation 126 by a 3 1 ratio over diyne cyclization to 125 (Eq. 21). In contrast, when the more electron-rich dichloromethylsilane was used as the reductant, diyne cyclization product 125 was preferred in a ratio of 4 1 [71]. Selectivities of up to 10 1 for enyne cyclization were observed, depending on the substrate employed [72],... 

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]. 

Novel pyrimidine enediynes 104 prepared by Russell and co-workers undergo Bergman cyclization to give tricyclic products 105 . Pyrimidines 104 were also shown to cleave dsDNA under appropriate conditions. 

In these reactions, a er-bond is formed at the expense of two re-bonds and, thus, the process leads to a net loss of one chemical bond that is intrinsically unfavorable thermodynamically. Formation of the new er-bond leads to ring closure, whereas the net loss of a bond leads to the formation of two radical centers, which can be either inside (the endo pattern in Scheme 1) or outside of the newly formed cycle (the exo pattern). Note that er-radicals are formed through the endo path, while exo-closures may produce either a er-radical when a triple bond is involved or a conjugated re-radical when the new bond is formed at the central carbon of an allene. The parent version of this process is the transformation of enediyne 1 into p-benzyne diradical2 (the Bergman cyclization), shown in Scheme 2. 

Whitlock et al.14 discovered a reductive cyclization of enediynes promoted by lithium naphthalenide that provides substituted fulvenes and suggested a dianionic mechanism (Scheme 6). However, even now it is still unclear whether the enediyne dianion is indeed the cyclizing species or whether the initially formed acyclic radical-anion cyclizes first to give a fulvene radical-anion which is further reduced by lithium to give the cyclic dianion. 

Scheme 5 Thermal and reductive cyclizations of cross-conjugated enediynes.

Scheme 6 Dianionic cyclization of enediynes promoted by double lithium naphthalenide reduction.

Fig. 7 Internal reaction coordinate (IRC) computations for the Bergman cyclization of model enediynes.

This analysis confirms that the effect of cyclic constraints is not purely steric but also has an electronic component. Another aspect of this dichotomy is shown in Fig. 11 which illustrates the decrease in the energy gap between the frontier in-plane rc-MOs. The decrease in the C1-C6 distance destabilizes the occupied MO where the interaction between the end orbitals is antibonding and, at the same time, stabilizes the empty MO where the 7i -orbitals overlap constructively. As a result, the efficiency of the photochemical Bergman cyclization should increase and, indeed, the most efficient photo-Bergman cyclizations reported in the literature involve cyclic enediynes.43 Again, the analogy with interrupted [2 + 2] photocycloaddition is instructive. 

While in the unbound enediyne the c-d distance is 4.1 A, this distance is diminished upon metal complexation 3.3 A for Pt(II) and Pd(II), and 3.4 A for Hg(II). The Pt and Pd species cyclize in the solid state at only slightly elevated temperatures, and give Bergman products below ambient temperature in solution. While the change in reactivity was attributed to the change in distance between the alkyne termini, an accelerating influence of the metal cannot be ruled out. 

Scheme 13 Bergman cyclization of enediynes bearing ort/zo-substituents.

Fig. 12 Correlation between the calculated activation energy of the Bergman cyclization and the product of natural charges at the terminal acetylenic atoms of benzannelated enediynes. Only para substituents obey the correlation. Adapted from reference49.

Since four-electron repulsion is the dominant factor in the reactant destabilization, any structural perturbation that either increases electron repulsion in the reactant or decreases the electron repulsion in the TS will decrease the activation energy for the cyclization. One way for placing an accelerating substituent in direct spatial proximity to the in-plane re-orbitals is to use appropriate ortho substituents in benzannelated enediynes. 

Table 1 provides examples of amino enediynes which become much more reactive toward the Bergman cyclization upon protonation on nitrogen because the presence of a positively charged ammonium moiety alleviates the re-re repulsion of the in-plane re-orbitals. 

An illustrative example of how rehybridization can be used to control the Bergman cyclization is provided by substituent effects at the alkyne termini of enediynes. This effect in cycloaromatization chemistry was first studied by Schreiner and coworkers, who found dramatic acceleration of the Bergman cyclization upon... 

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