Aromatic enediyne

S. L. Schreiber et al. carried out the total synthesis of the potent cytotoxin (+)-tri-0-methyl dynemicin A methyl ester. The key step was a regioselective Friedel-Crafts alkylation of an extremely sensitive aromatic enediyne with 3-bromo-4,7-dimethoxyphthalide. The coupling of these two fragments took place in the presence of silver triflate at 0 °C in 1 minute, and after methylation, gave a 1 1 mixture of diastereomers in 57% yield. 

Aral et al. investigated the photochemistry of the linear shaped aromatic enediynes (186) and (187). The quantum yield of both ( )- (Z) and (Z) ( ) isomerizations considerably decreased in (186) and (187) because of an increase in the number of photochemical processes that yielded nonfluorescent excited species. The compound (188) showed characteristic charge-transfer absorption due to the strong donor-acceptor chromo-phores. The enediynes (189) on Au nanoparticles underwent Bergman-type cyclization leading to a polymerized coating via biradical intermediates. 

Turro and co-workers showed that simple acyclic aromatic enediynes, such as 11, could also undergo Bergman cyclization under photochemical conditions. They proposed that the photo-Bergman cyclization of these substrates involved a diradical intermediate 2 identical to that of the thermal reaction."... 

SCHEME 30.2 Photochemical Bergman cyclization of aromatic enediynes. 

Cycloaromatization of enediynes by diradical pathways in the thermal-and metal-catalyzed routes allows nonfunctionalized benzene derivatives to be prepared. The aromatization of enediynes by the action of nucleophiles produces aromatic compounds retaining the respective nucleophilic residue [333, 334]. The ruthenium-catalyzed reaction gives rise to the synthesis of various functionalized benzene derivatives. Thus, adding water, alcohols, aniline, acetylacetone, pyrroles, and dimethyl malonate to acyclic and aromatic enediynes 3.711 at 100°C for 12-24 hours in the presence of TpRuPPh3(MeCN)2PF6 (10 mol%) led to the functionalized benzenes 3.712 in satisfactory yields (Scheme 3.79) [334]. This cyclization involves regioselective nucleophilic attack of enediyne 3.711 to form a, TT-vinylruthenium intermediate 3.714 which finally converts to the benzene derivative. Experiment with labeled hydrogen atoms showed that the ruthenium n-alkyne complexes 3.713 are catalytically active. 

While aromatic enediynes are fairly stable compounds, their cyclization temperature can be reduced sometimes even to the physiological level by... 

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]. 

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. 

The above analysis illustrates why it is helpful to consider the enediyne moiety as two independent re-systems. As discussed above, the conjugated out-of-plane 7r-system of the reactant is smoothly transformed into the conjugate 7r-system of the product (e.g., the aromatic system of benzene) without an overall change in the number of bonds. We will refer to this group of electrons as out-of-plane MOs or simply as the re-system . In contrast, the two in-plane re-bonds are transformed in a more drastic way to the new cr-bond and a pair of radical centers. We will refer to this system of orbitals as in-plane re-bonds or as the a system . 

Rotation of the aromatic ring out of the enediyne plane forces the aromatic 7r-orbitals to overlap with the in-plane 7r-orbitals of the enediyne system as illustrated... 

Fig. 23 Effect of orientation of the aromatic ring on the conjugation with the enediyne system.

Product stabilization is much more pronounced when the enediyne or ene-yne-allene starting materials are not already part of an aromatic system, since forming an aromatic system constitutes a much higher degree of stabilization than expanding an aromatic system (Fig. 24). Conjugation of the radical center provides additional stabilization to the 71-radical formed by the Myers-Saito and Schmittel cyclizations. 

Other researchers have reported that the cyclization step is believed to be rate determining in the cycloaromatization (Bergman) reaction of aliphatic enediynes." It has been found that the rate-limiting step is hydrogen abstraction by benzannelation. This effect should be attributable to the faster rate of retro-Bergman cyclization from the aromatic ring-condensed 1,4-didehydrobenzene diradicals and/or the slower rate of hydrogen abstraction by them. 

Finn et al. reported the first instance of a metal-catalyzed aromatization of enediynes via vinylidene intermediates [7]. Aromatization of unstrained enediynes is knovm as Bergman cyclization and occurs at 200-250 °C via diradical intermediates [8]. Ruthenium-vinylidene complex 7 was formed when 1,2-benzodiyne 6 was treated with RuCp(PMe3)2Cl and NH4PF6 at 100 °C, ultimately giving good naphthalene product 8 ingood yields (Scheme 6.4). This process mimics Myers-Saitocyclizationof5-allene-3-... 

Intramolecular transamidation in (3-lactam enediynes can induce concomitant Bergman type cycloaromatization. For instance, Scheme 67, amine 239, which can be stored as its hydrochloride salt in the freezer, reacts in THF at reflux in the presence of cyclohexadiene as a hydrogen donor to produce only trace amounts of the expanded lactam 240 along with aromatic compound 241 as the major compound [173]. 

Quantum chemical studies of cyclizations of enediynes and enyneallenes have been reviewed.180 The intermediates are computationally tractable as a result of the unrestricted broken spin symmetry (UBS) approach using GGA functionals for the description of open-shell biradicals. The intermediacy of biradicals in Cope-type rearrangements, to which the Bergman and Myers-Saito reactions belong, are shown to be predictable using a very simple rule biradicals are likely to be intermediates if they are stabilized either by allyl resonance or by aromaticity. 

Fiirstner and co-workers have demonstrated the utility of the PtCl2-catalyzed carboalkoxylation of protected o-alkynyl phenols in the synthesis of the pterocarpene nucleus of erypoegin H <2007AGE4760>. Naphthalene fused 2,3-dihydrofurans have been shown to be available through a Pt- and Ru-catalyzed aromatization of enediynes with concomitant intramolecular nucleophilic additions <2007S2050>. 

---