Acyclic Enediynes

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>. 

Bicyclic cis- and frans-isoxazolidinyldiynes have been prepared by intramolecular nitrone cycloaddition of the two side chains of an acyclic enediyne-nitrone precursor (Scheme 2.233) (731). 

For example, as shown by calicheamicin, cyclic enediynes have a lower activation barrier than acyclic enediynes. As suggested by Nicolaou in 1988, the distance between the acetylenic carbons that form the covalent bond influences the rate of cyclization. Another theory developed by Magnus and Snyder is based on the molecular strain between ground state and transition slate this seems to be more general, especially for strained cyclic systems. Often, as both the distance and the strain are not known, the development of suitable precursors remains difficult, as exemplified by the following enediyne, in which a slight change leads to a cycloaromatization ... 

Cycloaddition to a hydrocyclobutaindane.1 The framework of the sesquiterpenoid illudol (3) can be obtained in one step and high yield by a [2 + 2 + 2] cycloaddition of the acyclic enediyne 1 mediated by CpCo(CO)2. Transformation of 2 to 3 involves a number of standard reactions. The cycloaddition of 1 to 2 is the first instance of formation of three rings in a single step and with stereospecific generation of three contiguous chiral centers. 

O Connor, J. M., Friese, S. J., Tichenor, M. Ruthenium-Mediated Cycloaromatization of Acyclic Enediynes and Dienynes at Ambient... 

The reaction of dichlorocerium trimethylsilylacetylide with a /S.y-unsaturated ketone as shown in Scheme 298 has been reported. The reaction was followed by Pd(0)-assisted construction of the acyclic enediyne.1... 

Acyclic Z 3-ene-l,5-diynes, such as 6, undergo the classical Bergman thermal cycloaromatization only at elevated temperatures (a photochemical promoted Bergman-type cycloaromatization of acyclic enediynes can take place under milder conditions on particular substrates). However,... 

For the construction of the required acyclic enediyne, the method of choice is the Sonogashira coupling of terminal alkynes with Z dichloroethylene. The complete stereoselectivity for the Z double bond and the mild... 

This family of compounds, constituted mainly by a series of [7.3.1] derivatives, but including also [7.4.1], [8.3.1] and [9.3.1] polycyclic compounds, is characterized by the fact that the same synthetic strategy was followed for their preparation. That is, the formation of the cyclic enediyne system was achieved by the attack of the acyclic enediyne onto an aldehyde by one of the methods described above and illustrated in Scheme 19.17 for the formation of [7.3.1] systems. 

Basak, A. Bdour, H.M. Shain, J.C. Mandal, S. Rudra, K.R. Nag, S. DNA-cleavage studies on N-substituted monocyclic enediynes Enhancement of potency by incorporation of intercalating or electron poor aromatic ring and subsequent design of a novel phototriggerable acyclic enediyne. Bioorg. Med. Chem. Lett. 2000, 10, 1321-1325. 

Rawat, D.S. Zaleski, J.M. Syntheses and thermal reactivities of symmetrically and asymmetrically substituted acyclic enediynes steric control of Bergman cyclization temperatures. Chem. Commun. 2000, 2493-2494. 

A completely stereoselective, one-step assembly of a strained protoilindane framework can be achieved by cobalt-mediated cyclization of an appropriate acyclic enediyne precursor, which leads to a total synthesis of illudol (l) 1. 

Scheme 82. Bergman cyclization of (a) cyclic and (fo) acyclic enediynes by Ru-alkyne It complexation.

Activation of acyclic enediynes by ruthenium-catalyzed nucleophilic aroma-tization has also been reported (396). The importance of this cyclization is indicated by the regioselectivity of nucleophilic addition, which occurs only at... 

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

M. D. Shair, T. Yoon, S. J. Danishefsky, J. Org. Chem. 1994, 59, 3755-3757 synthesis of acyclic enediynes from alkenylbis(pheny-liodonium)triflates J. H. Ryan, P J. Stang,... 

A conceptually different approach for Bergman cyclization of acyclic enediynes (and stable cyclic enediynes) relies on the use of metal ion chelation to allow the reaction to proceed at lower temperatures.Metal ion chelation requires that the enediyne contain heteroatoms at appropriate positions within the enediyne scaffold. Buchwald et al. reported an elegant use of this approach for the cyclization of a bisphosphane-1,2-diaryl dijme 19. In this case, was found to be the optimal ion and allowed the Bergman cyclization to proceed at 61 °C, instead of 243 °C in the absence of a metal ion. The change in reactivity of the enediyne 19 under metal ion chelation conditions was attributed to both conformational and electronic effects. 

O Connor s group later reported that 24 could be used to mediate the cycloaromatization of acyclic enediynes 27 and 28 in good yields as well. Deuterium-labeling experiments supported the intermediacy of a p-benzyne rather than a vinylidene intermediate ... 

More recently, O Connor and co-workers have reported the first catalytic Bergman cyclization using an iron(II) complex 32 (0.3 equiv) to catalyze cycloaromatization of acyclic enediynes. Mild catalytic activity (3 turnovers) was achievable when photolysis was combined with iron catalysis, enabling decomplexation of the arene product from the iron complex to... 

Shortly after Finn s work came to light a catalytic rhodium(I) system was reported. An acyclic enediyne 40 was heated to 50 °C in the presence of just 0.05 equiv of RhCl(/-Pr2P)2 and EtjN in benzene to provide substituted arene 41 in 58% yield. The latter reaction is presumed to involve Myers-Saito cyclization of an in situ formed vinylidene complex. A catalytic cycle becomes possible due to steps involving /3-hydride elimination and reductive elimination. ... 

Branda and coworkers provided another example of an acyclic enediyne that undergoes a photochemical reaction different from a photo-Bergman ring closure [21 ]. In this case, photochemical Bergman in strained enediynes is slower than photochromic bx-electrocychc ring closures. Only the latter process is observed upon UV (365 nm) excitation of the strained enediyne shown in Scheme 30.8. Branda and coworkers used the reversibility of this process for an on-demand uncaging of thermally reactive enediynes by visible light (>525 nm). 

Acyclic enediynes undergo thermal cycloaromatization at temperatures above 200°C. The influence of aromaticity and electronic factors on the... 

In 1988, Nicolaou [19, 195] proposed a theory of c-d distances this states that the distance between the carbon atoms of the acetylene branches controls the rate of thermal cycloaromatization. A critical c-d distance 3.31-3.20 A was proposed for the acceptable half-life at room temperature. This value was later corrected, and empirically the critical distance for spontaneous cyclization at room temperature was widened to 3.40-2.90 A[26], This reaction has a high activation barrier for acyclic enediynes 3.433 ( a 27.4 kcal/mol), 3.434 and 3.436 (Scheme 3.5) [27, 29]. At the same time, cyclic enediynes, for example, 3.435, have lower activation energies and react at lower temperatures. 

It was found that cyclization of benzannulated enediynes can be initiated by irradiation to give the same products as were obtained by thermal Bergman cyclization [238]. Photo-Bergman cyclization, which is also related to the chemistry of benzyne, has not been so extensively investigated. Terminal acyclic enediynes capable of cycloaromatization by thermal C -C route do not undergo photochemical initiation. However, introduction of one or two phenyl substituents in the acetylenic branches facilitates the C -C photocyclization of acyclic enediynes, but any increase in steric hindrance raises the activation barrier and the photochemical yield is significantly lower than in the case of their cyclic... 

Scheme 3.28 Acyclic enediynes, benzoenediynes (3.519), cyclopentadieni-doenediynes (3.520), and iron enediynes (3.521).

A sharp change in the kinetics of Bergman cyclization was described [395] on the formation of metal ion chelates of acyclic enediynes. The metal was coordinated with bisphosphine 3.877 which was synthesized from the known l,6-bis(trimethylsilyl)-hex-3-ene-l,5-diyne 3.878 by desilylation followed by phosphorylation with chlorodiphenylphosphine in the presence of potassium er butoxide (Scheme 3.118) [24a, 395bj. 

Landis, C.A., Payne, M.M., Eaton, D.L. and Anthony, J.E. (2004) Tellurium-mediated cycloaromatization of acyclic enediynes under mild conditions. Journal of the American Chemical Society, 126(5), 1338-1339. 

Manabe, T., Yanagi, S.-L, Ohe, K. and Uemura, S. (1998) New examples of 1,6-and 1,7-hydrogen transfer promoted by an a-silyl group in rhodium(l)-catalyzed radical reactions of acyclic enediynes. Organometallics, 17(14), 2942-2944. 

Joshi et al. (2006) reported synthesis of some symmetrically and asymmetrically substituted acylic enediynes. In conventional heating method, preparation of such asymmetrical and symmetrical substituted acyclic enediyne takes 14-18 h, while same reaction was completed in 3-5 min using microwave irradiation. 

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