Advanced Review Enediynes, enyne-allenes, their reactions, and beyond Elfi Kraka∗ and Dieter Cremer Enediynes undergo a Bergman cyclization reaction to form the labile 1,4-didehy- drobenzene (p-benzyne) biradical. The energetics of this reaction and the related Schreiner–Pascal reaction as well as that of the Myers–Saito and Schmittel reac- tions of enyne-allenes are discussed on the basis of a variety of quantum chemical and available experimental results. The computational investigation of enediynes has been beneficial for both experimentalists and theoreticians because it has led to new synthetic challenges and new computational methodologies. The accurate description of biradicals has been one of the results of this mutual fertilization. Other results have been the computer-assisted drug design of new antitumor antibiotics based on the biological activity of natural enediynes, the investigation of hetero- and metallo-enediynes, the use of enediynes in chemical synthesis and C materials science, or an understanding of catalyzed enediyne reactions. " 2013 John Wiley & Sons, Ltd. How to cite this article: WIREs Comput Mol Sci 2013. doi: 10.1002/wcms.1174 INTRODUCTION symmetry-allowed pericyclic reactions, (ii) aromatic- ity as a driving force for chemical reactions, and (iii) review on the enediynes is necessarily an ac- the investigation of labile intermediates with biradical count of intense and successful interdisciplinary A character. The henceforth called Bergman cyclization interactions of very different fields in chemistry provided deeper insight into the electronic structure involving among others organic chemistry, matrix of biradical intermediates, the mechanism of organic isolation spectroscopy, quantum chemistry, biochem- reactions, and orbital symmetry rules. Remarkable in istry, natural product synthesis, drug design, medic- this connection is that Bergman already derived in inal chemistry, transition metal chemistry, or mate- his review article reasonable energetics of the reac- rials science. The roots of the enediyne chemistry tion on the basis of empirical considerations, decided can be found in a 1972 communication of Jones for a biradical as the most likely electronic struc- and Bergman in the J. Am. Chem. Soc.,inwhich ture of p-benzyne (in view of the trapping products, the cyclization of (Z)-hex-3-ene-1,5-diyne (the par- which also confirmed its existence as an intermedi- ent enediyne of 1 in Figure 1) is described and ev- ate), and related the cyclization reaction to observa- idence for the intermediate formation of the labile tions Masamune and co-workers3 had made for cyclic 1,4-didehydrobenzene (p-benzyne) provided (see 2 in enediynes also in the year 1972. These authors had Figure 1).1 Already 1 year later, Bergman2 published obtained products that suggested the intermediacy of areviewarticleonReactive 1,4-didehydroaromatics didehydronapthalene and 9,10-didehydroanthracene because the work of the previous year related to the biradicals. In summary, several of the topics, which hot topics of the early 1970s: (i) the energetics of became relevant in enediyne research much later, are already contained in the 1973 review article of The authors have declared no conflicts of interest in relation to this Bergman.2 article. Enediyne chemistry had a strong impact on a ∗Correspondence to: [email protected] number of fields where quantum chemistry should Computational and Theoretical Chemistry Group, Department of be mentioned first. The p-benzyne was the first non- Chemistry, Southern Methodist University, Dallas, TX, USA trivial biradical, for which, in view of the lack DOI: 10.1002/wcms.1174 of experimental data, a reliable quantum chemical C Volume 00, xxx 2013 " 2013 John Wiley & Sons, Ltd. 1 Advanced Review wires.wiley.com/wcms Bergman R 1 2 1 R C1–C6 6 2 R 3 Enediyne 4 R 5 6 R Schreiner–Pascal 5 6 1 R 3 (R = H) 1 C1–C5 Myers–Saito R 5 1 1 R C1–C6 R' 2 6 R' 7 3 R' Enyne-allene 7 4 C R' R 6 1 R' 5 Schmittel 6 2 7 6 (R = H) 4 C2–C6 R' FIGURE 1 Bergman, Schreiner–Pascal, Myers–Saito, and Schmittel reaction of enediynes and enyne-allenes. description was needed. This need was enhanced by this way (interaction of two in-plane ally radicals) the discovery of natural enediynes in the 1980s.4–6 although this would lead to the transition state of the The natural enediynes calicheamicin (1987),5 es- Cope rearrangement being identical to the intermedi- paramicin (1987),6 and dynemicin (1990)7 were soon ate p-benzyne biradical. In this situation, it is appro- after their discovery in the years 1987 and 1990 con- priate to follow the suggestion of Alabugin and co- sidered as possible leads for antitumor antibiotics workers14 and to speak in the case of the Bergman and where this hope was based on their relationship to Myers–Saito rearrangements (Figure 1) of cycloarom- neocarzinostatin.8 The latter compound had already atization reactions as a special class of ring-forming been discovered in 1965,9 and its biological activity reactions. was early known. Neocarzinostatin can be consid- The correct description of a singlet biradical ered as an enediyne with an epoxidized double bond, such as p-benzyne requires a methodology, which and therefore its biological activity was related to a was not available in the 1970s, however came into Bergman-type cyclization of an intermediate enyne- general use with the availability of coupled cluster cumulene.10 Hence, the discovery of the natural methods15 and perturbation theory corrected com- enediynes and their chemistry established the impor- plete active space methods in the late 1980s and early tance of the cycloaromatization reaction discovered 1990s, respectively.16 Acorrectquantumchemical by Jones, Bergman, and Masamune in the early 1970s. description of the Bergman cyclization implies more The Bergman reaction may be formally classi- than just a reliable description of an organic birad- fied as an electrocyclic reaction.11 However, it has to ical. It requires a balanced account of nondynamic be mentioned that for an electrocyclic reaction, the 6π (multireference) electron correlation effects (for the system orthogonal to the symmetry plane of 1 should biradical) and dynamic electron correlation effects be directly involved in the formation of the new CC (especially including three-electron effects for the cor- bond, which is not the case. Other authors have re- rect account of different types of electron delocaliza- lated the Bergman reaction to the Cope rearrange- tion in reactant and product). Even in the year 2013, ment and speak of a formal Cope rearrangement.12, 13 this problem cannot be considered to be fully solved Again, this can be questioned when considering just for the Bergman and the Bergman-related reactions the Bergman reaction whereas the Bergman and retro- (Figure 1) in the way that larger enediynes and enyne- Bergman reaction seen together (i.e., considering both allenes can be easily investigated. the formation of bond C1C6 to give 2 and the cleav- In this situation, quantum chemists focused on age of bond C3C4 in 2) may be formally seen in the possibilities of density functional theory (DFT),17 C 2 " 2013 John Wiley & Sons, Ltd. Volume 00, xxx 2013 WIREs Computational Molecular Science Enediynes, enyne-allenes, their reactions, and beyond which could be easily applied to larger systems and Thermodynamics and kinetics: Wenthold did not suffer as strongly as wave function theory provided an overview of all experimental from the basis set truncation error. It is fair to say r thermochemical properties of benzynes up that the study of enediynes and their reactions has led to 2010.23 An earlier summary of ben- to a better understanding of DFT as well as to the zyne chemistry complemented by a historic development of new DFT methods with multirefer- overview of their discovery and their appli- ence character. Hence, a review on enediynes has to cations in synthesis was given by Wentrup,24 sketch the close connection between quantum chemi- Recently, Schmittel et al. addressed the kinet- cal method development, especially in the 1990s and ics of the reaction bearing his name.25 their application in the course of the investigation of Vibrational spectroscopy:In1998,Sanderre- enediyne reactions. viewed the vibrational spectroscopy of m-and The possibility of using natural enediynes as r p-benzyne.26 antitumor antibiotics also triggered calculational Photochemistry:Recently,Alabuginandco- studies especially in connection with computer- workers reviewed the photochemistry of assisted drug design. These investigations were r enediynes.27 performed at a time when the medicinal work with natural enediynes had already suffered from setbacks Synthesis:Themajorityofrecentreviewson 8, 18 enediynes give an overview over synthetic ac- due to their toxicity so that after a period of r heavy publication activity, editors had a tendency of complishments. Joshi and Rawat published a “banning” enediyne articles from high-ranking jour- comprehensive summary of the developments 28 nals. However, these setbacks opened up new per- in enediyne chemistry. Nicolaou and Chen spectives rather than a decline of enediyne chemistry. reviewed the influence of enediynes on the 29 The focus was now on nontoxic synthetic enediynes development of total synthesis. Maretina derived from their natural counterparts, the extension summarized design strategies of enediynes to hetero- and metallo-enediynes, the use of enediynes and enyne-allenes stretching from organic 30 as polymers or other materials, and the application to metallorganic chemistry. Guleskaya and of Bergman-type reactions to discover new synthetic Tyaglivy reviewed the use of enediynes in het- 31 routes. Apart from this, it had already become a stan- erocyclic synthesis. dard to test new quantum chemical methods for their Biosynthesis:Lianghighlightedtheprogress accuracy by applying them to the benzyne biradicals in the understanding of how natural and the cycloaromatization reactions of the enediynes r enediynes are synthesized by nature.32 Kar and enyne-allenes.