Conjugated Enediynes—An Old Topic in a Different Light

Abstract

If Angewandte Chemie had published "Highlights" twenty years ago, the topic of this article would certainly have been addressed then. The most recent reports from the research groups led by Nicolaou,"] Diederich, I2] V~l l h a r d t , [~~ and MyersC4] prove that the chemistry of conjugated enediynes continues to flourish. What is more remarkable, however, is the difference in the goals of the investigations of enediynes then and now. Twenty years ago the syntheses of new 4n and (4n + 2) n-electron systems and tetrahedranes were the main points under consideration; today's motivation for examining these compounds comes from natural products chemistry and from interest in new modifications of carbon.Biologically Active Anticancer Antibiotics: Nicolaou et al. were not only the first to complete the synthesis of the anticancer antibiotic cdkheamycin indeed a preparative masterpiece, they also contributed to the understanding of the mode of action of the aglycon (1) responsible for the DNA cleavage.[' b, The incorporation of the enediyne unit in the ten-membered ring of the aglycon enhances the reactivity of the already labile planar 6n-electron system; after activation by attack of a nucleophile, the triple bonds are even closer together and ring closure to give a 1,4-diradical (Bergman c y~l i z a t i o n ) [~~ is induced. For the systematic study of the mechanism of DNA cleavage cyclodeca-3-ene-l,5-diyne (2) was prepared as the most strained member of a series of monocyclic conjugated enediynes; because of the short transannular distance between the triple bonds (d = 3.25 in l), its cyclization via the 1,4-diradical3 to give tetralin (4) proceeds even at 50 "C. By determining the strucwhich d < 3.2-3.31 A, spontaneous Bergman cyclizations can be expected.Kinetics and Mechanism: First evidence that cyclization of conjugated enediynes proceeds via 1,4-didehydrobenzene intermediates like 6 was reported by Bergman et al. about twenty years ago[*' in an elegant study of the dideuterated parent compound, cis-hexa-3-ene-I ,5-diyne (5). Recently, the same research group examined an expanded system, (Z,Z)-deca-3,7-diene-I ,5,9-triyne (7), and proved that the analogous double cycloaromatization gives rise to 2,6-didehydronaphthalene (9),16] which is isolated as naphthalene (10) after H abstraction from the solvent. The cyclizations of both 5 and 7 are first-order reactions. The rearrangement of 5 to give deuterated benzene proceeds almost quantitatively at 190 "C in dilute solution and has an activation energy of 32 kcalmolIn contrast, the reaction of 7 (at 190°C) provides naphthalene in only 10% yield. tures of a number of model compounds Nicolaou et al. were able to predict whether an enediyne would undergo Bergman cyclization at room temperature, and thus be a potential anticancer drug. The transannular separation of the triple bonds serves as the decisive parameter; in compounds in [lO]annulene is outlined in Scheme 1. Key steps include the Pd-catalyzed Heck coupling of 11 and 12 to give 13, the chain extension by mea...

The bergman cyclizations of the enediyne and its N‐substituted analogs using multiconfigurational second‐order perturbation theory

“…[9,10] The thermal Bergman cyclization of 1R has been extensively studied both experimentally and theoretically. [7,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] McMahon et al [21] determined the structure of 1R using Fourier transform microwave spectroscopy and the key parameter (the C 1 AC 6 distance, see Scheme 1) governing reactivity of the Bergman cyclization reaction was reported to be 4.321 Å . The activation enthalpy (DH = ) and reaction enthalpy (DH) of reaction 1 were experimentally determined to be 28.2 and 8.5 kcal/mol, 28 and 8 kcal/mol, and 32 and 14 kcal/mol by Roth et al, [29] Wenthold and Squires, [30] and Bergman and Jones, [11] respectively.…”

A unified view of the theoretical description of magnetic coupling in molecular chemistry and solid state physics

“…Magnetic states of metalloproteins, DNA and RNA damaged by radicals, or protein oxidation adducts with radicals are of increasing interest because of their relevance in the biological activity of important carcinogenic and antitumor compounds. [24][25][26][27][28][29][30][31][32] An in depth examination of the specialized literature reveals that the fundamental physics governing the magnetic properties of all these systems is essentially the same although often described using different languages for identical physical concepts.…”

Spin Symmetry Requirements in Density Functional Theory: The Proper Way to Predict Magnetic Coupling Constants in Molecules and Solids

“…Also, the description of magnetic states of damaged DNA, RNA or protein oxidation adducts by radicals has an increasing interest because of their relevance to understand the biological activity of important carcinogenic and antitumor compounds. This is also important to investigate the structure, conformation dynamics and spectroscopic properties of these complex biological molecules [9][10][11][12][13][14].…”