Bergman Cycloaromatization Research Articles

Intramolecular Ene Approach to the Bicyclic Subunit of Neocarzinostatin Chromophore: Tandem Ene Cyclization-Cycloaromatization Sequence

The first example of 10-(2,4) ene cyclization is described to afford a bicyclic subunit of neocarzinostatin chromophore, which triggers the Bergman cycloaromatization reaction in tandem.

Molecular design and chemical synthesis of potent enediynes. 1. Dynemicin model systems equipped with N-tethered triggering devices

In this article the molecular design and chemical synthesis of a series of enediynes (12-19, Chart I) related to the dynemicin A structure and carrying N-tethered triggering devices are described. The design envisioned the [(arylsulfonyl)ethoxy]carbonyl group attached at the nitrogen atom as a triggering device for the Bergman cycloaromatization reaction because of its ability to undergo β-elimination under basic conditions, liberating the labile free amine intermediate.A number of tethering groups on the aromatic ring were also installed in these systems for future incorporation of other desirable moieties such as delivery systems and solubility enhancers.The chemical synthesis of the desired systems proceeded from the corresponding quinoline intermediates through acetylide additions to quinoline(intermolecular) and carbonyl( intramolecular) functionalities as the key steps.Bergman cycloaromatisation experiments under basic and acidic conditions demonstrated the abilities of these compounds to generate benzenoid diradicals.A number of potent DNA-cleaving compounds and cytotoxuc agents emerged from these studies

Molecular design and chemical synthesis of potent enediynes. 2. Dynemicin model systems equipped with C-3 triggering devices and evidence for quinone methide formation in the mechanism of action of dynemicin A

Continuing the theme of the preceding article, this paper describes the synthesis and chemical properties of designed enediynes related to dynemicin A. These model systems are equipped with triggering devices at C-3 of the aromatic nucleus. The design of these compounds (1 and 2) was based on the hypothesis that a C-3 phenolic group generated in situ would be capable of promoting epoxide opening and subsequent Bergman cycloaromatization according to the dynemicin A cascade

Design, synthesis, and study of simple monocyclic conjugated enediynes. The 10-membered ring enediyne moiety of the enediyne anticancer antibiotics

Following the discovery of the enediyne anticancer antibiotics, investigations were initiated directed toward the design, synthesis, and study of simple monocyclic conjugated enediynes. In this article the synthesis of the parent 10-membered ring enediyne found in the enediyne natural products and its properties are described. In addition to the parent hydrocarbon 27, the synthetic methodology developed based on the Ramberg-Blcklund reaction delivers a series of higher ring homologs (17-22) and the water soluble version of the 10-membered ring compound 47. Molecular mechanics calculations on these systems led to a number of geometrical parameters which correlated well with their tendencies to undergo the Bergman cycloaromatization reaction. Kinetic studies on the Bergman cycloaromatization of the 10-membered ring enediynes 27 and 47 led to the following thermodynamic values: 27, energy of activation (E,) = 23.8 kcal/mol, AG* (37 C) = 24.6 kcal/mol; 47, energy of activation (E,) = 31.5 kcal/mol, AG' (37 C) = 24.8 kcal/mol. The designed enediyne 47 showed potent DNA-cleaving properties becoming the first synthetic molecule to mimic the action of the naturally occurring enediynes in this regard.

Synthesis and Reactivity of a p‐Methoxyphenyl‐Substituted Enediyne. A Case of Electronic Influence on the Rate of the Bergman Cycloaromatization

AbstractBicyclo[7.3.1]diynes 19a and 19b were prepared by using dibromo olefin 11 and ketone 12 as building blocks. The key step of the synthetic sequence is an intramolecular Nicholas reaction of 17 to give the bicyclo[7.3.1]diyn‐10‐one dicobalthexacarbonyl adducts 18a and 18b (66% total yield). Oxidative decomplexation of 18a and 18b with cer(IV) ammonium nitrate gave the diynes 19a and 19b, respectively. Both diynes 19a and 19b could be oxidatively converted into the enediyne 20 by using DDQ. In contrast to the unsubstituted enediyne 4, compound 20 can be isolated at room temperature Quantitative kinetic measurements of the rate of the Bergman cyclization of 20 gave ΔG# (37°C) = 111 kJ mol−1. This value is 12.3 kJ mol−1 higher than that of 4. The difference in the free activation energy between 20 and 4 is attributed to electronic effects.

ChemInform Abstract: Experimental Modeling of the Priming Mechanism of the Calicheamicin/Esperamicin Antibiotics: Actuation by the Addition of Intramolecular Nucleophiles to the Bridgehead Double Bond.

AbstractBecause external standard nucleophiles (thiolate, cyanide, cuprate) surprisingly do not add to the bridgehead double bond in (I) thereby triggering a Bergman cycloaromatization of the enediyne moiety (thought to be an essential step with respect to the biological activities of the title antibiotics towards diseased cells) the epoxy group of (I) is transformed to an intramolecular and properly placed nucleophilic one.