Cyclic Enediynes Research Articles

UDFT and MCSCF descriptions of the photochemical Bergman cyclization of enediynes.

Several singlet and triplet potential energy surfaces (PES) for the Bergman cyclization of cis-1,5-hexadiyne-3-ene (1a) have been computed by UDFT, CI, CASCI, CASSCF, and CASMP2 methods. It is found that the first six excited states of 1a can be qualitatively described as linear combinations of the configurations of weakly interacting ethylene and acetylene units. Although the symmetry relaxation from C2nu to C2 makes cyclization of the 13B state Woodward-Hoffmann allowed, it also increases the probability of competing cis-trans isomerization. Hydrogen atom abstraction is another plausible pathway because the terminal alkyne carbons possess a large radical character. In view of the competing processes, we conclude that the Bergman cyclization along the 13B path is unlikely despite its exothermicity (Delta = -42 kcal/mol). Calculations on cyclic analogues of 1a lead to similar conclusions. A less exothermic, but more plausible pathway for photochemical cyclization lies on the 2(1)A PES (Delta = -18 kcal/mol). Compared to the 1(1)A(1) and 1(3)B states, the 2(1)A state has less in-plane electron repulsion which may facilitate cyclization. The resulting p-benzyne intermediate has an unusual electronic structure combining singlet carbene and open-shell diradical features. Deactivation of the 2(1)A state of 1a is a competing pathway.

Intramolecular [2+2+2] Cyclization of Triynes and Enediynes Catalyzed by CoI2-Mn-Phosphine Ligand

Intramolecular [2+2+2] Cyclization of Triynes and Enediynes Catalyzed by CoI2-Mn-Phosphine Ligand

Intramolecular [2+2+2] Cyclization of Triynes and Enediynes Catalyzed by CoI2-Mn-Phosphine Ligand

Intramolecular [2+2+2] Cyclization of Triynes and Enediynes Catalyzed by CoI2-Mn-Phosphine Ligand

ChemInform Abstract: Nitrogen Substituted Cyclic Enediynes: Synthesis, Thermal Reactivity, and Complexation with Metal Ions.

A number of N-substituted cyclic enediynes (azaenediynes) have been synthesized via Pd(0)-catalysed ene–yne coupling followed by N-alkylation. The simplest of them, a 10-membered monocyclic enediyne 1, underwent Bergman cyclization (BC) at 23 °C with a half-life of 72 h. The kinetics of BC slowed down considerably by fusing a benzene ring onto the enediyne. Several novel bis(azaenediyne)s and bis(diazaenediyne)s 3–6 have been synthesized. Their onset temperatures for BC were lowered under metal ion complexation conditions.

A Direct and Stereocontrolled Route to Conjugated Enediynes

A unified synthetic route to 3-hex-en-1,5-diynes, a key building block found in many of the enediyne antitumor agents and designed materials, was developed. The method, which relies on a carbenoid coupling-elimination strategy is tolerant of a wide range of functionalities, and was applied to the synthesis of a variety of linear and cyclic enediynes. Reaction parameters can be adjusted to control stereoselectivity of the process, producing linear enediynes from 1:12 to >100:1 E:Z ratio, and in the case of cyclic enediynes, giving the exclusively Z C-9, C-10, or C-11 products. Key features of the process are the ready availability of precursors and the mildness and efficiency of the reaction. Application of the process in the design of materials precursors and preparation of enediyne antitumor agents are presented.

Nitrogen substituted cyclic enediynes: synthesis, thermal reactivity and complexation with metal ions

A number of N-substituted cyclic enediynes (azaenediynes) have been synthesized via Pd(0)-catalysed ene–yne coupling followed by N-alkylation. The simplest of them, a 10-membered monocyclic enediyne 1, underwent Bergman cyclization (BC) at 23 °C with a half-life of 72 h. The kinetics of BC slowed down considerably by fusing a benzene ring onto the enediyne. Several novel bis(azaenediyne)s and bis(diazaenediyne)s 3–6 have been synthesized. Their onset temperatures for BC were lowered under metal ion complexation conditions.

A new diastereoselective approach to simplified Dynemicin analogues

The stereoselective synthesis of new simplified Dynemicin analogues is reported: key steps of the sequence are the regio- and diastereo-selective functionalization of a quinoline nucleus, bearing a substituent with a stereogenic centre, and the formation of the 10-membered cyclic enediyne system by Pd-catalyzed Stille-like reaction.

Improvement of the diastereoselectivity of the cobalt-mediated [2+2+2] cycloaddition of substituted linear enediynes

The level of the diastereoselectivity of the cobalt-mediated [2+2+2] cyclization of linear enediynes was improved compared to that reported in the literature by substituting the triple or the double bond with ester, phosphine oxide or sulfoxide groups.

ChemInform Abstract: Synthesis and Chemistry of Nine‐Membered Cyclic Enediyne Chromophores of Chromoprotein Antitumor Antibiotics

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Rapid Bergman Cyclization of 1,2-Diethynylheteroarenes

The synthesis and cyclization of acyclic quinoxaline, pyridine, and pyrimidine enediynes (1−3) are described. These compounds were prepared using palladium(0) coupling of trimethylsilyl acetylene t...

Density Functional Study of Bergman Cyclization of Enediynes

Bergman cyclization of the enediynes (Z)-3-hexene-1,5-diyne (1), (Z)-3-heptene-1,5-diyne (2), (Z)-4-octene-2,6-diyne (3), (Z)-1-cyclononene-3,8-diyne (4), (Z)-1-cyclodecene-3,9-diyne (5), and (Z)-1-cycloundecene-3,10-diyne (6) has been studied by density functional methods. The reaction of 1 was first studied using the BP86, BLYP, BPW91, and B3LYP functionals with the 6-311G** basis set and the large ANO basis set for the latter two functionals. The BPW91/6-311G** calculations yielded results comparing well with those of high-level ab initio computations. Thus, BPW91/6-311G** was employed to study the reactions of 2−6. Geometry optimizations and harmonic frequency calculations were applied for every reactant, transition structure, and product; frequency calculations were also carried out for other optimized stationary points. The optimized structure of the conformer of 6 with the lowest energy agrees excellently with the X-ray diffraction crystallographic structure. IRC (intrinsic reaction coordinate) cal...

Cyclic enediynes: relationship between ring size, alkyne carbon distance, and cyclization barrier

This work presents the first detailed study on a series of cyclic hydrocarbon enediynes showing that the cyclization barrier depends upon the ground state energy differences of the biradical products, and that pure density functional methods can be used reliably to estimate the activation enthalpies of the Bergman reaction.

ChemInform Abstract: Thermal and Electron‐Transfer Induced Reactions of Enediynes and Enyne‐ Allenes. Part 9. Electron‐Transfer versus Acid Catalysis in Enediyne Cyclizations.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Synthesis and Biological Evaluation of Novel Cyclic Enediyne Compounds Related to Dynemicin A as Antitumor Agents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Thermal and Electron‐Transfer Induced Reactions of Enediynes and Enyne‐Allenes, 9. Electron‐Transfer versus Acid Catalysis in Enediyne Cyclizations

AbstractFour novel aryl‐substituted enediynes 3 have been synthesized. While their cyclization to the Bergman products 4 could be accomplished at temperatures of 240–320°C, α‐functionalization rather than cyclization was observed during anodic oxidation and in the presence of one‐electron oxidants. In contrast, enediyne 1a was cyclized in the presence of two one‐electron oxidants to the indenone 2a as indicated in the literature; mechanistic investigations clearly indicate the occurrence of an acid‐catalyzed mechanism.

ChemInform Abstract: Rational Design, Synthesis, and Reactivity of Lactendiynes, a New Class of Cyclic Enediynes ortho‐Fused with the β‐Lactam Ring.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Structure-activity relationships of cyclic enediynes related to dynemicin A—II. Synthesis and antitumor activity of 9- and 12-substituted enediynes equipped with aryl carbamate moieties

Novel enediyne compounds 4–8, simple analogues of dynemicin A ( 1) equipped with the phenyl or 4-chlorophenyl carbamate moiety, were synthesized and evaluated for DNA-cleaving ability, in vitro cytotoxicity, and in vivo antitumor activity. As a result of the SAR study, it was revealed that the size and character of the substituents (R 1 and R 2) at the C9 position critically influenced both the stability and antitumor activity of the enediyne compounds. We found that the 9-deoxy compound 6a, a stable and less bulky enediyne having a hydrogen as the R 1 and R 2 substituents, showed a significant in vivo activity with a T/C of 215% at a daily dosage of 2.0 mg/kg for 4 days. The incorporation of an oxygen-containing functional group as the R 3 substituent on a benzene ring resulted in considerable abolishing of both the in vitro and in vivo potencies. In a series of 9-acyloxy compounds, incorporation of the basic aromatic moiety such as 8e was effective for the in vitro activity, but it was ineffective for the in vivo activity. Furthermore, for the stereochemistry-activity relationships at the C9 position, the (9R ∗)- isomers of 8c, 8e, and 8f were found to show higher both in vitro and in vivo than the corresponding (9S ∗)- isomers . For the mechanistic studies, compound 6a underwent Bergman cycloaromatization via a diradical pathway under acidic conditions, whereas it scarcely showed DNA-cleaving activity due to the chemical stability of the aryl carbamate moiety under neutral conditions.

Structure-activity relationships of cyclic enediynes related to dynemicin A—I. Synthesis and antitumor activity of 9-acetoxy enediynes equipped with aryl carbamate moieties

A series of the 9-acetoxy enediyne compounds, 6a-k which were simplified from natural dynemicin A, and designed to be equipped with various aryl carbamate moieties, was synthesized and evaluated for DNA-cleaving ability, in vitro cytotoxicity, and in vivo antitumor activity. As a result of this study of the structure-activity relationships (SAR) with regard to the R 1 substituent, both compounds 6a and 6f with the phenyl carbamate and 4-chlorophenyl carbamate moiety, respectively, were found to exhibit significant activity ( T C > 200% ) against murine P388 leukemia in mice, in spite of having IC 50 values in the micromolar range. In particular, compound 6f showed the most potent activity with a maximum T C of 256% at a daily dosage of 4.0 mg/kg for four days. Furthermore, both compounds 6a and 6f were effective against Meth A sarcoma in mice and inhibited 71 and 77% of the tumor growth at 2.0 and 3.0 mg/kg dosages, respectively. In contrast to 6f, compound 6i possessing the 2-nitrophenyl carbamate moiety showed only a slight in vivo activity, while it had about one order of magnitude higher in vitro cytotoxicity than 6f. For the stereochemistry-activity relationships at the C9 position, the ( 9R ∗)- isomers of 6c, 6g, and 6j were found to show higher in vitro and in vivo potencies than the corresponding (9S ∗)- isomers .

Rational design, synthesis, and reactivity of lactendiynes, a new class of cyclic enediynes ortho-fused with the β-lactam ring

A series of 10-membered cyclic enediynes trans-fused with N-protected and N-unprotected β-lactams have been stereoselectively prepared. These compounds were found to be stable toward Bergman cycloaromatization, which, on the other hand, takes place readily when the azetidinone ring is opened.

Synthesis and biological evaluation of novel cyclic enediyne compounds related to dynemicin A as antitumor agents.

Novel cyclic enediyne compounds, which are simple functional analogs of dynemicin A (1) having the bicyclo-[7.3.1]tridec-4-ene-2,6-diyne system, were synthesized and evaluated for the DNA-cleaving ability, in vitro cytotoxicity and in vivo antitumor activity. All of the sulfones 19-24, which were equipped with a 2-(arylsulfonyl)-ethoxycarbonyl group or the 2-(methylsulfonyl)ethoxycarbonyl group as a triggering device, showed both potent DNA-cleaving activity and cytotoxicity against various tumor cell lines. However, these compounds were entirely inactive or only slightly active against murine P388 leukemia in mice. On the other hand, the enediyne 2a having a phenyl carbamate moiety as a stable N-protecting group showed effective antitumor activity both in vitro and in vivo. In particular, it exhibited significant antitumor activity against Lewis lung carcinoma in mice. These results show that the character of the carbamate moiety of the cyclic enediynes strikingly affects their biological activities, that is, the sulfonylethyl carbamate moiety is an effective triggering device for both DNA-cleaving activity and cytotoxicity, and the phenyl carbamate moiety is significant for antitumor activity in vivo. As part of a mechanistic study, the reactivities of 2a and 21 were examined under a weakly basic condition (pH 9.3); both compounds failed to give the Bergman cycloaromatization product.