Ring size effects in the C2–C6 biradical cyclisation of enyne–allenes and the relevance for neocarzinostatin

Schmittel, Michael; Steffen, Jens‐Peter; Maywald, Michael; Engels, Bernd; Helten, Holger; Musch, Patrick W.

doi:10.1039/b102380m

Cited by 43 publications

(25 citation statements)

References 57 publications

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“…This is in contrast, then, to the Bergman cycloaromatization of an enediyne, 30 which generates a diradical p -benzyne intermediate that is incapable of further closure owing to the instability of what would be a “Dewar benzyne” product. 31 The intramolecular HDDA is also in contrast with the Myers-Saito 32 and Schmittel 33 cycloaromatizations of enyne-allenes, which lead to α,3-didehydrotoluene and extracyclic fulvenoid diradical intermediates, respectively, 31e,34 and with the cycloaromatization of the enyne-cumulene neocarzinostatin chromophore, which leads to a 1,5-didehydroindene. 35 In none of these other cases are the radical centers able to react (intramolecularly) with one another to form a new bond (and ring): geometric constraints prevent such a closure.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of the Intramolecular Hexadehydro-Diels–Alder Reaction

et al. 2015

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Theoretical analysis of the mechanism of the intramolecular hexadehydro-Diels–Alder (HDDA) reaction, validated against prior and newly measured kinetic data for a number of different tethered yne-diynes, indicates that the reaction proceeds in a highly asynchronous fashion. The rate-determining step is bond formation at the alkyne termini nearest the tether, which involves a transition-state structure exhibiting substantial diradical character. Whether the reaction then continues to close the remaining bond in a concerted fashion or in a stepwise fashion (i.e., with an intervening intermediate) depends on the substituents at the remaining terminal alkyne positions. Computational modeling of the HDDA reaction is complicated by the significant diradical character that arises along the reaction coordinate, which leads to instabilities in both restricted singlet Kohn-Sham density functional theory (DFT) and coupled-cluster theory based on a Hartree-Fock reference wave function. A consistent picture emerges, however, from comparison of broken-symmetry DFT calculations and second-order perturbation theory based on complete-active-space self-consistent-field (CASPT2) calculations.

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Section: Resultsmentioning

confidence: 99%

Mechanism of the Intramolecular Hexadehydro-Diels–Alder Reaction

et al. 2015

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“…Upon exchange of the cyclopentene by a cyclohexene ( n = 2) or cycloheptene ( n = 3), a preference for the C 2 –C 6 cyclization mode is seen, because the marginal ring strain differences cannot override anymore the effect of the phenyl group at the alkyne terminus. Density functional theory (DFT) calculations revealed that the activation barrier of the C 2 –C 6 cyclization of cyclopent‐enyne–allene 62 ( n = 1; R 1 = R 2 = H) is about the same as that of the C 2 –C 7 mode (Δ G ‡ = 30.3 and 30.9 kcal mol ‐1 , respectively) . However, with increasing ring size, the C 2 –C 6 activation barrier becomes decisively lower (for n = 2: 24.2 versus 28.1 kcal mol ‐1 ; for n = 3: 22.2 versus 26.1 kcal mol ‐1 ).…”

Section: Factors Influencing the Schmittel (C2–c6) Cyclizationmentioning

confidence: 99%

The thermal C²–C⁶ (Schmittel)/ene cyclization of enyne–allenes – crossing the boundary between classical and nonstatistical kinetics

Schmittel

Vavilala

Çınar

2011

J of Physical Organic Chem

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The thermal C 2 -C 6 /ene cyclization of enyne-allenes has become an exciting venue for both mechanistic and synthetic studies. While at first most efforts were aimed at establishing the diradical nature of the thermal process and to derive therefrom efficient protocols for synthetic schemes, recent evidence has disclosed the C 2 -C 6 cyclization as a unique reaction heavily influenced by nonstatistical dynamic effects. Depending on the substituents at the enyne-allene, one can readily identify transitions between classical and nonstatistical behaviors on the basis of experimental data. We are grateful to him for his friendship and many scientific enlightenments.a M. Schmittel, C. Vavilala, M. E. Cinar FB 8 (

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“…For neocarzinostatin (13A) and related structures, conversion of the natural product to the enyne allene intermediate increases the ring strain for the triggered species to 15 kcal/mol above the σ, π-diradical energy [201]. Cycloaromatization can occur to a 2,6-or 2,7-diradical; the latter regioselectivity is believed to be favored for systems with a small, fused cyclopentane ring [202]. In the case of the C 10 enediynes, cleavage of the trisulfide linkage with a reductant, such as glutathione, causes a Michael addition to a constraining cyclohexenone ring (Fig.…”

Section: Structural Subtypesmentioning

confidence: 99%

Biosynthesis and function of polyacetylenes and allied natural products

Minto

Blacklock

2008

Progress in Lipid Research

291

228

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Polyacetylenic natural products are a substantial class of often unstable compounds containing a unique carbon-carbon triple bond functionality, that are intriguing for their wide variety of biochemical and ecological functions, economic potential, and surprising mode of biosynthesis. Isotopic tracer experiments between 1960 and 1990 demonstrated that the majority of these compounds are derived from fatty acid and polyketide precursors. During the past decade, research into the metabolism of polyacetylenes has swiftly advanced, driven by the cloning of the first genes responsible for polyacetylene biosynthesis in plants, moss, fungi, and actinomycetes, and the initial characterization of the gene products.The current state of knowledge of the biochemistry and molecular genetics of polyacetylenic secondary metabolic pathways will be presented together with an up-to-date survey of new terrestrial and marine natural products, their known biological activities, and a discussion of their likely metabolic origins.

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Ring size effects in the C2–C6 biradical cyclisation of enyne–allenes and the relevance for neocarzinostatin

Cited by 43 publications

References 57 publications

Mechanism of the Intramolecular Hexadehydro-Diels–Alder Reaction

Mechanism of the Intramolecular Hexadehydro-Diels–Alder Reaction

The thermal C²–C⁶ (Schmittel)/ene cyclization of enyne–allenes – crossing the boundary between classical and nonstatistical kinetics

Biosynthesis and function of polyacetylenes and allied natural products

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Ring size effects in the C2–C6 biradical cyclisation of enyne–allenes and the relevance for neocarzinostatin

Cited by 43 publications

References 57 publications

Mechanism of the Intramolecular Hexadehydro-Diels–Alder Reaction

Mechanism of the Intramolecular Hexadehydro-Diels–Alder Reaction

The thermal C2–C6 (Schmittel)/ene cyclization of enyne–allenes – crossing the boundary between classical and nonstatistical kinetics

Biosynthesis and function of polyacetylenes and allied natural products

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The thermal C²–C⁶ (Schmittel)/ene cyclization of enyne–allenes – crossing the boundary between classical and nonstatistical kinetics