Geometric and Electronic Control of Thermal Bergman Cyclization

Rawat, Diwan S.; Zaleski, Jeffrey M.

doi:10.1055/s-2004-815422

Synlett

2004

DOI: 10.1055/s-2004-815422

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Geometric and Electronic Control of Thermal Bergman Cyclization

Diwan S. Rawat¹,

Jeffrey M. Zaleski²

Abstract: The geometric and electronic contributions to Bergman cyclization of simple enediynes are compared and contrasted to those of recently developed metalloenediyne analogues. The comparison reveals that metals can have more diverse, subtle, and in some cases, more dramatic geometric effects upon Bergman cyclization than simple substitution chemistry. In addition to geometric consequences imposed by metals, electronic control of metalloenediyne cyclization is emerging as a complementary parameter in complex design. Show more

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Cited by 8 publications

References 141 publications

(299 reference statements)

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The Outliers: Metal-Mediated Radical Reagents for Biological Substrate Degradation

2019

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Conspectus The predictable and controllable interaction of small organic or peptidic molecules with biological substrates is the primary reason most pharmaceuticals are narrowly decorated carbon frameworks. The inhibition or activation binding models are measurable and without side reactions that can cause pathological angst. Yet many diseases, especially those involving rapid proliferation of cells (i.e., cancer) or aggregation of peptides (e.g., heart disease, Alzheimer’s disease) have not yet been cured by inhibition therapeutics. Additionally, interventional medicine is often required to alleviate such maladies by physical removal first, followed by molecular-level therapy as a second stage. Thus, there appears to be a niche for more aggressive therapeutics that may employ harsher chemical processes to realize clinical efficacy, albeit without causing catastrophic side effects. Molecules that may be considered for this challenge are not typically biomimetic, nor do they fit the traditional pharmaceutical paradigm. They may have unusual modes of action or undesired reactivity that can be lethal if not controlled. These are the outliers; potential pharmacophores that biology does not know how to manage or adapt to. This is why they may be an intriguing class of agents that needs continuous development. In this Account, we connect the under-developed enediyne family of compounds and our metalloenediyne derivatives to existing radical-based therapeutics such as bleomycin and doxorubicin to illustrate that controlled diradical reactivity, although an outlier mechanism, has a place in the therapeutic portfolio. This is self-evident in that of the 11 natural product enediynes known, 2 have clinical impact, a strong ratio. We expand on the chemical diversity of potential enediyne constructs and focus on the accessible trigger mechanisms to activate diradical formation as a method to control toxicity. Moreover, we further illustrate how electromagnetic fields can be employed to activate both molecular and larger nanomaterial constructs that carry highly concentrated payloads of reactive reagent. Finally, we describe how controlled diradical reactivity can reach beyond traditional therapeutic targets such as DNA, to peptide aggregates found in blood clots, neural fibrils, and membrane scaffolds. It is our belief that cleverly constructed frameworks with well-designed and controlled activation/reaction schemes can lead to novel therapeutics that can challenge evolving viral and bacterial invaders. From this evangelical perspective, our hope is that the conceptual framework, if not the specific designs in this Account, stimulate the readership to develop out-of-the-box therapeutic designs that may combat resistant disease targets.

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The Outliers: Metal-Mediated Radical Reagents for Biological Substrate Degradation

2019

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Anion Control of Lanthanoenediyne Cyclization

et al. 2019

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A suite of lanthanoenediyne complexes of the form Ln(macrocycle)X 3 (Ln = La 3+ , Ce 3+ , Eu 3+ , Gd 3+ , Tb 3+ , Lu 3+ ; X = NO 3 − , Cl − , OTf −) was prepared by utilizing an enediyne-containing [2 + 2] hexaaza-macrocycle (2). The solid-state Bergman cyclization temperatures, measured via DSC, decrease with the denticity of X (bidentate NO 3 − , T = 267−292 °C; monodentate Cl − , T = 238-262 °C; noncoordinating OTf − , T = 170-183 °C). 13 C NMR characterization shows that the chemical shifts of the acetylenic carbon atoms also rely on the anion identity. The alkyne carbon closest to the metal binding site, C A , exhibits a Δδ > 3 ppm downfield shift, while the more distal alkyne carbon, C B , displays a concomitant Δδ ≤ 2.5 ppm upfield shift, reflecting a depolarization of the alkyne on metal inclusion. For all metals studied, the degree of perturbation follows the trend 2 < NO 3 − < Cl − < OTf −. This belies a greater degree of electronic rearrangement in the coordinated macrocycle as the denticity of X and its accompanying shielding of the metal's Lewis acidity decrease. Computationally modeled structures of LnX 3 show a systematic increase in the lanthanide-2 coordination number (CN La-mc = 2 (NO 3 −), 4 (Cl −), 5 (H 2 O, model for OTf −)) and a decrease in the mean Ln−N bond length (La−N average = 2.91 Å (NO 3 −), 2.78 Å (Cl −), 2.68 Å (H 2 O)), further suggesting that a decrease in the anion coordination number correlates with an increase in the metal-macrocycle interaction. Taken together, these data illustrate a Bergman cyclization landscape that is influenced by the bonding of metal to an enediyne ligand but whose reaction barrier is ultimately dominated by the coordinating ability of the accompanying anion.

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Experiment and Computational Study on the Regioselectivity of Nucleophilic Addition to Unsymmetrical p-Benzynes Derived from Bergman Cyclization of Enediynes

et al. 2018

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The regioselectivity in addition of nucleophiles to the p-benzyne intermediates derived from unsymmetrical aza-substituted enediynes via Bergman cyclization was studied. Computational studies [using UB3LYP/6-31G(d,p) level of theory] suggest that the p-benzyne intermediate retains its similar electrophilic character at the two radical centers even under unsymmetrical electronic perturbation, thus supporting the predicted model of nucleophilic addition to p-benzyne proposed by Perrin and co-workers (Perrin et al. J. Am. Chem. Soc. 2007, 129, 4795-4799) and later by Alabugin and co-workers (Peterson et al. Eur. J. Org. Chem. 2013, 2013, 2505-2527). However, observed experimental results suggest that there was small but definite regioselectivity (∼5-25%), the extent varying with the electronic nature of the substituents. Differential solvated halide ion concentrations around the vicinity of two radical centers arising due to surrounding surface electrostatic potential (computationally calculated) may be one of the possible factors for such selectivity in some of the examined p-benzynes. However, other complicated dynamical issues like the trajectory of the attacking nucleophile to the radical center which can be influenced by electronic and/or steric perturbation of starting enediyne conformation cannot be ruled out. The overall yield of the anionic addition was in the range of 80-99%.

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Geometric and Electronic Control of Thermal Bergman Cyclization

Cited by 8 publications

References 141 publications

The Outliers: Metal-Mediated Radical Reagents for Biological Substrate Degradation

The Outliers: Metal-Mediated Radical Reagents for Biological Substrate Degradation

Anion Control of Lanthanoenediyne Cyclization

Experiment and Computational Study on the Regioselectivity of Nucleophilic Addition to Unsymmetrical p-Benzynes Derived from Bergman Cyclization of Enediynes

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