Oxa-azabenzobenzocyclooctynes (O-ABCs): heterobiarylcyclooctynes bearing an endocyclic heteroatom

Abstract

We report the synthesis of heterobiarylcyclooctynes bearing an endocyclic heteroatom, oxa-azabenzobenzocyclooctynes (O-ABCs). The integration of design strategies for accelerating strain-promoted azide–alkyne cycloadditions results in reactivity with organic azides that surpasses all cyclooctyne reagents reported to date. O-ABCs and related compounds provide insights into the effects of structural modifications on reactivity that can aid in the design of new reagents for click and bioorthogonal chemistry.

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Introduction

Click and bioorthogonal chemistry have transformed the landscape of the molecular sciences.^1,2 These strategies harness chemoselective reactions to efficiently link building blocks bearing appropriate functional groups. In chemical biology, the chemical reporter strategy provides a toolbox for studying native physiological processes; however, employed reactions must remain selective and, in applications within a cellular setting, reaction conditions cannot compromise cell viability.³

Alkynes and azides provide a well-matched pair for click reactivity.⁴ While the copper-catalyzed azide–alkyne cycloaddition (CuAAC) displays faster reaction kinetics than the uncatalyzed 1,3-dipolar cycloaddition reaction,⁵ cytotoxicity elicited by copper limits utility in many bioorthogonal applications. The strain-promoted azide–alkyne cycloaddition (SPAAC) overcomes this limitation,^2,6 where the distortion of bond angles within cyclic alkynes increases their inherent reactivity.⁷

Cyclooctynes possess great utility as SPAAC reagents (Fig. 1). Structural modifications enable tuning of reactivity and stability⁸—and have resulted in general activation strategies of reagent destabilization (i.e., increased predistortion)⁹ and transition state stabilization (i.e., electronic activation).¹⁰ Reagents designed to simultaneously harness both strategies have recently been reported.¹¹ Azabenzobenzocyclooctyne (ABC), benefits from a lowered LUMO, hyperconjugative transition state stabilization provided by the propargylic C–N bond,^10b,c and dipole-specific interactions with the pyridine nitrogen lone pair (H-bonding and/or n → π*).^11b These features result in rapid cycloaddition kinetics and increased stability in the presence of biological nucleophiles relative to less reactive dibenzocyclooctynes. We sought to further harness the integration of activation strategies within the well-established class of biarylcyclooctynes. Herein, we report the synthesis and SPAAC reactions of oxa-azabenzobenzocyclooctynes (O-ABCs).

Fig. 1 Evolution of biarylcyclooctynes: (A) exemplary dibenzocyclooctynes: DIBO,^9a DIBAC,^9b,c and ODIBO;^9f (B) heterobiarylcyclooctyne, ABC,^11b synthesized via carbene-mediated ring expansion; (C) two isomers of O-ABC, heterobiarylcyclooctynes bearing endocyclic oxygen atoms.

Results and discussion

Cyclooctyne synthesis

The concise synthesis of ABC from a commercially available precursor ketone enables access to a wide range of previously reported cyclooctynes (and derivatives).^11b,12 Beginning with dibenzo[b,e]oxapin-11(6H)one, we first synthesized oxa-dibenzocyclooctyne (ODIBO). This route enables the synthesis of the parent ODIBO, where electron-donating groups required in previously reported syntheses are absent.^9f ODIBO was obtained in excellent yields—90% for the final step and 72% overall (three steps from the commercial precursor). Having demonstrated the compatibility of these methods with an endocyclic oxygen atom, we next sought to synthesize target pyridine-containing compounds (O-ABCs).

Access to both O-ABC isomers required synthesis of their precursor ketones (see ESI†). Ketones 1 and 2 were facilely generated via a two-step substitution/Parham-type cyclization protocol employing aryl iodides. A Grignard-induced cyclization afforded ketone 2 in 73% yield from the Weinreb amide, while ketone 1 was obtained in 45% using n-BuLi to promote a Parham-type cyclization onto the nitrile.¹³

We next sought to synthesize O-ABC and O-ABC-II from the synthesized precursor ketones (Scheme 1).^11b,12a–c Nucleophilic addition of N-morpholinomethyl-5-lithiotetrazole, followed by acid hydrolysis gave intermediate tetrazoles 1′ and 2′ in good yields (>60% over two steps). These tetrazoles then underwent carbene-mediated ring expansion in the presence of carbodiimides to generate the desired cyclooctynes.

Scheme 1 Synthesis of oxacyclooctynes via carbene-mediated ring expansion from precursor ketones and their 1,3-dipolar cycloaddition reactions with benzyl azide. ^a Isolated yield (6%) determined by ¹H-NMR with internal standard (1,3,5-trimethoxybenzene); 30% yield of 3 from 1′ (in situ trapping with benzyl azide).

O-ABC was successfully formed and found to be stable to silica during flash chromatography. However, decomposition was observed upon concentration under reduced pressure and/or prolonged exposure to ambient air. Removal of the mobile phase used in chromatographic separation was achieved by immediately adding a suitable solvent (i.e., a solvent with a high boiling point; see ESI† for details). Following this protocol, we obtained a solution of O-ABC in DMSO-d₆ for characterization and investigation of 1,3-dipolar cycloaddition reactivity (vide infra).

Confirmation of O-ABC-II formation required in situ trapping with a 1,3-dipole,^6a,b as attempts at isolation were unsuccessful. Addition of benzyl azide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in one pot afforded cycloadduct 4 in 53% yield from the tetrahedral intermediate. These results confirm that O-ABC-II was successfully formed via the carbene-mediated ring expansion, illustrating the utility of this underutilized methodology in the future development of strained alkynes.

SPAAC reactivity

1,3-Dipolar cycloaddition reactions performed with benzyl azide proceeded efficiently with synthesized cycloalkynes. Reactions of both O-ABC and O-ABC-II formed a single regioisomer, as was previously reported for ABC.^11b The identity of the formed regioisomer was confirmed via X-ray diffraction of grown crystals (Fig. 2).

Fig. 2 Oak Ridge thermal ellipsoid plot (ORTEP) diagram at 50% probability of O-ABC (CCDC: 2259714†) and O-ABC-II (CCDC: 2286852†) cycloadducts formed in the 1,3-dipolar cycloaddition with benzyl azide. See ESI† for further details.

Second-order rate constants (k₂) for the SPAACs of ABC and ODIBO are ∼1–2 M⁻¹ s⁻¹.^8b,11b We conducted a competition experiment to determine the reactivity of O-ABC relative to ABC (Scheme 2). A 1 : 1 ratio of O-ABC : ABC was prepared in DMSO-d₆ using 1,3,5-trimethoxybenzene as an internal standard. Benzyl azide was added and reaction progress was monitored via¹H NMR spectroscopy. O-ABC was found to be highly reactive, with a product ratio of 8.4 : 1.

Scheme 2 Reactivity of O-ABC. The rate of the SPAAC between O-ABC and benzyl azide was estimated in a competition experiment against ABC. Inset: portion of ¹H NMR spectrum containing benzylic peaks of each product (integrated relative to 1,3,5-trimethoxybenzene as an internal standard).

The second-order rate constant (k₂) for the reaction with benzyl azide was estimated based on the value obtained for ABC (0.6 M⁻¹ s⁻¹). While the estimated k_2-OABC is >5 M⁻¹ s⁻¹, the true initial rate constant is likely even greater—ABC becomes more competitive as the O-ABC concentration decreases. Still, this result clearly shows that the SPAAC kinetics of O-ABC surpass known cyclooctyne reagents.

Computational analysis

Insight into the enhanced reactivity of O-ABC was provided by DFT calculations, performed using Gaussian 16 at the M06-2X/6-31G(d) level of theory, followed by single-point energy calculations at the M06-2X/6-311++G(d,p) level of theory including the PCM solvation model for DMSO.¹⁴ Modelling the reactions of methyl azide with DIBO, ODIBO, ABC, and O-ABC enabled elucidation of the effects embedded heteroatoms play within (hetero)biarylcyclooctynes. Further insights were obtained by performing a distortion/interaction (strain-activation) analysis both at the transition state (TS) and along the reaction coordinate. This analysis quantifies the energy required to distort individual reactants (ΔE_distortion) and the interactions between them (ΔE_interaction) along the calculated intrinsic reaction coordinate (IRC), which was then projected upon the average incipient C–N bond length.¹⁵

Both C–H → N substitution (DIBO → ABC) and CH₂ → O substitution (DIBO → ODIBO) result in lowered activation energies of 0.8 and 2.4 kcal mol⁻¹, respectively (Fig. 3). O-ABC integrates both structural modifications, eliciting a 3.2 kcal mol⁻¹ decrease in the activation energy relative to DIBO. At the transition state, O-ABC displays the lowest distortion energies—both alkyne and azide—overall (Fig. 3). Relatively long incipient bond lengths and a less bent azide suggest this observation results from an earlier TS. Thus, we focused our analysis on the distortion/interaction analysis throughout the reaction coordinate.

Fig. 3 Computational analysis of 1,3-dipolar cycloadditions between cyclooctynes and methyl azide performed at the M06-2X/6-311++G(d,p)-CPCM(DMSO)//M06-2X/6-31G(d) level of theory. Optimized starting material and transition state geometries, NBO charges, and relevant FMO energies (top); free energies of activation (kcal mol⁻¹) and distortion/interaction (strain-activation) analysis (bottom).

Modes of activation elicited by heteroatom incorporation were identified by comparing distortion and interaction energies of DIBO to various derivatives (ODIBO, ABC, O-ABC) along the reaction coordinate (Fig. 4). Interestingly, each heteroatom—the endocyclic oxygen and the nitrogen within the fused aryl ring—provides enhanced reactivity via a unique mode of activation. Importantly, O-ABC simultaneously benefits from both modes of activation.

Fig. 4 Distortion/interaction analysis for the 1,3-dipolar cycloaddition transition states between methyl azide and cyclooctynes (color-coded within the figure inset) calculated at the M06-2X/6-311++G(d,p)-CPCM(DMSO)//M06-2X/6-31G(d) level of theory. Total energies, solid lines; distortion energies, dashed lines; interaction energies, dotted lines.

Oxygen incorporation results in cycloalkynes (ODIBO, O-ABC) that benefit from stronger (more negative) interaction energies (Fig. 4). This result contrasts the values found at the TS, where the increased reactivity of oxa-cyclooctynes appears to result from lowered distortion energies (Fig. 3). This discrepancy is explained by the position of the transition state—an earlier transition state results from the strengthened (orbital) interactions (vide infra). Thus, the lower distortion energy values observed at the TS result from a lowered alkyne LUMO (or other low-lying unfilled frontier orbitals; see Fig. S7†),^11a,16 which decreases the extent of azide bending required to reach the TS.

The azabenzo-ring in ABC and O-ABC was found to decrease distortion energies relative to the dibenzo-systems (DIBO, ODIBO; Fig. 4). Examination of the TS's of ABC relative to DIBO and O-ABC relative to ODIBO, reveal that the TS position is similar for each parent-derivative set (Fig. 3). Azide distortions are within ∼0.5° and the average incipient C–N bond lengths are within 0.05 Å. Despite similar geometric distortions observed at the TS, azide distortion energies differ by ∼1.5 kcal mol⁻¹. How, then, does the energy required to distort the azide decrease as it approaches the TS for ABC and O-ABC?

This surprising result stems from a more favorable azide approach enabled by the azabenzo ring in ABC and O-ABC (Fig. 5). The flagpole hydrogens¹⁷ in DIBO and ODIBO force the azide substituent (Me) to rotate away from the plane of bond formation, while C–H → N substitution enables increased coplanarity (Δφ_azide >10°) and stereoelectronic interactions with high energy incipient bonds.

Fig. 5 Geometric parameters (φ_azide, φ₁, φ₂, φ₃, φ₄) reveal effects of heteroatoms on azide approach in cycloaddition transition states calculated at the M06-2X/6-311++G(d,p)-CPCM(DMSO)//M06-2X/6-31G(d) level of theory.

Dihedral angles (φ₁–φ₃) further reveal preferences for approach of the incoming azide dipole and within the (hetero)biarylcyclooctyne scaffolds (Fig. 5).^11c Stark differences were again observed between the dibenzo- (DIBO, ODIBO) and azabenzobenzo- (ABC, O-ABC) systems (Δφ₁ = 20°–22°; Δφ₂ = 4°–7°; Δφ₃ = 8°–11°), where steric repulsion between azide substituents and flagpole C–H bonds have been replaced by attractive n_N → σ*_C–H interactions.^11b This C–H⋯N hydrogen bond was quantified via natural bonding orbital (NBO) analysis (Fig. 6).¹⁹ Approach within the plane of the σ-framework (i.e., reaction with the in-plane π-system) is further facilitated by interactions between incipient bonds and the azabenzo ring (π → σ*_C–N; Fig. 6A).^10b,c,11b

Fig. 6 Stereoelectronic interactions in the cycloaddition of O-ABC with methyl azide quantified by second-order perturbations from NBO analysis. (A) Activation provided by the azabenzo ring. (B) Interactions in which the endocyclic oxygen acts as an acceptor. (C) Interactions in which the endocyclic oxygen acts as a donor.

O-incorporation was found to increase planarity of the anti-aryl ring relative to the in-plane π-system (φ₄). NBO analysis revealed both donor and acceptor interactions due to the chameleonic nature of oxygen atoms.¹⁸ The endocyclic oxygen acts as an acceptor via its two σ*_C–O orbitals (Fig. 6B). Simultaneous stabilization of partial positive charge at C4 of the forming 1,2,3-triazole is provided by oxygen lone pairs through the σ-framework (Fig. 6C). This push–pull effect is amplified by the acceptor interactions of the propargylic N of the azabenzo-ring (π_CC → σ*_CN). Together, both structural modifications in O-ABC amplify alkyne polarization in the cyclic alkyne scaffold (Fig. 3), which increases both reactivity and instability.^11c

Conclusions

In conclusion, we report the concise synthesis of biaryl- and heterobiarylcyclooctynes bearing endocyclic heteroatoms. The SPAAC reactivity of O-ABC was found to surpass known cyclooctyne reagents, as assessed in a competition reaction against ABC with benzyl azide. Both ABC and O-ABC were found to form a single regioisomer, which was confirmed via X-ray crystallography. Computational analysis revealed factors controlling the reactivity of (hetero)biarylcyclooctynes that can be harnessed in future reagent design.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by start-up funds from UNM and NMSU. High-performance calculations made use of resources at the UNM Center for Research Computing, which is supported in part by the National Science Foundation. MAMF was supported in part by a Ph.D. Scholarship from the Central Luzon State University Faculty Development Program. Work at UNM was performed on the traditional homelands of the Pueblo of Sandia; for more information, see: https://diverse.unm.edu/about/land-acknowledgement.html.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2259714, 2286852 and 2286853. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3ob01559a

‡ These authors contributed equally to this work—E. D. performed the majority of experiments; M. A. M. F. performed some experiments and all computations.

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