Experimental and Theoretical Analysis of the Thiol-Promoted Fragmentation of 2-Halo-3-tosyl-oxanorbornadienes

Experimental and Theoretical Analysis of the Thiol-Promoted Fragmentation of 2‑Halo-3-tosyl-oxanorbornadienes Marina Carranza, Ana T. Carmona, Claudio D. Navo, Inmaculada Robina, Simone Fratta, Carlos Newburn, Gonzalo Jiménez-Osés,*and Antonio J. Moreno-Vargas* Cite This: Org. Lett. 2023, 25, 7481−7485 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: 2-Halo-3-tosyl-oxanorbornadienes are able to accept two thiol molecules through an initial nucleophilic substitution, giving isolable oxabicyclic thiovinyl sulfones that, subsequently, can react with a second thiol molecule via thio-Michael addition. The resulting oxanorbornenic thioketals undergo retro-Diels−Alder (rDA) fragmentation to release a furan derivative and a ketene S,S-acetal. The substitution pattern of the oxanorbornadienic skeleton influences the rate of the rDA through electronic and steric factors examined by quantum mechanical calculations. Cleavable linkers are valuable chemical tools for chemical biology with applications in drug development, proteomics, imaging, and DNA sequencing. 1 In the particular case of antibody−drug conjugates (ADCs), this type of linkers is present in the majority of ADCs in clinical development. 2 Chemical systems acting as cleavable linkers should be able to form a stable bond between the protein and the cytotoxic agent (payload) in the circulating macromolecule and to fragment as a response to an intracellular stimulus. Biological thiols such as glutathione (GSH), which is abundant in the cytosol, 3 often play this role. 2b In this sense, Finn, Houk, and co-workers have recently explored the thiol-promoted fragmentation of electrophilic oxanorbornadienes (ONDs) in the search for thiol-responsive cleavable linkers for drug delivery systems (Scheme 1, previous ONDs). 4−6 As a result, an exhaustive (theoretical and experimental) study of the influence of the substitution pattern of ONDs in the rate of fragmentation via retro-Diels−Alder (rDA) reaction was reported. 5,6 Some of these ONDs were successfully applied in drug delivery systems. 7 Bercovici and co-workers recently extended this chemistry of ONDs to ylidenenorbornadiene carboxylate analogues. 8 From our side, we have recently reported that azanorbornadienes containing the bromovinyl sulfone functionality are useful reagents for the selective modification of proteins. 9 This functionality is crucial for the bioconjugation process as it allows the reaction with the thiol function of cysteine residues of proteins through nucleophilic vinylic substitution (SNVσ). We report herein a new family of electrophilic ONDs containing a halovinyl sulfone/ester/ phosphonate functionality that could be useful in linker chemistry (Scheme 1, this work). The novelty of our systems lies in their ability to accept two thiol molecules at different stages, the first one mimicking the Cys residue of a protein in the bioconjugation step and the second one the intracellular GSH for the cleavage of the linker. We present a detailed study of the reactivity of the new ONDs toward N-acetylcysteamine, as a simple model of a biological thiol. These studies allowed us to identify the most reactive system for the initial thiol- Received: August 3, 2023 Published: October 10, 2023 Scheme 1. Thiol-Promoted Fragmentation of ONDs: New and Previous Strategies Letterpubs.acs.org/OrgLett © 2023 The Authors. Published by American Chemical Society 7481 https://doi.org/10.1021/acs.orglett.3c02548 Org. Lett. 2023, 25, 7481−7485 This article is licensed under CC-BY 4.0 Downloaded via UNIV DE SEVILLA on November 6, 2023 at 15:06:10 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. substitution and, additionally, the most sensitive one toward the further thiol-promoted fragmentation. First, we carried out the synthesis of a collection of halo- ONDs (Figure 1). These compounds were obtained by the Diels−Alder reaction of the corresponding furan and the adequate electron-deficient alkyne (see the Supporting Information for details). Special effort was paid to introduce an amino-functionalized substituent on the furan derivative that could act as a handle for future cargo-delivery purposes. Then, competition experiments between pairs of halo-OND systems and N-acetylcyste- amine in DMF-phosphate buffer solution (PBS, pH 8.0) were performed (Table 1). The bromo-OND 1a was chosen as a reference for the competition experiments, pairing this compound with a selection of representative halo-ONDs (2a, 3a,4,5and 8a,Figure 1). All the reactions yielded a mixture of stable 2-thio-oxanorbornadienic (thio-ONDs) derivatives (1b/ Bb) in a fast (less than 15 min) and clean reaction (no byproducts were detected). These experiments allowed us to establish some structure− reactivity relationships: (i) the use of a −COOMe group as an electron-withdrawing group accelerated the substitution reaction with respect to the tosyl or phosphonate group, the latter being the less reactive one (entries 1 and 2); (ii) chloro/ bromo-oxanorbornadienes are more reactive than yododerivative in the SNVσ(entries 3 and 4); (iii) the steric hindrance of a substituent at C1, close to the C2 electrophilic center, was not significant (entry 5). Next, we explored the thiol-promoted fragmentation of selected thio-ONDs 1b,2b, and 6b−18b that were also obtained from bromo-OND precursors via nucleophilic displacement (Figure 1; see the Supporting Information for details). This fragmentation proceeded via a two-reaction sequence: a selective thio-Michael addition of N-acetylcyste- amine at C2 of the thiovinyl sulfone/ester/phosphonate function of the oxanorbornadiene, followed by a retro-Diels− Alder reaction to afford a furan derivative and the corresponding ketene S,S-acetal 19 or 20 (Scheme 2). Scheme 2shows the half-life (t1/2) for the transformation of the starting thio-OND into the final furan derivative. The parameter t1/2 was determined through 1H NMR by monitoring the concentration of the furan derivative vs time. In all the cases, except for thio-ONDs 8b and 13b, 10 the thioketal intermediate was formed quantitatively and immediately (detected by 1H NMR). Thus, the comparative study of the structural effects of the bicyclic skeleton in this series will only reflect the influence on the rDA but not the conjugate addition. Electronic as well as steric substituent effects might be responsible for the different rates observed for the rDA reactions. We observed that the presence of an ester group instead of a tosyl at C3 (compounds 2b and 9b) remarkably slowed down the reaction rate (1b vs 2b;6b vs 9b). This could be explained considering that the tosyl group is more electron-withdrawing than the methoxycarbonyl, which could provide a stronger dienophilic character to the forming ketene S,S-acetal. 11 This fact would help to improve the orbital interaction of this dienophile with the furanic diene, stabilizing the transition state of the rDA. This hypothesis is also plausible to explain the fact that OND- phosphonate 10b is less reactive toward the thio-Michael addition and, additionally, the corresponding thioketal adduct does not fragment. The presence of Me substituents at the bridgehead positions (C1 and/or C4) accelerated the rDA reaction (1b vs 6b,7b,8b;2b vs 9b), as previously demonstrated by Finn, Houk, and co-workers in other oxanorbornene systems. 4−7 As these authors indicated, the methyl group generally improves the electron-rich character of the forming furanic diene, which also enhances the interaction between orbitals of the diene and dienophile in the transition state. Surprisingly, a big difference was observed between regioisomers 7b and 8b. While the thioketal intermediate was detected by 1H NMR in the fragmentation of 7b, only fragmented products and starting OND were observed when monitoring the fragmentation of regioisomer 8b; a relatively short half-life (38 min) was measured for this compound. A similar behavior was observed for regioisomers 12b and 13b. While the thioketal intermediate is quantitatively and immediately formed for 12b, the corresponding thioketal is not observed when the fragmentation of 13b is monitored (t1/2 = 13 min). The different results obtained for the Figure 1. Structures of halo/thio-ONDs. Table 1. Competition Experiments: Reaction of a Mixture of Two Halo-ONDs with N-Acetylcysteamine a Entry Halo-ONDs Structural variation % Conversion into 1b:Bb 11a:2a EWG: Ts/COOMe 37:63 21a:3a EWG: Ts/P(�O)OEt258:42 31a:4X: Br/Cl 48:52 41a:5X: Br/I 62:38 51a:8a R: H/Me 54:46 a Reaction conditions: To an equimolar solution of ONDs 1a/Aa (0.072−0.15 mM each, 1.0 equiv each) and N-acetylcysteamine (0.9 equiv) in DMF (2.0 mL), a similar volume of phosphate buffer solution (pH 8.0) was added. The reaction mixture was stirred for 30 min at room temperature. After workup, the ratio 1b:Bb was analyzed by 1H NMR. Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.3c02548 Org. Lett. 2023, 25, 7481−7485 7482 fragmentations of C4-functionalized derivatives 11b,12b, and 14b, in comparison with 7b, reveal that the rate of the rDA is extremely sensitive to the topology/typology of the C4- substituent. In the particular case of 14b, with a pendant secondary amide on C4, its long half-life might be in part explained by a stabilizing intramolecular H-bonding between the amide group and the sulfone on C3, despite the effect of intramolecular H-bonding being mitigated in polar protic solvents. We also examined the simultaneous introduction of a sulfonamide-functionalized substituent and a Me group at the bridgehead carbons (15b and 16b). We observed that the presence of the sulfonamide substituent in C4 slowed down (5-fold) the fragmentation process (15b vs 8b). Regioisomers 15b and 16b could be directly compared only in DMSO-d6, 12 and no difference was observed in the fragmentation rate. This was also the case for the couple 17b/18b with the presence of a substituent on C5/C6 combined with the absence of substituents at C1 and C4; a similar t1/2 value was observed for both. In order to explore the importance of the thioketal function in the intermediate for the fragmentation, the reactivity of vinyl sulfone OND 21 (Scheme 3) toward N-acetylcysteamine was studied. In contrast to the result obtained with 1b (Scheme 2), the resulting thio-adduct 22 was stable and did not undergo rDA at 30 °C within a week. A similar result was obtained for oxanorbornenic ketal 23, 13 which proved to be stable to the fragmentation process. The influence of the substitution patterns of the oxabicycle in the rDA reaction was analyzed by quantum mechanics (see the Supporting Information for full computational methods). Methylsulfonyl and methylthioether/ketal groups were used as models for the tosyl and reacting N-acetylcysteaminyl groups, respectively. First, the propensity of the parent Br-OND 1a and thio-OND 1b to undergo the rDA reaction was analyzed (see the Supporting Information). Reactions from both derivatives have quite high calculated activation energies (ΔG⧧= 35.3 and 30.4 kcal mol−1, respectively) and are endergonic (ΔG= +9.9 and +4.9 kcal mol−1, respectively), in agreement with their lack of rDA reactivity observed experimentally. In agreement with previous studies performed by Finn, Houk, and co-workers for analogous systems, 4,6 a moderate correlation was found between the calculated rDA activation barriers and the experimentally observed half-lives (Figure 2a). Indeed, this correlation was excellent within the subset of substrates bearing methyl groups at different positions of the bicyclic scaffold (Figure 2a, in orange). Likewise, a moderate linear correlation between reaction (ΔGrxn) and activation (ΔG⧧) energies with a slope of ∼0.5 was found for the calculated rDA reactions; this is in agreement with the Hammond postulate and Marcus theory which state that for similar reactions ΔΔG⧧≈1/2ΔΔGrxn. 14 All the transition structures (TS) are concerted but asynchronous, with often a shorter distance for the breaking C3−C4 (1.96− 2.16 Å) bond and a longer distance for the C1−C2 (2.10−2.37 Å) bond, with some exceptions (Figure 2b). Of note, the presence of a methyl group at the bridgehead position (C1) adjacent to the thioketal (TS-8b) significantly lowers the activation energy for the fragmentation reaction (ΔG⧧= 21.4 vs 23.5 kcal mol−1in unsubstituted TS-1b); this is likely due to the combined effect of the electron-donating character and the steric hindrance exerted by the methyl group. In fact, the TS for this rDA reaction is the most asynchronous of all of the calculated ones. On the contrary, the presence of a methyl group in the opposite and less sterically hindered bridgehead position (C4) inverts the polarization of the forming furanic diene in TS-7b, leading to an inversion of the asynchronicity at the TS and exerting a smaller activating effect (ΔG⧧= 23.0 kcal mol−1). As expected, such effects are counterbalanced in C1,C4-dimethylated TS-6b, both geometrically and energetically (ΔG⧧= 22.5 kcal mol−1). Somewhat counterintuitively, Scheme 2. Half-Lives (t1/2) for the Fragmentation of Thio- ONDs a a Reaction conditions: To a solution of thio-OND in CD3OD (80 mM), a solution of N-acetyl cysteamine (1.1 equiv) and Et3N (1.2 equiv) in the same solvent was added (final concentration of thio- OND: 70 mM). The mixture was heated at 30 °C, and 1H NMR spectra were registered at different intervals; t1/2 (in h or min) was determined from the plot [concentration of the resulting furan] vs time. b Thioketal intermediate was not detected. c Slow thio-Michael addition (2 h) and rDA not observed. d DMSO-d6instead of CD3OD was used as solvent. Scheme 3. Studies on the Stabilities of Oxanorbornene Derivatives Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.3c02548 Org. Lett. 2023, 25, 7481−7485 7483 and in agreement with the experiments, substitutions with electron-donating methyl groups at C5/C6 positions of the forming diene have a destabilizing effect (ΔG⧧= 24.7 kcal mol−1for both TS-17b′and TS-18b′), 15 although this is not translated into significant changes in the breaking C−C bond distances. We also analyzed the triggering effect on the rDA reaction observed for the parent OND bearing a thioketal (TS-1b) versus those featuring a thioether (TS-22), a ketal (TS-23), or no substituents at C2 (TS-24) (Figure 2c). While the four transition structures are concerted and asynchronous, those lacking the two geminal sulfur atoms (TS-22,TS-23, and TS- 24) show an opposite asynchronicity trend: the breaking C1− C2 bonds are shorter (2.04−2.10 Å) than the breaking C3−C4 bonds (2.15−2.23 Å). Of note, the rDA reaction in these cases, especially from ketal 23, have much higher activation energies (ΔG⧧≈27−30 kcal mol−1) in agreement with the experiments (i.e., no reaction is observed from 22 or 23,Scheme 3). The unusual effect of the thioketal derived from OND 1b might be attributed to a higher fragmentation propensity resulting from their bulkier nature and the interactions between the S lone pairs (norbitals) and the antibonding σ*(C1−C2) and/or π*(C5−C6) orbitals (see HOMO and LUMO in Figure 2d); of note, the C−C breaking bonds are slightly elongated (i.e., distorted) in thioketal derived from 1b (∼1.58 Å) compared to its ketal counterpart 23. The smaller size and higher electronegativity of the oxygen atoms in 23 might prevent the interaction of the O lone pairs and the antibonding π*(C5−C6) orbitals, resulting in a lower interaction energy (as shown by a distortion/interaction analysis of the reaction; see the Supporting Information) and translating into a higher activation energy. In conclusion, electrophilic halo-oxanorbornadienic systems able to accept two thiol molecules at different stages have been developed. The second thiol molecule triggers the fragmentation of the OND system through conjugate addition, followed by a rDA reaction. The substitution pattern of the OND skeleton was crucial for the modulation of the fragmentation process, with a broad range of half-lives from 2 days to 13 min under rDA conditions. Part of the developed systems contain an amino-functionalized substituent that can act as a handle for the incorporation of biologically relevant molecules. These features make these ONDs amenable to thiol-sensitive linker chemistry in drug-delivery systems. ■ASSOCIATED CONTENT Data Availability Statement The data underlying this study are available in the published article and its Supporting Information. * sı Supporting Information The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.3c02548. Synthetic procedures, characterization data, computational details, and NMR spectra for the new compounds (PDF) ■AUTHOR INFORMATION Corresponding Authors Gonzalo Jiménez-Osés −Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain; orcid.org/0000-0003-0105-4337; Email: [email protected] Antonio J. Moreno-Vargas −Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla 41012, Spain; orcid.org/0000-0002-5771-2012; Email: [email protected] Figure 2. Computational studies on rDA reactions. (a) Observed halflife (t1/2) vs calculated activation energies (ΔG⧧) for model retro- Diels−Alder (rDA) reactions. (b, c) Transition structures and calculated activation energies for rDA from selected di-thio-ONDs, thioether 22, ketal 23, and unsubstituted alkene 24. (d) HOMO and LUMO in TS-1b and TS-23 (side view); potentially stabilizing orbital interactions are highlighted with red arrows. Calculations were performed at the PCM(MeOH)/M06-2X/6-311+G(d,p) level. Distances are given in angstroms. Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.3c02548 Org. Lett. 2023, 25, 7481−7485 7484 Authors Marina Carranza −Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla 41012, Spain Ana T. Carmona −Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla 41012, Spain; orcid.org/0000-0003-1058-7127 Claudio D. Navo −Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; orcid.org/0000-0003-0161-412X Inmaculada Robina −Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla 41012, Spain; orcid.org/0000-0003-1447-8032 Simone Fratta −Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla 41012, Spain Carlos Newburn −Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla 41012, Spain Complete contact information is available at: https://pubs.acs.org/10.1021/acs.orglett.3c02548 Notes The authors declare no competing financial interest. ■ACKNOWLEDGMENTS This work was supported by the Ministerio de Ciencia e Innovación (Grants PID2020-116460RB-100, PID2021- 125946OB-I00, and CEX2021-001136-S funded by MCIN/ AEI/10.13039/501100011033), the Consejería de Economía y Conocimiento-Junta de Andalucía (Grant P20_00532, Programa Operativo FEDER Andalucía-PAIDI 2020), and the European Union’s Horizon 2020 research and innovation programme under a Marie Sklodowska-Curie grant agreement (No. 671881, INTEGRATA). We also acknowledge Alex Bentley (Erasmus program University of Seville/University of York) for technical assistance and CITIUS Universidad de Sevilla (MS and NMR services). ■REFERENCES (1) Leriche, G.; Chisholm, L.; Wagner, A. Cleavable Linkers in Chemical Biology. Bioorg. Med. Chem. 2012,20, 571−582. (2) (a) Chia, C. S. B. A Patent Review on FDA-Approved Antibody- Drug Conjugates, Their Linkers and Drug Payloads. ChemMedChem 2022,17, No. e202200032. (b) Bargh, J. D.; Isidro-Llobet, A.; Parker, J. S.; Spring, D. R. Cleavable linkers in antibody−drug conjugates. Chem. Soc. Rev. 2019,48, 4361−4374. (3) Brulisauer, L.; Gauthier, M. A.; Leroux, J.-C. Disulfide-containing parenteral delivery systems and their redox-biological fate. J. Controlled Release 2014,195, 147−154. (4) Fell, J. S.; Lopez, S. A.; Higginson, C. J.; Finn, M. G.; Houk, K. N. Theoretical Analysis of the Retro-Diels−Alder Reactivity of Oxanorbornadiene Thiol and Amine Adducts. Org. Lett. 2017,19, 4504−4507. 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(15) Methyl-substituted models for 17b and 18b (labeled as TS- 17b′and TS-18b′, respectively) show a better correlation with the experimental data than the actual hydroxymethyl-substituted models (TS-17b and TS-18b, respectively, see the Supporting Information); this is likely due to the appearance of a spurious and overstabilizing hydrogen bond between the hydroxyl and sulfone groups in TS-17b, which are expected to be weak in the very polar solvents in which the reactions are performed. Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.3c02548 Org. Lett. 2023, 25, 7481−7485 7485