A Mechanistic Model for the Aziridine Aldehyde-Driven

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Cite This: J. Org. Chem. 2018, 83, 9119−9124

A Mechanistic Model for the Aziridine Aldehyde-Driven Macrocyclization of Peptides Lee Belding,†,§ Serge Zaretsky,‡,∥ Andrei K. Yudin,*,‡ and Travis Dudding*,† †

Department of Chemistry, Brock University, St. Catharines, Ontario L2S 3A1, Canada Department of Chemistry, University of Toronto, Toronto, Ontario M5S 2J7, Canada

‡

J. Org. Chem. 2018.83:9119-9124. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 08/17/18. For personal use only.

S Supporting Information *

ABSTRACT: Aziridine aldehyde-driven macrocyclization of peptides is a powerful tool for the construction of biologically active macrocycles. While this process has been used to generate diverse collections of cyclic molecules, its mechanistic underpinnings have remained unclear. To enable progress in this area we have carried out a mechanistic study, which suggests that the cyclization owes its efficiency to a combination of electrostatic attraction between the termini of a nitrilium ion intermediate and intramolecular hydrogen bonding. Our model adequately explains the experimentally observed trends, including diastereoselectivity, and should facilitate the development of other macrocyclization reactions.

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INTRODUCTION Cyclic peptides show promise as therapeutic agents, owing to their conformational rigidity, resistance to proteolytic degradation, and the possibility to achieve favorable pharmacokinetic profiles.1,2 As a result, innovative methods for the production of cyclic peptides and related macrocycles are in demand.3,4 Key challenges to macrocyclization include cyclooligomerization, polymerization, and C-terminal epimerization of the linear precursor.5,6 Recently, the Yudin group reported an isocyanide-based multicomponent cyclization reaction7,8 using aziridine aldehydes. This reaction allows for rapid and efficient cyclization of a wide range of peptide sequences (Scheme 1).9,10 A study into the selectivity and kinetics of the macrocyclization process suggested that, in addition to the macrocyclization product 4, there was a competing pathway with a novel product (5) formed from the aziridine aldehyde (1), isocyanide (3), and N-terminal α-amino amide components of the peptide. The practical utility of this macrocyclization process,11,12 along with its apparent departure from the traditional Ugi-based macrocyclization mechanism,10 merited further mechanistic investigation. The modeling of peptide cyclization mechanisms represents a significant challenge in computational chemistry.13 The conformational space and degrees of freedom associated with large and flexible molecules such as peptides complicates the direct application of quantum mechanical methods. Likewise, accounting for solvent and entropic effects becomes more important, yet more difficult and computationally demanding. As such, molecular mechanics-based algorithms are often used to study the conformational dynamics of cyclic peptides.14 © 2018 American Chemical Society

Nevertheless, computing properties of cyclic peptides is not beyond the grasp of current quantum mechanical methods.15 For instance, the conformation of peptide macrocycles derived from aziridine aldehyde-based methodologies have been investigated by a tandem computational method employing a broad molecular mechanics conformational search, followed by geometry and energetic refinement using DFT methods.16 The prospect of locating transition states for peptide macrocyclization, however, is decidedly more difficult and computationally demanding than ground state analyses. As such, computational approaches for studying the mechanisms of peptide cyclization have almost exclusively employed molecular dynamics simulations and/or analysis of conformational distributions, which are used to infer transition state energies or the probability of cyclization.25,17,18 To the best of our knowledge, there has been only a single instance of a quantum mechanical transition state analysis on a peptide cyclization: a dipeptide cyclization to form 2,5-diketopiperazines.19 Therein, Tang and co-workers found that, in addition to employing an implicit solvation model, an explicit solvent molecule was necessary to facilitate proton transfer in several key steps in the reaction mechanism. Despite the apparent difficulty in investigating the mechanism of aziridine aldehyde-driven peptide macrocyclization, we sought to apply a strategy of molecular mechanics conformational sampling, followed by reaction coordinate analysis with DFT methods, to shed light on the mechanistic features of the aziridine aldehyde-driven multicomponent macrocyclization of pentapeptides. Received: May 10, 2018 Published: July 2, 2018 9119

DOI: 10.1021/acs.joc.8b01198 J. Org. Chem. 2018, 83, 9119−9124

Article

The Journal of Organic Chemistry Scheme 1. General Scheme for Aziridine Aldehyde-Driven Multicomponent Peptide Macrocyclization

Figure 1. (a) Multicomponent piperazinone synthesis with aziridine aldehyde dimers. (b) Corresponding lowest energy isocyanide addition transition state assembly, Z-pro-(S); Schematic representation (left) of IEFPCM/MPWPW91/6-31G(d) (solvent = 2,2,2-trifluoroethanol)computed lowest energy transition state (right).

Figure 2. Lowest energy isocyanide addition transition states Z-pro(S)2a (left) and E-pro(R)2a (right). Carbon-bound hydrogen atoms have been removed for clarity.

We have previously reported a computational study on the mechanism of the reaction between the aziridine aldehyde dimer ((R)-1), L-proline (6), and tBu-isocyanide (3) to form a chiral piperazinone (7) (Figure 1a).20,21 Therein, the computations revealed that the observed high diastereoselectivity originated from transition state assembly Z-pro(S) (Figure 1b), involving a carboxylate directed isocyanide addition to a kinetically favored Z-iminium ion formed between L-proline and an aziridine aldehyde dimer. A distinct nitrilium ion intermediate was not observed, and the concerted asynchronous process of isocyanide addition and carboxylate attack was deduced to be the driving force behind the high diastereoselectivity. Based on this precedent, it was expected that the aziridine aldehyde multicomponent macrocyclization would possess similar mechanistic attributes, though several key questions remained. Specifically, carboxylate-mediated isocyanide addition would be unlikely given its distal relationship to the iminium ion, and thus the underlying origin of diastereoselectivity was unclear. Furthermore, the lack of observed

dimerization or polymerization byproducts was in stark contrast to conventional macrocyclization reports utilizing an Ugi reaction as the key ring closing step.22,23 The role of the peptide backbone in directing reactivity was also unclear, as the relationship between macrocyclization product yields and peptide sequence was not outwardly apparent.

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RESULTS AND DISCUSSION At the outset of this study, the macrocyclization mechanism was explored for the isocyanide addition to the in situ derived iminium ion of aziridine aldehyde dimer and PS(tBu)LY(tBu)F (2a), a peptide sequence with excellent selectivity for the macrocyclization product.18 Isocyanide addition transition states, conforming to re- and si-facial addition to the respective Z- and E-iminium ions, generated from condensation of an aziridine aldehyde dimer (R)-1 and the L-proline residue of 2a, were considered, thus providing four unique modes of isocyanide addition (i.e., E-pro(R)2a, E-pro(S)2a, Z-pro(R)2a, and Z-pro(S)2a). 9120

DOI: 10.1021/acs.joc.8b01198 J. Org. Chem. 2018, 83, 9119−9124

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Figure 3. Two possible mechanistic pathways from intermediate 8 (pathway A, left; pathway B, right).

Emerging from the calculations was the finding that synaddition modes Z-pro(S)2a and E-pro(R)2a, wherein isocyanide addition occurs proximal (i.e., syn to) to the L-proline amide carbonyl oxygen, corresponded to the favored stereofacial modes of addition (Figure 2). Notably, this result is consistent with our previous investigations of the disrupted Ugi reaction of L-prolinium ions,20,21 despite the increased complexity of the system and the presence of a prolineamide, rather than a proline-carboxylate, directing group. We attribute the origin of the lower Gibbs free energies of the syn-addition transition states Z-pro(S)2a and E-pro(R)2a, in large part, to weak yet favorable bonding interactions between the proline amide carbonyl oxygen and the incoming isocyanide. Specifically, the carbonyl oxygen forms stabilizing C−Hδ+···Oδ− interactions with the tert-butyl group and a C··· Oδ− interaction with the amphoteric isocyanide carbon (Figure 2, C−O distances of 3.34 and 3.24 Å, respectively). Supporting the involvement of these bonding interaction is Bader’s Quantum Theory of Atoms in Molecules (QTAIM) (see Supporting Information). This neighboring group effect (NGE) may form the basis of an amide-directed isocyanide addition platform for multicomponent reactions, such as the Ugi reaction. While less visible, a key contributor to these bonding interactions is an underlying general acid−general base interactionsa heteronuclear negative charge-assisted

hydrogen bond ((−)CAHB) between the carboxylate ion and the N−H bond of the proline amide (Figure 2, NH−O bond distances of 1.77 and 1.76 Å for Z-pro(S)2a and E-pro(R)2a, respectively). This (−)CAHB is present in the lowest transition state for each of the four addition modes (see Supporting Information for transition states Z-pro(R)2a and Epro(S)2a). Its prominence is important for several reasons. Not only does the carboxylate likely serve as a general base to strengthen the interactions between the proline amide and the incoming isocyanide, it also forces the peptide chain to adopt a highly organized, pseudocyclic geometry, in which the carboxylate is encaged within the interior of the peptide chain. This strong H-bonding interaction restricts the carboxylate from reacting with other peptides, which explains the lack of polymerization observed under the relatively concentrated reaction conditions. Moreover, this heteronuclear (−)CAHB holds the carboxylate in close spatiotemporal proximity to the amino terminus, well-positioned for the ensuing intramolecular cyclization. Notably, this also offers an explanation as to why peptides with a β-homoproline or Nmethyl amino acids in the second position were not productive in the macrocyclization reaction;10 these motifs do not permit the formation of this (−)CAHB.18 While the peptide backbone is effectively constrained in both E-pro(R)2a and Z-pro(S)2a by the aforementioned 9121

DOI: 10.1021/acs.joc.8b01198 J. Org. Chem. 2018, 83, 9119−9124

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Figure 4. Transition states for carboxylate attack (TSA1, left) and proline-amide attack (TSB1, right) on the open intermediate, 8.

Figure 5. Transition states for aziridine aldehyde attack on the mixed anhydride intermediate (TSA3i, left) and imidoanhydride intermediate (TSB4, right).

nucleophilic attack of the proline amide oxygen atom or the carboxylate group, and instead lead to “open” nitrilium ion intermediates, such as intermediate 8 shown in Figure 3. The existence of this intermediate was a surprising departure from our previous study, in which isocyanide addition was concomitant with attack by the carboxylate group of L-proline to furnish a mixed anhydride (akin to intermediate 10, Figure 23) in a concerted-asynchronous process. Given the experimental evidence for intermediate 11, in addition to the major product 4a, we investigated nucleophilic attack by the carboxylate ion (Figure 3, pathway A), as well as attack by the proline amide (Figure 3, pathway B), on the nitrilium carbon atom of intermediate 8. Using substrate 2a as a representative example, we found that pathway A proceeds through attack of the terminal carboxylate group on the nitrilium carbon center (TSA1, Figure 4) with a O···C bond forming distance of 2.20 Å and leads to mixed anhydride 9. Conversely, pathway B involves attack of the carbonyl oxygen of proline amide onto the nitrilium carbon (TSB1, Figure 4), with a O···C bond forming distance of 1.90 Å, affording imidoanhydride 11. The activation barriers of TSA1 and TSB1 were 1.1 and 6.4 kcal/ mol, respectively, and both transition states retained the (−)CAHB between the carboxylate and proline amide (NH− O distances of 1.83 and 1.73 Å, respectively). Analysis of the two products 9 and 11 suggested that attack of the carboxylate is not only kinetically favored but also thermodynamically preferred as well. Along pathway A, subsequent TFE-mediated dissociation of the aziridine aldehyde dimer from 9 (TSA2, Figure 5, ΔG‡ = 0.3 kcal/mol) leads to intermediate 10. The NH aziridine functionality in this intermediate is well-positioned for aminolysis of the mixed anhydride to afford the final product, which proceeds by way of TSA3i (Figure 5, ΔG‡ = 0.8 kcal/ mol). This low-barrier transition state leads to a tetrahedral

(−)CAHB, there are still noticeable differences in the two peptide geometries. In the lowest energy pro(R) conformation (E-pro(R)2a), the peptide chain adopts a conformation containing what could be considered an oxy-anion hole, where the carboxylate group acts as an acceptor to three amide N−H hydrogen bond donor residues. On the other hand, the lowest energy pro(S) transition state (Z-pro(S)2a) possesses only a single (−)CAHB, between the carboxylate and the proline amide. While the peptide backbone retains a highly ordered (through hydrogen bonding) arrangement, we believe the key factor in selectivity is the ability of the Z-iminium isomer to form a H-bond between the carboxylate and the hydroxyl group of the aziridine aldehyde backbone. We note here that a Z-pro(S)2a geometry with an oxy-anion hole, similar to that of E-pro(R)2a, was located, but was found to be higher in energy (see Supporting Information). Isocyanide addition was also modeled on the PGLGF (2b) and PGLGf (2c) peptide substrate (see Supporting Information). In each case the general trends paralleled those obtained for the PS(tBu)LY(tBu)F (2a) sequence. For instance, among the four stereofacial addition modes, those corresponding to syn-isocyanide addition (i.e., E-pro(R) and Z-pro(S)) were favored. Contributing to this preference for syn-addition were the same stabilizing interactions between the incoming isocyanide and the proline amide (i.e., the carbonyl oxygen of proline amide forms a C···Oδ− interaction with the amphoteric isocyanide carbon, as well as a C−Hδ+···Oδ− interaction with the tert-butyl group of the isocyanide (see Supporting Information for the corresponding QTAIM plots). Furthermore, in each case the Z-pro(S) transition state assembly was found to be energetically preferred and featured a (−)CAHB between the carboxylate ion and the proline amide. Another notable feature of these isocyanide addition transition states is that they occur without concerted 9122

DOI: 10.1021/acs.joc.8b01198 J. Org. Chem. 2018, 83, 9119−9124

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model reveals that the high diastereoselectivity in the aziridine aldehyde multicomponent macrocyclization arises from a stereoselective isocyanide addition, which is directed by the adjacent proline amide. Furthermore, a heteronuclear (−)CAHB between the terminal carboxylate group and the proline amide effectively sequesters the carboxylate to prevent oligomerization and facilitates intramolecular cyclization. It was found that isocyanide addition leads to a discrete nitrilium ion intermediate, which is attacked by either the proline amide oxygen atom (pathway B, leading to the observed amidine byproduct) or the terminal carboxylate (pathway A, leading to the cyclized product). One inference based on comparison of the computed results with those of experiment is that the strength of the (−)CAHB dictates the nucleophilicity of the proline amide and the carboxylate, which in turn changes the preference for the two reaction pathways. Pathway A leads to the final product through aziridine attack on mixed anhydride intermediate 10 (via TSA3i), while pathway B leads to the observed side-product by way of aziridine attack on imidoanhydride intermediate 12 (via TSB4). Thus, while this study did not support the intermediacy of the imidoanhydride in the productive macrocyclization pathway, it offered an alternative rationale to the substrate-dependent selectivity. The crucial nature of (−)CAHB interaction and the directing properties of the proline amide explain why peptides with Nalkyl amino acids in the second position, which would not have these key interactions, do not participate in the reaction. Thus, despite the substantial complexity of the system, and what are no doubt compounding approximations in our methodology, we have developed a simple and reasonable model that adequately accounts for the experimental observations. This study illuminates some of the principles behind zwitterionic control in peptide macrocyclization and lays the groundwork for further study in this field.

intermediate, which must subsequently undergo an elimination through a second transition state TSA3ii that, despite substantial efforts, could not be located without employing geometric constraints. Notwithstanding, given the overall exergonic nature for formation of the desired product 4a along pathway A, it is assumed herein that TSA3ii conforms to a low barrier process of little consequence. Along pathway B, TFE-mediated dissociation of the aziridine aldehyde dimer (TSB2, Figure 3, ΔG‡ = 0.3 kcal/mol) leads to imidoanhydride intermediate 12, for which there exists two probable downstream mechanistic outcomes. One scenario involves nucleophilic attack by the free aziridine on the iminoanhydride (TSB4) and the other being attack of the carboxylate on the iminoanhydride (TSB3). Aziridine attack leading to the experimentally observed amidine side-product 5a via TSB4 is associated with a low activation barrier of 1.8 kcal/mol (Figure 5). Conversely, carboxylate attack by TSB3 could not be located despite exhaustive attempts. The lack of experimental evidence for mixed anhydride intermediate 13, and the low-barrier pathway (via TSB4) to 5a, suggests a pathway intersecting and propagating from TSB3 is highly unlikely. Based on these results, it would appear that pathway A and pathway B diverge at the open nitrilium intermediate 8, where carboxylate attack leads to the desired product 4a and attack by the proline amide leads to side-product 5a. With this information, it may be possible to interpret the observed product distribution in the macrocyclization reaction with PS(tBu)LY(tBu)F (2a), PGLGF (2b), and PGLGf (2c) peptide sequences from the nature of their open nitrilium ion intermediates (8a, 8b, and 8c, respectively). To this end, the product distribution between these three substrates correlates well with the relative strength of their (−)CAHB, as determined by NBO analysis (Table 1). This relationship

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Table 1. Comparison of Macrocycle Selectivity and the Computed (−)CAHB Strength for Intermediate 8 between Three Peptide Sequences Substrate PS(tBu)LY(tBu)F (2a) Selectivity for macrocycle by NMR10 ENBO value for (−)CAHB strength in intermediate 8a, 8b, and 8c, respectively

Substrate PGLGF (2b)

COMPUTATIONAL METHODOLOGY The transition state geometries for isocyanide addition outlined in our previous work on L-proline20 served as templates for the peptide systems currently under investigation. For each transition state geometry the coordinates of the two carbon atoms undergoing C−C bond formation were frozen and conformational searches were performed using Macromodel of the Schrodinger suite of programs. The MMFF force field with the TNCG minimization algorithm and mixed Monte Carlo low-mode frequency sampling were employed for these searches. All conformers with visually different geometries residing within 21 kJ/mol (5 kcal/mol) above the lowest energy structure were then exported to the Gaussian G09 suite of programs for optimization at the DFT level of theory. DFT calculations were performed at the IEFPCM/ MPWPW91/6-31G(d) (solvent = 2,2,2-trifluoroethanol) level of theory. Explicit solvent molecules were included as deemed necessary. All minima were confirmed by the presence of only real vibrational frequencies, and transition states were confirmed to have only one imaginary frequency. Thermochemical quantities were evaluated at 298.15 K, and the IRC methodology was used to obtain the minima on either side of each transition state. Natural bond orbital analysis (NBO Version 3.1 as implemented in Gaussian 09) was used to quantify the electronic donor−acceptor interactions as secondorder perturbation energies (ENBO).

Substrate PGLGf (2c)

80%

45%

minor product

16.8 kcal/mol

26.1 kcal/mol

28.6 kcal/mol

supports the idea that the carboxylate acts as a general base, serving to increase the nucleophilicity of the proline amide while simultaneously decreasing its availability as a nucleophile. To generalize, we postulate that product distribution is determined by the relative preference for pathway A (carboxylate attack) over pathway B (proline amide attack) which is in turn controlled by the (−)CAHB strength, dictating the interrelated nucleophilicities of the proline amide and the carboxylate ion. In cases of shorter peptides, or where the peptide conformation does not position the carboxylate close to the nitrilium, TSB1 would be lower in energy and lead predominantly to amidine products.

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CONCLUSIONS In conclusion, we have developed a model for rationalizing aziridine aldehyde-driven macrocyclization of peptides. Our 9123

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(10) Zaretsky, S.; Hickey, J. L.; Tan, J.; Pichugin, D.; St. Denis, M. A.; Ler, S.; Chung, B. K. W.; Scully, C. C. G.; Yudin, A. K. Mechanistic investigation of aziridine aldehyde-driven peptide macrocyclization: the imidoanhydride pathway. Chem. Sci. 2015, 6, 5446−5455. (11) Zaretsky, S.; Tan, J.; Hickey, J. L.; Yudin, A. K. In Methods in Molecular Biology (Springer): Peptide Libraries; Derda, R., Ed.; Springer Science Business Media: New York, 2015; Vol. 6, pp 67−80. (12) Zaretsky, S.; Scully, C. C. G.; Lough, A. J.; Yudin, A. K. Exocyclic Control of Turn Induction in Macrocyclic Peptide Scaffolds. Chem. - Eur. J. 2013, 19, 17668−17672. (13) Yongye, A. B.; Li, Y.; Giulianotti, M. A.; Yu, Y.; Houghten, R. A.; Martinez-Mayorga, K. Modeling of Peptides Containing D-amino Acids: Implications on Cyclization. J. Comput.-Aided Mol. Des. 2009, 23, 677−689. (14) Wang, C. K.; Swedberg, J. E.; Northfield, S. E.; Craik, D. J. Effects of Cyclization on Peptide Backbone Dynamics. J. Phys. Chem. B 2015, 119, 15821−15830. (15) Caumes, C.; Fernandes, C.; Roy, O.; Hjelmgaard, T.; Wenger, E.; Didierjean, C.; Taillefumier, C.; Faure, S. Cyclic α,βTetrapeptoids: Sequence-Dependent Cyclization and Conformational Preference. Org. Lett. 2013, 15, 3626−3629. (16) Zaretsky, Z.; Hickey, J. L.; St. Denis, M. A.; Scully, C. C. G.; Roughton, A. L.; Tantillo, D. J.; Lodewyk, M. W.; Yudin, A. K. Predicting Cyclic Peptide Chemical Shifts Using Quantum Mechanical Calculations. Tetrahedron 2014, 70, 7655−7663. (17) Daidone, I.; Neuweiler, H.; Doose, S.; Sauer, M.; Smith, J. C. Hydrogen-Bond Driven Loop-Closure Kinetics in Unfolded Polypeptide Chains. PLoS Comput. Biol. 2010, 6, 276−288. (18) Besser, D.; Olender, R.; Rosenfeld, R.; Arad, O.; Reissmann, S. J. Pept. Res. 2000, 56, 337−345. (19) Li, Y.; Li, F.; Zhu, Y.; Li, X.; Zhou, Z.; Liu, C.; Zhang, W.; Tang. DFT Study on Reaction Mechanisms of Cyclic Dipeptide Generation. Struct. Chem. 2016, 27, 1165−1173. (20) Belding, L.; Zaretsky, S.; Rotstein, B. H.; Yudin, A. K.; Dudding, T. Shifting the Energy Landscape of Multicomponent Reactions Using Aziridine Aldehyde Dimers: A Mechanistic Study. J. Org. Chem. 2014, 79, 9465−9471. (21) Heine, N. B.; Kaldas, S. J.; Belding, L.; Shmatova, O.; Dudding, T.; Nenajdenko, V. G.; Studer, A.; Yudin, A. K. J. Synthesis of Chiral Piperazinones Using Amphoteric Aziridines Aldehyde Dimers and Functionalized Isocyanides. J. Org. Chem. 2016, 81, 5209−5216. (22) Wessjohann, L. A.; Neves Filho, R. A. W.; Puentes, A. R.; Morejon, M. C. In Multicomponent Reactions in Organic Synthesis; Zhu, J., Wang, Q., Wang, M.-X., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2015; pp 231−264. (23) Wessjohann, L. A.; Rivera, D. G.; Vercillo, O. E. Multiple Multicomponent Macrocyclizations (MiBs): A Strategic Development Toward Macrocycle Diversity. Chem. Rev. 2009, 109, 796.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01198.

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QTAIM plots for the PS(tBu)LY(tBu)F E-pro(R)2a and Z-pro(S)2a transition state assemblies; E-pro(R), Epro(S), Z-pro(R), and Z-pro(S) transition states, along with corresponding IRC precomplexes and products for peptide substrates 2a, 2b, and 2c; input parameters, atom coordinates, and thermochemical data for all computed structures (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Andrei K. Yudin: 0000-0003-3170-9103 Travis Dudding: 0000-0002-2239-0818 Present Addresses §

Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, Massachusetts 02138, USA. ∥ Present address: Chemical Development, Bristol−Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, USA. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank SHARCNET (www.sharcnet. ca) for computing resources. Financial support was provided in part by NSERC. L.B. is grateful for an NSERC CGS award.

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REFERENCES

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DOI: 10.1021/acs.joc.8b01198 J. Org. Chem. 2018, 83, 9119−9124