Catalytic Nanoassemblies Formed by Short Peptides Promote Highly

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Catalytic Nanoassemblies Formed by Short Peptides Promote Highly Enantioselective Transfer Hydrogenation Martin A Dolan, Prem N Basa, Oleksii Zozulia, Zsofia Lengyel, Rene Lebl, Eric Michael Kohn, Sagar Bhattacharya, and Ivan V Korendovych ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.9b03880 • Publication Date (Web): 17 Jul 2019 Downloaded from pubs.acs.org on July 17, 2019

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Catalytic Nanoassemblies Formed by Short Peptides Promote Highly Enantioselective Transfer Hydrogenation Martin A. Dolan,‡ Prem N. Basa,‡ Oleksii Zozulia, Zsófia Lengyel, René Lebl, Eric M. Kohn, Sagar Bhattacharya and Ivan V. Korendovych* Department of Chemistry, Syracuse University, 111 College Place, Syracuse NY, 13224, USA.

ABSTRACT: Self-assembly enables formation of

incredibly diverse supramolecular structures with practically important functions from simple and inexpensive building blocks. Here we show how a semi-rational, bottom-up approach to create emerging properties, can be extended to a design of highly enantioselective catalytic nanoassemblies. The designed peptides comprised of as few as two amino acid residues spontaneously self-assemble in the presence of metal ions to form supramolecular, vesicle-like nanoassemblies that promote transfer hydrogenation of ketones in aqueous phase with excellent conversion rates and enantioselectivities (90+ % ee).

Keywords: peptide, catalysis, self-assembly, micelle, vesicle, ATH, enantioselective Self-assembly enables formation of incredibly diverse supramolecular structures from simple building blocks, providing access to a number of practically important materials with applications ranging from photovoltaic devices and molecular wires to antimicrobial pharmaceuticals and self-replicators.1-8 Even catalysis that often requires multiple concerted interactions between functional groups and/or cofactors can be attained through self-assembly.9 Peptides are particularly well suited to form diverse and functional supramolecular structures as they provide easy access to various modes of hydrogen bonding, electrostatic and stacking interactions. Moreover, they can bind transition metal cofactors providing additional opportunities for promoting chemical reactions. Previously we demonstrated that self-assembly of short heptameric peptides in the presence of metal ions leads to formation of supramolecular structures with catalytic efficiencies comparable to those of natural enzymes by weight.1011 Here we show how a bottom-up approach to create

emerging properties through self-assembly can be extended to a design of a highly enantioselective peptide catalyst for asymmetric reduction of ketones. Nature evolved a remarkable variety of highly efficient and incredibly stereoselective enzymes. Nonetheless, the inherent complexity of large biological molecules limits their practical applications. Much effort has been dedicated to successfully reduce enzymes into smaller, more practical and significantly less costly bioinspired catalysts, albeit sometimes sacrificing activity and/or selectivity.12 Bioinspired metallopeptide-based catalysis has been particularly successful in promoting a wide range of different chemical reactions with impressive efficiencies.13-15 Highly diverse peptides can be easily prepared from readily available and inexpensive amino acid building blocks. Moreover, they can be potentially incorporated into larger, more complex protein structures.16 At the same time creating bioinspired metallopeptides with impressive enantioselectivities remains a challenge.17 Indeed, stereospecificity of enzymes is dependent on proper three-dimensional positioning of multiple functionalities in space maintained by protein fold, a feat that is difficult to fulfill by reducing large biomolecules into relatively small and often flexible peptides. Moreover, since in nearly all instances transition metal ions in enzymes are bound through amino acid side chains, locking metal-binding side chains in short peptides in a manner that would ensure unique and stereospecific approach of substrates is difficult. Notably, few naturally occurring motifs (e.g. ATCUN),18 that partially rely on main chain coordination, show that alternative functional coordination modes are possible. The N-terminal amino group in proteins has a relatively low pKa value ensuring easy transition metal coordination, and the rigid nature of peptide backbone provides options for

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the classic pseudo-C2 symmetric substituent arrangement found in many enantioselective small molecule catalysts (Scheme 1).19-20 We hypothesized that peptides capable of productive binding of transition metal ions upon self-assembly can adopt ordered chiral structures, which in turn will promote highly enantioselective catalysis. In a test case of the approach we focused on transition metal-assisted enantioselective reduction of ketones (Scheme 1). In a series of pioneering studies Ikariya and Noyori have shown that complexes of Ru, Rh and Ir with ligands based on the monotosylethylenediamine motif (TsDPEN) promote transfer hydrogenation, a process that utilizes formic acid or sodium formate as hydrogen sources without the inconvenience and hazard of using hydrogen gas at high pressure.21 Notably, iridium complexes catalyze this reaction under aerobic, near-ambient conditions in water.22 This reaction is of high practical significance, thus it has been extensively studied providing mechanistic knowledge and benchmarks. Fundamentally, the coordination environment of tosyl-ethylenediamine is chemically similar to that of the N-terminus of polypeptides: two donor nitrogen atoms, one in an amino group and the other, separated by a short linker, in the sulfonamide moiety (shown in blue in Scheme 1). The chirality of the ligand provided by substituents in the short linker determines the enantiomeric selectivity. Moreover, the stability of the iridium complexes with the tosyl-ethylenediamine ligand makes them ideal test cases for studies of emergence of enantioselectivity through self-assembly in peptide assemblies. RESULTS AND DISCUSSION The first question we set out to explore was whether we could replicate transfer hydrogenation with iridium-short peptide complexes. It takes at least two peptide residues to provide the minimum necessary coordination environment for the metal ion as well as for arranging side chains is a pseudo-C2 symmetrical fashion (Scheme 1). Scheme 1. A) Design of self-assembling peptide catalysts for transfer hydrogenation by replicating chemical functionalities of small molecule catalysts in a peptide. B) Assembly of peptide catalyst results in micelle and vesicletype structures.

Given that proline has been extensively used in enantioselective catalysis,23 we prepared a library of twenty HN-Pro-X-CONH2 dipeptides, where X represents all genetically encoded amino acids. Next, we investigated the ability of the dipeptides to bind the Ir-Cp* moiety and to promote reduction of acetophenone by sodium formate. The results of screening the peptides as ligands in Ir-promoted transfer hydrogenation are shown in Fig. S1, Supporting Information. Excitingly, nearly all dipeptide ligands promoted some degree of enantioselective reduction of ketones. Dipeptides containing His, Cys, Met (residues that are likely to form a strong bond with the transition metal ion) showed low yield and enantioselectivity. On the other hand, Ala, Thr, Leu and Trp -containing dipeptides show moderate ee values in agreement with previous work on protein- and peptide-like small molecule-assisted transfer hydrogenation.16, 2425 HN-Pro-Leu-CONH showed the best combination 2 of yield and selectivity, with ee values as high as 50% in Ir-promoted transfer hydrogenation of acetophenone (Fig. S1, Supporting Information). While the initial screen focused on the naturally occurring L-amino acids to establish the best combination of the substituents, in order to exert maximum enantioselectivity the substituents that determine chirality (R and R’, Scheme 1) need to be on the opposite sides of the plane defined by the iridium and the two nitrogen donor atoms in a pseudo-C2 fashion. Indeed, peptides with mixed stereochemistry i.e. HN-Pro-DLeu-CONH2 or its enantiomer HN-DPro-Leu-CONH2 show significant improvement in enantioselectivity reaching 80% ee in reduction of acetophenone (Fig. 1).


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a

b

Cp*Ir(DPL-C

16)

Cp*Ir(TsDPEN)

Figure 1. Performance of peptide catalysts in transfer hydrogenation. a) Enantiomeric excess shown by peptides of the general formula HN-DPro-Leu-CONHCn, with aliphatic tails of various lengths (n), in transfer hydrogenation of representative ketones (2.5 mol % of catalyst). b) Acetophenone conversion rates in transfer hydrogenation catalyzed by Cp*Ir(DPL-C16) (red) and Cp*Ir(TsDPEN) (blue) under identical experimental conditions (2.5 mol % of catalyst).

Self-assembly has emerged to be a powerful, yet still underutilized strategy to create catalytic function.9 Encouraged by the remarkable ability of simple dipeptides to promote asymmetric hydrogenation we explored the degree to which stereoselectivity of HNDPro-Leu-CONH 2 can be further improved by assembling it into supramolecular structures. Several examples of fusing hydrophobic moieties to short peptides that lead to self-assembly into functional nanosized materials have been already reported.26-29 Therefore, we investigated the effect of attaching saturated hydrocarbon chains to the C-terminus of the dipeptides to preserve the optimized metalbinding properties of the ligand while simultaneously inducing self-assembly. Introduction of C-terminal hydrocarbon tails into HN-Pro-Leu-CONH2 leads to further 3-fold improvement (from 9:1 to 27:1 ratio of the S to R enantiomers) of enantioselectivity in transfer hydrogenation for all substrates. The ligands containing chains of 12 or more carbons show particularly good results, with maximum selectivity observed for palmitoyl (C16) chains (Fig. 1a). The resulting Cp*Ir(HN-DPro-Leu-CONH-C16) complex is stable under the reaction conditions and shows turnover number of at least 3,500. Comparing performance of self-assembled catalysts to that of Cp*Ir(TsDPEN), the most commonly used complex for iridium-catalyzed transfer hydrogenation, provides independent benchmarks. HN-DPro-LeuCONH-C16 (referred to as DPL-C16) shows slightly higher enantioselectivity and similar reaction rates in reduction of acetophenone (93 % ee) than

Cp*Ir(TsDPEN), under identical experimental conditions (Fig. 1b, Table 1). We have explored the substrate scope of DPL-C16 for various substrates and found excellent enantioselectivity in all cases (Table 1). DPL-C16 performed particularly well in reducing difficult heteroaromatic and ortho-substituted substrates. The broad substrate scope of the selfassembled peptide catalysts can be very useful for synthetic schemes that require late stage diversification. Table 1. Transfer hydrogenation of ketones catalyzed by Cp*Ir(DPL-C16) and Cp*Ir(TsDPEN)

R

R’

Yield (ee), % Cp*Ir(DPL-C

16)

Cp*Ir(TsDPEN)

Ph

CH3

76 (93)

75 (91)

4-OMe-Ph

CH3

35 (91)

25 (79)

4-Br-Ph

CH3

88 (90)

86 (86)

4-F-Ph

CH3

77 (92)

79 (86)

4-CF3-Ph

CH3

99 (93)

>99 (91)

3-OMe-Ph

CH3

92 (91)

85 (90)

3-NO2-Ph

CH3

98 (83)

97 (73)

3,5-CF3-Ph

CH3

97 (94)

>99 (86)

2-OMe-Ph

CH3

68 (73)

27 (50)

2-OH-Ph

CH3

96 (90)

92 (66)

2-Me-Ph

CH3

27 (78)

15 (45)

2-Cl-Ph

CH3

99 (75)

67 (46)

Ph

CH2O H

92 (79)

87 (98)

Ph

CH2Cl

99 (92)

96 (95)

2-naphthyl

CH3

85 (91)

71 (88)

69 (95)

85 (94)

37 (91)

>99 (70)

indanone 4-Ac-pyridyl

CH3

3-Ac-pyridyl

CH3

37 (90)

99 (69)

3-Acthiophyl

CH3

77 (90)

74 (91)

pentyl

CH3

77 (17)a

94 (24)a

Yields (as determined by NMR) and enantiomeric excesses (as determined by HPLC or GC) in transfer hydrogenation of ketones were catalyzed by Cp*Ir(DPL-C16) and Cp*Ir(TsDPEN) at 2.5 mol % of catalyst. A 3.125 M solution of sodium formate was used. aReaction was run for 24 hours.


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Many transition metal-based catalysts, including Cp*Ir(TsDPEN), can be incorporated into proteins using covalent and/or non-covalent interactions.30 Following subsequent directed evolution, these unnatural metalloproteins can show high efficiencies and enantioselectivities for various substrates. Given the complexity of proteins, directed evolution has to be performed independently for enzymes to obtain different enantiomers and typically only one enantiomer can be produced with high ee values. The simplicity of the short peptide sequence DPL-C16 allows for easy stereochemistry reversal not practically feasible for large proteins. Indeed, Cp*Ir(PDL-C16) catalyzes reduction of ketones to produce the opposite enantiomers with the same ee (Fig. S4, Supporting Information). To further confirm the effect of self-assembly on the enantioselectivity of Cp*Ir(DPL-C16) we have performed transfer hydrogenation using 20% toluene. As shown by the DLS data (Fig. S5, Supporting Information) toluene suppresses the formation of higher order assemblies. The observed ee (69%) in reduction of acetophenone under these conditions was consistent with the ee values demonstrated by the non-assembling catalysts (Fig. 1, Table S1, Supporting Information). Importantly, the observed emerging property of enantioselectivity cannot be explained by purely micellular effects. Previous work on incorporating Cp*Ir(TsDPEN) into various micellular systems showed no improvement in enantioselectivity for essentially all of the substrates tested in the presence of detergent.31-32

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a

b

d

c

Figure 2. Characterization of Cp*Ir(DPL-C16) complex. A) DFT model of Cp*Ir(Cl)(DPL-C16) along with ESI-MS data for the complex (calculated isotopic pattern is shown in red). B) Dynamic light scattering data for Cp*Ir(H)(DPL-C16) (0.02 mM solution in 20% TFE/H2O). C) TEM images showing self-assembled vesicle structures formed by Cp*Ir(H)(DPL-C16). D) A fragment of crystal packing for DPF-C12.

DFT models of both pre-catalyst Cp*Ir(Cl)(DPL-C16) as well as the corresponding active species Cp*Ir(H)(DPL-C16) (Fig. 2A, Fig. S2, Supporting Information) shows bidentate coordination of iridium to the peptide backbone via the N-terminus and the deprotonated amide nitrogen of the leucine residue. Interestingly, the Ir-N (2.122 Å, 2.114 Å for IrNPro and Ir-NLeu, respectively) and Ir-H bond (1.600 Å) lengths, obtained from the model are very close to those calculated for Cp*Ir(H)(TsDPEN) (2.137 Å, 2.095 Å and 1.578 Å, respectively, for the corresponding distances),33 despite significant differences in the chemical structure of the ligand. The coordination of the metal to deprotonated backbone amide is further supported by massspectrometric data (Fig. 2A). While our efforts to crystallize Cp*Ir(Cl)(DPL-C16) so far have not been successful, we were able to obtain a crystal structure of DPF-C12, a close analog of DPL-C16. In the crystal, DPF-C stacks in a bilayer-like form driven by the van 12 der Waals packing of hydrophobic tails (Fig. 2D) that is likely to drive the self-assembly in both metal-free


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and metal-bound forms. It is possible that the hydrogen bonding interactions between the amide groups observed in this structure is also present on the self-assembling catalysts leading to rigidification of the metal coordination sphere and ultimately higher ee’s, but further structural and computational studies are needed to validate this hypothesis. This crystal structure also helps explain why slightly better stereoselectivity is observed at a 2:1 or higher peptide:metal ratios (Fig. S3, Supporting Information) as larger spacing between bulky Cp*Ir moieties are found under these conditions (Scheme 1). Dynamic light scattering (DLS) studies of the solution containing DPL-C16 shows aggregates of the average size of approximately 200 nm and the size of the aggregates does not change much upon formation of the catalyst (Fig. 2B, Fig. S5, Supporting Information). In agreement with the DLS data, transmission electron microscopy (TEM) of the complex shows structures of similar size. Interestingly, both micelle-like and vesicle-like structures can be observed on the grid (Fig. 2C, Fig. S7, Supporting Information). The vesicular structure of the assemblies is directly confirmed by gel filtration experiments, where a fluorescence dye is entrapped by the supramolecular assemblies (Figure S9, Supporting Information). We hypothesize that interconversion between different morphologies can promote substrate sequestration into the hydrophobic catalyst assembly. No self-assembled structures are found for HN-DPro-Leu-CONH2, or DPL-C 4 as well as their corresponding Cp*Ir complexes, consistent with the notion that selfassembly leads to high enantioselectivity. The vesicle-like morphology of the DPL-C16-based catalyst is consistent with the observations of vesicles for HNPro-Trp-CONH-C12, a molecule closely resembling DPL-C .34 16 CONCLUSIONS We have shown that a semi-rational approach that utilizes self-assembly of short peptides allows for development of highly efficient nanosized catalysts for enantioselective hydrogenation of a wide variety of substrates under mild, aerobic conditions in aqueous solution. The resulting catalyst combines high degree of the metal coordination sphere control characteristic of homogeneous catalyst with an ease of catalyst separation commonly observed in heterogeneous catalysis. DPL-C16, to our knowledge, is the first example of a self-assembling peptide that can catalyze an industrially important chemical

reaction with excellent efficiency, enantioselectivity and substrate scope. The chiral ligand, produced in a two-step synthesis from simple and inexpensive amino acid building blocks, can be manufactured in large quantities at a fraction of the cost of presently utilized ligands for transfer hydrogenation. Most importantly, this work demonstrates that the bottom-up self-assembly paradigm to create enantioselective catalysts presents an excellent alternative to the traditional approach where bulky substituents are combinatorially introduced into ligands to create increasingly rigid complex structures. Utilizing peptides with non-natural amino acids can offer incredible opportunities for tuning the properties of the metal ions and is likely to improve the functional properties of the assemblies even further. Additionally, the biocompatibility of the simple dipeptide catalytic moiety allows for potential incorporation of metalbinding fragments into proteins to allow for additional improvement using directed evolution. Given the ease with which we were able to create selfassembling catalysts for transfer hydrogenation from a very limited set of peptides we expect our approach to be generally applicable to a wide range of different metallopeptide-promoted transformations. METHODS Peptide synthesis. Peptides with C-terminal carboxamides were synthesized by manual fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis strategy as described before.35 Peptides with C-terminal alkyl tails were synthesized by solution-phase synthesis utilizing the tertbutyloxycarbonyl (Boc) peptide synthesis strategy as described in detail in the Supplementary Information. Transfer hydrogenation. In a typical reaction, peptide (11.3 mg, 25 µmol), Cp*2Ir2Cl2 (5.0 mg, 6.25 µmol) were dissolved in 0.2 mL of trifluoroethanol (TFE) in a 15 mL screw-capped tube equipped with magnetic stir bar. Note: this method allows for scalability and a pre-calculated stock solution can be created for multiple reactions to be run in parallel. The pre-catalyst solution was then stirred for 30 minutes in a sealed tube immersed into a pre-heated 40 °C oil bath. The solution was then transferred to separate glass-tapered microtubes followed by addition of 0.8 mL of aqueous sodium formate (0.8 mL, 3.125 M) and the substrate (0.5 mmol). The microtube(s) were then sealed with a rubber septum with a short needle inserted into the head space to vent CO2 and limit reaction mixture evaporation. The


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microtube(s) were agitated (1000 – 1200 rpm) for 3 hours at 40 °C in a Thermo-Mixer shaker (Fisher Scientific). For quick analysis, the crude reaction mixture was directly purified using column chromatography through a short silica plug (ca. 2.0 cm height) eluting with methyl-tert-butyl ether MTBE (50 – 100 mL) followed by solvent removal by rotary evaporation. Note: this method was not applied to heteroaromatic substrates. Alternatively, the product and the unreacted substrate were extracted from the aqueous layer with either dichloromethane or MTBE (2 x 5 mL). The combined organic extracts were washed with saturated brine (5 mL), dried over Na2SO4 or MgSO4, filtered through a fritted funnel. Finally, the solvent was removed by rotary evaporation. Reaction yields were determined by 1H NMR using mesitylene as an internal standard. Enantiomeric excess was then determined either by chiral HPLC (250 x 4.6 mm Phenomenex Lux-Cellulose 1 on a Shimadzu Prominence UFLC instrument, the enantiomeric selectivity was estimated using integration of signals at 254 nm) or GC (30 m x 0.25 mm x 0.25 µm Agilent J&W Cyclodex-B column on an Agilent 7820A instrument). DFT Modeling. All simulations were carried out with the Gaussian 16 Rev. B.01 software package.36 The geometries of the structures were optimized with density functional theory (DFT) employing the parameter-free Perdew-Burke-Ernzerhof (PBE0) hybrid functional37 and the valence triple-zeta polarization basis set (def2-TZVP) for all atoms.38 Convergence cutoffs on forces and step sizes were tightened using the keyword, opt=tight, and the integration grid was set to 99 radial shells and 590 angular points per shell with the keyword, integral (grid=ultrafine). Transmission Electron Microscopy (TEM). TEM measurements were performed on a JEOL 2000EX instrument operated at 120 kV with a tungsten filament at N.C. Brown Center for Ultrastructure studies at SUNY-ESF. The particle size was analyzed manually by modeling each self-assembled structure as sphere. Detailed procedures for sample preparation are provided in the Supporting Information. Dynamic Light Scattering (DLS). DLS measurements were performed on a Malvern Zetasizer Nano ZS instrument utilizing a 173° backscattering detector. The hydrodynamic diameter (Dh) and Z-average (Zave) were calculated using CONTIN analysis. Detailed procedures for sample

preparation are Information

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provided

in

the

Supporting

Single crystal X-ray diffraction. Single crystal structural analysis was carried out using a Bruker KAPPA APEX DUO diffractometer equipped with APEX II CCD and LT-II low temperature device. The diffraction data were collected at 100 K using Cu-Kα radiation using the omega scan technique. The unit cell and space group were determined using the SAINT+ program. The structure was solved using SHELXL-2014/719. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were positioned based on electron density within the refined solved structure. The structure has been deposited into CCDC (1884477). Details of crystal growth and refinement statistics are given in the Supporting Information. ASSOCIATED CONTENT Details of experimental procedures are provided in the Supporting Information. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author

[email protected] Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally. Funding Sources

This work was supported by the NIH (grant GM119634), the CRDF (grant OISE-18-63891-0), the Ralph E. Powe Junior Enhancement Award, the Nappi Family Award and the Alexander von Humboldt Foundation.

ACKNOWLEDGMENT We thank Prof. Dan Clark for useful discussions, Prof. Timothy Korter for performing DFT modeling, Prof. Nancy Totah for providing access to a GC instrument, Prof. Mathew Maye for providing access to a DLS instrument and Dr. Adam Zaczek for assistance with Xray crystallography.

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Catalytic Nanoassemblies Formed by Short Peptides Promote Highly

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