Synthesis of Nonnatural Helical Polypeptide via ... - ACS Publications

Jul 5, 2017 - techniques using SHELXL-2014/7.49. Non-hydrogen atoms were refined anisotropically. The H atoms were generated by the riding model...
0 downloads 0 Views 2MB Size
Download PDF
Article pubs.acs.org/Macromolecules

Synthesis of Nonnatural Helical Polypeptide via Asymmetric Polymerization and Reductive Cleavage of N−O Bond Yuki Ishido, Naoya Kanbayashi,* Taka-aki Okamura, and Kiyotaka Onitsuka* Department of Macromolecular Science Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan S Supporting Information *

ABSTRACT: Herein, we present a novel synthetic strategy, to amino-acid-free peptide synthesis based on postpolymerization conversion, for chiral nonnatural polypeptides. Optically active poly-N-alkoxyamides were prepared by our asymmetric polymerization as precursors of polypeptides, and the reductive cleavage of N−O bonds using a SmI2−THF complex was carried out. The reaction proceeded smoothly with quantitative conversion to afford a nonnatural polypeptide. The resulting polypeptide adopted a one-handed stable helical structure in solution, which was established by circular dichroism (CD) and theoretical calculations using density functional theory (DFT). The simulated spectra by timedependent (TD) DFT methods clearly indicated the validity of the proposed structure. The synthetic approach is a promising candidate for the synthesis of nonnatural polypeptides.

■

INTRODUCTION Proteins are typical optically active polymers with the ability to adopt well-defined folding of the polypeptide chain. They exhibit biological functions such as catalysis, energy transduction, and molecular recognition. These excellent functions are inseparably linked to the higher-order structure arising from the sophisticated secondary structures. Therefore, identifying and synthesizing new structural building blocks that contain the programmed design required for folding are important. In the past two decades, nonnatural oligopeptides1−4 containing various spacers, such as aliphatic5−8 or aromatic9−13 groups, have been designed and synthesized to develop functional materials and to understand the relationship between the primary structure, folding, and function in natural proteins. The resulting oligopeptides can fold into a well-defined unique folded structure according to the designed backbone, which shows interesting functional properties.14−20 The diversity of the backbones can lead to new motifs and functions. In general, most of nonnatural oligopeptides are produced by precise stepwise elongation of enantiomerically pure nonnatural amino acids or convergent segment-doubling strategy.21,22 This method can realize oligopeptides of perfectly defined lengths and sequence. In a polymer approach, nonnatural polypeptides were synthesized by the ring-opening polymerization of chiral lactams,23 which is a popular approach for the synthesis of highmolecular-weight polypeptide. Previously, we achieved the asymmetric polymerization24−26 of achiral monomers based on asymmetric allylic substitution catalyzed by planar−chiral cyclopentadienylruthenium complexes (I)27−29 to afford poly-N-alkoxyamide (Scheme 1a, poly1). The presence of asymmetric carbons in the main chain of © XXXX American Chemical Society

the resulting polymer was precisely controlled. Furthermore, poly-1 could be easily modified via its side chains, using the thiol−ene reaction as a postpolymerization method to enable the quantitative introduction of a wide range of substituents (poly-2).30 In spite of these efforts, poly-1 and poly-2 do not form stable secondary structures like the aforementioned peptidic oligomers, even though the asymmetric centers in the monomer unit are strictly controlled like natural polypeptides. The main chains of poly-N-alkoxyamide are probably more flexible than those of polypeptides because the rotational barrier of the N−C bonds in the N-alkoxyamide moiety is relatively low compared with that in amides. The N-alkoxyamide group can be transformed to amide groups by the reductive cleavage of N−O bonds.31−37 Therefore, poly-2 can be regarded as a precursor of polypeptides (i.e., poly(amino acid)s)38 (Scheme 1b). If this conversion can be applied to poly-2, the rotation around the N−CO bond would be locked, resulting in a secondary structure. To realize our strategy, it is essential to overcome several problems faced in postpolymerization, such as complete chemoselectivity, high conversion, and racemization of asymmetric carbons in the main chain. Herein, we present the synthesis of nonnatural polypeptide using our asymmetric polymerization followed by reductive cleavage of the N−O bonds to afford a completely new artificial polypeptide that contains p-phenylene units in the main chain and adopts a stable helical structure in solution. This method is called “amino-acid-free peptide synthesis” which does not Received: July 5, 2017

A

DOI: 10.1021/acs.macromol.7b01426 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules Scheme 1. Synthetic Approach to Nonnatural Polypeptides

require precise stepwise elongation of enantiomerically pure amino acids. This is a novel approach to the synthesis of nonnatural helical polypeptides.

■

RESULTS AND DISCUSSION The samarium(II) iodide−tetrahydrofuran (SmI2−THF) complex32,33,39 was selected as a reagent for reducing the N−O bond of N-alkoxyamide after exploring the appropriate methods. The model reaction was conducted using SmI2− THF under optimized conditions. The expected peptide compound was selectively obtained in >99% yield, with no racemization or side reactions (see the Supporting Information). Therefore, the reaction system was applied to poly-2.30 In this study, poly-2a (R′ = C12H25, Mw = 51 000, Mw/Mn = 2.5, n = 110) was used as a standard polymer, which was prepared according to the reported procedure using (R)-I as a catalyst.25,30 The treatment of poly-2a with SmI2 in THF ([N− O of poly-2a]/[SmI2] = 1/4.6) also resulted in the quantitative conversion of N-alkoxyamide moieties into amide groups even for polymer. This is the first example in which the SmI2 complex was applied in postpolymerization. Poly-3a was isolated in 83% yield after purification. The 1H NMR spectrum of poly-3a in CDCl3 at 25 °C is shown in Figure 1c, in comparison with those obtained with poly-2a (Figure 1a) and model compound 3 (Figure 1b). The reductive reaction was confirmed by the disappearance of the proton signals (c-H, f-H, and g-H) (Figure 1a) and appearance of a new broad signal (c′H) in poly-3a (Figure 1c), which is similar to the spectrum of 3 (Figure 1b). The 1H NMR signals of poly-3a were broader than those of poly-2a, which probably due to intermolecular aggregation of the polymer at the concentration of NMR measurement ([poly-3a] = 134 mM). Indeed, after addition of 2,2,2-trifluoroethanol (TFE)-d3 as a hydrogen-bond competitor to a CDCl3 solution of poly-3a, the signals of (c′-H) became sharper (Supporting Information, Figure S10). Although the N−H signal was not clearly observed in the 1H NMR spectrum of poly-3a, the NH stretching band was detected at 3319 cm−1 in the IR spectrum of poly-3a (Figure 2). The molecular weight of poly-3a was determined by size-exclusion chromatography (SEC) using polystylene standard, Mw = 39 000 (n = 108, Mw/ Mn = 2.6).40 This reaction maintained the polymer backbone, and any undesired side reaction could not be observed. The scope of this reaction for poly-2 with different side chains, including oligoetherthio or N-(tert-butoxycarbonyl)amino

Figure 1. 1H NMR (500 MHz, in CDCl3 at 25 °C) spectra of (a) poly-2a, (b) model compound 3, and (c) poly-3a. Concentration: [poly-3a] = 134 mM. The asterisk denotes impurity, and the filled circle denotes CHCl3.

ethylthio group as substituents on the side chain (poly-2b, poly-2c),30 was also examined. The reaction of both polymers proceeded with almost quantitative conversion (poly-3b; 65% isolated yield, Mw = 38 000, Mw/Mn = 2.0, poly-3c, 72% isolated yield, Mw = 39 000, Mw/Mn = 2.8).41,42 In spite of the protic NH proton of N-(tert-butoxycarbonyl)amino group, poly-2c produced the corresponding polymer. The resulting polymers exhibited a wide range of solubilities, depending on the substituents (Supporting Information, Table S1). Next, the polymer conformation of isolated poly-3a was investigated by means of UV absorption and circular dichroism (CD) spectroscopy in THF at 25 °C (Figure 3a). The CD spectrum of poly-3a showed a large bisignate Cotton effect at 238 and 258 nm that differed from those of the corresponding B

DOI: 10.1021/acs.macromol.7b01426 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules

Figure 2. IR spectra of (a) poly-2a, (b) model compound 3, and (c) poly-3a (KBr tablet).

Figure 3. CD and UV spectra of (a) poly-3a and 4 in THF at 25 °C. The vertical axis is normalized for the benzene unit. (b) 4−6 in THF at 25 °C. Concentration: [poly-3a] = 0.32 mM, [4] = 0.17 mM, [5] = 0.11 mM, and [6] = 0.01 mM.

Scheme 2. Reductive Cleavage of N−O Bond of Poly-2

−87°, which closely matches the dihedral angle observed in the crystal structure of 3′ (ϕ = −85°).44,45 Additionally, the density functional theory (DFT) and time-dependent density functional theory (TD)-DFT calculation of 4 was based on the crystal structure of 3′ and conducted at the B3LYP/6-31G** level of theory. The calculated UV and CD spectra were in close agreement with those of 4 (Figure S20). Next, the spectra of dimer 5 (n = 2) was analyzed. Because the carbonyl group and benzene rings are generally regarded as coplanar, two different possible conformations based on the optimized structure of 4 can be assumed according to the orientation of the vicinal unit: turn (5turn) and zigzag (5zig) type (Figure 4). After geometrical optimizations of 5turn and 5zig by DFT calculation, TD-DFT calculation was conducted in the same manner as that for 4. The calculated UV and CD spectra of 5turn were in close agreement with the observed spectra of 5, showing the positive and negative CD signals at 240−260 nm. Thus, the bisignate Cotton effect of 5 originated from the turn conformation (5turn). In Figure 3b, the peak of the positive Cotton effect was shifted to a longer wavelength (from 250 to 254 nm) with the elongation of the peptide chain (5, 6 (n = 2 to 4)) and approached the peak position observed for poly-3a (258 nm). The results indicated that longer oligomer lengths form the stable turn type conformation. A model structure of poly-3a′ was constructed based on the optimized structure of 5turn. As shown in Figure 5, poly-3a′ (n = 12, R′ = Et) exhibits a right-handed (P) 31-helix structure.46 The helix could not form hydrogen bonds between the units, unlike natural polypeptides.11,47 The pitch was calculated to be 16 Å. The intensity of the Cotton effect at 258 nm showed a molecular-weight dependence (Figure 6a). The CD signals sharply increased with the degree of polymerization (n) below 130 and leveled off to a constant value at higher n (Figure 6b). The helix structure was likely to be more stable at n > 130, as the ratio of the flexible terminal moieties was reduced.

monomer (4); such an intense signal was not observed for poly-2a (see Supporting Information). The CD and UV signals of poly-3a did not change over the concentration range of 0.034−32 mM or after addition of the TFE as a hydrogen-bond competitor to a THF solution (Figure S18). These results indicate that the polymers do not adopt a chiral higher order aggregation at the concentration of CD measurement. Therefore, additional chirality to that derived from the asymmetric carbon in the main chain was present, which suggested a onehanded helical structure for poly-3a. The CD and UV spectra of poly-3b and poly-3c were also analyzed. Both of the polymers also exhibited CD spectrum similar to that of poly-3a (Figure S19). To reveal the origin of the Cotton effect of poly-3a, the UV and CD spectroscopic analyses of oligomers 4−6 (n = 1, 2, 4) were conducted (Figure 3b). In monomer 4 (n = 1), two positive Cotton effects were observed at 241 and 274 nm. On the other hand, dimer 5 (n = 2) showed new bisignate Cotton effects at 229 and 250 nm, similar to that of poly-3a, which shifted to longer wavelengths as the monomer units were elongated (from n = 2 to 4). NMR studies were carried out to investigate the conformation in solution (see Supporting Information). In the 1H NMR spectrum of 4, applying the Karplus equation10,43 to the coupling constant of the internal NH proton JHN−CH indicates a HN−CH dihedral angle of ϕ = C

DOI: 10.1021/acs.macromol.7b01426 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules

Additionally, little appreciable change in the Cotton effect at 258 nm was observed at temperatures from −15 to 45 °C (Figure 6c). This finding suggested that the resulting unnatural polypeptide poly-3a was constrained the conformational fluctuations and mainly adopted the proposed helix conformation in THF. In this synthetic approach, the reverse helix can be easily prepared from the same achiral monomer using the opposite catalyst. Indeed, (M)-poly-3a was prepared using (S)-1 as the catalyst, and the resulting polymer exhibited a CD spectrum that was the mirror image of the right-handed helix (Figure 7).

■

CONCLUSIONS In conclusion, a new synthetic strategy to nonnatural helical polypeptides was demonstrated, which involved the use of asymmetric polymerization and reduction of N−O bonds. The reaction proceeds smoothly regardless of the substituents on the side chains to afford a nonnatural polypeptide that contains a p-phenylene unit in the main chain, which is a new type of polypeptide. The resulting polymer exhibits a one-handed helical conformation. This method does not require enantiomerically pure amino acids and its condensation on stepwise synthetic chemistry and affords a long peptidic chain, whose asymmetric centers were controlled. The precursor polymer (poly-2) containing various arylene spacers (R) on the main chain and bearing a wide range of substituents in the side chain could be synthesized (Scheme 1a).30 Since the cleavage of N− O bonds of N-alkoxyamide can be achieved with simple SmI2− THF systems under very mild conditions with high chemoselectivity in organic synthesis,36 the present method can be used to obtain numerous varieties of custom-made nonnatural polypeptides with various combinations of main chain and side chains. Further development of optically active synthetic polymers based on this concept is now in progress.

Figure 4. Simulated CD and UV spectra of (A) 5zig and (B) 5turn by TD-DFT (B3LYP/6-31**).

■

EXPERIMENTAL SECTION

General. Unless otherwise indicated, all reactions were carried out under an Ar atmosphere, whereas the workup was performed in air. 1H NMR spectra were recorded in CDCl3, toluene-d8, and benzene-d6 on Bruker AVANCE700, JEOL JNM-ECS400, and JEOL JNM-ECA500 spectrometers using SiMe4 as an internal standard. IR spectra ware recorded on SHIMADZU IR Prestige-21 in KBr tablet. HR-MS measurement (CID) was carried out on Thermo Fisher Scientific LTQ-Orbitrap XL. Retention time of polymers were measured by size-

Figure 5. Plausible helical conformation of poly-3a′ (n = 12, R = Et) based on the conformation of 5turn.

Figure 6. (a) Dependence of CD and UV spectra on molecular weight of poly-3a. The vertical axis is normalized on the basis of the absorption at 238 nm. (b) Dependence of CD intensity at 258 nm on polymerization degree (n) of poly-3a. (c) Temperature dependence of CD intensity. D

DOI: 10.1021/acs.macromol.7b01426 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules

Figure 7. CD and UV spectra of nonnatural helical polypeptides (P)-poly-3a and (M)-poly-3a in THF at 25 °C. exclusion chromatography (SEC) analyses carried out at 40 °C and a flow rate of 0.7 mL min−1 with CHCl3 as the eluent. The enantiomeric excess was determined by HPLC analysis using a Shimadzu LC-10 and SPD-10AV equipped with DAICEL Chiralcel OD-H, Chiralpak AD-H, and IA column. CD spectra were obtained by a JASCO J-720WO with cryostat at −75 to 85 °C. UV−vis spectra were obtained by a Shimadzu UV 3100PC. Materials. All solvents used for reactions were passed through purification columns just before use, and tetrahydrofuran was dried by sodium benzophenone and distilled under argon. Planar−chiral Cp′Ru complexes (R)-I, (S)-I, poly-1, and poly-2 were prepared as reported previously.1 Cinamyl chloride was purchased from TCI. Standard Method of Reductive Cleavage Using SmI2−THF Complex. To a THF solution (0.15 M) of the polymer (poly-2) was added THF solution of SmI2−THF complex (4.6 equiv) at room temperature, dropwise via syringe. After stirring it for 2.5 h at room temperature, the reaction was quenched with a 10% solution of Na2S2O3·H2O and then diluted with CH2Cl2. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were concentrated in vacuo. The crude product was purified by using an SEC column (Shodex; KF 2003 × 2; flow rate 3.0 mL min−1) to give the target product. Poly-3a. According to the standard method of reductive cleavage using the SmI2−THF complex, poly-3a was obtained as a pale brown solid (83%). 1H NMR (CDCl3, 500 MHz): δ 8.20−7.06 (br, 4H, Ar), 7.11−6.25 (br, 1H, NH), 5.69−4.66 (br, 1H, −CHCH2CH2S−), 3.41−2.00 (br, 6H, −CHCHHCH2S−, −CHCH2CH2SCH2−), and −CHCH2CH2S−), 1.58 (br, 2H, CHCH2CH2SCH2CH2−), 1.42− 1.10 (br, 18H, −CH2−), 0.87 (br, 3H, CH3). 13C NMR (CDCl3, 176 MHz): δ 168.2, 148.2, 132.1, 128.5, 126.5, 54.9, 36.5, 32.7, 32.3, 30.4, 29.7, 29.4, 23.0, 14.5. IR (KBr) 3319, 2922, 2850, 1633, 1530 cm−1. Poly-3b. According to the standard method of reductive cleavage using the SmI2−THF complex, poly-3b was obtained as a pale brown solid (65%). 1H NMR (CDCl3, 500 MHz): δ 8.00−7.06 (br, 4H, Ar), 6.90−6.51 (br, 1H, NH), 5.59−4.96 (br, 1H, −CHCH2CH2S−), 3.78−3.56 (br, 8H, −OCH 2 CH 2 O−), 355−3.45 (br, 2H, −SCH2CH2O−) 3.42−3.24 (br, 3H, OCH3), 3.01−2.52 (br, 2H, −SCH2CH2O−), 2.70−2.48 (br, 2H, −CHCH2CH2S−), 2.34−2.22 (br, 2H, −CHCH2CH2S). Poly-3c. According to the standard method of reductive cleavage using the SmI2−THF complex, poly-3c was obtained as a pale brown solid (72%). 1H NMR (CDCl3, 400 MHz): δ 8.00−7.06 (br, 4H, Ar), 6.90−6.61 (br, 1H, NH), 5.59−5.14 (br, 1H, −CHCH2CH2S−), 5.10−4.91 (br, 1H, −SCH 2 CH 2 NH−), 3.78−3.56 (br, 8H, −OCH2CH2NH−), 3.55−3.45 (br, 2H, −SCH2CH2NH−), 2.95− 2.41 (br, 4H, −CHCH2CH2S− and −SCH2CH2NH−), 2.37−2.20 (br, 1H, −CHCH2CH2S), 2.14−1.99 (br, 1H, −CHCH2CH2S), 1.48− 1.38 (br, 9H, tBu).

CD and UV Spectra. UV and CD spectra were recorded on a JASCO J-720WO using 1 mm path length quartz cuvettes. The concentration-dependence experiment on the CD signal was measured using 10, 1, and 0.1 mm path length quartz cuvettes; the additive experiment of TFE was measured using 10 mm path length quartz cuvettes. Twenty scans were averaged for each sample. Δε (mol L−1 cm−1) was calculated using the equation

Δε = (4π log e × θobs × M 0)/180l × 1000c where θobs is the measured ellipticity in millidegrees, while M0 is the molecular weight or molecular weight per unit in the polymer, l is path length in centimeter (0.1 cm), and c is the concentration of the sample. X-ray Crystallography. Structural determination: A colorless platelet crystal of C18H21NOS (3′) having approximate dimensions of 0.250 × 0.050 × 0.020 mm was mounted on MicroMount 200 μm. Data collection was made on a Rigaku Rapid II imaging plate area detector with Mo Kα radiation (0.710 75 Å) using a MicroMax-007HF microfocus rotating anode X-ray generator and VariMax-Mo optics. The structure was solved by direct methods48 and expanded Fourier techniques using SHELXL-2014/7.49 Non-hydrogen atoms were refined anisotropically. The H atoms were generated by the riding model. Computational Details. Geometry optimizations were performed using Becke’s three-parameter hybrid functionals (B3LYP) in Gaussian 0950 program packages. 6-31G** basis set was employed. The crystal structure of X-ray model compound (3′) was used for the initial structures of oligomer (n = 1, 2, and 4). Oligomer (n = 1) was made from 3′ by adding the CONHCH3 group. Oligomers (n = 2 and 3) were made from oligomer (n = 1 or 2) and 3′ by fusing the phenyl group of 3′ and benzene ring of oligomer (n = 1 or 2). All initial structures are manipulated on the software ChemBio3D (ver. 13.0.2.3021, Cambridge Soft). The optimized geometry was analyzed by MolStudio R4.0 (NEC Corp., Japan) and GaussView 5.0 (Gaussian, Inc.). The CD and UV spectra of oligomers were simulated by timedependent (TD) DFT calculations after the geometrical optimization in tetrahydrofuran using the polarizable continuum model (PCM) as the self-consistent reaction field (SCRF) method.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.7b01426. E

DOI: 10.1021/acs.macromol.7b01426 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules

■

(16) Jewginski, M.; Granier, T.; Langlois d’Estaintot, B.; Fischer, L.; Mackereth, C. D.; Huc, I. Self-Assembled Protein−Aromatic Foldamer Complexes with 2:3 and 2:2:1 Stoichiometries. J. Am. Chem. Soc. 2017, 139, 2928−2931. (17) Liu, D.; DeGrado, W. F. De Novo Design, Synthesis, and Characterization of Antimicrobial β-Peptides. J. Am. Chem. Soc. 2001, 123, 7553−7559. (18) Müller, M. M.; Windsor, M. A.; Pomerantz, W. C.; Gellman, S. H.; Hilvert, D. A Rationally Designed Aldolase Foldamer. Angew. Chem., Int. Ed. 2009, 48, 922−925. (19) Mowery, B. P.; Lee, S. E.; Kissounko, D. A.; Epand, R. F.; Epand, R. M.; Weisblum, B.; Stahl, S. S.; Gellman, S. H. Mimicry of Antimicrobial Host-Defense Peptides by Random Copolymers. J. Am. Chem. Soc. 2007, 129, 15474−15476. (20) Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H. Antibiotics: Non-haemolytic β-amino-acid Oligomers. Nature 2000, 404, 565−565. (21) Li, X.; Qi, T.; Srinivas, K.; Massip, S.; Maurizot, V.; Huc, I. Synthesis and Multibromination of Nanosized Helical Aromatic Amide Foldamers via Segment-Doubling Condensation. Org. Lett. 2016, 18, 1044−1047. (22) Wender, P. A.; Jessop, T. C.; Pattabiraman, K.; Pelkey, E. T.; VanDeusen, C. L. An Efficient, Scalable Synthesis of the Molecular Transporter Octaarginine via a Segment Doubling Strategy. Org. Lett. 2001, 3, 3229−3232. (23) Hashimoto, K. Ring-opening Polymerization of Lactams. Living Anionic Polymerization and Its Applications. Prog. Polym. Sci. 2000, 25, 1411−1462. (24) Kanbayashi, N.; Hosoda, K.; Okamura, T.; Aoshima, S.; Onitsuka, K. Enantio-and Diastereoselective Polymerization: Asymmetric Allylic Alkylation Catalyzed by a Planar-chiral Cp’Ru Complex. Polym. Chem. 2016, 7, 3691−3699. (25) Kanbayashi, N.; Okamura, T.; Onitsuka, K. New Method for Asymmetric Polymerization: Asymmetric Allylic Substitution Catalyzed by a Planar-Chiral Ruthenium Complex. Macromolecules 2014, 47, 4178−4185. (26) Kanbayashi, N.; Okamura, T.; Onitsuka, K. New Synthetic Approach for Optically Active Polymer Bearing Chiral Cyclic Architecture: Combination of Asymmetric Allylic Amidation and Ring-Closing Metathesis Reaction. Macromolecules 2015, 48, 8437− 8444. (27) Kanbayashi, N.; Hosoda, K.; Kato, M.; Takii, K.; Okamura, T.; Onitsuka, K. Enantio- and Diastereoselective Asymmetric Allylic Alkylation Catalyzed by a Planar-chiral Cyclopentadienyl Ruthenium Complex. Chem. Commun. 2015, 51, 10895−8. (28) Kanbayashi, N.; Takenaka, K.; Okamura, T.; Onitsuka, K. Asymmetric Auto-Tandem Catalysis with a Planar-Chiral Ruthenium Complex: Sequential Allylic Amidation and Atom-Transfer Radical Cyclization. Angew. Chem., Int. Ed. 2013, 52, 4897−4901. (29) Kanbayashi, N.; Yamazawa, A.; Takii, K.; Okamura, T.; Onitsuka, K. Planar-Chiral Cyclopentadienyl-Ruthenium-Catalyzed Regio- and Enantioselective Asymmetric Allylic Alkylation of Silyl Enolates under Unusually Mild Conditions. Adv. Synth. Catal. 2016, 358, 555−560. (30) Kanbayashi, N.; Miyamoto, S.; Ishido, Y.; Okamura, T.; Onitsuka, K. Post-polymerization Modification of the Side Chain in Optically Active Polymers by Thiol−ene Reaction. Polym. Chem. 2017, 8, 985−994. (31) Cesario, C.; Tardibono, L. P.; Miller, M. J. Titanocene(III) Chloride-Mediated Reductions of Oxazines, Hydroxamic Acids, and N-Hydroxy Carbamates. J. Org. Chem. 2009, 74, 448−451. (32) Keck, G. E.; McHardy, S. F.; Murry, J. A. Total Synthesis of (+)-7-Deoxypancratistatin: A Radical Cyclization Approach. J. Am. Chem. Soc. 1995, 117, 7289−7290. (33) Keck, G. E.; McHardy, S. F.; Wager, T. T. Reductive cleavage of N-O bonds in hydroxylamine and hydroxamic acid derivatives using SmI2/THF. Tetrahedron Lett. 1995, 36, 7419−7422.

Experimental details for synthetic procedures, spectroscopic data (NMR, IR), UV-CD spectra, and details of computational results (PDF) X-ray crystallographic data for 3′ (CIF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail [email protected] (N.K.). *E-mail [email protected] (K.O.). ORCID

Yuki Ishido: 0000-0003-4248-1124 Naoya Kanbayashi: 0000-0001-8934-2389 Taka-aki Okamura: 0000-0002-9005-4015 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by a grant-in-aid for young scientists (B) (JP16K21154) from JSPS KAKENHI, the Ogasawara Foundation for the Promotion of Science & Engineering, and the Kyoto Technoscience Center. We thank the group of Prof. Takahiro Sato (Osaka University) for CD measurement.

■

REFERENCES

(1) Gellman, S. H. Foldamers: A Manifesto. Acc. Chem. Res. 1998, 31, 173−180. (2) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Foldamers as versatile frameworks for the design and evolution of function. Nat. Chem. Biol. 2007, 3, 252−262. (3) Hecht, S.; Huc, I.; Diederich, F. Foldamers: Structure, Properties, and Applications; Wiley-VCH: 2007. (4) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. A Field Guide to Foldamers. Chem. Rev. 2001, 101, 3893−4012. (5) Arndt, H.-D.; Ziemer, B.; Koert, U. Folding Propensity of Cyclohexylether-δ-peptides. Org. Lett. 2004, 6, 3269−3272. (6) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. β-Peptides: From Structure to Function. Chem. Rev. 2001, 101, 3219−3232. (7) Chi, Y.; Guo, L.; Kopf, N. A.; Gellman, S. H. Enantioselective Organocatalytic Michael Addition of Aldehydes to Nitroethylene: Efficient Access to γ2-Amino Acids. J. Am. Chem. Soc. 2008, 130, 5608−5609. (8) Vasudev, P. G.; Chatterjee, S.; Shamala, N.; Balaram, P. Gabapentin: A Stereochemically Constrained γ Amino Acid Residue in Hybrid Peptide Design. Acc. Chem. Res. 2009, 42, 1628−1639. (9) Huc, I. Aromatic Oligoamide Foldamers. Eur. J. Org. Chem. 2004, 2004, 17−29. (10) Kudo, M.; Maurizot, V.; Kauffmann, B.; Tanatani, A.; Huc, I. Folding of a Linear Array of α-Amino Acids within a Helical Aromatic Oligoamide Frame. J. Am. Chem. Soc. 2013, 135, 9628−9631. (11) Okamura, T.; Seno, S. Strategic Construction of Chiral Helices: Expanded Poly(L-leucine) Containing p-Phenylene Moieties. Macromolecules 2017, 50, 3500−3509. (12) Okamura, T.; Iwamura, T.; Seno, S.; Yamamoto, H.; Ueyama, N. Right-Handed Helical Structure of Expanded Oligo(L-leucine) Containing [Ru(terpyridine)2]2+ Moieties. J. Am. Chem. Soc. 2004, 126, 15972−15973. (13) Zhang, D.-W.; Zhao, X.; Hou, J.-L.; Li, Z.-T. Aromatic Amide Foldamers: Structures, Properties, and Functions. Chem. Rev. 2012, 112, 5271−5316. (14) Berl, V.; Huc, I.; Khoury, R. G.; Krische, M. J.; Lehn, J.-M. Interconversion of Single and Double Helices Formed from Synthetic Molecular Strands. Nature 2000, 407, 720−723. (15) Gan, Q.; Ferrand, Y.; Bao, C.; Kauffmann, B.; Grélard, A.; Jiang, H.; Huc, I. Helix-Rod Host-Guest Complexes with Shuttling Rates Much Faster than Disassembly. Science 2011, 331, 1172−1175. F

DOI: 10.1021/acs.macromol.7b01426 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules (34) Mattingly, P. G.; Miller, M. J. Titanium Trichloride Reduction of Substituted N-Hydroxy-2-azetidinones and Other Hydroxamic Acids. J. Org. Chem. 1980, 45, 410−415. (35) Miller, M. J.; Mattingly, P. G.; Morrison, M. A.; Kerwin, J. F. Synthesis of.beta.-lactams from substituted hydroxamic acids. J. Am. Chem. Soc. 1980, 102, 7026−7032. (36) Szostak, M.; Spain, M.; Procter, D. J. Recent Advances in the Chemoselective Reduction of Functional Groups Mediated by Samarium(II) Iodide: a Single Electron Transfer Approach. Chem. Soc. Rev. 2013, 42, 9155−9183. (37) Yus, M.; Radivoy, G.; Alonso, F. Lithium/DTBB-Induced Reduction of N-Alkoxyamides and Acyl Azides. Synthesis 2001, 2001, 0914−0918. (38) In this paper, poly-3 is classified as polypeptide (i.e., poly(amino acid)s) because the monomer units of the polymer are composed of amino acids containing p-phenylene spacer. (39) Chiara, J. L.; Destabel, C.; Gallego, P.; Marco-Contelles, J. Cleavage of N−O Bonds Promoted by Samarium Diiodide: Reduction of Free or N-Acylated O-Alkylhydroxylamines. J. Org. Chem. 1996, 61, 359−360. (40) The calculation value is similar to that of using synthetic oligomers 4−6 as calibration references (Mw 41 000, n = 120, Mw/Mn = 2.6) (see Supporting Information). (41) The technical difficulties in the isolation of poly-3b resulting in low yield. (42) Estimated by SEC analysis using polystyrene standards. (43) Habeck, M.; Rieping, W.; Nilges, M. Bayesian Estimation of Karplus Parameters and Torsion Angles from Three-bond Scalar Couplings Constants. J. Magn. Reson. 2005, 177, 160−165. (44) The dodecylthio group of 3 was replaced by an ethylthio group. (45) A summary of crystal data for 3′ is given in the Supporting Information. CCDC 1554046 (3′) contains the supplementary crystallographic data for this paper. (46) The result also corresponded with exciton chirality CD method, see: (a) Tanatani, A.; Yokoyama, A.; Azumaya, I.; Takakura, Y.; Mitsui, C.; Shiro, M.; Uchiyama, M.; Muranaka, A.; Kobayashi, N. Yokozawa,; Helical Structures of N-alkylated Poly (p-Benzamide)s. J. Am. Chem. Soc. 2005, 127, 8553−8561. (b) Harada, N.; Nakanishi, K.; Circular Dichroic Spectroscopy: Exciton Coupling in Organic Stereochemistry; University Science Books: Mill Valley, CA, 1983. (47) The expanded poly(α-amino acid)s containing p-phenylene moieties were reported, which was synthesized by stepwise elongation. The reluting polymer formed one-handed helical structure without hydrogen bond. (48) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, M.; Giacovazzo, C.; Guagliardi, A.; Polidori, G. A Program for Automatic Solution of Crystal Structures by Direct Methods. J. Appl. Crystallogr. 1994, 27, 435. (49) Sheldrick, G. M. A Short History of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122. (50) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Jr., J. A, M.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2010.

G

DOI: 10.1021/acs.macromol.7b01426 Macromolecules XXXX, XXX, XXX−XXX