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Communication

Peptide Diversification through Addition Reaction of Free Carboxylic Acids to Ynamides

by
Zhefan Zhang
,
Lingchao Cai
* and
Liangliang Song
*
Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, Jiangsu Key Lab of Biomass-Based Green Fuels and Chemicals, International Innovation Center for Forest Chemicals and Materials, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China
*
Authors to whom correspondence should be addressed.
Processes 2023, 11(8), 2262; https://doi.org/10.3390/pr11082262
Submission received: 11 July 2023 / Revised: 24 July 2023 / Accepted: 25 July 2023 / Published: 27 July 2023
(This article belongs to the Section Catalysis Enhanced Processes)
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Abstract

:
Peptide modification has emerged as an important topic in the academic community and pharmaceutical industry. However, they are primarily focused on the diversification of amines, thiols, and alcohols. Direct and chemoselective modification of acid residues in peptides is relatively underdeveloped. In this context, we report a novel and efficient method for the direct functionalization of acid residues in peptides. By using ynamides as reaction partners, the adducts are rapidly obtained in moderate to excellent yields at room temperature in water. This approach shows excellent chemoselectivity and a broad scope including dipeptides bearing unprotected Trp or Tyr residue and free Ser or Gln residue.

1. Introduction

In contrast with small molecules, peptide therapeutics have recently obtained more interest from the pharmaceutical industry due to the distinct protein–protein interactions and superior specificity for their targets [1,2]. Post-translational modification of peptides has emerged as a vital issue in modulating activity under physiological conditions [3,4]. Considering unnatural peptides showing improved pharmacokinetics and bioactivity, the chemoselective modification of peptides has emerged as an important task because of its ability to fine-tune structural characteristics in helping regulate physicochemical and biological properties [5,6,7]. Furthermore, chemoselectively modified peptides could improve metabolic stability and membrane permeability and/or tune bioactive conformation [8,9]. Although many strategies for the diversification of OH-, SH-, and NH2-groups in peptides have been developed [10,11], direct and chemoselective modification of COOH-group in peptides is relatively less common. In addition to classical esterification and amidation, carbodiimides have been used to directly modify the carboxylic acid residues of peptides, while the adducts are highly reactive and not stable (Figure 1a) [12,13,14]. Additionally, Raines developed an interesting esterification of carboxylic acids and diazo compounds [15,16], and Jørgensen reported a stereoselective oxidative bioconjugation between the carboxylic acid residues of peptides and aldehydes (Figure 1c) [17]. Alternatively, decarboxylative methods have been explored to generate decorated peptides [18,19,20], especially with the aid of photoredox catalysis (Figure 1b) [21,22,23]. Despite major advances, most of them have limited functional-group tolerance, requiring extra protections for certain special amino acids, such as Trp, Tyr, Ser, and Gln. In addition, they are primarily performed in organic solvents and are not compatible with water as a solvent, largely restricting the synthetic utility. Therefore, it is highly desirable to develop an efficient strategy for the direct peptide modifications starting from free carboxylic acids under mild reaction conditions using water as a solvent.
Ynamides, a special kind of electron-rich heteroatom-substituted alkynes, have emerged as important building blocks in synthetic chemistry during the past decade [24,25,26]. The electron-withdrawing groups on the nitrogen atom offer enhanced stability. Notably, the nitrogen atom could impose an electronic bias, leading to highly regioselective nucleophilic α-addition via keteniminium intermediates [27,28]. Based on this, ynamides have been successfully used in the preparation of novel N-containing molecules and versatile N-heterocycles [29,30]. Within our program on the efficient peptide modification [5,7,31,32,33], we herein disclose a direct peptide modification protocol in an aqueous solution at room temperature through the addition reaction of free carboxylic acids to ynamides (Figure 1d).

2. Materials and Methods

2.1. General Information

All reagents were used as received from commercial sources. Reactions were monitored through thin-layer chromatography (TLC) on 0.25-mm silica gel plates and visualized under UV light. Flash column chromatography (FCC) was performed using Flash silica gel (90-Å pore size, 200–300 μm). NMR spectra were recorded on a Bruker Avance-400 or -600 instrument, calibrated to CD(H)Cl3 as the internal reference (7.26 and 77.0 ppm for 1H and 13C NMR spectra, respectively) and CD(H)3OD(H) as the internal reference (3.31 and 49.0 ppm for 1H and 13C NMR spectra, respectively). 1H NMR spectral data were reported in terms of the chemical shift (δ, ppm), multiplicity, coupling constant (Hz), and integration. 13C NMR spectral data were reported in terms of the chemical shift (δ, ppm). The following abbreviations indicated multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad. High-resolution mass spectra were recorded using a SCIEX X500R LC-Q-TOF, ESI ion Source.

2.2. Synthesis of Product 3

In a microcentrifuge tube, 1 (0.05 mmol, 1 equiv), 2 (0.075 mmol, 1.5 equiv), H2O (450 µL), and MeOH (50 µL) were added. The reaction mixture was put in a constant-temperature oscillating metal bath and stirred at r.t. for 24 h. The solvent was removed in vacuo and the remaining residue was purified by silica gel column chromatography (petroleum ether/EtOAc or methanol/dichloromethane) to afford the products 3a–3m.
Following the general procedure, 1a (22.0 mg, 0.05 mmol, 1 equiv) and 2a (15.7 mg, 0.075 mmol, 1.5 equiv) were used to give 3a (18.5 mg, 57%). white solid. Rf = 0.5 (Petroleum ether/EtOAc, 1:4). 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.36–7.30 (m, 4H), 6.76 (d, J = 7.9 Hz, 1H), 5.57 (s, 1H), 4.81 (d, J = 2.7 Hz, 1H), 4.69 (td, J = 8.1, 5.1 Hz, 1H), 4.51–4.46 (m, 1H), 4.43 (d, J = 7.2 Hz, 2H), 4.25 (t, J = 7.1 Hz, 1H), 3.96 (d, J = 5.7 Hz, 2H), 3.78 (s, 3H), 3.01 (s, 3H), 2.58–2.46 (m, 2H), 2.45 (s, 3H), 2.36–2.21 (m, 1H), 2.13–2.05 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 171.7, 170.3, 169.1, 156.5, 147.3, 144.3, 143.8, 141.3, 133.1, 129.6, 128.0, 127.7, 127.1, 125.1, 120.0, 99.6, 67.3, 52.7, 51.6, 47.1, 44.4, 37.7, 30.1, 26.6, 21.6. HRMS (ESI, m/z) calcd for C33H36N3O9S [M + H]+: 650.2167, found: 650.2167.
Following the general procedure, 1b (23.5 mg, 0.05 mmol, 1 equiv), 2a (15.7 mg, 0.075 mmol, 1.5 equiv) were used to give 3b (18.7 mg, 55%). white solid. Rf = 0.6 (Petroleum ether/EtOAc, 1:4). 1H NMR (400 MHz, CDCl3) δ 7.80–7.77 (m, 2H), 7.75–7.68 (m, 2H), 7.62 (s, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.36–7.30 (m, 4H), 7.20 (s, 1H), 5.94 (s, 1H), 4.80 (d, J = 3.3 Hz, 1H), 4.68–4.63 (m, 1H), 4.46–4.41 (m, 2H), 4.34 (s, 1H), 4.24 (s, 1H), 4.11 (s, 1H), 3.99 (s, 1H), 3.78 (s, 3H), 3.66 (s, 1H), 3.29 (d, J = 10.5 Hz, 1H), 3.00 (s, 3H), 2.54 (d, J = 6.1 Hz, 1H), 2.48 (d, J = 5.0 Hz, 1H), 2.44 (s, 3H), 2.31 (s, 2H). Mixture of rotamers. 13C NMR (101 MHz, CDCl3) δ 171.9, 171.1, 170.4, 147.4, 141.3, 130.0, 129.6, 128.0, 127.8, 127.3, 127.1, 125.2, 120.0, 99.5, 67.4, 63.0, 55.7, 52.8, 51.8, 47.1, 37.8, 30.2, 26.2, 21.6. HRMS (ESI, m/z) calcd for C34H38N3O10S [M + H]+: 680.2273, found: 680.2274.
Following the general procedure, 1c (28.5 mg, 0.05 mmol, 1 equiv), 2a (15.7 mg, 0.075 mmol, 1.5 equiv) were used to give 3c (13.2 mg, 34%). white solid. Rf = 0.4 (Petroleum ether/EtOAc, 1:4). 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.80 (d, J = 7.7 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 8.6 Hz, 2H), 7.47–7.41 (m, 3H), 7.37–7.32 (m, 4H), 7.22 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 6.54 (d, J = 7.7 Hz, 1H), 5.55 (s, 1H), 4.85 (s, 1H), 4.65 (s, 1H), 4.57 (s, 1H), 4.46 (s, 2H), 4.44–4.36 (m, 1H), 4.27–4.19 (m, 1H), 3.69 (s, 3H), 3.53 (d, J = 15.0 Hz, 1H), 3.13–3.23 (m, 1H), 3.03 (s, 3H), 2.46 (s, 3H), 2.30 (s, 1H), 2.18 (d, J = 11.4 Hz, 2H), 1.87 (q, J = 10.7 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 174.6, 171.5, 171.4, 170.3, 156.0, 147.5, 144.5, 143.7, 141.3, 136.4, 132.8, 130.0, 129.7, 128.1, 127.8, 127.6, 127.3, 127.1, 125.2, 123.8, 122.2, 120.0, 118.3, 111.8, 100.6, 67.3, 60.4, 52.6, 51.4, 47.1, 38.0, 28.0, 26.9, 21.6, 20.4. HRMS (ESI, m/z) calcd for C42H43N4O9S [M + H]+: 779.2745, found: 779.2732.
Following the general procedure, 1d (27.3 mg, 0.05 mmol, 1 equiv), 2a (15.7 mg, 0.075 mmol, 1.5 equiv) were used to give 3d (11.3 mg, 30%). white solid. Rf = 0.6 (Petroleum ether/EtOAc, 1:2). 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.59 (t, J = 6.9 Hz, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.37–7.31 (m, 4H), 7.01 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.58 (s, 1H), 6.09 (s, 1H), 5.29 (d, J = 8.6 Hz, 1H), 4.86 (d, J = 2.7 Hz, 1H), 4.60 (td, J = 7.9, 4.4 Hz, 1H), 4.51 (d, J = 8.0 Hz, 2H), 4.46 (d, J = 2.8 Hz, 1H), 4.39 (s, 1H), 4.23 (t, J = 6.8 Hz, 1H), 3.73 (s, 3H), 3.25 (d, J = 14.0 Hz, 1H), 3.02 (s, 3H), 2.90–2.81 (m, 1H), 2.45 (s, 3H), 2.38 (t, J = 7.4 Hz, 1H), 2.32 (t, J = 7.0 Hz, 1H), 2.28–2.21 (m, 1H), 1.94 (d, J = 8.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 171.5, 171.0, 170.3, 147.4, 144.6, 143.9, 143.6, 141.3, 132.7, 130.6, 129.7, 128.1, 127.8, 127.2, 125.1, 120.0, 115.9, 100.8, 67.1, 56.0, 52.7, 51.5, 47.2, 38.0, 37.2, 29.8, 26.8, 21.6. HRMS (ESI, m/z) calcd for C40H42N3O10S [M + H]+: 756.2586, found: 756.2581.
Following the general procedure, 1e (27.3 mg, 0.05 mmol, 1 equiv), 2a (15.7 mg, 0.075 mmol, 1.5 equiv) were used to give 3e (24.8 mg, 69%). white solid. Rf = 0.5 (Methanol/Dichloromethane, 1:20). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.4 Hz, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 6.3 Hz, 2H), 7.42 (d, J = 7.5 Hz, 2H), 7.36–7.29 (m, 4H), 6.24 (s, 1H), 6.11 (d, J = 7.4 Hz, 1H), 5.76 (s, 1H), 4.81 (s, 1H), 4.65 (s, 1H), 4.49 (s, 1H), 4.38 (d, J = 7.2 Hz, 2H), 4.23 (t, J = 7.4 Hz, 1H), 3.76 (s, 3H), 3.30 (s, 1H), 3.00 (s, 3H), 2.96 (s, 1H), 2.52 (s, 1H), 2.47 (s, 1H), 2.44 (s, 3H), 2.42 (s, 1H), 2.32–2.23 (m, 1H), 2.15 (s, 1H), 2.12–2.05 (m, 2H). Mixture of rotamers. 13C NMR (101 MHz, CDCl3) δ 172.1, 171.7, 170.2, 156.4, 147.2, 145.0, 144.4, 143.9, 141.3, 141.3, 133.2, 130.0, 129.6, 128.0, 127.7, 127.3, 127.1, 125.2, 125.2, 120.0, 99.9, 67.2, 52.7, 51.6, 47.1, 43.5, 37.7, 33.1, 30.2, 26.4, 25.0, 21.6. HRMS (ESI, m/z) calcd for C36H41N4O10S [M + H]+: 721.2538, found: 721.2542.
Following the general procedure, 1a (22.0 mg, 0.05 mmol, 1 equiv), 2b (21.4 mg, 0.075 mmol, 1.5 equiv) were used to give 3f (27.2 mg, 75%). white solid. Rf = 0.5 (Petroleum ether/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.81–7.74 (m, 4H), 7.61 (d, J = 6.7 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.36–7.29 (m, 9H), 6.66 (d, J = 7.9 Hz, 1H), 5.49 (s, 1H), 4.92 (d, J = 2.6 Hz, 1H), 4.67–4.59 (m, 2H), 4.52 (s, 1H), 4.47 (d, J = 3.3 Hz, 1H), 4.43 (d, J = 7.1 Hz, 2H), 4.25 (t, J = 7.1 Hz, 1H), 3.93 (d, J = 5.6 Hz, 2H), 3.77 (s, 3H), 2.45 (s, 3H), 2.37–2.30 (m, 2H), 2.23–2.14 (m, 1H), 2.02–1.91 (m, 1H). Mixture of rotamers. 13C NMR (101 MHz, CDCl3) δ 171.7, 169.7, 144.2, 143.8, 141.3, 135.4, 129.7, 128.6, 128.5, 128.0, 127.9, 127.8, 127.1, 125.1, 120.0, 104.1, 67.3, 53.0, 52.7, 51.6, 47.1, 38.6, 30.2, 26.7, 21.6. HRMS (ESI, m/z) calcd for C39H40N3O9S [M + H]+: 726.2480, found: 726.2480.
Following the general procedure, 1a (22.0 mg, 0.05 mmol, 1 equiv) and 2c (19.9 mg, 0.075 mmol, 1.5 equiv) were used to give 3g (34.9 mg, 99%). White solid. Rf = 0.6 (Petroleum ether/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.82–7.72 (m, 4H), 7.62 (d, J = 7.4 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.37–7.29 (m, 4H), 6.69 (d, J = 7.8 Hz, 1H), 5.52 (s, 1H), 5.05 (s, 1H), 4.77 (s, 1H), 4.67 (q, J = 7.5 Hz, 1H), 4.44 (d, J = 7.2 Hz, 2H), 4.26 (d, J = 6.9 Hz, 1H), 3.95 (s, 2H), 3.78 (s, 3H), 3.30 (t, J = 7.7 Hz, 2H), 2.48 (d, J = 8.5 Hz, 1H), 2.44 (s, 3H), 2.34 (s, 1H), 2.29–2.20 (m, 1H), 2.14–1.93 (m, 2H), 1.51 (t, J = 7.6 Hz, 2H), 0.90 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 171.7, 169.8, 169.0, 144.0, 143.8, 141.3, 130.2, 129.5, 127.9, 127.8, 127.5, 127.1, 125.1, 120.0, 103.5, 67.4, 52.7, 51.6, 47.7, 47.1, 36.7, 30.3, 26.7, 25.4, 22.3, 21.6. HRMS (ESI, m/z) calcd for C37H44N3O9S [M + H]+: 706.2793, found: 706.2794.
Following the general procedure, 1a (22.0 mg, 0.05 mmol, 1 equiv) and 2d (20.3 mg, 0.075 mmol, 1.5 equiv) were used to give 3h (17.1 mg, 48%). White solid. Rf = 0.4 (Petroleum ether/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.8 Hz, 2H), 7.71–7.60 (m, 4H), 7.47–7.39 (m, 3H), 7.39–7.29 (m, 7H), 7.26 (s, 1H), 6.66 (d, J = 8.3 Hz, 1H), 5.51 (s, 1H), 4.95 (s, 1H), 4.88 (s, 1H), 4.71–4.61 (m, 1H), 4.45 (t, J = 8.2 Hz, 2H), 4.31–4.21 (m, 1H), 3.93 (d, J = 6.0 Hz, 2H), 3.77 (s, 3H), 2.83 (s, 3H), 2.45 (s, 2H), 2.25–2.19 (m, 1H), 2.06–2.00 (m, 1H). Mixture of rotamers. 13C NMR (101 MHz, CDCl3) δ 169.8, 143.8, 141.3, 129.9, 129.6, 129.4, 128.8, 128.0, 127.8, 127.1, 125.1, 120.0, 101.2, 67.3, 52.8, 51.6, 47.1, 38.6, 30.3, 26.6, 21.7. HRMS (ESI, m/z) calcd for C38H38N3O9S [M + H]+: 712.2324, found: 712.2312.
Following the general procedure, 1a (22.0 mg, 0.05 mmol, 1 equiv) and 2e (21.4 mg, 0.075 mmol, 1.5 equiv) were used to give 3i (16.7 mg, 46%). White solid. Rf = 0.5 (Petroleum ether/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 8.00–7.91 (m, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.71–7.58 (m, 4H), 7.43 (d, J = 6.7 Hz, 2H), 7.38–7.30 (m, 4H), 7.19–7.10 (m, 3H), 6.68 (d, J = 7.8 Hz, 1H), 5.53 (s, 1H), 4.91 (s, 1H), 4.84 (s, 1H), 4.65 (d, J = 7.5 Hz, 1H), 4.50–4.40 (m, 2H), 4.26 (d, J = 7.2 Hz, 1H), 3.94 (s, 2H), 3.77 (s, 3H), 2.48 (s, 1H), 2.45 (s, 3H), 2.35 (s, 3H), 2.23 (d, J = 9.4 Hz, 1H), 2.11–1.95 (m, 2H). Mixture of rotamers. 13C NMR (101 MHz, CDCl3) δ 171.7, 171.4, 169.9, 144.2, 143.8, 141.3, 138.9, 136.3, 135.8, 130.9, 130.6, 130.0, 129.6, 129.4, 129.2, 128.7, 128.0, 127.8, 127.1, 125.2, 125.0, 120.0, 100.7, 67.4, 52.8, 51.6, 47.1, 43.5, 30.3, 26.6, 21.7, 21.2. HRMS (ESI, m/z) calcd for C39H40N3O9S [M + H]+: 726.2480, found: 726.2472.
Following the general procedure, 1a (22.0 mg, 0.05 mmol, 1 equiv) and 2f (21.1 mg, 0.075 mmol, 1.5 equiv) were used to give 3j (22.4 mg, 62%). White solid. Rf = 0.4 (Petroleum ether/EtOAc, 1:2). 1H NMR (400 MHz, CDCl3) δ 7.87–7.76 (m, 4H), 7.62 (d, J = 7.4 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 7.36–7.30 (m, 2H), 7.04–6.95 (m, 2H), 6.69 (d, J = 7.9 Hz, 1H), 5.54 (s, 1H), 5.05 (s, 1H), 4.80 (s, 1H), 4.66 (d, J = 6.8 Hz, 1H), 4.44 (d, J = 6.7 Hz, 2H), 4.26 (d, J = 7.2 Hz, 1H), 3.95 (s, 2H), 3.87 (s, 3H), 3.78 (s, 3H), 3.34–3.24 (m, 2H), 2.48–2.37 (m, 2H), 2.28–2.20 (m, 1H), 2.08–1.96 (m, 2H), 1.50 (d, J = 7.6 Hz, 2H), 0.90 (d, J = 5.4 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 171.7, 169.8, 169.1, 163.2, 144.1, 143.8, 141.3, 130.1, 127.8, 127.1, 125.1, 120.0, 114.1, 103.7, 67.3, 55.7, 52.7, 51.5, 47.5, 47.1, 36.7, 30.3, 26.8, 25.4, 22.3. HRMS (ESI, m/z) calcd for C37H44N3O10S [M + H]+: 722.2742, found: 722.2735.
Following the general procedure, 1a (22.0 mg, 0.05 mmol, 1 equiv) and 2g (23.9 mg, 0.075 mmol, 1.5 equiv) were used to give 3k (20.5 mg, 54%). White solid. Rf = 0.4 (Petroleum ether/EtOAc, 1:1). 1H NMR (600 MHz, CDCl3) δ 8.10–7.98 (m, 2H), 7.89–7.77 (m, 4H), 7.62 (d, J = 7.4 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 6.64 (d, J = 7.4 Hz, 1H), 5.47 (s, 1H), 5.09 (s, 1H), 4.85 (s, 1H), 4.66 (d, J = 7.7 Hz, 1H), 4.45 (d, J = 7.2 Hz, 2H), 4.27 (d, J = 8.1 Hz, 1H), 3.93 (s, 2H), 3.78 (s, 3H), 3.34 (t, J = 7.5 Hz, 2H), 2.41 (q, J = 7.6 Hz, 2H), 2.29–2.17 (m, 1H), 2.10–1.91 (m, 2H), 1.52 (d, J = 7.4 Hz, 2H), 0.92 (d, J = 5.9 Hz, 6H). Mixture of rotamers. 13C NMR (101 MHz, CDCl3) δ 171.7, 169.7, 169.0, 143.7, 141.3, 128.4, 127.8, 127.1, 126.1, 125.1, 120.0, 104.5, 67.3, 52.8, 51.4, 51.0, 47.7, 47.1, 36.7, 30.1, 26.9, 25.4, 22.3. HRMS (ESI, m/z) calcd for C39H41F3N3O9S [M + H]+: 760.2510, found: 760.2502.
Following the general procedure, 1a (22.0 mg, 0.05 mmol, 1 equiv) and 2h (22.2 mg, 0.075 mmol, 1.5 equiv) were used to give 3l (19.5 mg, 53%). White solid. Rf = 0.4 (Petroleum ether/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 5.49 (d, J = 6.0 Hz, 1H), 5.11 (s, 1H), 4.92 (s, 1H), 4.68–4.59 (m, 1H), 4.45 (d, J = 7.2 Hz, 2H), 4.26 (t, J = 7.2 Hz, 1H), 3.92 (d, J = 5.5 Hz, 2H), 3.78 (s, 3H), 3.36 (t, J = 7.5 Hz, 2H), 2.40 (q, J = 8.2 Hz, 2H), 2.25–2.18 (m, 1H), 1.95–1.88 (m, 1H), 1.61 (d, J = 7.0 Hz, 1H), 1.51 (q, J = 7.2 Hz, 2H), 0.92 (d, J = 6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 171.7, 169.6, 169.0, 150.3, 143.7, 142.8, 141.3, 129.1, 127.8, 127.1, 125.1, 124.2, 120.1, 105.0, 67.4, 52.9, 51.3, 47.5, 47.1, 44.5, 36.7, 30.1, 27.1, 25.4, 22.3. HRMS (ESI, m/z) calcd for C36H41N4O11S [M + H]+: 737.2487, found: 737.2503.
Following the general procedure, 1a (22.0 mg, 0.05 mmol, 1 equiv) and 2i (10.0 mg, 0.075 mmol, 1.5 equiv) were used to give 3m (13.5 mg, 47%). White solid. Rf = 0.5 (Petroleum ether/EtOAc, 1:4). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 6.72 (d, J = 8.0 Hz, 1H), 5.52 (s, 1H), 4.94 (s, 1H), 4.85 (s, 1H), 4.71 (d, J = 6.4 Hz, 1H), 4.44 (d, J = 7.2 Hz, 2H), 4.26 (t, J = 7.3 Hz, 1H), 3.93 (s, 2H), 3.77 (s, 3H), 3.11 (s, 3H), 2.99 (s, 3H), 2.82 (s, 1H), 2.56 (d, J = 8.3 Hz, 1H), 2.37–2.27 (m, 1H), 2.03 (d, J = 15.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 171.8, 170.2, 169.1, 143.7, 141.3, 127.7, 127.1, 125.0, 120.0, 99.0, 67.3, 52.8, 51.3, 47.0, 44.4, 37.3, 36.3, 29.9, 26.8. HRMS (ESI, m/z) calcd for C38H46N3O6 [M + H]+: 574.1854, found: 574.1858.

3. Results

Our investigation started with the addition reaction of dipeptide 1a bearing a Gly residue and ynamide 2a using H2O/MeOH (9:1) (Figure 2). Fortunately, product 3a was afforded in 57% yield. Next, diverse dipeptides with functionalized amino acids were examined. Dipeptides bearing free Ser or Gln residue were tolerated, giving the corresponding products 3b (55%) and 3e (69%), respectively. Dipeptides bearing unprotected Trp or Tyr residue worked well, delivering products 3c (34%) and 3d (30%), respectively. For these cases, only the addition reaction of free carboxylic acids to ynamides was observed, proving the excellent chemoselectivity of this method. Moreover, various ynamides were also explored. Diverse aliphatic and aromatic groups on the nitrogen atom were tolerated, resulting in products 3f–3i in 46–99% yields. The results suggested that aliphatic groups on the nitrogen atom are favorable to delivering high yields. The electron-donating and electron-withdrawing groups on the phenylsulfonyl moiety were compatible with the reaction conditions, without a significant impact on this transformation, affording products 3j–3l in 53–62% yields. Interestingly, methylsulfonyl-based ynamide was applicable to form products 3m in 47% yield.

4. Conclusions

In conclusion, an efficient and novel reaction between carboxylic acid residues of peptides and ynamides has been developed. By performing the reaction in water, the adducts are delivered in moderate to excellent yields at room temperature in a green and rapid manner. This method features excellent chemoselectivity and a broad scope including dipeptides bearing unprotected Trp or Tyr residue and free Ser or Gln residue.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pr11082262/s1. Refs. [34,35,36] are cited in the Supplementary Materials.

Author Contributions

Conceptualization, L.C. and L.S.; formal analysis, Z.Z.; investigation, Z.Z.; writing—review and editing, L.C. and L.S.; project administration, L.C. and L.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Natural Science Foundation of Jiangsu Province (BK20220409), the Natural Science Research of Jiangsu Higher Education Institutions of China (22KJB150008), and the National Natural Science Foundation of China (22001124).

Data Availability Statement

Data are contained within the article or Supplementary Material.

Conflicts of Interest

The authors declare no conflict of interest.

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Processes 11 02262 g001 550
Figure 1. Modification of acid residues in peptides and this work.
Figure 1. Modification of acid residues in peptides and this work.
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Processes 11 02262 g002 550
Figure 2. Scope for the addition reaction of free carboxylic acids to ynamides. Condition: 1 (0.05 mmol), 2 (0.075 mmol), H2O (450 μL), MeOH (50 μL), isolated yield.
Figure 2. Scope for the addition reaction of free carboxylic acids to ynamides. Condition: 1 (0.05 mmol), 2 (0.075 mmol), H2O (450 μL), MeOH (50 μL), isolated yield.
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Zhang, Z.; Cai, L.; Song, L. Peptide Diversification through Addition Reaction of Free Carboxylic Acids to Ynamides. Processes 2023, 11, 2262. https://doi.org/10.3390/pr11082262

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Zhang Z, Cai L, Song L. Peptide Diversification through Addition Reaction of Free Carboxylic Acids to Ynamides. Processes. 2023; 11(8):2262. https://doi.org/10.3390/pr11082262

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Zhang, Zhefan, Lingchao Cai, and Liangliang Song. 2023. "Peptide Diversification through Addition Reaction of Free Carboxylic Acids to Ynamides" Processes 11, no. 8: 2262. https://doi.org/10.3390/pr11082262

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