CC BY-NC-ND 4.0 · SynOpen 2021; 05(03): 167-172
DOI: 10.1055/a-1533-3823
paper
Virtual Collection in Honor of Prof. Issa Yavari

Synthesis of Depsipeptides via Isocyanide-Based Consecutive Bargellini–Passerini Multicomponent Reactions

Hassan Farhid
a   Faculty of Chemistry, Shahid Beheshti University, G.C., P.O. Box 19396-4716, Tehran, Iran
,
Mohammad Mahdi Rostami
a   Faculty of Chemistry, Shahid Beheshti University, G.C., P.O. Box 19396-4716, Tehran, Iran
,
a   Faculty of Chemistry, Shahid Beheshti University, G.C., P.O. Box 19396-4716, Tehran, Iran
b   Рeoples’ Friendship University of Russia (RUDN University), 6, Miklukho-Maklaya Street, Moscow, 117198, Russian Federation
,
Behrouz Notash
c   Department of Inorganic Chemistry and Catalysis, Shahid Beheshti University, Evin, Tehran, Iran
› Author Affiliations
This work has been supported by the Research Council of Shahid Beheshti University and the RUDN University Strategic Academic Leadership Program (A. Shaabani).
 


Abstract

An efficient and straightforward approach has been established for the preparation of a new class of depsipeptide structures via isocyanide-based consecutive Bargellini–Passerini multicomponent reactions. 3-Carboxamido-isobutyric acids bearing an amide bond were obtained via Bargellini multicomponent reaction from isocyanides, acetone, and chloroform in the presence of sodium hydroxide. Next, via a Passerini multicomponent-reaction strategy, a new class of depsipeptides was synthesized using the Bargellini reaction products, isocyanides, and aldehydes. The depsipeptides thus prepared have more flexible structures than their pseudopeptidic analogues.


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Peptides and proteins accomplish critical functions in numerous biological and physiological operations. In recent years they have received much attention as drug candidates, but their therapeutic applications are limited by low metabolic stability, poor bioavailability, and low receptor affinity.[1] Consequently, chemists have developed efficient strategies for designing and synthesizing peptidomimetics, which have improved pharmacological properties over their natural peptide analogues.[2] A significant branch of peptidomimetics is that of the depsipeptides that are generated by replacing one or more amide bonds by an ester functionality.[3] This modification obviates to some degree intra- and intermolecular hydrogen bonding, which can be advantageous for organ penetration, targeting, and oral bioavailability.[4] Remarkably, depsipeptides have less rotational barriers for cis-trans isomerization compared to their peptide analogues because of reduced resonance delocalization in the ester functionality relative to an amide moiety, and thus have more flexible scaffolds.[3] [5] Furthermore, depsipeptides possess a wide variety of biological properties such as antibacterial, antiviral, antifungal, anti-inflammatory, antitumor, and immunosuppressive activity.[6] For instance, the natural product romidepsin is an FDA-approved anticancer drug utilized to treat cutaneous T-cell lymphoma.[7] Other cases of biologically active depsipeptides are azinomycin B[8] (antitumor activity) and valinomycin[9] (antibiotic) that are presented in Figure [1].

Zoom Image
Figure 1 Some biologically active depsipeptides

Isocyanide-based multicomponent reactions (IMCRs) are highly efficient strategies for peptidomimetic synthesis.[10] Among the IMCRs, the Ugi four-component reaction has been demonstrated as an extremely powerful approach for the synthesis of pseudopeptidic structures.[11] The Ugi reaction products are often observed as a mixture of rotamers due to the high rotational barriers of the tertiary amide bonds.[12] The Passerini three-component reaction (3-CR) that involves an isocyanide, an oxo-component, and a carboxylic acid, is a potent tool in combinatorial chemistry due to its efficiency for producing diverse structures, providing brevity, molecular complexity, and operational simplicity.[13] [14] In general, the Passerini reaction products have more flexible structures than the Ugi reaction products due to possessing an ester functionality instead of the tertiary amide. This is very significant from a drug design viewpoint, because creating faster rotation around a hindered bond is one of the best strategies to overcome the challenge of conformational isomerism.[15]

The scope of MCRs, specially IMCRs, can be further advanced by combination with other sequential reactions[16] and, in this regard, consecutive MCRs can be a superior selection.[17] In consecutive MCRs, the product of the first MCR is utilized as the precursor in the next MCR. Accordingly, the diversity, efficiency, and atom economy that are the benefits of MCRs, are extended. In view of our interests in design of combinatorial MCRs,[18] we herein report isocyanide-based consecutive Bargellini–Passerini MCRs as a straightforward and efficient strategy for the synthesis of depsipeptide-based frameworks.

In this program, we focused on the using 3-carbox­amido-isobutyric acids as the products of Bargellini 3-CRs in the Passerini 3-CRs. 3-Carboxamido-isobutyric acids bearing an amide functionality were synthesized via the 3-CR of acetone, chloroform, and an isocyanide in the presence of sodium hydroxide.[19] Primarily, compound 4a was employed in the Passerini 3-CR under various reaction conditions (Table [1]). The 3-CRs of cyclohexyl isocyanide (3a), benzaldehyde (5a), and compound 4a were investigated in various solvents such as dichloromethane, toluene, tetrahydrofuran, ethyl acetate, and methanol, and the desired depsipeptide 6a was achieved in moderate yields (24–58%, Table­ [1], entries 1–5). We also examined the model reaction under solvent-free conditions, which led to the depsipeptide 6a in 61% yield (Table [1], entry 6). Finally, the reaction was carried out in water as a solvent at ambient temperature and a significant rate enhancement was observed with the production of compound 6a in 79% yield (Table [1], entry 7). By increasing the reaction temperature to 50 °C, depsipeptide 6a was produced in 90% yield after 2 h (Table [1], entry 8). It is noteworthy that the use of water not only speeds up the MCR, but also makes isolation much easier due to the insolubility of the products. The acceleration of the MCR in water can be related to the hydrophobic effect and the high cohesive energy density of water.[20] Cohesive energy density is a property of solvents and has units corresponding to a pressure.[21] The effect of water on the acceleration of MCRs is very similar to the effect of pressure on reactions that result in a decrease in molecularity.

Table 1 Optimization of the Second-Step Reaction Conditionsa

Entry

Solvent

Temp (°C)

Time (h)

Yield (%)b

1

CH2Cl2

r.t.

24

56

2

toluene

r.t.

24

48

3

THF

r.t.

24

58

4

EtOAc

r.t.

24

24

5

MeOH

r.t.

24

36

6

80

18

61

7

H2O

r.t.

5

79

8

H2O

50

2

90

a Reaction conditions: 3a (1 mmol), 4a (1 mmol), 5a (1 mmol), solvent (4 mL).

b Isolated yield.

With the optimized reaction conditions in hand, we synthesized a series of depsipeptides 6al in high yields (Scheme [1]). Various aromatic aldehydes with electron-donating­, electron-withdrawing, and halogen groups and isocyanides (tert-butyl, cyclohexyl) were employed for demonstrating the diversity of approach. 3-Pyridinecarb­aldehyde, 2-naphthaldehyde, and aromatic aldehydes with electron-withdrawing and halogen substitutions afforded the products in excellent yields. 4-Methylbenzaldehyde reacted more slowly in the final Passerini step, requiring 48 h to achieve a relatively poor 66% yield. The highly electron-rich 4-methoxybenzaldehyde failed to produce any product even after 48 h.

Zoom Image
Scheme 1 Scope and yields of the synthesized depsipeptides 6al. Reaction conditions of the second-step reaction: 3-carboxamido-isobutyric acid 4 (1 mmol), aldehyde 5 (1 mmol), isocyanide 3 (1 mmol), water (4 mL), stirring at r.t. for 5 min and then at 50 °C for 2 h. Reaction time for 6e is 48 h.

The structures of all depsipeptides 6al were verified by their IR, 1H NMR, 13C NMR, mass spectra, and CHN analysis data. For instance, the 1H NMR spectrum of depsipeptide 6a in CDCl3 as a solvent demonstrated a multiplet for the aromatic protons (δ = 7.43–7.39 ppm, 5 H), two broad singlets for the NH groups (δ = 6.90 and 6.40 ppm, 2 H), a singlet for the benzylic CH (δ = 6.06 ppm, 1 H), a broad singlet for the NH–CH of the cyclohexyl rings (δ = 3.80 ppm, 2 H), and a multiplet for the aliphatic protons (δ = 1.92–1.17 ppm, 26 H). The 1H-decoupled 13C NMR spectrum of 6a exhibited three carbonyl groups corresponding to the ester and amide functionalities. The mass spectra of the products showed molecular ion peaks at the accurate m/z values. It is noteworthy that the 1H NMR spectra of the depsipetides 6ag displayed one singlet peak for the benzylic CH group in both CDCl3 and DMSO-d 6. Moreover, all the 1H-decoupled 13C NMR spectra showed the presence of three carbonyl groups for the depsipeptide scaffolds, which also confirmed the lower rotational barriers for these depsipeptides compared to their corresponding pseudopeptidic structures.[18d] In addition, the effect of temperature on compound 6a was investigated at 24–80 °C using variable-temperature 1H NMR spectroscopy. As shown in Figure [2], no significant changes (except in the chemical shifts of exchangeable NH groups) were observed with increasing temperature in the spectra. The full width at half maximum for the benzylic CH group peak is almost constant at investigated temperatures. Therefore, the prepared depsipeptides are demonstrated to have more flexible structures than their pseudopeptidic analogues­.

Zoom Image
Figure 2 The 1H NMR spectra of compound 6a at 24–80 °C (DMSO-d 6, 300 MHz); spectrum A: at 24 °C, spectrum B: at 25 °C, spectrum C: at 30 °C, spectrum D: at 40 °C, spectrum E: at 45 °C, spectrum F: at 50 °C, spectrum G: at 55 °C, spectrum H: at 60 °C, spectrum I: at 80 °C.

Finally, the structure of 6a was unambiguously verified by single-crystal X-ray analysis, which is presented in Figure [3] (for detailed information, see the Supporting Information).

Zoom Image
Figure 3 ORTEP diagram for 6a

In summary, a convenient and efficient method has been developed for the preparation of biologically interesting depsipeptides via consecutive Bargellini–Passerini multicomponent reactions. The present method, having the advantages of both IMCRs, leads to the ready creation of depsi­peptide scaffolds from cheap and readily available starting materials. The synthesized depsipeptides have more flexible scaffolds than their pseudopeptidic analogues.

General Information

All commercially available chemicals and reagents were purchased from Merck Chemical Company and used without further purification. Melting points were measured on an Electrothermal 9200 apparatus. IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1H NMR spectra were recorded on a Bruker DRX-300 Avance spectrometer at 300 MHz. 13C NMR spectra were recorded on a Bruker DRX-300 Avance spectrometer at 75 MHz. NMR spectra were obtained in CDCl3and DMSO-d 6. Mass spectra of the products were obtained with an HP (Agilent technologies) 5973 mass selective detector. Elemental analyses were performed on an Elementar Analysensysteme GmbH VarioEL.


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General Procedure for the Synthesis of 3-Carboxamido-isobutyric Acids

In a round-bottom flask, acetone (5 mmol), chloroform (7.5 mmol), sodium hydroxide (7.5 mmol), and the requisite isocyanide (1 mmol) were mixed and stirred at 0 °C for 30 min and then at ambient temperature overnight. The reaction mixture was diluted with water, which was acidified to pH 2 with 2 M HCl and extracted with EtOAc (three times). The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the pure product.[19a]


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General Procedure for the Synthesis of Depsipeptides 6a–l

A mixture of the 3-carboxamido-isobutyric acid derivative (1 mmol), an aldehyde (1 mmol), and an isocyanide (1 mmol) in water (4 mL) was stirred at room temperature for 5 min and then at 50 °C for the appropriate time (Scheme [1]). The water was then removed by decantation, and the crude product was recrystallized from EtOH (2 mL) to afford the pure product.


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Characterization Data of 6a–l


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2-(Cyclohexylamino)-2-oxo-1-phenylethyl 3-(cyclohexylamino)-2,2-dimethyl-3-oxopropanoate (6a)

White powder: 385 mg, 90% yield; mp 145–147 °C. IR (KBr): 3265, 3087, 2931, 2852, 1745, 1676, 1641 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.43–7.39 (m, 5 H, HAr), 6.90 (br s, 1 H, NH), 6.40 (br s, 1 H, NH), 6.06 (s, 1 H, CH-O), 3.80 (br s, 2 H, CHN), 1.92–1.17 (m, 26 H, HAliphatic). 13C NMR (75 MHz, CDCl3): δ = 172.54, 171.98, 167.51, 135.40, 128.92, 128.72, 127.50, 75.96, 50.62, 48.83, 48.51, 32.77, 32.65, 32.58, 25.49, 24.89, 23.33. MS: m/z = 429 [M++ 1] (2.52), 428 (M+, 0.92), 347 (41.69), 303 (86.77), 234 (7.85), 216 (15.15), 188 (61.60), 169 (100), 140 (10.33), 118 (10.82), 98 (26.33), 83 (30.12), 55 (10.81). Anal. Calcd for C25H36N2O4: C, 70.06; H, 8.47; N, 6.54. Found: C, 70.31; H, 8.59; N, 6.44.


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2-(tert-Butylamino)-2-oxo-1-phenylethyl 3-(cyclohexylamino)-2,2-dimethyl-3-oxopropanoate (6b)

White powder: 366 mg, 91% yield; mp 173–175 °C. IR (KBr): 3284, 3080, 2931, 2865, 1741, 1662, 1637 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H, HAr), 6.62 (br s, 1 H, NH), 6.33 (br s, 1 H, NH), 5.96 (s, 1 H, CH-O), 3.79–3.75 (m, 1 H, CHN), 1.90–1.12 (m, 25 H, HAliphatic). 13C NMR (75 MHz, CDCl3): δ = 172.79, 171.56, 167.59, 135.43, 128.99, 128.82, 127.52, 76.04, 51.77, 50.57, 48.78, 32.70, 28.59, 25.53, 24.91, 23.51, 23.38. MS: m/z = 403 [M++ 1] (3.56), 402 [M+] (1.54), 321 (52.20), 303 (89.34), 277 (18.59), 212(7.54), 196 (36.77), 169 (100), 140 (13.69), 106 (46.66), 83 (19.57), 57 (20.78). Anal. Calcd for C23H34N2O4: C, 68.63; H, 8.51; N, 6.96. Found: C, 68.78; H, 8.43; N, 6.81.


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1-(4-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl 3-(tert-butylamino­)-2,2-dimethyl-3-oxopropanoate (6c)

White powder: 419 mg, 87% yield; mp 133–135 °C. IR (KBr): 3265, 3080, 2935, 2854, 1749, 1651, 1560 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.50 (d, J = 8.1 Hz, 2 H, HAr), 7.32–7.29 (m, 3 H, HAr and NH), 6.02 (s, 1 H, CHO), 5.80 (br s, 1 H, NH), 3.77–3.73 (m, 1 H, CHN), 1.94–1.18 (m, 25 H, HAliphatic). 13C NMR (75 MHz, CDCl3): δ = 172.40, 172.11, 166.92, 134.71, 131.79, 129.15, 122.96, 75.20, 51.79, 51.23, 48.59, 32.75, 32.56, 28.58, 25.50, 24.99, 24.92, 23.32. MS: m/z = 482 [M++ 2] (1.18), 481 [M++ 1] (3.14), 467 (7.41), 383 (18.51), 357 (87.60), 294 (16.43), 268 (50.11), 186 (23.68), 170 (37.50), 143 (100), 114 (37.00), 87 (83.60), 57 (44.81). Anal. Calcd for C23H33BrN2O4: C, 57.38; H, 6.91; N, 5.82. Found: C, 57.51; H, 6.80; N, 5.69.


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2-(tert-Butylamino)-1-(4-chlorophenyl)-2-oxoethyl 3-(tert-butylamino)-2,2-dimethyl-3-oxopropanoate (6d)

White powder: 366 mg, 89% yield; mp 149–151 °C. IR (KBr): 3296, 3074, 2972, 2931, 1745, 1664, 1647 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.35–7.28 (m, 4 H, HAr), 6.88 (br s, 1 H, NH), 5.94 (s, 1 H, CHO), 5.91 (br s, 1 H, NH), 1.47–1.37 (m, 24 H, HAliphatic). 13C NMR (75 MHz, CDCl­3): δ = 172.33, 171.96, 167.17, 134.78, 134.31, 128.91, 128.84, 75.31, 51.78, 51.70, 51.15, 28.58, 28.54, 23.43, 23.37. MS: m/z = 412 [M++ 2] (0.62), 411 [M++ 1] (2.25), 311 (93.36), 255 (7.26), 224 (14.92), 196 (67.58), 170 (29.77), 143 (100), 114 (18.80), 87 (46.69), 57 (39.92). Anal. Calcd for C21H31ClN2O4: C, 61.38; H, 7.60; N, 6.82. Found: C, 61.51; H, 7.73; N, 6.67.


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2-(Cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl 3-(cyclohexylamino)-2,2-dimethyl-3-oxopropanoate (6e)

White powder: 292 mg, 66% yield; mp 132–134 °C. IR (KBr): 3253, 3078, 2933, 2854, 1743, 1668, 1635 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.29–7.14 (m, 4 H, HAr), 6.79 (br s, 1 H, NH), 6.46 (br s, 1 H, NH), 5.99 (s, 1 H, CHO), 3.79–3.68 (m, 2 H, CHN), 2.34 (s, 3 H, HMe-Ar), 1.87–1.14 (m, 26 H, HAliphatic). 13C NMR (75 MHz, CDCl3): δ = 172.64, 171.97, 167.69, 138.84, 132.37, 129.40, 127.49, 75.85, 50.57, 48.80, 48.46, 32.71, 32.56, 25.46, 24.87, 23.31, 21.21. MS: m/z = 443 [M++ 1] (2.99), 442 [M+] (1.01), 361 (21.02), 317 (93.32), 230 (29.57), 202 (67.44), 169 (100), 140 (13.94), 120 (23.23), 98 (34.03), 83 (38.50), 55 (13.39). Anal. Calcd for C26H38N2O4: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.78; H, 8.82; N, 6.18.


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2-(tert-Butylamino)-1-(2-nitrophenyl)-2-oxoethyl 3-(tert-butylamino)-2,2-dimethyl-3-oxopropanoate (6f)

Pale yellow powder: 392 mg, 93% yield; mp 155–157 °C. IR (KBr): 3303, 3078, 2974, 2875, 1747, 1685, 1647 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.96 (d, J = 8.2 Hz, 1 H, HAr), 7.66–7.50 (m, 3 H, HAr), 6.98 (br s, 1 H, NH), 6.54 (s, 1 H, CHO), 6.22 (br s, 1 H, NH), 1.44–1.36 (m, 24 H, HAliphatic). 13C NMR (75 MHz, CDCl3): δ = 172.52, 171.89, 166.10, 148.49, 133.49, 130.37, 130.29, 129.72, 124.91, 71.56, 51.94, 51.71, 51.29, 28.57, 28.54, 23.56, 23.38. MS: m/z = 423 [M++ 2] (0.73), 422 [M++ 1] (2.90), 406 (25.57), 322 (27.87), 253 (49.63), 188 (19.15), 170 (100), 135 (77.73), 114 (33.31), 84 (25.99), 57 (51.08). Anal. Calcd for C21H31N3O6: C, 59.84; H, 7.41; N, 9.97. Found: C, 59.63; H, 7.28; N, 10.16.


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2-(Cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl 3-(cyclohexylamino)-2,2-dimethyl-3-oxopropanoate (6g)

White powder: 365 mg, 85% yield; mp 184–186 °C. IR (KBr): 3302, 3057, 2931, 2855, 1743, 1685, 1657 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.72–8.59 (m, 2 H, HAr), 7.81–7.77 (m, 1 H, HAr), 7.39–7.29 (m, 2 H, HArand NH), 6.14 (br s, 1 H, NH), 6.12 (s, 1 H, CHO), 3.83–3.75 (m, 1 H, CHN), 1.93–1.17 (m, 26 H, HAliphatic). 13C NMR (75 MHz, CDCl3): δ = 172.16, 171.99, 166.71, 149.99, 148.49, 135.25, 131.58, 123.50, 73.60, 50.75, 48.88, 48.68, 32.88, 32.71, 32.52, 25.46, 24.87, 23.27. MS: m/z = 430 [M++ 1] (0.20), 429 (M+, 0.62), 348 (20.78), 304 (33.35), 235 (15.58), 196 (18.70), 169 (100), 108 (39.53), 83 (46.61), 55 (50.62). Anal. Calcd for C24H35N3O4: C, 67.11; H, 8.21; N, 9.78. Found: C, 67.30; H, 8.15; N, 9.89.


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1-(4-Bromophenyl)-2-(tert-butylamino)-2-oxoethyl 3-(cyclo­hexylamino)-2,2-dimethyl-3-oxopropanoate (6h)

White powder: 424 mg, 88% yield; mp 168–170 °C. IR (KBr): 3253, 3078, 2933, 2856, 1745, 1639, 1560 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.51 (d, J = 8.0 Hz, 2 H, HAr), 7.29 (d, J = 8.0 Hz, 2 H, HAr), 6.58 (br s, 1 H, NH), 6.33–6.30 (m, 1 H, NH), 5.91 (s, 1 H, CHO), 3.81–3.75 (m, 1 H, CHN), 1.90–1.16 (m, 25 H, HAliphatic). 13C NMR (75 MHz, CDCl3): δ = 172.41, 171.55, 167.12, 134.62, 131.93, 129.14, 123.12, 75.29, 51.83, 50.57, 48.77, 32.78, 32.67, 28.56, 25.48, 24.85, 23.35, 23.27. MS: m/z = 482 [M++ 2] (1.53), 481 [M++ 1] (3.61), 480 [M+] (0.72), 401 (24.73), 383 (90.62), 268 (16.27), 242 (53.65), 196 (62.58), 169 (100), 140 (26.15), 98 (37.81), 83 (44.83), 57 (40.60). Anal. Calcd for C23H33BrN2O4: C, 57.38; H, 6.91; N, 5.82. Found: C, 57.23; H, 6.75; N, 5.73.


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2-(Cyclohexylamino)-1-(naphthalen-2-yl)-2-oxoethyl 3-(tert-butylamino­)-2,2-dimethyl-3-oxopropanoate (6i)

White powder: 407 mg, 90% yield; mp 178–180 °C. IR (KBr): 3257, 3080, 2933, 2856, 1745, 1645, 1537 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.91–7.83 (m, 4 H, HAr), 7.53–7.49 (m, 3 H, HAr), 7.30–7.18 (m, 1 H, NH), 6.23 (s, 1 H, CHO), 5.99 (br s, 1 H, NH), 3.79 (br s, 1 H, CHN), 1.92–1.19 (m, 25 H, HAliphatic). 13C NMR (75 MHz, CDCl3): δ = 172.51, 172.39, 167.36, 133.42, 133.06, 132.87, 128.63, 128.20, 127.70, 127.45, 126.59, 126.41, 124.63, 76.21, 51.73, 51.22, 48.59, 32.81, 32.62, 28.60, 25.51, 24.98, 24.91, 23.44, 23.40. MS: m/z = 453 [M++ 1] (0.38), 452 [M+] (0.05), 327 (82.67), 266 (17.26), 238 (12.03), 170 (42.50), 143 (100), 127 (13.21), 87 (13.57), 57 (14.45). Anal. Calcd for C27H36N2O4: C, 71.65; H, 8.02; N, 6.19. Found: C, 71.84; H, 8.23; N, 6.01.


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2-(Cyclohexylamino)-1-(4-nitrophenyl)-2-oxoethyl 3-(cyclohexylamino)-2,2-dimethyl-3-oxopropanoate (6j)

Pale yellow powder: 450 mg, 95% yield; mp 148–-150 °C. IR (KBr): 3269, 3084, 2931, 2860, 1722, 1637, 1529 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.21 (d, J = 8.6 Hz, 2 H, HAr), 7.62 (d, J = 8.6 Hz, 2 H, HAr), 7.42 (br s, 1 H, NH), 6.15 (s, 1 H, CHO), 5.95 (br s, 1 H, NH), 3.81–3.71 (m, 2 H, CHN), 1.92–1.18 (m, 26 H, HAliphatic). 13C NMR (75 MHz, CDCl3): δ = 172.09, 171.63, 166.21, 147.95, 142.46, 128.05, 123.67, 74.52, 50.71, 48.82, 48.68, 32.84, 32.58, 25.32, 24.74, 23.02. MS: m/z = 474 [M++ 1] (1.86), 473 [M+] (0.34), 392 (43.27), 348 (88.05), 279 (22.05), 233 (23.97), 196 (19.87), 169 (100), 140 (11.12), 98 (24.68), 83 (36.12), 55 (13.51). Anal. Calcd for C25H35N3O6: C, 63.41; H, 7.45; N, 8.87. Found: C, 63.27; H, 7.33; N, 8.98.


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2-(tert-Butylamino)-1-(naphthalen-2-yl)-2-oxoethyl 3-(cyclo­hexylamino)-2,2-dimethyl-3-oxopropanoate (6k)

White powder: 403 mg, 89% yield; mp 173–175 °C. IR (KBr): 3276, 3074, 2929, 2856, 1743, 1661, 1636 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.89–7.84 (m, 4 H, HAr), 7.54–7.49 (m, 3 H, HAr), 6.68 (br s, 1 H, NH), 6.41–6.36 (m, 1 H, NH), 6.14 (s, 1 H, CHO), 3.80 (br s, 1 H, CHN), 1.95–1.14 (m, 25 H, HAliphatic). 13C NMR (75 MHz, CDCl3): δ = 172.86, 171.60, 167.59, 133.49, 133.08, 132.75, 128.88, 128.20, 127.76, 127.53, 126.73, 126.53, 124.51, 76.25, 51.87, 50.62, 48.79, 32.68, 28.61, 25.53, 24.91, 23.55, 23.39. MS: m/z = 454 [M++ 2] (0.31), 453 [M++ 1] (0.90), 353 (76.95), 240 (9.21), 212 (19.90), 196 (64.18), 169 (100), 141 (37.57), 126 (7.04), 83 (15.64), 57 (14.97). Anal. Calcd for C27H36N2O4: C, 71.65; H, 8.02; N, 6.19. Found: C, 71.88; H, 8.28; N, 6.04.


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1-(4-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl 3-(tert-butylamino­)-2,2-dimethyl-3-oxopropanoate (6l)

White powder: 385 mg, 88% yield; mp 147–149 °C. IR (KBr): 3315, 3064, 2933, 2854, 1747, 1660, 1545 cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 8.31–8.28 (m, 1 H, NH), 7.63–7.46 (m, 4 H, HAr), 7.21 (br s, 1 H, NH), 5.86 (s, 1 H, CHO), 3.51 (br s, 1 H, CHN), 1.75–1.09 (m, 25 H, HAliphatic). 13C NMR (75 MHz, DMSO-d 6): δ = 173.08, 172.31, 167.26, 135.16, 133.74, 129.42, 128.93, 75.04, 51.30, 51.15, 48.22, 32.62, 32.40, 28.72, 25.61, 24.81, 23.63, 23.51. MS: m/z = 438 [M++ 2] (0.90), 437 [M++ 1] (3.20), 421 (9.24), 337 (25.53), 311 (92.67), 250 (20.69), 222 (65.41), 170 (24.96), 143 (100), 125 (26.01), 87 (49.15), 57 (22.25). Anal. Calcd for C23H33ClN2O4: C, 63.22; H, 7.61; N, 6.41. Found: C, 63.11; H, 7.70; N, 6.58.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

  • References

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Corresponding Author

Ahmad Shaabani
Faculty of Chemistry, Shahid Beheshti University
G.C., P.O. Box 19396-4716, Tehran
Iran   

Publication History

Received: 18 May 2021

Accepted after revision: 18 June 2021

Publication Date:
22 June 2021 (online)

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  • References

    • 1a Lenci E, Trabocchi A. Chem. Soc. Rev. 2020; 49: 3262
    • 1b Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M. Drug Discov. Today 2010; 15: 40
  • 2 Nielsen PE. Pseudo-Peptides in Drug Discovery . Wiley-VCH; Weinheim: 2004
  • 3 Avan I, Hall CD, Katritzky AR. Chem. Soc. Rev. 2014; 43: 3575
    • 4a Abdelraheem EM, Kurpiewska K, Kalinowska-Tłuścik J, Dömling A. J. Org. Chem. 2016; 81: 8789
    • 4b Bucci R, Dapiaggi F, Macut H, Pieraccini S, Sironi M, Gelmi ML, Erba E, Pellegrino S. Amino Acids 2020; 52: 15
  • 5 Kang YK, Byun BJ. J. Phys. Chem. B 2008; 112: 9126
    • 6a Ballard C, Yu H, Wang B. Curr. Med. Chem. 2002; 9: 471
    • 6b Sarabia F, Chammaa S, Ruiz AS, Ortiz LM, Herrera FL. Curr. Med. Chem. 2004; 11: 1309
    • 6c Biswas S, Avan I, Basak AK, Abo-Dya NE, Asiri A, Katritzky AR. Amino Acids 2013; 45: 159
  • 7 VanderMolen KM, McCulloch W, Pearce CJ, Oberlies NH. J. Antibiot. 2011; 64: 525
  • 8 Liu C, Kelly GT, Watanabe CM. Org. Lett. 2006; 8: 1065
  • 9 Jaitzig J, Li J, Süssmuth RD, Neubauer P. ACS Synth. Biol. 2014; 3: 432
    • 10a Dömling A. Chem. Rev. 2006; 106: 17
    • 10b Wessjohann LA, Rhoden CR, Rivera DG, Vercillo OE. Cyclic Peptidomimetics and Pseudopeptides from Multicomponent Reactions . In Synthesis of Heterocycles via Multicomponent Reactions I . Springer; Berlin, Heidelberg: 2010: 199
    • 10c Khalesi M, Halimehjani AZ, Franz M, Schmidtmann M, Martens J. Amino Acids 2019; 51: 263
    • 11a Pelliccia S, Alfano IA, Galli U, Novellino E, Giustiniano M, Tron GC. Symmetry 2019; 11: 798
    • 11b Fouad MA, Abdel-Hamid H, Ayoup MS. RSC Adv. 2020; 10: 42644
    • 11c Farhid H, Khodkari V, Nazeri MT, Javanbakht S, Shaabani A. Org. Biomol. Chem. 2021; 19: 3318
    • 12a Gouge V, Jubault P, Quirion J.-C. Tetrahedron Lett. 2004; 45: 773
    • 12b Szczesniak P, Maziarz E, Stecko S, Furman B. J. Org. Chem. 2015; 80: 3621
    • 12c Peshkov AA, Peshkov VA, Pereshivko OP, Van der Eycken EV. Tetrahedron 2015; 71: 3863
    • 12d Nazeri MT, Nowee AB, Shaabani A. New J. Chem. 2021; 45: 3479
    • 12e Nazeri MT, Farhid H, Mohammadian R, Shaabani A. ACS Comb. Sci. 2020; 22: 361
  • 13 Reza KazemizadehA, Ramazani A. Curr. Org. Chem. 2012; 16: 418
    • 14a Kumar B, Maity J, Shankar B, Kumar S, Prasad AK. Carbohydr. Res. 2021; 500: 108236
    • 14b Gulevich AV, Shpilevaya IV, Nenajdenko VG. Eur. J. Org. Chem. 2009; 3801
    • 14c Rostovskii NV, Koronatov AN, Sakharov PA, Agafonova AV, Novikov MS, Khlebnikov AF, Rogacheva EV, Kraeva LA. Org. Biomol. Chem. 2020; 18: 9448
    • 14d Zarezin DP, Shmatova OI, Nenajdenko VG. Org. Biomol. Chem. 2018; 16: 5987
    • 15a Al-Horani RA, Desai UR. Tetrahedron 2012; 68: 2027
    • 15b Clayden J, Moran WJ, Edwards PJ, LaPlante SR. Angew Chem. Int. Ed. 2009; 48: 6398
    • 15c Glunz PW. Bioorg Med. Chem. Lett. 2018; 28: 53
    • 16a Bariwal J, Kaur R, Voskressensky LG, Van der Eycken EV. Front. Chem. 2018; 6: 557
    • 16b Sharma UK, Sharma N, Vachhani DD, Van der Eycken EV. Chem. Soc. Rev. 2015; 44: 1836
    • 16c Mohammadkhani L, Heravi MM. Mol. Diversity 2020; 24: 841
    • 17a Zhi S, Ma X, Zhang W. Org. Biomol. Chem. 2019; 17: 7632
    • 17b Zarganes Tzitzikas T, Chandgude AL, Dömling A. Chem. Rec. 2015; 15: 981
    • 17c Dömling A. Curr. Opin. Chem. Biol. 2000; 4: 318
    • 17d Heublein N, Moore JS, Smith CD, Jensen KF. RSC Adv. 2014; 4: 63627
    • 17e Yang L, Zhang Z, Cheng B, You Y, Wu D, Hong C. Sci. China Chem. 2015; 58: 1734
    • 18a Nazeri MT, Mohammadian R, Farhid H, Shaabani A, Notash B. Tetrahedron Lett. 2020; 61: 151408
    • 18b Shaabani S, Shaabani A, Ng SW. ACS Comb. Sci. 2014; 16: 176
    • 18c Hooshmand SE, Ghadari R, Mohammadian R, Shaabani A, Khavasi HR. ChemistrySelect 2019; 4: 11893
    • 18d Farhid H, Nazeri MT, Shaabani A, Armaghan M, Janiak C. Amino Acids 2021; 53: 1
    • 19a Giustiniano M, Pelliccia S, Galli U, Amato J, Travagin F, Novellino E, Tron GC. J. Org. Chem. 2016; 81: 11467
    • 19b Serafini M, Murgia I, Giustiniano M, Pirali T, Tron GC. Molecules 2021; 26: 558
  • 20 Pirrung MC, Sarma KD. J. Am. Chem. Soc. 2004; 126: 444
  • 21 Pirrung MC, Sarma KD. Tetrahedron 2005; 61: 11456

Zoom Image
Figure 1 Some biologically active depsipeptides
Zoom Image
Scheme 1 Scope and yields of the synthesized depsipeptides 6al. Reaction conditions of the second-step reaction: 3-carboxamido-isobutyric acid 4 (1 mmol), aldehyde 5 (1 mmol), isocyanide 3 (1 mmol), water (4 mL), stirring at r.t. for 5 min and then at 50 °C for 2 h. Reaction time for 6e is 48 h.
Zoom Image
Figure 2 The 1H NMR spectra of compound 6a at 24–80 °C (DMSO-d 6, 300 MHz); spectrum A: at 24 °C, spectrum B: at 25 °C, spectrum C: at 30 °C, spectrum D: at 40 °C, spectrum E: at 45 °C, spectrum F: at 50 °C, spectrum G: at 55 °C, spectrum H: at 60 °C, spectrum I: at 80 °C.
Zoom Image
Figure 3 ORTEP diagram for 6a