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Article

Atroposelective Amination of Indoles via Chiral Center Induced Chiral Axis Formation

by
Yong Wang
,
Jingxue Yan
,
Yiqing Jiang
,
Zexuan Wei
,
Zhenlin Tu
,
Chao Dong
,
Tao Lu
,
Yadong Chen
* and
Jie Feng
*
Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, China
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(24), 9008; https://doi.org/10.3390/molecules27249008
Submission received: 29 October 2022 / Revised: 9 December 2022 / Accepted: 11 December 2022 / Published: 17 December 2022
(This article belongs to the Special Issue Atroposelective Synthesis of Novel Axially Chiral Molecules)
Browse Figures
Versions Notes

Abstract

:
The construction of an N–C chiral axis for N-aryl indole derivatives is meaningful as they widely exist in functionalized molecules. This work provides a novel method for this purpose via amination of amino acid derivatives at the C2 position of the indole and chiral center induced chiral axis formation. The protocol of this transformation is easily accessible, not requiring metal or an organic chiral catalyst, endowing this method with great potential in the construction of axis chiral N-aryl indoles.

1. Introduction

Atropisomers around the C–N chiral axis, which have a typical chiral axis connecting a substituted nitrogen and the aryl-related hindrance, are one of the most important classes of axially chiral compounds. For example, Murrastifoline F was isolated from murraya alkaloid, which possesses anti-HIV activity [1,2,3]. Moreover, such skeletons have been used as chiral organocatalysts and ligands in enantioselective reactions, due to their specific electronic properties among biaryls (Scheme 1a) [4,5,6].
Given the importance of C−N axially chiral biaryls in pharmaceuticals, organic synthesis, and materials, catalytic asymmetric syntheses of these C–N axially chiral compounds and their applications to asymmetric transformations are of current interest [7,8,9,10,11,12,13,14,15,16,17]. Additionally, it would be meaningful to introduce axial chirality into the indole skeleton, as the indole skeleton is widely apparent in many natural products and drug molecules. Catalytic asymmetric synthesis of indole-based heterobiaryl axially chiral compounds was disclosed by the Shi [18,19,20], Tan [21], Fu [22,23], and Yan [24] groups, etc. The chiral axis was normally built at the C2 or C3 position of the indole ring [25,26,27,28,29,30,31], while recent literature has reported the stereoselective synthesis of axially chiral indole derivatives possessing a sterically hindered phenyl group on the nitrogen atom [32,33,34,35]. Despite these promising achievements, asymmetric synthesis of indole-based atropisomers, especially with an N–C chiral axis, is still a synthetic challenge and remains largely unexplored (Scheme 1b).
This study tackles this synthetic defiance considering the asymmetric catalysis free and easy formation of indole-based heterobiaryl axially chiral compounds, in line with strategies such as chiral center induced chiral axis formation and the central-to-axial chirality conversion [36,37,38]. It is worth noting that the Yu’s group described a series of examples for atroposelective coupling of indoles at the C2 position with chiral amino acid-based sulfonamides via a central-to-axial chirality conversion strategy [39,40]. Encouraged by that, we rationalized that the construction of an N–C chiral axis for N-aryl indole derivatives possessing a sterically hindered N-phenyl group via amination at the C2 position of the indole and sequence chiral center induced chiral axis formation would represent a novel strategy for constructing indole-based N–C atropisomers (Scheme 1c).

2. Results and Discussion

To start this work, N-phenyl indole 1a and tert-butyl ((4-nitrophenyl)sulfonyl)-L-valinate 2a were used as the model substrate to test the feasibility for the C–N amination (Table 1). Product 3a was afforded using an aqueous NaClO solution with 1a in different solvents. The solvent was also crucial to both the yield and diastereoisomers (dr) value. The optimal solvent was found to be DCM in 65% yield and 3.5/1 dr value (entry 1–6). Only a trace product was observed in the protic solvent (entry 4). The yield loss was due to the formation of byproduct 4a and oxidative byproduct 5a. Interestingly, biaxial chirality was observed as the chlorine atom brings steric hindrance at the C3 position. In Yu’s work, excellent dr value was observed at the C–N axis chirality at the indole C2 position. Similar high dr was tracked for compound 4a (entry 1).
In should be mentioned that the protecting group of valinate also significantly affected the yield and dr (Table 2). The p-nitrobenzene sulfonyl group (Ns) was favorable for this transformation (entry 2). Other sulfonyl protecting groups yielded the product 3a in less than 5% yield. The benzyl protecting group (Bn) and tert-butoxycarbonyl group (Boc) were conductive to produce byproduct 5a.
In order to show the generality of this strategy, the couplings of various indoles with N-Ns protected amino acid derivatives were investigated under the optimal conditions. First, a series of substituted indole derivatives at different positions reacted with 2a to give product 3a–3j in moderate yield (Scheme 2, 3a–3h). The electron-donating group bearing indoles at the C4-C5 position had lower yields but improved dr value (3d, 3e vs. 3a, 3b, 3i). For substrate 3j, the C-3 chlorination product 4j was produced at the same time. The dr value of 3j was around 5/1, but its side product 4j had excellent dr value. A similar dr value with the model substrate 3a was obtained for C-6 substituted indoles (3h, 3i). One example using the heterocyclic indole analogue with 1-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine was also conducted with 43% yield and good dr value (3k). Next, we explored the variations at the N-aryl ring of the indole. A less bulky ortho-substituted substrate resulted in lower dr value (3l). In the case of substitutions at the meta position, 1:1 of two diastereomers were observed (3m).
After that, we continued to investigate the reactivity and stereoselectivity of the reactions of N-phenylindole (1a) with various amino acid derivatives (Scheme 3). Generally, the steric hindrance of amino acid derivatives had a positive influence on the stereoselectivity. To our delight, excellent dr value was shown with amino acid derivatives such as L-Isoleucine (3p), L-Norvaline (3q). But the yield was slightly decreased with bulker amino acid. As for the L-Cyclohexyl glycine derivative 3s and 2-Amino-1-propanol derivative 3t, byproducts 4s and 4t were tracked, respectively.
The absolute configuration of axially chiral product 3a was determined to be (Ra,S) by single-crystal X-ray diffraction analysis (Scheme 4) (CCDC 2222365 for the major diastereomer of 3a, see the Supporting Information for details). Thus, the absolute configurations of other axially chiral products were assigned to be (Ra,S) by analogy with 3a. Next, we investigated the configurational stability and the rotational barrier of product 3a and other isomers (S1–S4, Scheme 4) via DFT calculations (Scheme 4). It was discovered that the indole C2–N axis was unstable (the rotate barrier was 24.1 kcal/mol and 23.5 kcal/mol, respectively, for TS2 and TS4), which will rapidly disappear under room temperature. However, the N–Caryl axis had good configurational stability due to the fact that the rotational barrier was high (28.5 kcal/mol for TS3, 27.6 kcal/mol for TS1). As the amino acid was optically pure, the diastereo ratio may come from the atropisomerism of an N–Caryl axis.
In summary, we present here an atroposelective coupling of indoles with chiral amino acid-based sulfonamides mediated by hypo-halides through chiral center induced chiral axis formation strategy. The reaction delivers 2-amido-N-arylindoles with an N–C chiral axis in a moderate to good dr value. The substrates and reaction protocol of this transformation are easily accessible, not requiring chiral catalyst, endowing this method with great potential in the construction of axis chiral N-arylindoles.

3. Materials and Methods

Unless otherwise noted, all reactants or reagents including dry solvents were obtained from commercial suppliers and used as received. NaClO (Sodium hypochlorite solution reagent grade, available chlorine 4.00–4.99%) was purchased from Lingfeng reagent company, Shanghai, China. All the reactions were conducted using reaction tube (10 mL) under argon atmosphere. Analytical thin layer chromatography (TLC) was performed using Silica Gel 60 F25 plates. Column chromatograph was performed on silica gel 100~200 mesh. 1H and 13C NMR spectra were obtained in CDCl3 or DMSO using 300 MHz, 400 MHz Varian NMR spectrometer. Chemical shifts in 1H NMR spectra are reported in parts per million (ppm) on the δ scale from an internal standard of residual CDCl3 (7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, and coupling constant in Hertz (Hz). Chemical shifts in 13C NMR spectra are reported in ppm on the δ scale from the central peak of residual CDCl3 (77.16 ppm).

3.1. General Procedures for Indole C2 Amination with N-Ns Protected Amino Acid

A 10 mL round bottom flask was equipped with a rubber septum and magnetic stir bar and was charged with 1 (0.2 mmol), 2 (0.6 mmol), NaClO (0.6 mmol, 774 μL, 5% in water) in DCM (4 mL) at room temperature for 24 h. Upon completion of the reaction, the mixture was washed with saturated Na2CO3 aqueous solution (4 mL), water, and saturated brine (4 mL) in sequence. The organic layer was concentrated and purified via a flash column (PE/EA from 50/1 to 30/1).

3.2. Characterization Data for Compounds

tert-butyl N-(1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate 3a. According to the general procedure, purification by flash chromatography, 3a (75.4 mg, 65%, dr = 3.5:1) was obtained as a yellow solid from 1a (0.2 mmol, 44.6 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, CDCl3) δ 8.33 (d, J = 9.0 Hz, 2H × 0.78), 8.26 (d, J = 9.0 Hz, 2H × 0.22), 7.99 (d, J = 9.0 Hz, 2H × 0.78), 7.83 (d, J = 9.0 Hz, 2H × 0.22),7.56–7.37 (m, 3H), 7.14–6.89 (m, 4H), 6.57–6.54 (m, 1H), 6.01 (s, 1H × 0.22), 6.00 ((s, 1H × 0.78), 3.91 (d, J = 9.0 Hz, 1H × 0.78)), 3.56 (d, J = 9.0 Hz, 1H × 0.22), 3.50 (s, 3H × 0.78), 3.47 (s, 1H × 0.22), 1.55–1.41 (m, 1H × 0.78), 1.05 (s, 9H × 0.22), 0.94 (s, 9H × 0.78), 0.54 (d, J = 6.6 Hz, 3H × 0.22), 0.47 (d, J = 6.5 Hz, 3H × 0.78), 0.14 (d, J = 6.7 Hz, 3H × 0.78). 13C NMR (75 MHz, Chloroform-d) δ 167.4, 156.5, 150.5, 145.0, 137.2, 132.7, 130.6, 125.0, 124.8, 123.8, 123.5, 121.3, 121.0, 120.5, 111.7, 111.4, 104.6, 82.3, 72.1, 55.3, 29.1, 27.9, 19.6, 19.5. HRMS Calcd. For C30H33N3NaO7S [M+Na]+: 602.1931; found: 602.1920.
tert-butyl N-(5-chloro-1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate 3b. According to the general procedure, purification by flash chromatography, 3b (66.2 mg, 51%, dr = 2.3:1) was obtained as a yellow solid from 1b (0.2 mmol, 51.5 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.51 (d, J = 6.0 Hz, 2H × 0.70), 8.42 (d, J = 6.0 Hz, 2H × 0.30), 8.23 (d, J = 6.0 Hz, 2H × 0.7), 8.16–8.12 (m, 1H), 8.04 (d, J = 6.0 Hz, 2H × 0.3), 7.64–7.59 (m, 2H), 7.46–7.38 (m, 1H), 7.32–7.16 (m, 3H), 6.88 (d, J = 8.7 Hz, 1H), 6.19 (s, 1H × 0.32), 6.10 (1H × 0.76), 4.33–4.17 (m, 1H), 3.82–3.79 (m, 3H), 1.82–1.79 (m, 1H × 0.70), 1.43 (s, 9H × 0.30), 1.31 (s, 9H × 0.70), 1.13–1.09 (m, 3H × 0.30), 0.90 (d, J = 9.0 Hz, 3H × 0.30), 0.81 (d, J = 9.0 Hz, 3H × 0.3), 0.55 (d, J = 9.0 Hz, 3H × 0.70). 13C NMR (75 MHz, Chloroform-d) δ 167.3, 156.2, 150.4, 144.8, 135.2, 132.4, 132.1, 131.0, 130.8, 130.5, 128.7, 126.2, 126.1, 125.7, 124.3, 124.2, 123.9, 123.8, 123.4, 121.4, 120.3, 120.2, 113.0, 111.5, 104.1, 82.4, 77.4, 71.8, 66.0, 55.5, 55.3, 30.4, 29.2, 28.1, 27.9, 27.9, 27.8, 19.7, 19.4, 19.2. HRMS Calcd. For C30H32ClN3NaO7S [M+Na]+: 636.1542; found: 636.1530.
tert-butyl N-(5-bromo-1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate 3c According to the general procedure, purification by flash chromatography, 3c (3.88 mg, 28%, dr =5:1) was obtained as a yellow solid from 1c (0.2 mmol, 60.4 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.39 (d, J = 9.0 Hz, 2H × 0.83), 8.34 (d, J = 9.0 Hz, 2H × 0.17), 8.30 (d, J = 9.0 Hz, 2H × 0.17) 8.12–8.00 (m, 2H × 0.83), 8.02 (d, J = 9.0 Hz, 2H × 0.17), 7.91 (d, J = 6.0 Hz, 2H), 7.86 (d, J = 3.0 Hz, 1H × 0.83), 7.66 (d, J = 3.0 Hz, 1H × 0.17), 7.53–7.47 (m, 1H), 7.42 (dd, J = 9.0 Hz, 3.0 Hz, 1H × 0.83), 7.32 (dd, J = 9.0 Hz, 3.0 Hz, 1H × 0.17), 7.19–7.14 (m, 1H), 7.07–7.04 (m, 1H), 6.73 (d, J = 8.7 Hz, 1H × 0.17), 6.62 (d, J = 8.7 Hz, 1H × 0.83), 6.05 (s, 1H × 0.17), 5.98 (s, 1H × 0.83), 4.20 (d, J = 9.2 Hz, 1H × 0.83), 4.07 (d, J = 9.2 Hz, 1H × 0.17), 3.70 (s, 3H × 0.17), 3.67 (s, 3H × 0.83), 2.15–1.58 (m, 1H), 1.31 (s, 9H × 0.17), 1.20 (s, 9H × 0.83), 1.00–0.42 (m, 6H). Crude 13C NMR (101 MHz, Chloroform-d) δ 171.2, 168.9, 167.3, 156.2, 150.4, 150.2, 144.8, 136.0, 132.4, 131.9, 131.9, 131.7, 131.0, 130.9, 130.5, 129.6, 129.6, 128.7, 127.3, 126.5, 124.2, 124.2, 123.8, 123.4, 123.3, 121.4, 113.8, 113.4, 111.5, 104.0, 103.7, 84.1, 84.0, 82.4, 82.3, 71.8, 66.0, 60.5, 55.5, 55.3, 53.6, 30.4, 29.2, 28.1, 28.0, 27.9, 27.9, 19.7, 19.4, 19.4, 19.2, 14.3. HRMS of 3c Calcd. For C30H32BrN3NaO7S [M+Na]+: 680.1037; found: 680.1032.
tert-butyl N-(5-methoxy-1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate3d. According to the general procedure, purification by flash chromatography, 3d (42.7 mg, 35%, dr =5:1) was obtained as a yellow solid from 1d (0.2 mmol, 50.7 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.39 (d, J = 9.0 Hz, 2H × 0.83), 8.30 (d, J = 9.0 Hz, 2H × 0.17), 8.14 (d, J = 9.0 Hz, 2H × 0.83), 7.92 (d, J = 9.0 Hz, 2H × 0.17), 7.56–7.45 (m, 2H), 7.36 (t, J = 2.2 Hz, 1H), 7.18–7.11 (m, 1H), 7.04 (dd, J = 8.3, 1.3 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.86–6.83 (m, 1H), 6.74 (d, J = 8.9 Hz, 1H), 6.03 (s, 1H × 0.17), 5.92 (s, 1H × 0.8), 4.21 (d, J = 9.4 Hz, 1H), 3.84 (s, 3H), 3.68 (s, 3H), 1.74–1.71 (m, 1H), 1.29 (s, 9H), 0.97 (d, J = 6.0 Hz, 3H × 0.17), 0.79 (d, J = 6.0 Hz, 3H × 0.17), 0.70 (d, J = 6.0 Hz, 3H × 0.83), 0.43 (d, J = 6.0 Hz, 3H × 0.83). 13C NMR (101 MHz, Chloroform-d) δ 167.4, 157.5, 156.4, 150.4, 145.1, 137.8, 132.7, 130.6, 130.6, 129.8, 124.9, 123.7, 121.7, 121.4, 119.1, 111.5, 110.8, 104.7, 94.7, 82.2, 72.1, 55.7, 55.3, 29.1, 28.0, 27.9, 19.6, 19.5. HRMS Calcd. For C31H35N3NaO8S [M+Na]+: 632.2037; found: 632.2037.
tert-butyl N-(6-methoxy-1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate3e. According to the general procedure, purification by flash chromatography, 3e (46.3 mg, 38%, dr =9:1) was obtained as a yellow solid from 1e (0.2 mmol, 50.7 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.40 (d, J = 9.0 Hz, 2H × 0.90), 8.31(d, J = 9.0 Hz, 2H × 0.1) 7.95 (d, J = 6.0 Hz, 1H), 7.59–7.49 (m, 1H), 7.40 (d, J = 8.6 Hz, 1H × 0.9), 7.34 (d, J = 8.6 Hz, 1H × 0.1), 7.20 (d, J = 1.3 Hz, 1H), 7.07 (dd, J = 8.4, 1.3 Hz, 1H), 6.81 (dd, J = 8.7, 2.3 Hz, 1H), 6.29 (d, J = 2.3 Hz, 1H), 6.03 (s, 1H × 0.1), 5.93 (d, J = 0.72 Hz, 1H × 0.90), 4.22 (d, J = 9.4 Hz, 1H × 0.9), 3.97 (d, J = 9.4 Hz, 1H × 0.1), 3.74 (s, 3H), 3.71 (s, 3H), 1.77–1.70 (m, 1H), 1.33–1.21 (m, 9H), 0.84–0.43 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 167.45, 157.55, 156.41, 150.35, 145.08, 137.84, 132.70, 130.60, 130.56, 129.82, 128.77, 124.85, 124.31, 123.73, 121.78, 121.71, 121.38, 119.12, 111.47, 110.84, 104.72, 94.68, 82.18, 77.48, 77.16, 76.84, 72.09, 55.74, 55.30, 29.07, 27.99, 27.87, 19.64, 19.49, 19.21. HRMS Calcd. For C31H35N3NaO8S [M+Na]+: 632.2037; found: 632.2037.
tert-butyl N-(1-(2-methoxyphenyl)-4-methyl-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate3f. According to the general procedure, purification by flash chromatography, 3f (45.1 mg, 38%, dr =3:1) was obtained as a yellow solid from 1f (0.2 mmol, 47.5 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.57–8.48 (m, 2H), 8.32–8.05 (m, 3H), 7.65 (d, J = 7.8 Hz, 1H), 7.36–7.21 (m, 3H), 7.10–7.08 (m, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.30 (s, 1H × 0.25), 6.17 (s, 1H × 0.75), 4.34 (d, J = 9.6 Hz, 1H), 3.85 (s, 3H), 2.57 (s, 3H), 1.97–1.87 (m, 1H), 1.49 (s, 9H × 0.25), 1.38 (s, 9H × 0.75), 1.17 (d, J = 6.0 Hz, 3H × 0.25), 0.97 (d, J = 6.0 Hz, 3H × 0.25), 0.90 (d, J = 6.0 Hz, 3H × 0.75), 0.61 (d, J = 6.0 Hz, 3H × 0.75). 13C NMR (75 MHz, Chloroform-d) δ 167.4, 156.5, 150.4, 145.0, 136.8, 132.6, 130.8, 130.7, 130.6, 130.4, 130.3, 125.0, 124.9, 123.6, 121.3, 120.7, 120.6, 111.4, 109.4, 103.1, 82.2, 72.2, 58.6, 55.3, 29.0, 28.0, 27.9, 19.6, 19.5, 18.7, 18.6. HRMS Calcd. For C31H35N3NaO7S [M+Na]+: 616.2088; found: 616.2074.
tert-butyl N-(7-methoxy-1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate 3g. According to the general procedure, purification by flash chromatography, 3g (37.4 mg, 34 %, dr = 1.1:1) was obtained as a yellow solid from 1g (0.2 mmol, 50.6 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). Crude 1H NMR of 3g. 1H NMR (300 MHz, Chloroform-d) δ 8.40 (d, J = 8.8 Hz, 2H × 0.52), 8.30 (d, J = 8.5 Hz, 2H × 0.48), 8.14–7.94 (m, 2H), 7.43–7.34 (m, 2H), 7.19–6.89 (m, 5H), 6.66 (d, J = 7.8 Hz, 1H), 6.15 (s, 1H × 0.48), 6.01 (s, 1H × 0.52), 4.26–4.07 (m, 1H), 3.79 (s, 3H × 0.48), 3.79 (s, 3H × 0.52), 3.50 (s, 3H × 0.52), 3.50 (s, 3H × 0.48), 1.75–1.60 (m, 1H), 1.35 (s, 9H × 0.48), 1.23 (s, 9H × 0.52), 0.95–0.41 (m, 6H). Crude 13C NMR (75 MHz, Chloroform-d) δ 167.4, 157.3, 155.8, 150.2, 150.0, 147.6, 145.7, 144.9, 131.4, 131.0, 130.6, 130.3, 130.1, 129.7, 129.3, 127.5, 127.1, 126.8, 124.7, 124.6, 123.6, 123.1, 120.6, 120.5, 120.3, 120.1, 117.2, 115.9, 113.9, 111.4, 110.1, 105.2, 105.1, 104.9, 82.1, 71.9, 56.4, 55.9, 55.1, 53.5, 29.0, 27.9, 27.8, 19.6, 19.4, 1.1. HRMS of 3g Calcd. For C31H35N3NaO8S [M+Na]+: 632.2037; found: 632.2024.
tert-butyl N-(6-bromo-1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-alaninate 3h. According to the general procedure, purification by flash chromatography, 3h (37.8 mg, 30%, dr =3.2:1) was obtained as a yellow solid from 1h (0.2 mmol, 60.4 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.38 (d, J = 9.0 Hz, 2H × 0.76), 8.30 (d, J = 9.0 Hz, 2H × 0.24), 8.10 (d, J = 9.0 Hz, 2H × 0.76), 8.03–8.78 (m, 1H × 1.48), 7.58–7.46 (m, 1H), 7.40–7.36 (m, 1H), 7.28–7.21 (m, 1H), 7.21–6.99 (m, 3H), 6.09 (s, 1H × 0.23), 6.00 (s, 1H), 4.21–4.05 (m, 1H), 3.72 (s, 3H × 0.23), 3.69 (s, 3H × 0.77), 1.30 (s, 9H × 0.23), 1.19 (s, 9H × 0.74), 1.01–0.41(m, 6H). 13C NMR (101 MHz, Chloroform-d) δ 167.4, 156.3, 150.4, 144.8, 138.0, 132.5, 131.5, 131.0, 130.6, 129.4, 128.8, 124.2, 123.8, 122.6, 121.4, 120.6, 114.6, 111.6, 104.8, 87.9, 82.4, 71.9, 55.4, 29.2, 28.0, 27.9, 19.7, 19.4. HRMS of 3h Calcd. For C30H32BrN3NaO7S [M+Na]+: 680.1037; found: 680.1026.
tert-butyl N-(6-fluoro-1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate3i. According to the general procedure, purification by flash chromatography, 3i (58.6 mg, 49%, dr =2.9:1) was obtained as a yellow solid from 1i (0.2 mmol, 48.3 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). HPLC retention time and peak area %: 4.54 min of 71.39%, and 5.05 min of 24.63%. 1H NMR (300 MHz, Chloroform-d) δ 8.39 (d, J = 9.3 Hz, 2H × 0.26), 8.34 (d, J = 9.3 Hz, 2H × 0.26), 8.12 (d, J = 8.9 Hz, 2H × 0.74), 8.02 (d, J = 8.9 Hz, 2H × 0.74), 7.92 (d, J = 7.6 Hz, 1H), 7.53–7.40 (m, 2H), 7.17 (m, 1H), 7.06 (d, J = 9.7 Hz, 1H), 6.89 (m, 1H), 6.52 (dd, J = 9.8, 2.3 Hz, 1H), 6.10 (s, 1H × 0.26), 6.00 (s, 1H × 0.74), 4.20 (d, J = 9.4 Hz, 1H × 0.74), 4.07 (d, J = 9.4 Hz, 1H × 0.76), 3.69 (s, 3H × 0.74), 2.93 (s, 1H × 0.26), 2.15–2.05 (m, 1H × 0.26), 1.74–1.66 (m, 1H × 0.74), 1.26 (s, 9H × 0.24), 1.19 (s, 9H × 0.76), 0.99 (d, J = 3.0 Hz, 1H), 0.78 (d, J = 6.6 Hz, 3H × 0.24), 0.69 (d, J = 6.6 Hz, 3H × 0.76), 0.42 (d, J = 6.6 Hz, 3H × 0.74). 13C NMR (75 MHz, Chloroform-d) δ 168.9, 167.4, 162.4, 159.3, 156.2, 150.4, 150.0, 144.9, 137.2, 137.0, 132.4, 131.3, 131.0, 130.8, 130.5, 128.7, 124.4, 124.3, 123.8, 122.1, 121.9, 121.4, 121.3, 111.5, 109.7, 109.4, 104.7, 98.1, 97.8, 82.3, 77.4, 71.9, 66.0, 55.3, 30.4, 29.1, 27.9, 27.8, 19.6, 19.2. HRMS Calcd. For C30H32FN3NaO7S [M+Na]+: 620.1837; found: 620.1826.
tert-butyl N-(1-(2-methoxyphenyl)-5-methyl-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate3j. According to the general procedure, purification by flash chromatography, 3j (49.9 mg, 42%, dr =5:1) and 4j (23.7 mg, 20%, dr > 20:1) was obtained as a yellow solid from 1j (0.2 mmol, 47.5 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). HPLC retention time and peak area %: 3.48 min of 2.05%, 3.82 min of 25.50%, 4.18 min of 4.11% and 4.83 min of 62.76%. Crude 1H NMR of 3j and 4j (300 MHz, Chloroform-d) δ 8.38–8.26 (m, 2.5H), 8.13–7.89 (m, 2.5H), 7.50–7.43 (m, 2H), 7.35–7.28 (m, 2H), 7.18–6.99 (m, 5H), 6.74 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 8.4 Hz, 0.5 H), 6.01 (s, 1H × 0.16), 5.90 (s, 1H × 0.83), 4.21–4.05 (m, 1.3H), 3.79–3.67 (m, 4H), 2.42 (s, 3H), 2.38 (s, 1H), 1.78–1.66 (m, 1H), 1.32–1.20 (m, 12H), 1.01–0.42 (m, 8H). 13C NMR (75 MHz, CDCl3) δ 167.42, 156.46, 155.54, 150.32, 145.05, 139.11, 135.36, 134.16, 132.63, 132.23, 130.99, 130.80, 130.63, 130.47, 129.70, 129.44, 128.75, 125.36, 125.21, 125.00, 124.95, 124.27, 123.72, 121.31, 121.28, 120.45, 112.73, 111.40, 110.44, 104.18, 82.20, 72.01, 56.01, 55.30, 29.08, 27.99, 27.95, 27.88, 21.54, 21.16, 19.67, 19.47. HRMS Calcd. For C31H35N3NaO7S [M+Na]+: 616.2088; found: 616.2075.
tert-butyl N-(1-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate3k. According to the general procedure, purification by flash chromatography, 3k (49.9 mg, 43 %, dr = 9:1) was obtained as a yellow solid from 1k (0.2 mmol, 44.9 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.40–8.38 (m, 3H × 0.9), 8.35–8.28 (m, 3H × 0.1), 8.10–8.05 (d, J = 7.9 Hz, 2H × 0.9), 8.03–7,85 (m, 2H × 0.1),7.53–7.47 (m, 1H), 7. 20–7.05 (m, 3H), 6.20 (s, 1H × 0.1), 6.09 (s, 1H × 0.9), 4.21 (d, J = 9.2 Hz, 1H), 3.66 (s, 3H × 0.1), 3.66 (s, 3H × 0.9), 1.79–1.69 (m, 1H), 1.32 (s, 9H × 0.1), 1.22 (s, 9H × 0.9), 0.79–0.44 (m, 6H). 13C NMR (75 MHz, Chloroform-d) δ 167.6, 156.6, 150.4, 147.5, 145.6, 144.8, 132.3, 132.1, 131.1, 130.5, 129.5, 123.9, 123.9, 121.3, 118.1, 117.1, 112.0, 103.4, 82.4, 71.6, 55.7, 29.2, 28.0, 27.9, 19.8, 19.4. HRMS Calcd. For C29H33N4O7S [M+H]+:581.2064; found: 581.2050.
tert-butyl N-(1-(2-chlorophenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate3l. According to the general procedure, purification by flash chromatography, 3l (42.0 mg, 36%, dr = 1.2:1) was obtained as a yellow solid from 1l (0.2 mmol, 45.5 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.43–8.40 (m, 2H × 0.55), 8.40–8.30 (m, 2H × 0.45), 8.17–8.11 (m, 3H), 7.62–7.48 (m, 4H), 7.22–7.12 (m, 1H), 6.90–6.84 (m, 1H), 6.09 (s, 1H × 0.45), 5.91 (s, 1H × 0.55), 4.23 (m, 1H), 0.89–0.79 (m, 1H), 1.31 (s, 9H × 0.45), 1.15 (s, 9H × 0.55), 0.83–0.75 (m, 3H), 0.83–0.52 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 167.2, 150.5, 150.2, 144.6, 136.1, 134.0, 133.4, 130.8, 130.8, 130.5, 130.5, 128.3, 125.2, 124.9, 124.1, 124.1, 123.8, 123.2, 121.3, 121.2, 121.1, 121.0, 111.8, 105.2, 82.6, 73.1, 53.6, 29.8, 29.1, 28.0, 27.8, 19.8, 18.7. HRMS Calcd. For C29H30ClN3O6S [M+H]+:606.1436; found: 606.1434.
tert-butyl N-(1-(3-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate3m. According to the general procedure, purification by flash chromatography, 3m (47.5 mg, 41%) was obtained as a yellow solid from 1m (0.2 mmol, 44.7 mg), 2a (0.6 mmol, 215.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.39 (d, J = 8.6 Hz, 2H), 8.12 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.26–7.10 (m, 5H), 7.07–7.02 (m, 1H), 6.06 (s, 1H), 4.29 (d, J = 8.5 Hz, 1H), 3.87 (s, 3H), 1.65–1.63 (m, 1H), 1.19 (s, 9H), 0.59 (dd, J = 20.8, 6.6 Hz, 6H). 13C NMR (75 MHz, Chloroform-d) δ 167.4, 160.5, 150.4, 145.1, 137.5, 136.8, 131.3, 130.5, 129.9, 125.2, 123.9, 121.5, 121.1, 120.9, 114.7, 111.5, 104.9, 82.5, 71.5, 55.8, 30.3, 27.9, 20.1, 19.0.HRMS Calcd. For C30H33N3NaO7S [M+Na]+: 602.19314; found: 602.1919.
methyl N-(1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate3n. According to the general procedure, purification by flash chromatography, 3n (30.1 mg, 28%, dr = 5:1) was obtained as a yellow solid from 1a (0.2 mmol, 44.6 mg), 2n (0.6 mmol, 189.8 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.439 (d, J = 9.0 Hz, 2H × 0.83), 8.33 (d, J = 9.0 Hz, 2H × 0.17), 8.09 (d, J = 9.0 Hz, 2H × 0.83), 8.03 (d, J = 9.0 Hz, 2H × 0.17), 7.82 (d, J = 7.8 Hz, 1H), 7.55–7.47 (m, 2H), 7.21–7.02 (m, 4H), 6.83 (d, J = 8.4 Hz, 1H), 6.02 (s, 1H × 0.16), 5.96 (s, 1H × 0.83), 4.31 (d, J = 9.9 Hz, 1H), 3.70 (1H × 0.16), 3.67 (s, 9H × 0.83), 3.46 (s, 3H × 0.16), 3.36 (s, 3H × 0.83), 1.86–1.78 (m, 1H), 0.88–0.45 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 168.7, 156.6, 150.5, 144.3, 132.5, 130.6, 125.1, 124.7, 121.3, 121.0, 120.2, 111.7, 111.4, 72.1, 55.6, 51.7, 28.6, 19.6. HRMS Calcd. For C31H35N3NaO7S [M+Na]+: 616.2088; found: 616.2074.
ethyl N-(1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-valinate3o. According to the general procedure, purification by flash chromatography, 3o (44.1 mg, 40%, dr = 6:1) was obtained as a yellow solid from 1a (0.2 mmol, 44.6 mg), 2o (0.6 mmol, 198.2 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.40–8.37 (m, 2H × 0.86), 8.40–8.37 (m, 2H × 0.14), 8.13–7.86 (m, 3H), 7.53–7.47 (m, 2H), 7.21–7.03 (m, 4H), 6.84 (d, J = 9.6 Hz, 1H), 6.03 (s, 1H × 0.14), 5.94 (s, 1H × 0.86), 4.30 (d, J = 10.0 Hz, 1H), 3.92–3.79 (m, 1H), 3.71 (s, 3H × 0.14), 3.67 (s, 3H × 0.86), 3.29 (t, J = 7.1 Hz, 1H), 1.87–1.71 (m, 1H), 1.16–0.89 (m, 3H), 0.80–0.43 (m, 6H). Crude 13C NMR (75 MHz, Chloroform-d) δ 168.7, 156.9, 150.9, 145.0, 137.4, 132.9, 131.6, 131.1, 128.6, 125.4, 125.1, 124.9, 124.1, 124.0, 121.7, 121.4, 120.9, 112.1, 111.9, 103.8, 61.4, 55.7, 42.7, 30.2, 29.1, 20.1, 19.9, 14.7, 14.2. HRMS Calcd. For C28H29N3NaO7S [M+Na]+: 574.1618; found: 574.1602.
tert-butyl N-(1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-isoleucinate 3p. According to the general procedure, purification by flash chromatography, 3p (49.9 mg, 42%, dr = 25:1) was obtained as a yellow solid from 1a (0.2 mmol, 44.6 mg), 2p (0.6 mmol, 223.5 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.37 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.7 Hz, 2H), 8.00 (d, J = 7.9 Hz, 1H), 7.56–7.47 (m, 2H), 7.21–7.07 (m, 4H), 6.84 (d, J = 8.3 Hz, 1H), 6.27 (s, 1H), 4.40 (d, J = 6.6 Hz, 1H), 3.67 (s, 3H), 1.50–1.42 (m, 1H), 1.23 (s, 9H), 1.09–0.88 (m, 2H), 0.57–0.48 (m, 6H).13C NMR (101 MHz, Chloroform-d) δ 167.9, 156.0, 150.3, 145.0, 136.9, 132.2, 131.1, 130.6, 130.3, 125.0, 124.8, 123.7, 123.4, 121.3, 121.0, 120.4, 111.9, 111.5, 105.2, 82.2, 69.4, 55.2, 35.7, 28.0, 27.2, 15.7, 11.5.HRMS Calcd. For C31H35N3NaO7S [M+Na]+: 616.2088; found: 616.2076.
methyl (R)-2-((N-(1-(2-methoxyphenyl)-1H-indol-2-yl)-4-nitrophenyl)sulfonamido)pentanoate3q. According to the general procedure, purification by flash chromatography, 3q (30.1 mg, 28%, dr = 8:1) was obtained as a yellow solid from 1a (0.2 mmol, 44.6 mg), 2q (0.6 mmol, 189.8 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.41 (d, J = 8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 7.78–7,75 (m, 1H), 7.7–7.51 (m, 2H), 7.27–7.16 (m, 3H), 7.09 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.38 (s, 1H × 0.89), 6.27 (s, 1H × 0.11), 4.61 (t, J = 7.4 Hz, 1H), 3.71 (s, 3H × 0.89), 3.70 (s, 1H × 0.11), 3.52 (s, 3H × 0.11), 3.43 (s, 3H × 0.89), 1.88–0.72 (m, 6H). 13C NMR (75 MHz, Chloroform-d) δ 170.8, 170.0, 156.0, 150.3, 144.6, 136.9, 132.0, 131.3, 130.5, 130.3, 125.2, 124.6, 123.8, 123.6, 123.6, 121.2, 121.0, 120.7, 120.6, 111.7, 111.5, 111.5, 103.8, 64.4, 55.4, 55.2, 52.4, 52.0, 32.0, 20.1, 19.3, 14.3, 13.9. HRMS Calcd. For C27H27N3NaO7S [M+Na]+: 560.1462; found: 560.1452.
methyl N-(1-(2-methoxyphenyl)-1H-indol-2-yl)-N-((4-nitrophenyl)sulfonyl)-D-alaninate3r. According to the general procedure, purification by flash chromatography, 3r (28.5 mg, 28%, dr = 6:1) was obtained as a yellow solid from 1a (0.2 mmol, 44.6 mg), 2r (0.6 mmol, 173.0 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.34–8.24 (m, 2H), 7.99 (d, J = 9.0 Hz, 2H × 0.86), 7.91 (d, J = 9.0 Hz, 2H × 0.13), 7.66–7.46 (m, 3H), 7.20–7.02 (m, 4H), 6.86 (d, J = 8.1 Hz, 1H), 6.51 (s, 1H × 0.86), 6.33 (1H × 0.14), 4.73 (q, J = 7.3 Hz, 1H), 3.63 (s, 3H), 3.58 (s, 3H × 0.14), 3.48 (s, 3H × 0.86), 1.19 (d, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.7, 156.0, 150.3, 144.8, 137.0, 131.8, 130.4, 125.3, 124.6, 123.7, 121.2, 120.6, 111.8, 111.4, 104.4, 55.3, 52.4, 15.7. HRMS Calcd. For C25H23N3NaO7S [M+Na]+: 532.1149; found: 532.1137.
tert-butyl (R)-2-cyclohexyl-2-((N-(1-(2-methoxyphenyl)-1H-indol-2-yl)-4-nitrophenyl)sulfonamido)acetate3s and tert-butyl (R)-2-((N-(3-chloro-1-(2-methoxyphenyl)-1H-indol-2-yl)-4-nitrophenyl)sulfonamido)-2-cyclohexylacetate 4s. According to the general procedure, purification by flash chromatography, 3s (48.3 mg, 39%, dr = 5:1) and 4s (34.0 mg, 26%, >20:1) was obtained as a yellow solid from 1a (0.2 mmol, 44.6 mg), 2s (0.6 mmol, 239.1 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). 1H NMR (300 MHz, Chloroform-d) δ 8.32–8.25 (m, 2H × 0.83), 8.25–8.21 (m, 2H × 0.17), 8.08–8.05 (m, 2H × 0.83), 8.08–8.05 (m, 2H × 0.17),8.05–7.93 (m, 1H × 0.55, from 4s), 7.84–7.82 (m, 1H), 7.62–7.59 (m, 1H), 7.43–7.17 (m, 5H), 7.14–6.93 (m, 8H), 6.76–6.73 (m, 1.5 H), 6.46–6.43 (m, 1 H × 0.55 from 4s), 5.96 (s, 1H × 0.17), 5.71 (s, 1H × 0.83), 4.20 (m, 1H), 3.71 (s, 3H × 0.55 from 4s), 3.65 (s, 3H × 0.83), 3.65 (s, 3H × 0.17), 1.63–13.2 (m, 9H), 1.10(s, 9H × 0.55, from 4s), 1.09 (s, 9H × 0.17), 1.07 (s, 9H × 0.83), 0.90–0.42 (m, 8H). 13C NMR (75 MHz, CDCl3) δ 168.4, 167.0, 156.0, 155.5, 150.3, 145.0, 141.4, 136.7, 132.3, 131.8, 131.1, 131.0, 130.6, 130.3, 129.4, 129.1, 124.8, 124.8, 124.6, 124.2, 123.8, 123.5, 123.4, 121.4, 121.3, 121.2, 120.9, 120.8, 120.5, 120.4, 112.7, 111.7, 111.7, 110.6, 104.2, 82.2, 72.3, 56.0, 55.5, 55.2, 37.7, 30.2, 29.9, 27.9, 27.7, 26.3, 26.2, 26.1. HRMS Calcd. For C33H37N3NaO7S [M+Na]+: 642.2244; found: 642.2231.
(R)-N-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(1-(2-methoxyphenyl)-1H-indol-2-yl)-4-nitrobenzenesulfonamide 3t and (R)-N-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(3-chloro-1-(2-methoxyphenyl)-1H-indol-2-yl)-4-nitrobenzenesulfonamide 4t. According to the general procedure, purification by flash chromatography, 3t (44.1 mg, 37%, dr > 20:1) and 4t (23.3 mg, 19%, dr > 20:1) was obtained as a yellow solid from 1a (0.2 mmol, 44.6 mg), 2v (0.6 mmol, 224.7 mg), and NaClO (0.6 mmol, 774 μL, 5% in water). Crude 13H NMR of 3t and 4t (300 MHz, Chloroform-d) δ 8.44–8.34 (m, 2H, from 3t), 8.44–8.34 (m, 1H, from 4t), 8.17–8.09 (m, 3H, from 3t and 4t), 7.91–7.84 (m, 1H from 3t, 0.5H from 4t), 7.62–7.47 (m, 2H from 3t, 1H from 4t), 7.20–7.05 (m, 4H from 3t, 2H from 4t), 6.8 (m, 1H from 3t, 0.5H from 4t), 6.03 (s, 1H, from 3t), 4.08–3.87 (m, 1H from 3t, 0.5H from 4t), 3.70 (s, 3H from 3t), 3.67 (s, 1.5H from 4t), 3.43–2.5 (m, 2H from 3t, 1H from 4t), 0.96–0.86 (m, 3H from 3t, 1.5H from 4t), 0.78 (s, 9H from 3t, 4,5H from 4t), −0.11 (s, 6H from 3t), −0.14 (s, 3H from 4t). Crude 13C NMR of 3t and 4t (75 MHz, Chloroform-d) δ 156.3, 155.8, 150.4, 146.7, 145.5, 136.5, 135.6, 132.2, 131.9, 130.9, 130.3, 130.2, 130.0, 129.6, 127.7, 125.1, 124.8, 124.5, 124.5, 124.3, 124.1, 123.5, 123.4, 121.5, 121.2, 121.1, 120.9, 120.6, 118.8, 112.0, 111.8, 111.7, 111.4, 103.2, 77.4, 65.9, 65.4, 61.4, 58.9, 55.5, 55.4, 25.9, 25.8, 18.2, 16.4, 15.7, −5.3, −5.4, −5.4. HRMS of 3t Calcd. For C30H37N3NaO6SSi [M+Na]+: 618.2065; found: 618.2068. HRMS of 4t Calcd. For C30H36ClN3NaO6SSi [M+Na]+: 652.1675; found: 652.1687.

Supplementary Materials

1H and 13 C NMR of all compounds.can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27249008/s1.

Author Contributions

Conceptualization, Y.W. and J.F.; methodology, Y.W., J.Y. and Y.J.; software, Z.W.; formal analysis, Y.W. and J.F.; investigation, Y.W.; resources, Z.T. and C.D.; data curation, Y.W.; writing—review and editing, Y.W. and J.F.; supervision, J.F., T.L. and Y.C.; project administration, J.F.; funding acquisition, J.F. and Y.C. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the National Natural Science Foundation of China (Program Nos. 81973182 and 81673301) and “Double First-Class” University Project from China Pharmaceutical University (Program No. CPU2018GF02).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank Hui-Min Xu of The Public Laboratory Platform at China Pharmaceutical University for assistance with NMR techniques.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

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Molecules 27 09008 sch001 550
Scheme 1. Functionalized axially chiral indole-based molecules and outline for indole axially chiral construction.
Scheme 1. Functionalized axially chiral indole-based molecules and outline for indole axially chiral construction.
Molecules 27 09008 sch001
Molecules 27 09008 sch002 550
Scheme 2. Substrates scope for various 1-(2-methoxyphenyl)-1H-indoles for construction of C–N axially chirality. reaction conditions: indoles (0.2 mmol), amino acid (0.6 mmol), 5% NaClO (0.6 mmol), DCM (4 mL), rt, 24 h.
Scheme 2. Substrates scope for various 1-(2-methoxyphenyl)-1H-indoles for construction of C–N axially chirality. reaction conditions: indoles (0.2 mmol), amino acid (0.6 mmol), 5% NaClO (0.6 mmol), DCM (4 mL), rt, 24 h.
Molecules 27 09008 sch002
Molecules 27 09008 sch003 550
Scheme 3. Substrates scope for various amino acid for construction of C–N axially chirality. reaction conditions: indoles (0.2 mmol), amino acid (0.6 mmol), 5% NaClO (0.6 mmol), DCM (4 mL), rt, 24 h.
Scheme 3. Substrates scope for various amino acid for construction of C–N axially chirality. reaction conditions: indoles (0.2 mmol), amino acid (0.6 mmol), 5% NaClO (0.6 mmol), DCM (4 mL), rt, 24 h.
Molecules 27 09008 sch003
Molecules 27 09008 sch004 550
Scheme 4. DFT calculations for rotate barrier for C–N axis and N-aryl axis and absolute configuration of 3a.
Scheme 4. DFT calculations for rotate barrier for C–N axis and N-aryl axis and absolute configuration of 3a.
Molecules 27 09008 sch004
Table
Table 1. Solvent screening for indole C–N axially chiral construction.
Table 1. Solvent screening for indole C–N axially chiral construction.
Molecules 27 09008 i001
EntrySolventYield/%aDr
1DCM65 (10 b)3.5/1 (15/1 c)
2DCE552.4/1
3PhCF3382.5/1
4MeOH<5-/-
5PhMe282.2/1
61,4-dioxane182.5/1
a reaction conditions: indoles (0.2 mmol), amino acid (0.6 mmol), 5% NaClO (0.6 mmol), DCM (4 mL), rt, 24 h; b yield of 4a; c dr value of 4a.
Table
Table 2. Protecting group screening for indole C–N axially chiral construction.
Table 2. Protecting group screening for indole C–N axially chiral construction.
Molecules 27 09008 i002
EntryProtecting GroupYield/%aDr
1PG1<53.5/1
2PG2652.4/1
3PG3<52.5/1
4PG4<5 (60b)-/-
5PG5<5 (71b)-/-
a reaction conditions: indoles (0.2 mmol), amino acid (0.6 mmol), 5% NaClO (0.6 mmol), DCM (4 mL), rt, 24 h. b yield of 5a.
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Wang, Y.; Yan, J.; Jiang, Y.; Wei, Z.; Tu, Z.; Dong, C.; Lu, T.; Chen, Y.; Feng, J. Atroposelective Amination of Indoles via Chiral Center Induced Chiral Axis Formation. Molecules 2022, 27, 9008. https://doi.org/10.3390/molecules27249008

AMA Style

Wang Y, Yan J, Jiang Y, Wei Z, Tu Z, Dong C, Lu T, Chen Y, Feng J. Atroposelective Amination of Indoles via Chiral Center Induced Chiral Axis Formation. Molecules. 2022; 27(24):9008. https://doi.org/10.3390/molecules27249008

Chicago/Turabian Style

Wang, Yong, Jingxue Yan, Yiqing Jiang, Zexuan Wei, Zhenlin Tu, Chao Dong, Tao Lu, Yadong Chen, and Jie Feng. 2022. "Atroposelective Amination of Indoles via Chiral Center Induced Chiral Axis Formation" Molecules 27, no. 24: 9008. https://doi.org/10.3390/molecules27249008

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