Abstract
An asymmetric Mannich reaction has been developed to generate chiral β-amino esters in good yields with excellent enantiomeric excesses (ee, up to 99%) using a chiral bifunctional thiourea catalyst derived from (R,R)-cyclohexyldiamine. This is the first report on the addition of 3-indolinone-2-carboxylates to N-Boc-benzaldimines generated in situ from α-amidosulfones, which proceeds under mild conditions.
Introduction
Chiral ß-amino esters are useful building blocks for the synthesis of ß-lactams and unnatural peptides.1 They found widespread applications in drug discovery.2 On the other hand, a chiral 2,2-disubstituted indolin-3-one skeleton3 is often present in several biologically active natural products such as (+)-isatisine A, trigonoliimine C, mersicarpine, etc.4,5 They are known to exhibit potent antiviral properties.6 Consequently, a few methods have been reported for the enantioselective conversion of 3-indolinone-2-carboxylates into chiral compounds.7 However, the construction of a chiral quaternary stereocenter is a challenging task for a synthetic chemist.8 Furthermore, an asymmetric Mannich reaction is a powerful strategy to produce chiral ß-amino ketones and ß-amino esters.9 Inspired by their fascinating structural features and potent biological activities, we were interested in producing chiral 2,2-disubstituted indolin-3-one derivatives. Indeed, there are no reports on the direct asymmetric Mannich-type addition of 3-indolinone-2-carboxylates to N-Boc-benzaldimines generated in situ from α-amidosulfones Figure 1.
Figure 1.
Examples of 3-indolinone natural products.
Following our interest in asymmetric synthesis,10 we herein report an enantioselective Mannich reaction of 2-substituted indolin-3-ones for the synthesis of chiral β-amino esters, using a thiourea catalyst derived from trans-(R,R)-1,2-diaminocyclohexane. Our investigation began with the reaction of 3-indolinone-2-carboxylate (1) with N-Boc-benzaldimine (2) using quinidine 4a as a catalyst in the presence of Na2CO3 in toluene (Table 1, entry a) at room temperature. Interestingly, the desired product 3a was obtained in 60% yield with 10% enantiomeric excesses (ee) and 92:8 diastereoselectivity. Next, we attempted the same reaction with dihydroquinidine 4b as a catalyst, and no significant improvement in yield and ee of product 3a was observed. Furthermore, the reaction was performed using a bifuntional Takemoto’s catalyst 4c, 5 mol %, and Na2CO3 in toluene at room temperature. Interestingly, the desired product 3a was obtained in 80% yield with 55% ee and 93:7 diastereoselectivity (Table 1, entry c). To enhance the enantio- and diastereoselectivity, the reaction was further performed with 5 mol % catalyst 4d under similar conditions (Table 1, entry d). A slight improvement was observed in enantio- and diastereoselectivity. Therefore, the reaction was further performed using a 5 mol % catalyst 4e under identical conditions. To our delight, the yield and ee were improved significantly (Table 1, entry e). To evaluate other thiourea catalysts (Scheme 1), the reaction was further carried out using a 5 mol % bis-thiourea catalyst 4f derived from trans-(R,R)-1,2-diaminocyclohexane. However, the product 3a was obtained with low enantio- and diastereoselectivity. To improve the enantio- and diastereoselectivity, the reaction was repeated using 5 mol % thiourea catalysts 4g and 4h derived from trans-1,2-diaminoindane and trans-1-amino-2-indanol, respectively. The desired product 3a was obtained in poor yield and with low selectivity (Table S1, entries g and h). Therefore, the next reaction was carried out using a thiourea catalyst 4i derived from 1,1′-binaphthyl-2,2′-diamine (Table 1, entry i). However, the catalyst 4i was found to be inferior than other catalysts. To know the effect of base, the reaction was conducted in toluene using different bases like Na2CO3, K2CO3, Cs2CO3, NaOH, and CsOH (Table 1, entries i–m). Among them, Na2CO3 in toluene was found to be the best for this transformation (Table 1, entry m). To our surprise, only 30% conversion was observed using 10% Na2CO3 solution and 60% conversion was observed with 50% Na2CO3 solution. Interestingly, 98% conversion was obtained with a sat. Na2CO3 solution, which was prepared using 32 g of Na2CO3 in 100 mL of water at 27 °C. Furthermore, we examined the effect of different solvents such as o-xylene, methyl tert-butyl ether, benzene, and dichloroethane on the conversion under similar reaction conditions (Table 1, entries n–r). None of these solvents produced better results than o-xylene (Table 1, entry n). Finally, we tested the effect of temperature, ranging from 25 to −78 °C, on the conversion. The best results were obtained using 5 mol % catalyst 4e and Na2CO3 in xylene at 0 °C. Due to the low freezing point of xylene (−25 °C), further reactions were conducted in toluene. However, there was no reaction in toluene at −78 °C under similar conditions (Table 1, entry u).
Table 1. Optimization of Reaction Conditions in the Formation of 3aa.
| entry | catalyst | base (aq.) | solvent T (°C) | time (days) | yield (%)b | dr (3a:3aa)c | ee (%)c | entry | catalyst | base (aq.) | solvent | T (°C) | time (days) | yield (%)b | dr (3a:3aa)c | ee (%)d,e |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| a | 4a | Na2CO3 | toluene 25 | 3 | 45 | 92:8 | 10 | l | 4e | NaOH | toluene | 25 | 1 | 20 | 90:10 | 5 |
| b | 4b | Na2CO3 | toluene 25 | 2 | 60 | 93:7 | 5 | m | 4e | CsOH | toluene | 25 | 1 | 25 | 95:5 | 10 |
| c | 4c | Na2CO3 | toluene 25 | 4 | 80 | 93:7 | 55 | n | 4e | Na2CO3 | xylene | 0 | 3 | 98 | 99:1 | 99 |
| d | 4d | Na2CO3 | toluene 25 | 3 | 85 | 98:2 | 60 | o | 4e | Na2CO3 | toluene | 0 | 3 | 60 | 99:1 | 65 |
| e | 4e | Na2CO3 | toluene 25 | 2 | 90 | 99:1 | 85 | p | 4e | Na2CO3 | MTBE | 0 | 3 | 50 | 99:1 | 30 |
| f | 4f | Na2CO3 | toluene 25 | 4 | 40 | 95:5 | 50 | q | 4e | Na2CO3 | benzene | 0 | 3 | 55 | 99:1 | 40 |
| g | 4g | Na2CO3 | toluene 25 | 5 | 45 | 89:11 | 30 | r | 4e | Na2CO3 | DCE | 0 | 3 | 35 | 99:1 | 20 |
| h | 4h | Na2CO3 | toluene 25 | 4 | 50 | 88:22 | 25 | s | 4e | Na2CO3 | xylene | –20 | 4 | 35 | 99:1 | 40 |
| i | 4i | Na2CO3 | toluene 25 | 5 | 40 | 90:10 | 30 | t | 4e | Na2CO3 | toluene | –40 | 5 | 30 | 99:1 | 30 |
| j | 4e | K2CO3 | toluene 25 | 2 | 80 | 99:1 | 70 | u | 4e | Na2CO3 | toluene | –78 | 2 | |||
| k | 4e | Cs2CO3 | toluene 25 | 2 | 65 | 95:5 | 20 |
All reactions were performed at 0.21 mmol of 1, 0.25 mmol of 2, 5 mol % 4e and 0.2 mL of aqueous base in 5 mL of solvent.
Isolated yields after column chromatography.
Diastereomeric ratio was determined by 1H NMR.
Enantiomeric excess was determined by chiral high-performance liquid chromatography (HPLC).
Enantiomeric ratio of the major diastereomer.
Scheme 1. Catalyst Screening in the Asymmetric Mannich Reaction.
After having optimized conditions in hand, the scope of this method was examined with different substrates, and the results are summarized in Table 2. The substituent present on the aromatic ring of aldimine had shown some effect on the conversion. Ortho- and meta-substituted benzaldimines afforded the corresponding product in excellent yield with excellent enantioselectivity (Table 2, entries 3b, 3c, 3i, and 3k). The substrate bearing electron-withdrawing substituents such as nitro- and cyano- on the aromatic ring of aldimine gave the desired product in high yield with excellent enantiomeric excess (Table 2, entries 3h, 3i, 3j, and 3k). Conversely, the substrate having electron-donating groups like methyl- and methoxy on the aromatic ring gave the product with low ee (Table 2, entries 3f and 3g). Next, we examined the effect of substituents that are present at the 5th position of methyl 3-oxoindoline-2-carboxylate. The desired products were obtained in good yields but with low ee (Table 2, entries 3o, 3p, and 3q). The scope of this process was further extended to polyaromatic and heterocyclic systems. Interestingly, the aldimines derived from heteroaromatic aldehydes gave the products in excellent yield with excellent enantiomeric excess (Table 2, entries 3m and 3r). Furthermore, a sterically hindered naphthyl derivative also gave the desired product in good yield with excellent selectivity (Table 2, entry 3s). In addition, we have screened the N-substituted 3-oxo-indoline-2-carboxylate; in this, free NH and N-phenyl-substituted substrates failed to give the product, whereas the N-benzoyl 3-oxo-indoline-2-carboxylate participated smoothly in the present reaction and afforded the corresponding product (Table 2, entry 3n) in good yield and with excellent enantio- and diastereoselectivity. However, a slight decrease in the enantioselectivity was observed in the case of N-benzoyl 3-oxo-indoline-2-carboxylate (Table 2, entry 3n) compared to that of N-acetyl 3-oxo-indoline-2-carboxylate (Table 2, entry 3c).
Table 2. Substrate Scopea.
All reactions were performed at 0.21 mmol of 1, 0.25 mmol of 2, 5 mol % 4e, and 0.2 mL of aqueous base in 5 mL of solvent.
Isolated yields after column chromatography.
Diastereomeric ratio was determined by 1H NMR.
Enantiomeric excess was determined by chiral HPLC.
Enantiomeric ratio of the major diastereomer.
According to X-ray crystallography (CCDC 1842015), the structure and relative configuration of 3h were determined (Figure 2).11
Figure 2.
Oak Ridge thermal-ellipsoid plot program (ORTEP) diagram of 3h.
The absolute stereochemistry was established by single-crystal X-ray crystallography of 3t, which is having heavy atoms in its structure (Figure 3).11 As depicted in the ORTEP diagram, the absolute stereochemistry of 3t was assigned as R,S.
Figure 3.
ORTEP diagram of 3t.
Finally, we tried to convert the product 3a into a spirolactam to demonstrate its synthetic application. To our surprise, the compound 3a failed to undergo cyclization under basic conditions (Scheme 2).
Scheme 2. Spirolactam Formation.
Mechanistically, the reaction proceeds through the formation of an enolate ion from 3-indolinone-2-carboxylate 3a by a tertiary amine moiety of the ligand 4e through deprotonation. A subsequent activation of N-Boc-benzaldimine by a thiourea moiety of the ligand 4e through hydrogen bonding generates a ternary complex, which is shown in Figure S3. A preferential Re-face attack of the enolate formed from 3-indolinone-2-carboxylate onto N-Boc-benzaldimine would give the desired product 3a, Figure 4.
Figure 4.
Plausible transition state.
Conclusions
In summary, we have successfully developed an organocatalytic asymmetric Mannich reaction for the synthesis of chiral β-amino esters, which are key intermediates for the synthesis of biologically active molecules. The reaction proceeds under mild conditions and is compatible with diverse range of substituents that are present on the aromatic ring of aldimines. This method works with a wide range of substrates including aryl, naphthyl, and heteroaryl cyclic ß-ketoesters.
General Methods
All solvents were dried according to standard literature procedures. The reactions were conducted under a nitrogen atmosphere. Melting points (mp) were obtained on Buchi B-540. 1H and 13C NMR (proton-decoupled) spectra were recorded in the CDCl3 solvent at 300, 400, or 500 MHz on an NMR spectrometer. Chemical shifts (δ) were reported in parts per million (ppm) with respect to tetramethylsilane as an internal standard. Coupling constants (J) are quoted in hertz (Hz). Mass spectra and high-resolution mass spectrometry (HRMS) were recorded on a mass spectrometer by the electrospray ionization (ESI) or atmospheric pressure chemical ionization technique. Optical rotations were recorded on an Anton Paar MCP-200 polarimeter. Enantiomeric excesses (ee’s) were determined by HPLC analysis using DAICEL Chiralpak OD-H, AS-H, IC, IA columns. The precursors were prepared according to the procedure reported in the literature.12
General Procedure for the Asymmetric Mannich Reaction (3a)
To a suspension of 2-substituted 3-indolinones 11 (50 mg, 1.0 equiv, 0.21 mmol %) and α-amidosulfones 22 (1.2 equiv, 0.25 mmol %) in xylene (5 mL) at 0 °C were added catalyst 4c3 (5 mol %) and saturated Na2CO3 (0.2 mL) successively. The resulting mixture was stirred for 3 days at 0 °C and then with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the crude product, which was purified by column chromatography using a gradient mixture of ethyl acetate/hexane (2:8) as the eluent to afford the product 3a.
All other reactions were carried out according to the general procedure for the synthesis of 3a to 3s. The racemic samples were prepared by the following general procedure, using quinine and quinidine (1:1) as catalysts instead of thiourea 4c. In the absence of quinine and quinidine, the racemic reaction was very sluggish and takes more than 5 days for the completion with low yield.
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-3-oxoindoline-2-carboxylate (3a)
(0.084 g, 92% yield) white solid. Mp 130–132 °C. IR (neat) ν 3409.7, 3007.4, 2978.2, 1763.6, 1706.2, 1476.0, 1339.9, 1291.4, 1164.4, 1048.1, 770.8, 693.3 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.2 Hz, 1H), 7.50–7.41 (m, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.98 (s, 6H), 6.70 (s, 1H), 5.97 (s, 1H), 3.76 (s, 3H), 2.38 (s, 3H), 1.45 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 194.5, 167.8, 165.2, 155.2, 137.8, 127.8, 127.6, 126.9, 126.6, 124.8, 124.0, 114.5, 79.5, 74.4, 55.9, 53.4, 28.4, 25.6. HRMS (Orbitrap ESI): exact mass calcd for C24H26N2O6Na [M + Na]+: 461.1683. Found: 461.1696. HPLC analysis (DAICEL Chiralpak OD-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (7.23 min), minor (8.50 min), ee: 97.25; [α]D20 −40.2 (c = 0.15, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-(2-bromophenyl)((tert-butoxycarbonyl)amino)methyl)-3-oxoindoline-2-carboxylate (3b)
(0.106 g, 96% yield) white solid. Mp 130–132 °C. IR (neat) ν 3415.7, 3007.5, 2978.3, 1765.0, 1706.8, 1607.1, 1499.7, 1470.3, 1333.3, 1266.2, 1166.0, 971.1, 770.9, 609.2 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 5.6 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.32 (s, 1H), 7.2–6.9 (m, 3H), 6.83 (s, 2H), 6.63 (s, 1H), 6.30 (s, 1H), 3.76 (s, 3H), 2.47 (s, 3H), 1.44 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 194.9, 168.2, 165.4, 155.0, 152.7, 137.6, 132.6, 129.3, 129.1, 126.5, 124.9, 124.2, 114.9, 79.7, 74.3, 55.3, 53.2, 28.4, 25.7. HRMS (Orbitrap ESI): exact mass calcd for C24H25N2O6BrNa [M + Na]+: 539.0788. Found: 539.0810. HPLC analysis (DAICEL Chiralpak AS-H), n-hexane/2-PrOH = 85:15, 1 mL/min, minor (11.55 min), ee: 96.83; [α]D20 −88 (c = 0.15, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(3-chlorophenyl)methyl)-3-oxoindoline-2-carboxylate (3c)
(0.099 g, 98% yield) white solid. Mp 130–132 °C. IR (neat) ν 3411.1, 3011.5, 2978.1, 1761.6, 1716.1, 1606.7, 1500.1, 1434.3, 1374.2, 1334.2, 1265.9, 1165.6, 761.5, 614.5 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.5 Hz, 1H), 7.53–7.48 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.02–6.84 (m, 5H), 6.69 (s, 1H), 5.94 (s, 1H), 3.76 (s, 3H), 2.41 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz,) δ 194.1, 167.8, 165.0, 155.2, 152.0, 139.5, 138.0, 133.6, 128.9, 128.0, 127.3, 125.4, 125.0, 124.2, 114.5, 79.8, 74.0, 55.4, 53.4, 28.4, 25.6. HRMS (Orbitrap ESI): exact mass calcd for C24H25N2O6ClNa [M + Na]+: 495.1293. Found: 495.1312. HPLC analysis (DAICEL Chiralpak AS-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (5.58 min), minor (8.8 min), ee: 98.90; [α]D20 −61 (c = 0.5, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(4-fluorophenyl)methyl)-3-oxoindoline-2-carboxylate (3d)
(0.086 g, 88% yield) white solid. Mp 135–137 °C. IR (neat) ν 3410.5, 3010.5, 2979.8, 1764.5, 1707.2, 1606.5, 1471.9, 1371.4, 1324.3, 1238.3, 1164.1, 1065.5, 752.8, 619.1 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 5.6 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.32 (s, 1H), 7.08–6.91 (m, 3H), 6.83 (s, 2H), 6.63 (s, 1H), 6.30 (s, 1H), 3.76 (s, 3H), 2.47 (s, 3H), 1.44 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 194.5, 167.8, 165.3, 155.2, 140.6, 140.4, 137.8, 132.9, 130.3, 128.7, 127.4, 127.3, 126.8, 126.3, 124.8, 124.0, 114.7, 79.6, 55.7, 53.4, 28.4, 25.6. HRMS (Orbitrap ESI): exact mass calcd for C24H25N2O6FNa [M + Na]+: 479.1588. Found: 479.1605. HPLC analysis (DAICEL Chiralpak IC), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm major (6.24 min), minor (9.40 min), 96.97; [α]D20 −74 (c = 0.1, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(4-chloro-2-fluorophenyl)methyl)-3-oxoindoline-2-carboxylate (3e)
(0.096 g, 92% yield) white solid. Mp 170–172 °C. IR (neat) ν 3410.7, 3032.4, 2956.5, 1760.4, 1728.9, 1684.5, 1606.2, 1463.5, 1376.2, 1339.6, 1297.6, 1155.0, 1093.9, 759.9, 647.7 cm–1. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 7.4 Hz, 1H), 7.54–7.46 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.00–6.84 (m, 4H), 6.69 (s, 1H), 5.95 (s, 1H), 3.76 (s, 3H), 2.41 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 194.5, 191.9, 167.9, 165.3, 155.2, 140.6, 140.4, 137.8, 128.7, 127.4, 126.8, 126.3, 124.8, 124.0, 114.7, 79.6, 74.4, 55.7, 53.4, 28.4, 25.7. HRMS (Orbitrap ESI): exact mass calcd for C24H24ClFN2O6Na [M + Na]+: 513.1198. Found: 513.1225. HPLC analysis (DAICEL Chiralpak AS-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (5.02 min), minor (6.83 min), ee: 88.65; [α]D20 −34.2 (c = 0.15, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(p-tolyl)methyl)-3-oxoindoline-2-carboxylate (3f)
(0.077 g, 80% yield) white solid. Mp 147–149 °C. IR (neat) ν 3399.8, 3021.3, 2969.8, 1735.6, 1710.6, 1680.3, 1585.6, 1465.8, 1369.7, 1322.5, 1165.6, 1029.5, 765.6, 660.7 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 6.6 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.81–6.74 (m, 5H), 6.66 (s, 1H), 5.93 (s, 1H), 3.76 (s, 3H), 2.38 (s, 3H), 2.12 (s, 3H), 1.45 (s, 9H). 13C NMR (101 MHz) δ 194.6, 167.8, 165.3, 155.1, 152.1, 137.7, 137.4, 134.2, 128.3, 126.8, 124.8, 123.9, 114.5, 79.4, 74.5, 55.6, 53.3, 28.4, 25.6, 20.9. HRMS (Orbitrap ESI): exact mass calcd for C25H28N2O6Na [M + Na]+: 475.1839. Found: 475.1850. HPLC analysis (DAICEL Chiralpak OD-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (4.88 min), minor (6.09 min), ee: 66.97; [α]D20 −49 (c = 0.15, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(3,4-dimethoxyphenyl)methyl)-3-oxoindoline-2-carboxylate (3g)
(0.102 g, 96% yield) white solid. Mp 130–132 °C. IR (neat) ν 3411.5, 2956.9, 2924.1, 1785.7, 1727.3, 1689.1, 1589.4, 1464.7, 1379.9, 1345.6, 1224.7, 1155.1, 770.9 cm–1. 1H NMR (500 MHz, CDCl3) 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 7.3 Hz, 1H), 7.51 (ddd, J = 8.6, 7.3, 1.4 Hz, 1H), 7.14 (t, J = 7.5 Hz, 2H), 6.67 (d, J = 5.3 Hz, 1H), 6.14–6.09 (m, 3H), 5.92 (s, 1H), 3.76 (s, 3H), 3.55 (s, 6H), 2.39 (s, 3H), 1.47 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 13C NMR (101 MHz, 3>) δ 194.6, 191.9, 167.7, 165.2, 160.1, 155.2, 152.1, 139.6, 137.9, 124.7, 124.0, 114.7, 107.1, 105.0, 100.4, 79.6, 74.2, 56.10, 55.0, 53.4, 28.4, 28.2, 25.7. HRMS (Orbitrap ESI): exact mass calcd for C26H30N2O8Na [M + Na]+: 521.1894. Found: 521.1910. HPLC analysis (DAICEL Chiralpak OD-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (6.67 min), minor (11.68 min), ee: 82.73; [α]D20 −17 (c = 0.1, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(4-nitrophenyl)methyl)-3-oxoindoline-2-carboxylate (3h)
(0.091 g, 88% yield) yellow solid. Mp 158–160 °C. IR (neat) ν 3409.5, 3079.5, 2979.0, 1763.8, 1708.0, 1606.1, 1523.3, 1498.6, 1471.6, 1344.8, 1237.7, 1163.4, 1027.7, 752.3, 611.6 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.54–7.49 (m, 1H), 7.18 (m, 4H), 6.81 (s, 1H), 6.08 (d, J = 4.9 Hz, 1H), 3.77 (s, 3H), 2.42 (s, 3H), 1.44 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 193.7, 168.0, 164.7, 155.2, 151.8, 147.4, 145.1, 138.4, 128.0, 125.2, 124.6, 124.3, 122.9, 114.7, 80.1, 73.7, 55.7, 53.6, 28.3, 25.6. HRMS (Orbitrap ESI): exact mass calcd for C24H25N3O8Na [M + Na]+: 506.1533. Found: 506.1553. HPLC analysis (DAICEL Chiralpak AS-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm major (12.60 min), minor (19.34 min), ee: 95.63; [α]D20 −57.5 (c = 0.5, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(2-nitrophenyl)methyl)-3-oxoindoline-2-carboxylate (3i)
(0.093 g, 90% yield) yellow solid. Mp 160–162 °C. IR (neat) ν 3409.9, 3076.2, 2978.1, 1764.6, 1706.8, 1606.5, 1525.1, 1499.5, 1470.1, 1343.2, 1235.2, 1165.2, 1022.6, 759.3, 615.2 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.60–7.49 (m, 3H), 7.41 (s, 1H), 7.21–7.10 (m, 4H), 6.65 (s, 2H), 3.73 (s, 3H), 2.43 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 194.0, 168.45, 165.2, 155.1, 152.2, 149.5, 137.6, 131.7, 131.4, 130.0, 128.6, 124.8, 124.5, 124.1, 116.1, 80.1, 7.6, 53.4, 52.0, 28.3, 24.7. HRMS (Orbitrap ESI): exact mass calcd for C24H25N3O8Na [M + Na]+: 506.1533. Found: 506.1551. HPLC analysis (DAICEL Chiralpak AS-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (10.19 min), minor (12.78 min), ee: 91.21; [α]D20 −52.3 (c = 0.15, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(4-cyanophenyl)methyl)-3-oxoindoline-2-carboxylate (3j)
(0.087 g, 90% yield) yellow solid. Mp 156–158 °C. IR (neat) ν 3401.6, 3009.8, 2978.9, 2230.1, 1763.7, 1707.8, 1676.5, 1606.3, 1499.8, 1417.3, 1339.5, 1239.2, 1164.2, 1025.6, 754.7, 615.6 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.5 Hz, 1H), 7.54 (ddd, J = 8.6, 7.4, 1.4 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.20–7.09 (m, 4H), 6.77 (s, 1H), 6.01 (s, 1H), 3.76 (s, 3H), 2.40 (s, 3H), 1.44 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 193.8, 168.0, 164.8, 155.2, 151.9, 143.0, 138.4, 131.5, 127.8, 125.1, 124.5, 118.3, 114.7, 111.7, 80.0, 73.7, 55.8, 53.6, 28.3, 25.6. HRMS (Orbitrap ESI): exact mass calcd for C25H25N3O6Na [M + Na]+: 486.1635. Found: 486.1645. HPLC analysis (DAICEL Chiralpak OD-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (12.27 min), minor (16.12 min), ee: 97.63; [α]D20 −68.5 (c = 0.5, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(2-cyanophenyl)methyl)-3-oxoindoline-2-carboxylate (3k)
(0.091 g, 90% yield) yellow solid. Mp 162–164 °C. IR (neat) ν 3404.0, 3008.5, 2978.5, 2230.8, 1763.7, 1708.6, 1677.2, 1606.6, 1472.2, 1340.1, 1241.1, 1165.4, 1025.9, 758.2, 616.5 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.6 Hz, 1H), 7.54 (ddd, J = 8.6, 7.3, 1.4 Hz, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.20–7.08 (m, 4H), 6.77 (s, 1H), 6.01 (s, 1H), 3.76 (s, 3H), 2.40 (s, 3H), 1.44 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 193.7, 168.0, 164.7, 155.2, 151.9, 143.1, 138.4, 131.5, 127.8, 125.1, 124.5, 118.3, 114.7, 111.7, 80.0, 73.7, 55.8, 53.6, 28.3, 25.6. HRMS (Orbitrap ESI): exact mass calcd for C25H25N3O6Na [M + Na]+: 486.1635. Found: 486.1640. HPLC analysis (DAICEL Chiralpak AS-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (9.99 min), minor (10.98 min), ee: 97.76; [α]D20 −79.8 (c = 0.5, CHCl3).
Methyl (R)-2-((S)-[1,1′-Biphenyl]-4-yl((tert-butoxycarbonyl)amino)methyl)-1-acetyl-3-oxoindoline-2-carboxylate (3l)
(0.095 g, 85% yield) yellow solid. Mp 118–120 °C. IR (neat) ν 3403.5, 3009.2, 2924.3, 1762.3, 1729.9, 1682.6, 1606.6, 1463.2, 1375.3, 1337.6, 1297.4, 1259.5, 1155.0, 1126.5, 750.4, 698.6 cm–1. 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 6.4 Hz, 1H), 7.46–7.41 (m, 1H), 7.38–7.34 (m, 4H), 7.30 (dd, J = 6.1, 2.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.13–7.01 (m, 4H), 6.73 (s, 1H), 6.03 (s, 1H), 3.77 (s, 3H), 2.40 (s, 3H), 1.47 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 194.5, 191.9, 167.8, 165.3, 155.2, 140.6, 140.4, 137.8, 130.3, 128.7, 127.4, 127.3, 126.8, 126.3, 124.9, 124.8, 124.0, 114.7, 101.5, 79.6, 55.7, 53.46, 28.4, 25.7. HRMS (Orbitrap ESI): exact mass calcd for C30H30N2O6Na [M + Na]+: 537.1996. Found: 537.2018. HPLC analysis (DAICEL Chiralpak AS-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (9.46 min), minor (14.22 min), ee: 83.25; [α]D20 −48.6 (c = 0.2, CHCl3).
Methyl (R)-1-Acetyl-2-((R)-(4-bromothiophen-2-yl)((tert-butoxycarbonyl)amino)methyl)-3-oxoindoline-2-carboxylate (3m)
(0.106 g, 95% yield) yellow solid. Mp 118–120 °C. IR (neat) ν 3441.2, 3015.3, 2976.5, 1771.5, 1730.6, 1690.5, 1602.9, 1499.8, 1383.8, 1334.6, 1270.4, 1167.4, 1098.6, 761.9, 650.6 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.5 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.39 (s, 1H), 7.18 (t, J = 7.5 Hz, 1H), 6.84 (s, 1H), 6.66 (d, J = 9.9 Hz, 2H), 6.22 (d, J = 5.5 Hz, 1H), 3.75 (s, 3H), 2.49 (s, 3H), 1.48 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 193.8, 167.9, 164.7, 155.0, 152.7, 142.2, 138.2, 128.6, 125.5, 125.2, 124.4, 122.1, 114.9, 108.6, 80.1, 74.0, 53.5, 51.9, 28.3, 25.7. HRMS (Orbitrap ESI): exact mass calcd for C22H23BrN2O6SNa [M + Na]+: 545.0340. Found: 545.0368. HPLC analysis (DAICEL Chiralpak OD-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (8.66 min), minor (10.14 min), ee: 98.71; [α]D20 −80.5 (c = 0.15, CHCl3).
Methyl (R)-1-Benzoyl-2-((S)-((tert-butoxycarbonyl)amino)(3-chlorophenyl)methyl)-3-oxoindoline-2-carboxylate (3n)
(0.086 g, 96% yield) yellow solid. Mp 172–174 °C. IR (neat) ν 3417.7, 3009.8, 2978.1, 1762.2, 1710.0, 1607.3, 1500.8, 1471.1, 1338.6, 1235.4, 1166.2, 1048.1, 752.5, 611.6 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.9 Hz, 2H), 7.24–6.79 (m, 9H), 6.12 (s, 1H), 5.80 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H), 1.47 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 194.2, 167.8, 164.9, 155.2, 153.0, 139.9, 137.1, 134.6, 133.9, 131.8, 129.3, 129.1, 128.1, 127.8, 127.4, 125.3, 124.6, 124.3, 124.1, 115.6, 79.7, 74.2, 55.7, 53.6, 28.4. HRMS (Orbitrap ESI): exact mass calcd for C29H27ClN2O6Na [M + Na]+: 557.1449. Found: 557.1428. HPLC analysis (DAICEL Chiralpak AS-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (11.54 min), minor (15.97 min), ee: 80.79; [α]D20 −45 (c = 0.7, CHCl3).
Methyl (R)-1-Acetyl-5-bromo-2-((S)-((tert-butoxycarbonyl)amino)(3-chlorophenyl)methyl)-3-oxoindoline-2-carboxylate (3o)
(0.070 g, 80% yield) yellow solid. Mp 168–170 °C. IR (neat) ν 3412.0, 3073.3, 2922.5, 1759.5, 1730.5, 1695.3, 1574.7, 1429.8, 1340.1, 1260.5, 1142.6, 1074.1, 771.9, 667.9 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.58 (dd, J = 8.9, 2.1 Hz, 1H), 6.99 (dt, J = 11.1, 8.1 Hz, 4H), 6.86 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 5.93 (s, 1H), 3.76 (s, 3H), 2.39 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 192.9, 167.7, 164.5, 155.1, 150.9, 140.5, 139.2, 134.4, 133.8, 130.4, 128.2, 127.4, 125.0, 117.3, 116.2, 80.0, 74.5, 55.5, 53.6, 28.3, 25.5. HRMS (Orbitrap ESI): exact mass calcd for C24H24BrClN2O6Na [M + Na]+: 573.0398. Found: 573.0423. HPLC analysis (DAICEL Chiralpak AS-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm major (6.57 min), minor (7.35 min), ee: 40; [α]D20 −148 (c = 1.6, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(3-chlorophenyl)methyl)-5-methyl-3-oxoindoline-2-carboxylate (3p)
(0.090 g, 92% yield) yellow solid. Mp 147–149 °C. IR (neat) ν 3402.6, 3073.3, 2925.5, 1753.6, 1721.5, 1681.1, 1586.5, 1488.5, 1378.9, 1344.7, 1230.6, 1123.6, 1069.3, 770.4, 640.7 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.08–6.83 (m, 5H), 6.72 (s, 1H), 5.94 (s, 1H), 3.75 (s, 3H), 2.38 (s, 3H), 2.33 (s, 3H), 1.46 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 194.1, 167.7, 164.8, 155.2, 150.2, 139.5, 139.2, 134.4, 133.5, 128.9, 127.9, 127.3, 125.1, 124.6, 114.3, 79.7, 74.1, 55.42, 53.4, 28.4, 25.5, 20.4. HRMS (Orbitrap ESI): exact mass calcd for C25H27ClN2O6Na [M + Na]+: 509.1449. Found: 509.1471. HPLC analysis (DAICEL Chiralpak OD-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm major (8.03 min), minor (11.46 min), ee: 90.47; [α]D20 −103 (c = 0.55, CHCl3).
Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(3-chlorophenyl)methyl)-5-chloro-3-oxoindoline-2-carboxylate (3q)
(0.080 g, 85% yield) yellow solid. Mp 166–168 °C. IR (neat) ν 3410.5, 3007.8, 2978.3, 1765.6, 1710.2, 1680.3, 1501.1, 1470.8, 1371.1, 1337.1, 1290.1, 1166.3, 1049.2, 765.0, 686.9 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.44 (dd, J = 8.9, 2.3 Hz, 1H), 7.13–6.91 (m, 4H), 6.86 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 5.92 (s, 1H), 3.76 (s, 3H), 2.40 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 193.0, 167.7, 164.8, 155.3, 150.6, 139.1, 137.0, 133.1, 130.7, 129.8, 128.3, 127.8, 125.6, 124.9, 124.2, 115.5, 79.7, 74.5, 55.0, 53.1, 28.8, 25.4. HRMS (Orbitrap ESI): exact mass calcd for C24H24Cl2N2O6Na [M + Na]+: 529.0898. Found: 529.0930. HPLC analysis (DAICEL Chiralpak OD-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (6.08 min), minor (7.19 min), ee: 57.6; [α]D20 −110 (c = 0.15, CHCl3).
Methyl (R)-4-Acetyl-5-((S)-((tert-butoxycarbonyl)amino)(3-chlorophenyl)methyl)-6-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-5-carboxylate (3r)
(0.092 g, 92% yield) yellow solid. Mp 178–180 °C. IR (neat) ν 3394.7, 3009.9, 2978.5, 1761.5, 1685.5, 1512.2, 1454.9, 1371.6, 1323.3, 1235.9, 1129.7, 989.5, 752.6, 582.4 cm–1. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 5.1 Hz, 1H), 7.09–6.96 (m, 4H), 6.84 (d, J = 6.5 Hz, 1H), 6.67 (d, J = 5.0 Hz, 1H), 5.95 (d, J = 6.4 Hz, 1H), 3.79 (s, 3H), 2.29 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 184.2, 165.8, 164.4, 163.6, 155.2, 145.5, 139.5, 133.7, 128.9, 128.1, 127.3, 125.2, 122.8, 114.9, 79.7, 79.5, 55.3, 53.5, 28.4, 24.0. HRMS (Orbitrap ESI): exact mass calcd for C22H23ClN2O6SNa [M + Na]+: 501.0881. Found: 501.0880. HPLC analysis (DAICEL Chiralpak AS-H), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (9.71 min), minor (11.68 min), ee: 96.97; [α]D20 −205 (c = 0.55, CHCl3).
Methyl (R)-1-Benzoyl-2-((S)-((tert-butoxycarbonyl)amino)(3-chlorophenyl)methyl)-3-oxo-2,3-dihydro-1H-benzo[f]indole-2-carboxylate (3s)
(0.097 g, 94% yield) yellow solid. Mp 148–150 °C. IR (neat) ν 3411.9, 3011.5, 2979.6, 1776.7, 1740.5, 1690.8, 1610.5, 1501.6, 1465.7, 1465.7, 1395.6, 1335.7, 1260.5, 1225.6, 1166.5, 1096.4, 776.1, 649.6 cm–1. 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.53–7.28 (m, 6H), 7.20–7.15 (m, 2H), 7.04–6.96 (m, 4H), 6.18 (s, 1H), 6.04 (s, 1H), 3.81 (s, 3H), 1.49 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 194.7, 168.4, 165.2, 155.2, 145.6, 140.1, 137.8, 134.8, 134.0, 131.7, 130.3, 130.3, 129.4, 129.0, 128.1, 128.0, 127.9, 127.5, 126.5, 126.1, 125.2, 124.0, 112.3, 79.7, 74.5, 55.6, 53.6, 28.4. HRMS (Orbitrap ESI): exact mass calcd for C33H29ClN2O6Na [M + Na]+: 607.1606. Found: 607.1631. HPLC analysis (DAICEL Chiralpak IA), n-hexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (6.80 min), minor (7.43 min), ee: 90.27; [α]D20 −150 (c = 0.15, CHCl3).
Ethyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(3-chlorophenyl)methyl)-6-chloro-3-oxoindoline-2-carboxylate (3t)
(0.070 g, 76% yield) pale yellow solid. Mp 135–137 °C. IR (neat) ν 3309.8, 3006.6, 2968.2, 1765.3, 1711.5, 1688.2, 1502.1, 1471.3, 1372.0, 1337.2, 1291.1, 1164.2, 1049.1, 765.2, 682.8 cm–1. 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 8.1 Hz, 1H), 7.11 (dd, J = 8.3, 1.4 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.00–6.95 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.67 (s, 1H), 5.91 (s, 1H), 4.40–4.12 (m, 2H), 2.40 (s, 3H), 1.45 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.0, 167.7, 164.2, 155.1, 144.7, 133.8, 129.1, 128.2, 127.0, 125.6, 125.0, 114.8, 79.9, 74.7, 62.9, 55.5, 28.4, 25.5, 13.9. HRMS (Orbitrap ESI): exact mass calcd for C25H26Cl2N2O6Na [M + Na]+: 543.1055. Found: 543.1049. HPLC analysis (DAICEL Chiralpak IA), n-hexane/2-PrOH = 85:15, 1 mL/min, 254 nm, major (24.55 min), minor (21.23 min), ee: 90.00; [α]D20 −38 (c = 0.3, CHCl3).
Acknowledgments
G.R.K. thanks UGC, New Delhi, for the award of a fellowship.
Supporting Information Available
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02132.
The authors declare no competing financial interest.
Supplementary Material
References
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