Organocatalytic Enantioselective Mannich Reaction: Direct Access to

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Article Cite This: ACS Omega 2019, 4, 2168−2177

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Organocatalytic Enantioselective Mannich Reaction: Direct Access to Chiral β‑Amino Esters G. Ravi Kumar,† Boora Ramesh,† Suresh Yarlagadda,† Balasubramanian Sridhar,‡ and B. V. Subba Reddy*,† †

Fluoro & Agrochemicals and ‡Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India

ACS Omega 2019.4:2168-2177. Downloaded from pubs.acs.org by 91.200.82.193 on 01/30/19. For personal use only.

S Supporting Information *

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.

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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 2,2disubstituted 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 3indolinone-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-3one 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 αamidosulfones Figure 1. 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 enantioand 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 Received: August 24, 2018 Accepted: January 11, 2019 Published: January 29, 2019

Figure 1. Examples of 3-indolinone natural products. © 2019 American Chemical Society

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4a 4b 4c 4d 4e 4f 4g 4h 4i 4e 4e

a b c d e f g h i j k

Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 K2CO3 Cs2CO3

base (aq.)

toluene 25 toluene 25 toluene 25 toluene 25 toluene 25 toluene 25 toluene 25 toluene 25 toluene 25 toluene 25 toluene 25

solvent T (°C) 3 2 4 3 2 4 5 4 5 2 2

time (days) 45 60 80 85 90 40 45 50 40 80 65

yield (%)b 92:8 93:7 93:7 98:2 99:1 95:5 89:11 88:22 90:10 99:1 95:5

dr (3a:3aa)c 10 5 55 60 85 50 30 25 30 70 20

ee (%)c l m n o p q r s t u

entry 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e

catalyst NaOH CsOH Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3

base (aq.) toluene toluene xylene toluene MTBE benzene DCE xylene toluene toluene

solvent 25 25 0 0 0 0 0 −20 −40 −78

T (°C) 1 1 3 3 3 3 3 4 5 2

time (days) 20 25 98 60 50 55 35 35 30

yield (%)b

90:10 95:5 99:1 99:1 99:1 99:1 99:1 99:1 99:1

dr (3a:3aa)c

5 10 99 65 30 40 20 40 30

ee (%)d,e

a 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. bIsolated yields after column chromatography. cDiastereomeric ratio was determined by 1H NMR. dEnantiomeric excess was determined by chiral high-performance liquid chromatography (HPLC). eEnantiomeric ratio of the major diastereomer.

catalyst

entry

Table 1. Optimization of Reaction Conditions in the Formation of 3aa

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Scheme 1. Catalyst Screening in the Asymmetric Mannich Reaction

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). According to X-ray crystallography (CCDC 1842015), the structure and relative configuration of 3h were determined (Figure 2).11 The absolute stereochemistry was established by singlecrystal 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. 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). 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 Reface attack of the enolate formed from 3-indolinone-2carboxylate onto N-Boc-benzaldimine would give the desired product 3a, Figure 4.

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). 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-2carboxylate. 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 Nsubstituted 3-oxo-indoline-2-carboxylate; in this, free NH and

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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.

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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 B2170

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Table 2. Substrate Scopea

a

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. bIsolated yields after column chromatography. cDiastereomeric ratio was determined by 1H NMR. dEnantiomeric excess was determined by chiral HPLC. e Enantiomeric ratio of the major diastereomer.

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Figure 2. Oak Ridge thermal-ellipsoid plot program (ORTEP) diagram of 3h.

Figure 4. Plausible transition state.

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

Figure 3. ORTEP diagram of 3t.

Scheme 2. Spirolactam Formation

540. 1H and 13C NMR (proton-decoupled) spectra were recorded in the CDCl3 solvent at 300, 400, or 500 MHz on an 2172

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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]20 D −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]20 D −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]20 D −49 (c = 0.15, CHCl3). Methyl (R)-1-Acetyl-2-((S)-((tert-butoxycarbonyl)amino)(3,4-dimethoxyphenyl)methyl)-3-oxoindoline-2carboxylate (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), nhexane/2-PrOH = 80:20, 1 mL/min, 254 nm, major (6.67 min), minor (11.68 min), ee: 82.73; [α]20 D −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

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]20 D −40.2 (c = 0.15, CHCl3). Methyl (R)-1-Acetyl-2-((S)-(2-bromophenyl)((tertbutoxycarbonyl)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]20 D −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]20 D −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 2173

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(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]20 D −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/2PrOH = 80:20, 1 mL/min, 254 nm, major (10.19 min), minor (12.78 min), ee: 91.21; [α]20 D −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/2PrOH = 80:20, 1 mL/min, 254 nm, major (12.27 min), minor (16.12 min), ee: 97.63; [α]20 D −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/2PrOH = 80:20, 1 mL/min, 254 nm, major (9.99 min), minor (10.98 min), ee: 97.76; [α]20 D −79.8 (c = 0.5, CHCl3). Methyl (R)-2-((S)-[1,1′-Biphenyl]-4-yl((tertbutoxycarbonyl)amino)methyl)-1-acetyl-3-oxoindoline2-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]20 D −48.6 (c = 0.2, CHCl3). Methyl (R)-1-Acetyl-2-((R)-(4-bromothiophen-2-yl)((tert-butoxycarbonyl)amino)methyl)-3-oxoindoline-2carboxylate (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]20 D −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]20 D −45 (c = 0.7, CHCl3). Methyl (R)-1-Acetyl-5-bromo-2-((S)-((tertbutoxycarbonyl)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]20 D −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, 2174

DOI: 10.1021/acsomega.8b02132 ACS Omega 2019, 4, 2168−2177

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(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]20 D −38 (c = 0.3, CHCl3).

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]20 D −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]20 D −110 (c = 0.15, CHCl3). Methyl (R)-4-Acetyl-5-((S)-((tert-butoxycarbonyl)amino)(3-chlorophenyl)methyl)-6-oxo-5,6-dihydro-4Hthieno[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]20 D −205 (c = 0.55, CHCl3). Methyl (R)-1-Benzoyl-2-((S)-((tert-butoxycarbonyl)amino)(3-chlorophenyl)methyl)-3-oxo-2,3-dihydro-1Hbenzo[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]20 D −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

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02132. Copies of 1H and 13C NMR spectra, HPLC chromatogram of products, X-ray data for compounds 3h and 3t (PDF) Products 3h (CIF) (CIF)

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AUTHOR INFORMATION

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*E-mail: [email protected]. Fax: 91-40-27160512. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS G.R.K. thanks UGC, New Delhi, for the award of a fellowship. REFERENCES

(1) (a) Weiner, B.; Szymański, W.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Recent advances in the catalytic asymmetric synthesis of β-amino acids. Chem. Soc. Rev. 2010, 39, 1656. (b) Ashfaq, M.; Tabassum, R.; Ahmad, M. M.; Hassan, N. A.; Oku, H.; Rivera, G. Enantioselective synthesis of β-amino acids: A review. Med. Chem. 2015, 5, 7. (c) Li, L.; Song, B.-A.; Bhadury, P. S.; Zhang, Y.-P.; Hu, D.Y.; Yang, S. Enantioselective synthesis of β-amino esters bearing a benzothiazole moiety via a Mannich-type reaction catalyzed by a Cinchona alkaloid derivative. Eur. J. Org. Chem. 2011, 4743. (d) Josephson, K.; Hartman, M. C. T.; Szostak, J. W. Ribosomal synthesis of unnatural peptides. J. Am. Chem. Soc. 2005, 127, 11727. (e) Cabrele, C.; Martinek, T. A.; Reiserg, O.; Berlicki, L. Peptides containing β-amino acid patterns: Challenges and successes in medicinal chemistry. J. Med. Chem. 2014, 57, 9718. (2) (a) Scott, W. L.; Martynow, J. G.; Huffman, J. C.; O’Donnell, M. J. Solid-phase synthesis of multiple classes of peptidomimetics from versatile resin-bound aldehyde intermediates. J. Am. Chem. Soc. 2007, 129, 7077. (b) Elashal, H. E.; Sim, Y. E.; Raj, M. Serine promoted synthesis of peptide thioester-precursor on solid support for native chemical ligation. Chem. Sci. 2017, 8, 117. (c) Kamath, A.; Ojima, I. Advances in the chemistry of β-lactam and its medicinal applications. Tetrahedron 2012, 68, 10640. (d) Jamieson, A. G.; Boutard, N.; Sabatino, D.; Lubell, W. D. Peptide scanning for studying structureactivity relationships in drug discovery. Chem. Biol. Drug Des. 2013, 81, 148. (3) (a) The Chemistry of Indoles; Sundberg, R. J., Ed.; Academic press: New York, 1996. (b) Yap, W.-S.; Gan, C.-Y.; Low, Y.-Y.; Choo, Y.-M.; Etoh, T.; Hayashi, M.; Komiyama, K.; Kam, T.-S. Grandilodines A-C, biologically active indole alkaloids from Kopsiagrandifolia. J. Nat. Prod. 2011, 74, 1309. (c) Umehara, A.; Ueda, H.; Tokuyama, H. Total syntheses of Leuconoxine, Leuconodine B, and Melodinine E by oxidative cyclic aminal formation and diastereoselective ring-closing metathesis. Org. Lett. 2014, 16, 2526. (d) Bass, P. D.; Gubler, D. A.; Judd, T. C.; Williams, R. M. Mitomycinoid alkaloids: Mechanism of 2175

DOI: 10.1021/acsomega.8b02132 ACS Omega 2019, 4, 2168−2177

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action, biosynthesis, total syntheses, and synthetic approaches. Chem. Rev. 2013, 113, 6816. (e) Lim, K.-H.; Kam, T.-S. New indole alkaloids from Kopsia. Alkaloid variation in Kopsiasingapurensis. Helv. Chim. Acta 2007, 90, 31. (f) Xu, Z.; Wang, Q.; Zhu, J. Total syntheses of (−)-Mersicarpine, (−)-Scholarisine G, (+)-Melodinine E, (−)-Leuconoxine, (−)-Leuconolam, (−)-Leuconodine A, (+)-Leuconodine F, and (−)-Leuconodine C: Self-induced diastereomeric anisochronism (SIDA) phenomenon for Scholarisine G and Leuconodines A and C. J. Am. Chem. Soc. 2015, 137, 6712. (g) Steven, A.; Overman, L. E. Total synthesis of complex cyclotryptamine alkaloids: Stereocontrolled construction of quaternary carbon stereocenters. Angew. Chem., Int. Ed. 2007, 46, 5488. (h) Pearson, W. H.; Mi, Y.; Lee, I. Y.; Stoy, P. Total synthesis of the Kopsialapidilecta alkaloid (±)-Lapidilectine B. J. Am. Chem. Soc. 2001, 123, 6724. (i) Guengerich, F. P.; Sorrells, J. L.; Schmitt, S.; Krauser, J. A.; Aryal, P.; Meijer, L. Generation of new protein kinase inhibitors utilizing cytochrome p450 mutant enzymes for indigoid synthesis. J. Med. Chem. 2004, 47, 3236. (j) Petkovic, M.; Nasufovic, V.; Djukanovic, D.; Vujosevic, Z. T.; Jadranin, M.; Matovic, R.; Savic, V. Cyclative cascades of allenamides derived from amino acids: Synthesis of annulated indoxyl derivatives. Eur. J. Org. Chem. 2016, 1279. (k) Patel, P.; Reddy, B. N.; Ramana, C. V. The synthesis of the central tricyclic core of the isatisine A: Harmonious orchestration of [metal]-catalyzed reactions in a sequence. Tetrahedron 2014, 70, 510. (4) (a) Tan, C.-J.; Di, Y.-T.; Wang, Y.-H.; Zhang, Y.; Si, Y.-K.; Zhang, Q.; Gao, S.; Hu, X.-J.; Fang, X.; Li, S.-F.; Hao, X.-J. Three new indole alkaloids from Trigonostemon lii. Org. Lett. 2010, 12, 2370. (b) Han, S.; Movassaghi, M. Concise total synthesis and stereochemical revision of all (−)-trigonoliimines. J. Am. Chem. Soc. 2011, 133, 10768. (c) Qi, X.; Bao, H.; Tambar, U. K. Total synthesis of (±)-Trigonoliimine C via oxidative rearrangement of an unsymmetrical bis-tryptamine. J. Am. Chem. Soc. 2011, 133, 10050. (d) Reddy, B. N.; Ramana, C. V. A modular total synthesis of (±)-trigonoliimine C. Chem. Commun. 2013, 49, 9767. (e) Han, S.; Morrison, K. C.; Hergenrother, P. J.; Movassaghi, M. Total synthesis, stereochemical assignment, and biological activity of all known (−)-trigonoliimines. J. Org. Chem. 2014, 79, 473. (f) Liu, S.; Hao, X.-J. A biomimetic synthesis of the skeleton of trigonoliimine C. Tetrahedron Lett. 2011, 52, 5640. (5) (a) Wu, P.-L.; Hsu, Y.-L.; Jao, C.-W. Indole alkaloids from Cephalanceropsisgracilis. J. Nat. Prod. 2006, 69, 1467. (b) Dend, Z.; Peng, X.; Huang, P.; Jiang, L.; Ye, D.; Liu, L. A multi-functionalized strategy of indoles to C2-quaternary indolin-3-ones via a TEMPO/Pdcatalyzed cascade process. Org. Biomol. Chem. 2017, 15, 442. (c) Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.; Prinsep, M. R. Marine natural products. Nat. Prod. Rep. 2014, 31, 160. (d) Baran, P. S.; Corey, E. J. A short synthetic route to (+)-austamide, (+)-deoxyisoaustamide, and (+)-hydratoaustamide from a common precursor by a novel palladium-mediated indole → dihydroindoloazocine Cyclization. J. Am. Chem. Soc. 2002, 124, 7904. (6) (a) Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Chen, Y.-T.; Zheng, J.-J.; Zhang, X.-M.; Ma, Y.-B. Isatisine A, a novel alkaloid with an unprecedented skeleton from leaves of Isatisindigotica. Org. Lett. 2007, 9, 4127. (b) Karadeolian, A.; Kerr, M. A. Total synthesis of (+)-isatisine A. Angew. Chem., Int. Ed. 2010, 49, 1133. (c) Lee, J.; Panek, J. S.Total synthesis of the Hsp90 inhibitor Geldanamycin. Org. Lett. 2011, 13, 502. (d) Kumar, C. V. S.; Puranik, V. G.; Ramana, C. V. InCl3mediated addition of indole to isatogens: An expeditious synthesis of 13-deoxy-isatisine A. Chem. - Eur. J. 2012, 18, 9601. (e) Gu, W.; Zhang, Y.; Hao, X.-J.; Yang, F. M.; Sun, Q.-Y.; Morris-Natschke, S. L.; Lee, K.H.; Wang, Y.-H.; Long, C.-L. Indole alkaloid glycosides from the aerial parts of Strobilanthescusia. J. Nat. Prod. 2014, 77, 2590. (7) (a) Chen, S.; Wang, Y.; Zhou, Z. Organo-catalyzed asymmetric Michael addition of 1-acetylindolin-3-ones to β,γ-unsaturated αketoesters: An access to chiral indolin-3-ones with two adjacent tertiary stereogenic centers. J. Org. Chem. 2016, 81, 11432. (b) Chen, T.-G.; Fang, P.; Hou, X.-L.; Dai, L.-X. Palladium-Catalyzed asymmetric allylic alkylation reaction of 2-monosubstituted indolin-3-ones. Synthesis 2015, 47, 134. (c) Yin, Q.; You, S.-L. Chiral phosphoric acid-catalysed Friedel−Crafts alkylation reaction of indoles with racemic spiroindolin-3-ones. Chem. Sci. 2011, 2, 1344. (d) Guo, J.; Lin, Z.-H.; Chen,

K.-B.; Xie, Y.; Chen, A. S. C.; Weng, J.; Lui, G. Asymmetric amination of 2-substituted indolin-3-ones catalyzed by natural cinchona alkaloids. Org. Chem. Front. 2017, 4, 1400. (e) Liu, Y.-Z.; Zhang, J.; Xu, P.-F.; Luo, Y.-C. Organocatalytic asymmetric Michael addition of 1-acetylindolin3-ones to α,β-unsaturated aldehydes: Synthesis of 2-substituted indolin-3-ones. J. Org. Chem. 2011, 76, 7551. (f) Jin, C.-Y.; Wang, Y.; Liu, Y.-Z.; Shen, C.; Xu, P.-F. Organocatalytic asymmetric Michael addition of oxindoles to nitroolefins for the synthesis of 2,2disubstituted oxindoles bearing adjacent quaternary and tertiary stereocenters. J. Org. Chem. 2012, 77, 11307. (g) Zhao, Y.-L.; Wang, Y.; Cao, J.; Liang, Y.-M.; Xu, P.-F. Organocatalytic asymmetric MichaelMichael cascade for the construction of highly functionalized N-fused piperidino-indoline derivatives. Org. Lett. 2014, 16, 2438. (h) Mahajan, S.; Chauhan, P.; Loh, C. C. J.; Uzungelis, S.; Raabe, G.; Enders, D. Organocatalytic asymmetric domino Michael/Henry reaction of indolin-3-ones with O-formyl-β-nitrostyrenes. Synthesis 2015, 47, 1024. (i) Sun, W.; Hong, L.; Wang, R. Chem. - Eur. J. 2011, 17, 6030. (j) Ni, Q.; Raabe, G.; Enders, D.; Song, X. N-Heterocyclic carbenecatalyzed enantioselective annulation of indolin-3-ones with bromoenals. Chem. - Asian J. 2014, 9, 1535. (k) Rueping, M.; Raja, S.; Nunez, A. Asymmetric Brønsted acid-catalyzed Friedel−Crafts reactions of indoles with cyclic imines: Efficient generation of nitrogen substituted quaternary carbon centers. Adv. Synth. Catal. 2011, 353, 563. (l) Nakamura, S.; Matsuda, N.; Ohara, M. Organocatalytic enantioselective aza-Friedel-Crafts reaction of cyclic ketimines with pyrroles using imidazoline-phosphoric acid catalysts. Chem. - Eur. J. 2016, 22, 1. (m) Parra, A.; Alfaro, R.; Marzo, L.; Moreno-Carrasco, A.; Ruano, J. L. G.; Alema, J. Enantioselective aza-Henry reactions of cyclic α-carbonyl ketimines under bifunctional catalysis. Chem. Commun. 2012, 48, 9759. (n) Yin, Q.; You, S.-L. Chiral phosphoric acid-catalysed Friedel−Crafts alkylation reaction of indoles with racemic spiroindolin-3-ones. Chem. Sci. 2011, 2, 1344. (o) Schendera, E.; Lerch, S.; Drathen, T. V.; Unkel, L.-N.; Brasholz, M. Phosphoric acid catalyzed 1,2-rearrangements of 3-hydroxyindolenines to indoxyls and 2oxindoles: Reagent-controlled regioselectivity enabled by dual activation. Eur. J. Org. Chem. 2017, 22, 3134. (p) Kumar, C. V. S.; Puranik, V. G.; Ramana, C. V. InCl3-mediated addition of indole to isatogens: An expeditious synthesis of 13-deoxy-isatisine A. Chem. - Eur. J. 2012, 18, 9601. (8) (a) Liu, R.-R.; Ye, S.-C.; Lu, C.-J.; Gao, G.-L.; Zhuang, J.-R.; Jia, Y.X. Dual catalysis for the redox annulation of nitroalkynes with indoles: Enantioselective construction of indolin-3-ones bearing quaternary stereocenters. Angew. Chem., Int. Ed. 2015, 54, 11205. (b) Gajulapalli, V. P. R.; Jafari, E.; Kundu, D. S.; Mahajan, S.; Peuronen, A.; Rissanen, K.; Enders, D. Organocatalytic asymmetric synthesis of 2,3′-connected bis-indolinones by Mannich reactions of N-acetylindolin-3-ones with isatin N-Boc-ketimines. Synthesis 2017, 49, 4986. (c) Rueping, M.; Rasappan, R.; Raja, S. Asymmetric proline-catalyzed addition of aldehydes to 3H-indol-3-ones: Enantioselective synthesis of 2,3dihydro-1H-indol-3-ones with quaternary stereogenic centers. Helv. Chim. Acta 2012, 95, 2296. (d) Yan, W.; Wang, D.; Feng, J.; Li, P.; Zhao, D.; Wang, R. Synthesis of N-alkoxycarbonyl ketimines derived from isatins and their application in enantioselective synthesis of 3aminooxindoles. Org. Lett. 2012, 14, 2512. (e) Zhao, K.; Shu, T.; Jia, J.; Raabe, G.; Enders, D. An organocatalytic Mannich/denitration reaction for the asymmetric synthesis of 3-ethylacetate-substitued 3-amino-2oxindoles: Formal synthesis of AG-041R. Chem. - Eur. J. 2015, 21, 3933. (f) Hara, N.; Nakamura, S.; Sano, M.; Amura, R.; Funahashi, Y.; Shibata, N. Enantioselective synthesis of AG-041R by using Nheteroarenesulfonyl cinchona alkaloid amides as organocatalysts. Chem. - Eur. J. 2012, 18, 9276. (g) Liu, Y.-L.; Zhou, J. Organocatalytic asymmetric cyanation of isatin derived N-Boc-ketoimines. Chem. Commun. 2013, 49, 4421. (9) (a) Cai, X.-H.; Xie, B. Recent advances on organo-catalysed asymmetric Mannich reactions. ARKIVOC 2013, 264. (b) Ishitani, H.; Ueno, M.; Kobayashi, S. Enantioselective Mannich-type reactions using a novel chiral zirconium catalyst for the synthesis of optically active βamino acid derivatives. J. Am. Chem. Soc. 2000, 122, 8180. (c) Zhuang, W.; Saaby, S.; Jørgensen, K. A. Direct organocatalytic enantioselective 2176

DOI: 10.1021/acsomega.8b02132 ACS Omega 2019, 4, 2168−2177

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Mannich reactions of ketimines: An approach to optically active quaternary α-amino acid derivatives. Angew. Chem., Int. Ed. 2004, 43, 4476. (d) Verkade, J. M. M.; Hemert, L. J. C. V.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Organo-catalysed asymmetric Mannich reactions. Chem. Soc. Rev. 2008, 37, 29−41. (e) Córdova, A. The direct catalytic asymmetric Mannich reaction. Acc. Chem. Res. 2004, 37, 102. (f) Trost, B. M.; Saget, T.; Hung, C.-I. Direct catalytic asymmetric Mannich reactions for the construction of quaternary carbon stereocenters. J. Am. Chem. Soc. 2016, 138, 3659. (10) (a) Yarlagadda, S.; Reddy, C. R.; Ramesh, B.; Kumar, G. R.; Sridhar, B.; Reddy, B. V. S. Organocatalytic enantioselective Michael addition of 3-indolinone-2-carboxylates to maleimides. Eur. J. Org. Chem. 2018, 1364. (b) Yarlagadda, S.; Sridhar, B.; Reddy, B. V. S. Oxidative asymmetric aza-Friedel−Crafts alkylation of indoles with 3indolinone-2-carboxylates catalyzed by a BINOL phosphoric acid and promoted by DDQ. Chem. - Asian J. 2018, 1327. (c) Yarlagadda, S.; Sankaram, G. S.; Sridhar, B.; Reddy, B. V. S. Asymmetric Robinson annulation of 3-indolinone-2-carboxylates with cyclohexenone: Access to chiral bridged tricyclic hydrocarbazole. Org. Lett. 2018, 20, 4195. (11) CCDC 1842015 and 1887364 contains supplementary Crystallographic data for the structures 3h and 3t. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html. (12) (a) Yarlagadda, S.; Ramesh, B.; Reddy, C. R.; Srinivas, L.; Sridhar, B.; Reddy, B. V. S. Organocatalytic enantioselective amination of 2substituted indolin-3-ones: A strategy for the synthesis of chiral αhydrazino esters. Org. Lett. 2017, 19, 170. (b) Wang, Q.; Leutzsch, M.; Gemmeren, M. V.; List, B. Disulfonimide-catalyzed asymmetric synthesis of β-amino esters directly from N-Boc-amino sulfones. J. Am. Chem. Soc. 2013, 135, 15334. (c) Blom, J.; Vidal-Albalat, A.; Jørgensen, J.; Barløse, C. L.; Jessen, K. S.; Iversen, M. V.; Jørgensen, K. A. Directing the activation of Donor−Acceptor cyclopropanes towards stereoselective 1,3-dipolar cycloaddition reactions by Brønsted base catalysis. Angew. Chem., Int. Ed. 2017, 56, 11831.

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DOI: 10.1021/acsomega.8b02132 ACS Omega 2019, 4, 2168−2177