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Asymmetric Construction of Bispiro[oxindole-pyrrolidine-rhodanine]s via Squaramide-Catalyzed Domino Michael/Mannich [3 + 2] Cycloaddition of Rhodanine Derivatives with N-2,2,2-Trifluoroethylisatin Ketimines Yong-Xing Song, and Da-Ming Du J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01245 • Publication Date (Web): 29 Jun 2018 Downloaded from http://pubs.acs.org on June 30, 2018

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The Journal of Organic Chemistry

Asymmetric Construction of bispiro[oxindole-pyrrolidine-rhodanine]s via

Squaramide-Catalyzed

Domino

Michael/Mannich

[3

+

2]

Cycloaddition of Rhodanine Derivatives with N-2,2,2-Trifluoroethylisatin Ketimines Yong-Xing Song and Da-Ming Du* School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, People’s Republic of China E-mail: [email protected]

ABSTRACT Squaramide catalyzed asymmetric domino Michael/Mannich [3 + 2] cycloaddition reaction between rhodanine derivatives and N-2,2,2-trifluoroethylisatin ketimines has been developed to synthesize various bispiro[oxindole-pyrrolidine-rhodanine]s with good to excellent yields (up to 99%) and excellent stereoselectivities (up to >99% ee and >99:1 dr). The biologically active rhodanine, oxindole and pyrrolidine moieties were embedded in these novel bispirocyclic products, which will provide some support for the enrichment of chiral heterocyclic compounds databases with potential medical value.

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INTRODUCTION Chiral pyrrolidines have long been considered as the "parent nuclear structure" in many natural bioactive products and pharmaceuticals.1 As an important branch of the pyrrolidine molecule, spiro pyrrolidine2 has many special biological activities and so it is always an extremely attractive synthetic target as the intermediate for the further synthesis of complex molecules.3 Chiral spirocyclic compounds, characterized by an interesting connection of two rings through a quaternary carbon atom, are usually found in many natural products and bioactive compounds.4 Due to its unique structural properties, spirocycles have been demonstrated a wide range of therapeutic potentials, which present great challenges for chemists to prepare such compounds using mild conditions from simple and easy-to-get raw materials.5 Meanwhile, owing to the fluorine atom has small atomic radius and high electronegativity,6 organofluorine compounds always play a very important role in pharmaceuticals and pesticides.7 Among the fluorinated compounds, the trifluoromethyl group occupies a special position, especially when the trifluoromethyl is in the α-position of the nitrogen atom, meanwhile the N atom is considered as a low basic amide, which is considered to be one of the key factors affecting the affinity of the drug receptor.8 However, the methodological choice of introducing the trifluoromethyl group to the desired location is still limited compared to the mono-fluorination process.9 Therefore, the development of diverse synthetic strategies and methods to synthesize trifluoromethyl-containing compounds has been pursued by chemists in recent decades.10 F O

O HN O

S

N H OMe

potent agonist

H N

O

F

O

O

S CF3

N H

S N Me O

antidiabetic

COOH

N S

Br

antibacterial

Figure 1. Biologically active thiazolidinones and spirooxindole On the other hand, 2-thioxo-1,3-thiazolidin-4-one, commonly named as rhodanine, has long been sought after by pharmacologists as an important compound in medicinal chemistry.11 As a peculiar


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structure with pharmacological activity (Figure 1), the modification of rhodamine attracted the attention of chemists.12 Up to now, only a few cases of asymmetric synthetic methods have been reported for the preparation of chiral thiazolidinone derivatives (Scheme 1).13 In 2012, Ye and co-workers first disclosed to synthesize various spirocyclic compounds via a diamine-catalyzed asymmetric tandem reaction between α,β-unsaturated ketones and rhodanine derivatives.13a Then in 2013, Ye and co-workers reported the synthesis of various spirocyclic compounds via trienamine catalyzed asymmetric Diels– Alder reaction between 2,4-dienals and rhodanine/hydantoin derivatives.13b In 2015, Peng and coworkers developed an efficient and convenient one-pot, three-component tandem reaction for the asymmetric synthesis of diverse spirocyclic drug-like skeletons.13c In the same year, Deng and coworkers reported a highly efficient asymmetric 1,3-dipolar cycloaddition of azomethine ylides to 5alkylidene thia(oxa)zolidine-2,4-diones catalyzed by a chiral N,O-ligand/Cu(CH3CN)4BF4 system.13d From a comprehensive point of view, the corresponding asymmetric studies on thiazolidinone derivatives were based on the mono-spirocyclic structures. Therefore, combining the three classes of key heterocyclic motifs (oxindole, pyrrolidine, rhodanine) and CF3 group through two unique spiroquaternary stereogenic carbons would rebuild structurally novel bispiro[oxindole-pyrrolidinerhodanine]s containing trifluoromethyl group. The resulting novel bispirocyclic heterocycles may provide some unprecedented benefits to medicinal chemistry, with the hope of finding valuable applications in drug discovery. Recently, N-2,2,2-trifluoroethylisatin ketimines serving as efficient azomethine ylide precursors have been used to generate structurally diverse CF3-containing spiro-pyrrolidine-oxindole derivatives.14 Meanwhile, based on our continuing interest in the construction of diverse complex and novel spirocyclic

oxindole

skeletons

with

organocatalysis,15

we

envisioned

that

CF3-containing

bispiro[oxindole-pyrrolidine-rhodanine]s 3 with multiple stereocenters, including two spiro quaternary centers, could be constructed by the domino Michael/Mannich [3 + 2] cycloaddition reactions between the rationally designed isatin-derived CF3-containing azomethine ylides 2 with rhodamine derivatives 1.



Page 4 of 34

Scheme 1. Asymmetric Study of Thiazolidinone Derivatives

RESULTS AND DISCUSSION The

initial

investigation

commenced

with

the

reaction

of

ethyl

2-(4-oxo-3-phenyl-2-

thioxothiazolidin-5-ylidene)acetate 1a and N-2,2,2-trifluoroethylisatin ketimine 2a in dichloromethane at room temperature. Using quinine-derived squaramide C1 as the catalyst, the reaction could give the bispirocyclic compound 3aa in 97% yield with 88% ee and >99:1 dr after 12 h (Table 1, entry 1). Inspired by this good result, a series of bifunctional organocatalysts C2‒C12 (Figure 2) were evaluated for this cascade reaction under the same experimental conditions. It was found that a cinchona alkaloid


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skeleton was essential for achieving high asymmetric induction (Table 1, entries 1‒9 and 12 vs. entries 10 and 11). Although catalyst C3 is superior to catalyst C1 in terms of yield and enantioselectivity, it is significantly reduced in diastereoselectivity (Table 1, entry 3). The catalyst C4 has better enantioselectivity than the catalyst C1, but the yield and the diastereoselectivity decrease (Table 1, entry 4). The catalyst C5 and catalyst C9 showed similar effects, but the enantioselectivity decreased, especially the catalyst C9 (Table 1, entries 5 and 9). Catalyst C12 decreased slightly in the aspect of stereoselectivity (Table 1, entry 12). The experimental results show that the catalysts C2, C6, C7, and C8 are superior to the catalyst C1, in particular, the catalytic effect of the catalyst C2 (Table 1, entries 2, 6, 7 and 8).

Figure 2. Structures of screened organocatalysts



Page 6 of 34

Table 1. Optimization of Reaction Conditionsa

Entry

Solvent

Catalyst

Yieldb (%)

drc

eed (%)

1 CH2Cl2 C1 97 >99:1 88 2 CH2Cl2 C2 99 99:1 94 C3 98 86:14 95 3 CH2Cl2 4 CH2Cl2 C4 92 97:3 ‒90 C5 98 >99:1 86 5 CH2Cl2 6 CH2Cl2 C6 98 99:1 92 C7 99 >99:1 90 7 CH2Cl2 8 CH2Cl2 C8 99 99:1 93 C9 98 >99:1 76 9 CH2Cl2 10 CH2Cl2 C10 94 95:5 14 C11 96 99:1 32 11 CH2Cl2 12 CH2Cl2 C12 99 96:4 84 C2 94 99:1 95 13 CHCl3 14 toluene C2 79 94:6 95 15 THF C2 99 81:19 55 16 Et2O C2 84 90:10 90 17 dioxane C2 39 82:18 37 18 CH3CN C2 96 5:95 0, 2 DCE C2 85 98:2 94 19 20 xylene C2 79 96:4 96 CH2Cl2 C2 99 98:2 96 21e 22f CH2Cl2 C2 97 99:1 95 CH2Cl2 C2 95 98:2 95 23g 24h CH2Cl2 C2 98 99:1 95 a Reaction conditions: 1a (0.10 mmol), 2a (0.12 mmol), and catalyst (10 mol%) in solvent (1.0 mL) was stirred at room temperature for 12 h. b Isolated yield after column chromatography purification. c Diastereomeric ratio (dr) was determined by HPLC analysis. d Enantiomeric excess (ee) was determined by HPLC analysis. e The reaction was performed with 5 mol% catalyst for 12 h. f The reaction was performed with 2.5 mol% catalyst for 24 h. g The reaction was performed at 0 C for 16 h. h The reaction was performed at 10 C for 24 h.

With optimal catalyst C2 identified, the screening of a variety of solvents including chloroform, toluene, THF, diethyl ether, dioxane, acetonitrile, 1,2-dichloroethane (DCE) and xylene was performed (Table 1, entries 13‒20). Dichloromethane was the best solvent for this reaction under the same experimental conditions. When lowering the catalyst loading from 10 mol% to 5 mol%, there was no effect on the reactivity and stereoselectivity (Table 1, entry 21). Further decreasing the catalyst loading to 2.5 mol%, an excellent yield and diastereo- and enantiocontrol could still be achieved but with a prolonged reaction time (Table 1, entry 22). When the reaction temperature decreased, there was no


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significant difference in the results of the reaction except for the prolonged reaction time (entries 23 and 24). As the conditions of choice, we utilized rhodamine derivatives and N-2,2,2-trifluoroethylisatin ketimines at a molar ratio of 1:1.2 in dichloromethane with 5 mol% catalyst C2 at room temperature for 12 h. Table 2. Substrate Scope of Rhodamine Derivatives 1a R2 N

O R1

N R2

S

N S

S

CF3

S

S

NH O

S

N Bn 3aa, 99% yield 99:1 dr, 96% ee

Ph

OBoc

N

CF3

S

NH O

S

Ph S

OCO2Et

N

CF3

S

NH O

Bn

OPh

N CF3

NH O

N Bn 3aa-3na

OCN

N

CF3

S

2a

Ph

OCO2Et

N

S

5 mol% C2 CH2Cl2, r.t., 12 h

Bn

1

Ph

CF3 O

+

OR1

N

S

NH O

S

N Bn

N Bn

N Bn

3ba, 96% yield 99:1 dr, 93% ee

3ca, 95% yield 92:8 dr, 83% ee

CF3 NH O N Bn

3da N.R.

3ea, 85% yield 99:1 dr, 97% ee H3C

S

H3C

OCO2Et

N

CF3

S

S

NH O N Bn

N S

OCO2Et CF3 NH O

N S

S

N Bn

3fa, 94% yield 99:1 dr, >99% ee

S

S

N

CF3

N Bn 3ka, 97% yield 99:1 dr, 90% ee

S

S

S

NH O

N Bn 3la, 90% yield 98:2 dr, 91% ee

S

NH O

S

N Bn

OCO2Et CF3 NH O N Bn

3ia, 65% yieldb >99:1 dr, 57% ee

3ja, 97% yield 99:1 dr, 90% ee Br

OCO2Et CF3

N

CF3

S

Cl

OCO2Et NH O

CF3 NH O

3ha, 97% yield 99:1 dr, >99% ee

F

N

OCO2Et

HN

N Bn

3ga, 93% yield 98:2 dr, 95% ee

H3CO

OCO2Et

N S

S


3ma, 98% yield 99:1 dr, 90% ee

N S

S


3na, 99% yield 98:2 dr, 91% ee

a Unless noted otherwise, the reaction was carried out with 1 (0.10 mmol), 2a (0.12 mmol), and catalyst C2 (0.005 mmol) in CH2Cl2 (1.0 mL) at r.t. for 12 h. The yields were isolated after column chromatography. The dr and ee values were determined by chiral HPLC analysis. bThe reaction time is 60 h.

Having identified the optimal reaction conditions (Table 1, entry 21), we then explored the generality of this Michael/Mannich cycloaddition reaction. Firstly, the scope of the rhodamine derivatives 1 was



Page 8 of 34

examined (Table 2). As illustrated in Table 2, the reaction showed good functional group tolerance, and a variety of bispiro[oxindole-pyrrolidine-rhodanine]s 3aa‒3na were obtained in high yields (65‒99%) with excellent enantio- and diastereoselectivities (92:8‒>99:1 dr and 57‒>99% ee). The effect of the substituents R1 on the rhodamine derivatives were first investigated. When R1 = Boc, the reaction can still proceed with very high yield and stereoselectivity; and when R1 = CN, the enantioselectivity and diastereoselectivity of the reaction are reduced. However, when R1 = Ph, the reaction cannot occur. We tried to synthesize alkyl-substituted rhodamine derivatives, but unfortunately we failed to obtain the corresponding substrates. Then we studied the effect of substituent R2 on the nitrogen atom of rhodamine. The experimental results show that regardless of the R2 substituent (aliphatic or aromatic), the reaction proceeds smoothly with high yield and stereoselectivity (Table 2, 3ea‒3ha). However, when R2 = H, the reaction time becomes longer and the yield and enantioselectivity decrease. We believe that this substrate may bind to the catalyst and reduce the catalytic activity of the catalyst. It was found that either electron-donating (1j and 1k) or electron-withdrawing substituents (1l‒1n) on the benzene ring were tolerated and delivered the desired bispiro[oxindole-pyrrolidine-rhodanine]s 3ja‒3na in excellent yields (90‒99%) with excellent diastereoselectivities (98:2‒99:1 dr) and enantioselectivities (90‒91% ee) (Table 2, 3ja‒3na). Further exploration of the substrate scope was focused on the N-2,2,2-trifluoroethylisatin ketimines 2b‒2m bearing various substituents (Table 3). As shown in Table 3, a series of ketamines 2b‒2m tolerated the reaction and furnished the corresponding products 3ab‒3am in high to excellent yields (8099%) with high to excellent stereoselectivity (86:14‒>99:1 dr and 80‒>99% ee). For example, the ketimines bearing electron-donating groups (MeO- and Me-) or electron-withdrawing groups (Cl- and Br-) at the 5-position of the indolinone ring led to the similar enantioselectivity of 93‒>99% ee and 93:7‒99:1 dr (Table 3, 3ab, 3ac, 3af and 3ah). However, when the substrate 2d with 5,7-dimethyl group was used, the yield and diastereoselectivity of the corresponding product was decreased (Table 3, 3ad). When R3 is 5-F, the stereoselectivity of the reaction was decreased (Table 3, 3ae). When Cl was in the 6-position of the ketimine, the yield and stereoselectivity of the reaction was also decreased (Table 3,


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3ag). Moreover, we also evaluated the substitution at the 1-position of ketamines. As summarized in Table 3, with or without the substituent at the 1-position, N-(2,2,2-trifluoroethyl)-ketimine showed good reactivity, and the [3 + 2] cycloaddition reaction gave the products in high to excellent yields with high to excellent stereoselectivities (Table 3, 3ai‒3am). Table 3. Substrate Scope of Ketimines 2a

a

Unless noted otherwise, the reaction was carried out with 1a (0.10 mmol), 2 (0.12 mmol), and catalyst C2 (0.005 mmol) in CH2Cl2 (1.0 mL) at r.t. for 12 h. The yields were isolated after column chromatography. The dr and ee values were determined by chiral HPLC analysis.

In order to demonstrate the practical utility and robustness of this asymmetric domino Michael/Mannich [3 + 2] cycloaddition, the reaction between 1a and 2a was conducted on a gram scale (3.0 mmol) using our standard conditions, and the bispirocyclic product 3aa could be obtained in 95%



Page 10 of 34

yield with >99:1 dr and 91% ee (Scheme 2). In addition, regioselective N-methylation of 3ai (88% ee) was achieved at the N1 position of indolinone, and product 3aj was obtained in 96% yield with 99:1 dr and 88% ee (Scheme 3a). Finally, we also tried to demonstrate the synthetic transformation of these products. The rhodanine moiety could be easily oxidized to thiazolidine-2,4-dione using chromium trioxide as the oxidant, and the corresponding new type bispirocyclic heterocycle 4 was obtained in 87% yield (Scheme 3b).

Scheme 2. Gram-scale Experiment

Scheme 3. Synthetic Transformations of the Bispiro[oxindole-pyrrolidine-rhodanine]s.

To determine the absolute configurations of the target products, a single crystal of compound 3na was obtained by recrystallization from petroleum ether/ethyl acetate. As show in Figure 3, the absolute


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configuration of 3na was determined to be (3S,3'R,4'S,5'S). The absolute configurations of the other products were assigned by analogy with 3na.16

Br

OCO2Et

N S

(R)

S

(S)

(S)

CF3

(S)

NH O

N Bn 3na

Figure 3. X-ray crystal structure of compound 3na (displacement ellipsoids are drawn at the 50% probability level) As shown in Figure 4, based on our experiments and previously reported17 dual activation model, we proposed a plausible mechanism for this domino Michae/Mannich [3 + 2] cycloaddition reaction. In the first Michael addition step, catalyst C2 initially promoted the formation of transition state A through deprotonation of the N-2,2,2-trifluoroethylisatin ketimine 2a. Then both 1a and 2a were simultaneously activated via hydrogen bonding interactions with catalyst C2. Afterwards, the rhodanine is attacked by the deprotonated N-2,2,2-trifluoroethylisatin ketimine from the Si-face via transition state B, which undergoes an intermolecular Michael addition. Subsequently, the resulting nucleophilic rhodanine anion attacks the C=N double bond of the imine in a Mannich cyclization reaction via intermediate C, which delivers the observed bispirocyclic product 3aa and regenerates the bifunctional catalyst C2 after a protonation process.



O

F3C

Ph S

H

OCO2Et

N

CF3

S

O

N H

N

HN

OMe C2

CF3

N

NH O

N O

N Bn 3aa

F3C

O

O

N H

N H

N Bn 2a

chiral scaffold N

CF3

CF3

S N Ph O

F3C

O

N

H

CF3 H

N

N Bn H N

H

O

N

N CF3 S S

C

N

N Bn

Ph H

O

EtO2C

O

N N

CF3 N H N

O Si-face attack

H

N

A O

chiral scaffold

H

O

O chiral scaffold

EtO2C

S

O

N

H

O

N

chiral scaffold

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 34

N Bn

O EtO2C S 1a

N Ph S

B

Figure 4. Proposed mechanism for the domino Michael/Mannich [3 + 2] cycloaddition reaction

CONCLUSIONS In conclusion, we have developed a highly diastereo- and enantioselective domino Michael/Mannich [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines with rhodamine derivatives. In the presence of a squaramide-tertiary amine catalyst, a wide range of CF3-containing bispiro[oxindolepyrrolidine-rhodanine]s bearing four consecutive stereocenters, including two vicinal spiro-quaternary chiral centers, were efficiently obtained with excellent results (up to 99% yield, >99:1 dr, and >99% ee).


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A large-scale experiment and further transformation of the products were also successfully performed to demonstrate the promising applicability of the methodology. We expect that the availability of these CF3-containing bispiro[oxindole-pyrrolidine-rhodanine]s will provide promising drug candidates for chemical biology and drug discovery.

EXPERIMENTAL SECTION General Information. All commercial reagents were used without further purification. Solvents were distilled according to the purification procedures. Column chromatography was performed with silica gel (200–300 mesh). Melting points were determined with an XT-4 melting-point apparatus and are uncorrected. 1H NMR spectra were measured with 400 MHz spectrometer, chemical shifts were reported in δ (ppm) units relative to tetramethylsilane (TMS) as internal standard.

13

C NMR spectra

were measured at 176 MHz with 700 MHz spectrometer, chemical shifts are reported in ppm relative to tetramethylsilane and referenced to solvent peak (CDCl3, δ C = 77.00 ppm).

19

F NMR spectra were

measured at 376 MHz. Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). High-resolution mass spectra were recorded with an Agilent 6520 Accurate-Mass-Q-TOF MS system equipped with an electrospray ionization (ESI) source. Enantiomeric excesses were determined by chiral HPLC analysis using an Agilent 1200 LC instrument with a Daicel Chiralpak IA, IB, IC and AD-H column. Optical rotations were measured with a polarimeter at the indicated concentration with the units of g/100 mL. 1a‒1n were prepared according to the literature.18 2a‒2m were prepared according to literature reported by Wang and co-workers and slightly modified.14a The squaramide organocatalysts were prepared by following the reported procedures.19 General Procedure for Asymmetric Domino Michael/Mannich [3 + 2] Cycloaddition Reaction. Rhodamine derivatives 1 (0.10 mmol) and N-2,2,2-trifluoroethylisatin ketimines 2 (0.12 mmol), and catalyst C2 (5 mol%) in CH2Cl2 (1.0 mL) was stirred at room temperature for 12 h. After completion of the reaction (monitored by TLC analysis), the crude product was purified by flash column



Page 14 of 34

chromatography on silica gel (PE/EtOAc 8:1) to afford the pure product 3. The chiral catalyst was replaced by Et3N, and the other conditions remain unchanged to obtain racemates of 3. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)dispiro-

[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3aa). Obtained as a light yellow solid (60.5 mg, 99% yield), mp 94‒96 ℃. HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 14.0 min (minor), tR = 8.8 min (major); minor diastereoisomer: tR = 32.7 min (minor), tR = 6.9 min (major); 99:1 dr, 96% ee for the major diastereoisomer. [α]D20 = 189.7 (c 4.01, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 8.2 Hz, 1H), 7.18 (t, J = 7.6 Hz, 3H), 7.11 (t, J = 7.2 Hz, 2H), 7.04 (t, J = 7.6 Hz, 1H), 6.70‒6.66 (m, 3H), 5.25 (d, J = 10.8 Hz, 1H), 5.22 (d, J = 16.8 Hz, 1H), 4.65‒4.55 (m, 1H), 4.41‒4.33 (m, 2H), 4.27‒4.19 (m, 1H), 2.93 (d, J = 8.0 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.0, 173.3, 170.8, 167.1, 143.6, 134.8, 134.5, 131.3, 129.6, 129.4, 128.7, 127.9, 127.6, 127.3, 126.6, 124.6 (q, 1JCF = 280.4 Hz), 123.6, 122.7, 109.5, 73.8, 73.2, 62.5, 60.3 (q, 2JCF = 32.8 Hz), 51.4, 44.6, 14.2 ppm.

19

F NMR (376 MHz,

CDCl3): δ 71.60 ppm. HRMS (ESI): m/z calcd. for C30H25F3N3O4S2 [M + H]+ 612.1233, found 612.1243. (3S,3'R,4'S,5'S)-tert-Butyl

1-benzyl-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)dispiro-

[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ba). Obtained as a light yellow solid (61.4 mg, 96% yield), mp 164‒167 ℃. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 7.3 min (minor), tR = 6.2 min (major); minor diastereoisomer: tR = 25.9 min (minor), tR = 5.5 min (major); 99:1 dr, 93% ee for the major diastereoisomer. [α]D20 = 187.5 (c 2.75, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.35‒7.25 (m, 3H), 7.18 (t, J = 7.2 Hz, 3H), 7.12‒7.03 (m, 3H), 6.67 (d, J = 8.0 Hz, 3H), 5.23 (d, J = 15.6 Hz, 1H), 5.19 (d, J = 10.0 Hz, 1H), 4.58‒4.52 (m, 1H), 4.37 (d, J = 15.6 Hz, 1H), 2.88 (d, J = 7.2 Hz, 1H), 1.49 (s, 9H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.3, 173.4, 170.7, 166.0, 143.6, 134.8, 134.6, 131.3, 129.6, 129.4, 128.7, 127.9, 127.6, 127.4, 126.6, 124.7 (q, 1JCF =


Page 15 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


280.4 Hz), 123.6, 122.7, 109.5, 83.9, 73.9, 73.5, 60.3 (q, 2JCF = 32.6 Hz), 51.7, 44.6, 27.9 ppm. 19F NMR (376 MHz, CDCl3): δ 71.53 ppm. HRMS (ESI): m/z calcd. for C32H29F3N3O4S2 [M + H]+ 640.1546, found 640.1562. (3S,3'R,4'S,5'S)-1-benzyl-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)dispiro[indoline3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carbonitrile (3ca). Obtained as a light yellow solid (53.4 mg, 95% yield), mp 110‒113 ℃. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 7.6 min (minor), tR = 18.1 min (major); minor diastereoisomer: tR = 14.8 min (minor), tR = 9.5 min (major); 92:8 dr, 83% ee for the major diastereoisomer. [α]D20 = 28.8 (c 1.83, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.6 Hz, 1H), 7.48‒7.33 (m, 5H), 7.18 (s, 4H), 7.13 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 5.2 Hz, 2H), 6.78 (d, J = 8.0 Hz, 1H), 5.21 (d, J = 15.6 Hz, 1H), 5.05 (d, J = 9.2 Hz, 1H), 4.54‒4.45 (m, 2H), 3.27 (d, J = 9.6 Hz, 1H) ppm.

13

C NMR (176 MHz, CDCl3): δ 193.0, 171.7, 171.2, 143.3, 134.2, 134.1, 131.8, 130.0, 129.6,

129.0, 128.0, 127.9, 127.3, 127.1, 125.5, 124.1, 123.6, 123.5 (q, 1JCF = 280.2 Hz), 114.8, 110.2, 74.1, 70.9, 63.1 (q, 2JCF = 33.1 Hz), 44.7, 38.3 ppm.

19

F NMR (376 MHz, CDCl3): δ 72.68 ppm. HRMS

(ESI): m/z calcd. for C28H20F3N4O2S2 [M + H]+ 565.0974, found 565.0969. (3S,3'R,4'S,5'S)-Ethyl

1,3''-dibenzyl-2,4''-dioxo-2''-thioxo-5'-(trifluoromethyl)dispiro[indoline-

3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ea). Obtained as a light yellow solid (53.2 mg, 85% yield), mp 90‒93 ℃. HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 13.3 min (minor), tR = 11.5 min (major); minor diastereoisomer: tR = 8.0 min (minor), tR = 8.9 min (major); 99:1 dr, 97% ee for the major diastereoisomer. [α]D20 = 331.3 (c 2.12, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 7.6 Hz, 1H), 7.25‒7.18 (m, 6H), 7.11 (t, J = 7.4 Hz, 1H), 7.04‒6.97 (m, 3H), 6.84 (d, J = 7.6 Hz, 2H), 6.56 (d, J = 8.0 Hz, 1H), 5.35 (d, J = 9.6 Hz, 1H), 5.04‒4.93 (m, 3H), 4.52‒4.46 (m, 2H), 4.15‒4.07 (m, 1H), 3.97‒3.89 (m, 1H), 2.76 (d, J = 7.2 Hz, 1H), 1.01 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.8, 173.8, 170.9, 166.6, 143.6, 134.9, 133.7, 131.2, 128.6, 128.4, 127.7, 127.64, 127.57, 126.8, 124.6 (q, 1JCF = 280.6 Hz), 122.9, 122.5, 109.7, 72.93, 72.88, 62.2, 59.7 (q, 2JCF = 32.9 Hz), 51.5,



47.6, 44.5, 13.8 ppm.

19

Page 16 of 34

F NMR (376 MHz, CDCl3): δ 71.38 ppm. HRMS (ESI): m/z calcd. for

C31H27F3N3O4S2 [M + H]+ 626.1390, found 626.1402. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-3''-cyclohexyl-2,4''-dioxo-2''-thioxo-5'-(trifluoromethyl)dispiro-

[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3fa). Obtained as a light yellow solid (58.3 mg, 94% yield), mp 190‒193 ℃. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 15.4 min (minor), tR = 58.9 min (major); minor diastereoisomer: tR = 7.3 min (minor), tR = 6.0 min (major); 99:1 dr, >99% ee for the major diastereoisomer. [α]D20 = 207.0 (c 1.58, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.29 (d, J = 6.8 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.23‒5.19 (m, 2H), 4.53‒4.46 (m, 2H), 4.41 (d, J = 15.6 Hz, 1H), 4.30‒4.22 (m, 1H), 4.16‒4.08 (m, 1H), 2.76 (d, J = 7.2 Hz, 1H), 2.14 (q, J = 12.0 Hz, 1H), 1.76 (d, J = 12.8 Hz, 1H), 1.66 (d, J = 10.8 Hz, 1H), 1.55‒1.45 (m, 3H), 1.30‒1.23 (m, 1H), 1.18 (t, J = 7.0 Hz, 3H), 1.09‒1.07 (m, 2H), 0.71‒0.68 (d, J = 10.4 Hz, 1H) ppm. 13C NMR (176 MHz, CDCl3): δ 196.0, 173.7, 170.9, 167.0, 143.6, 135.1, 131.2, 128.7, 128.2, 127.8, 126.6, 124.7 (q, 1JCF = ‒280.4 Hz), 123.3, 122.5, 109.1, 73.2, 70.3, 62.2, 60.0 (q, 2JCF = 32.7 Hz), 58.5, 51.0, 44.7, 27.2, 26.6, 25.77, 25.75, 24.7, 14.1 ppm.

19



1-benzyl-3''-methyl-2,4''-dioxo-2''-thioxo-5'-(trifluoromethyl)dispiro-

[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ga). Obtained as a light yellow solid (51.2 mg, 93% yield), mp 79‒82 ℃. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 8.1 min (minor), tR = 16.3 min (major); minor diastereoisomer: tR = 5.6 min (minor), tR = 6.5 min (major); 98:2 dr, 95% ee for the major diastereoisomer. [α]D20 = 239.6 (c 2.56, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 7.6 Hz, 1H), 7.32‒7.26 (m, 5H), 7.22 (t, J = 8.0 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.22‒5.18 (m, 2H), 4.58‒4.47 (m, 2H), 4.26‒4.20 (m, 1H), 4.15‒4.08 (m, 1H), 3.21 (s, 3H), 2.83 (d, J = 7.6 Hz, 1H), 1.55 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.2, 173.4, 171.4, 166.8,


Page 17 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


143.5, 135.0, 134.5, 131.2, 128.7, 127.8, 127.6, 126.7, 124.6 (q, 1JCF = ‒280.4 Hz ), 123.7, 122.6, 109.5, 73.0, 72.6, 62.3, 60.0 (q, 2JCF = 32.7 Hz ), 52.3, 44.4, 31.6, 14.0 ppm. 19F NMR (376 MHz, CDCl3): δ 71.71 ppm. HRMS (ESI): m/z calcd. for C25H23F3N3O4S2 [M + H]+ 550.1077, found 550.1073. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-2,4''-dioxo-3''-propyl-2''-thioxo-5'-(trifluoromethyl)dispiro-

[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ha). Obtained as a light yellow solid (56.3 mg, 97% yield), mp 152‒155 ℃. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 95:5, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 15.0 min (minor), tR = 27.8 min (major); minor diastereoisomer: tR = 9.1 min (minor), tR = 12.9 min (major); 99:1 dr, >99% ee for the major diastereoisomer. [α]D20 = 274.6 (c 2.44, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.27 (d, J = 8.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 5.25 (d, J = 9.6 Hz, 1H), 5.20 (d, J = 15.6 Hz, 1H), 4.55‒4.43 (m, 2H), 4.28‒4.20 (m, 1H), 4.14‒4.06 (m, 1H), 3.82‒3.66 (m, 2H), 2.80 (d, J = 7.2 Hz, 1H), 1.22 (t, J = 7.4 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H), 0.50 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.2, 173.6, 171.0, 166.8, 143.6, 135.1, 131.2, 128.7, 127.9, 127.8, 126.7, 124.6 (q, 1JCF = ‒280.5 Hz), 123.3, 122.5, 109.4, 73.1, 72.5, 62.2, 60.0 (q, 2JCF = 32.7 Hz), 51.6, 46.2, 44.5, 19.7, 13.9, 10.5 ppm.

19

F NMR (376 MHz, CDCl3): δ 71.56 ppm. HRMS (ESI): m/z calcd. for C27H27F3N3O4S2

[M + H]+ 578.1390, found 578.1373. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-2,4''-dioxo-2''-thioxo-5'-(trifluoromethyl)dispiro[indoline-3,2'-

pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ia). Obtained as a white solid (34.8 mg, 65% yield), mp 104‒107 ℃. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 12.2 min (minor), tR = 29.0 min (major); minor diastereoisomer: tR = 9.0 min (major); >99:1 dr, 57% ee for the major diastereoisomer. [α]D20 = 124.5 (c 1.59, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 9.16 (br s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.31‒7.23 (m, 7H), 7.03 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 5.20 (d, J = 9.6 Hz, 1H), 5.14 (d, J = 15.6 Hz, 1H), 4.57‒4.48 (m, 2H), 4.35‒4.27 (m, 1H), 4.21‒4.13 (m, 1H), 2.79 (d, J = 6.8 Hz, 1H), 1.23 (t, J = 7.2 Hz, 3H) ppm.

13

C NMR (176 MHz, CDCl3): δ 194.2, 173.4, 171.5, 166.9, 143.6, 134.9, 131.4, 128.8,



Page 18 of 34

127.8, 127.5, 126.8, 124.6 (q, 1JCF = ‒280.4 Hz), 123.6, 122.7, 109.8, 76.0, 73.0, 62.6, 60.6 (q, 2JCF = 32.7 Hz), 52.2, 44.5, 13.9 ppm. 19F NMR (376 MHz, CDCl3): δ 71.60 ppm. HRMS (ESI): m/z calcd. for C24H21F3N3O4S2 [M + H]+ 536.0920, found 536.0914. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-2,4''-dioxo-2''-thioxo-3''-(p-tolyl)-5'-(trifluoromethyl)dispiro-

[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ja). Obtained as a light yellow solid (61.0 mg, 97% yield), mp 175‒177 ℃. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 75:25, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 11.2 min (minor), tR = 26.2 min (major); minor diastereoisomer: tR = 9.1 min (minor), tR = 6.5 min (major); 99:1 dr, 90% ee for the major diastereoisomer. [α]D20 = 115.8 (c 2.81, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.21‒7.11 (m, 7H), 7.03 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.59 (br s, 2H), 5.24 (d, J = 9.6 Hz, 1H), 5.19 (d, J = 15.6 Hz, 1H), 4.64‒4.55 (m, 1H), 4.42 (d, J = 15.6 Hz, 1H), 4.38‒4.32 (m, 1H), 4.27‒4.19 (m, 1H), 2.92 (d, J = 7.6 Hz, 1H), 2.37 (s, 3H), 1.28 (t, J = 6.8 Hz, 3H) ppm.

13

C NMR (176 MHz, CDCl3): δ 195.2, 173.3, 170.9, 167.1, 143.6, 139.8, 134.8, 131.8,

131.3, 130.1, 128.7, 127.6, 127.5, 127.4, 126.6, 124.6 (q, 1JCF = ‒280.4 Hz), 123.7, 122.7, 109.5, 73.8, 73.1, 62.4, 60.4 (q, 2JCF = 32.6 Hz), 51.4, 44.6, 22.3, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.62 ppm. HRMS (ESI): m/z calcd. for C31H27F3N3O4S2 [M + H]+ 626.1390, found 626.1381. (3S,3'R,4'S,5'S)-Ethyl 1-benzyl-3''-(4-methoxyphenyl)-2,4''-dioxo-2''-thioxo-5'-(trifluoromethyl)dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ka). Obtained as a light yellow solid (62.5 mg, 97% yield), mp 141‒143 ℃. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 25.6 min (minor), tR = 43.5 min (major); minor diastereoisomer: tR = 15.6 min (minor), tR = 20.2 min (major); 99:1 dr, 90% ee for the major diastereoisomer. [α]D20 = 168.9 (c 2.80, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.6 Hz, 1H), 7.28‒7.12 (m, 6H), 7.03 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.0 Hz, 1H), 6.62 (br s, 2H), 5.24‒5.19 (m, 2H), 4.63‒4.57 (m, 1H), 4.40 (d, J = 16.0 Hz, 1H), 4.38‒4.31 (m, 1H), 4.27‒4.19 (m, 1H), 3.80 (s, 3H), 2.93 (d, J = 8.0 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.4, 173.3, 171.0, 167.1, 160.1, 143.5, 134.8, 131.3, 129.0, 128.8, 127.6, 127.4,


Page 19 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


126.9, 126.6, 124.6 (q, 1JCF = ‒280.4 Hz), 123.7, 114.7, 109.5, 73.8, 72.9, 62.4, 60.3 (q, 2JCF = 32.6 Hz), 55.4, 51.4, 44.6, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.63 ppm. HRMS (ESI): m/z calcd. for C31H27F3N3O5S2 [M + H]+ 642.1339, found 642.1331. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-3''-(4-fluorophenyl)-2,4''-dioxo-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3la). Obtained as a light yellow solid (56.7 mg, 90% yield), mp 85‒88 ℃. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 13.6 min (minor), tR = 25.9 min (major); minor diastereoisomer: tR = 12.0 min (minor), tR = 7.8 min (major); 98:2 dr, 91% ee for the major diastereoisomer. [α]D20 = 180.6 (c 2.55, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 7.6 Hz, 1H), 7.30‒7.19 (m, 4H), 7.14 (t, J = 7.0 Hz, 2H), 7.07‒7.00 (m, 3H), 6.70 (d, J = 7.6 Hz, 3H), 5.25‒5.20 (m, 2H), 4.65‒4.56 (m, 1H), 4.41‒4.32 (m, 2H), 4.28‒4.20 (m, 1H), 2.94 (d, J = 8.0 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.9, 173.2, 170.9, 167.2, 162.8 (d, 1JCF = 250.8 Hz), 143.5, 134.8, 131.4, 130.2 (d, 4JCF = 2.8 Hz), 129.9 (d, 3JCF = 9.0 Hz), 128.8, 127.7, 127.4, 126.6, 124.6 (q, 1JCF = ‒280.4 Hz), 122.9, 116.5 (d, 2JCF = 22.9 Hz), 109.5, 73.8, 72.9, 62.5, 60.4 (q, 2JCF = 32.6 Hz), 51.5, 44.6, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.67, 110.32 ppm. HRMS (ESI): m/z calcd. for C30H24F4N3O4S2 [M + H]+ 630.1139, found 630.1132. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-3''-(4-chlorophenyl)-2,4''-dioxo-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ma). Obtained as a light yellow solid (63.4 mg, 98% yield), mp 94‒96 ℃. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 23.1 min (minor), tR = 35.1 min (major); minor diastereoisomer: tR = 20.7 min (minor), tR = 11.9 min (major); 99:1 dr, 90% ee for the major diastereoisomer. [α]D20 = 155.3 (c 2.91, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.6 Hz, 1H), 7.31‒7.19 (m, 6H), 7.13 (t, J = 7.2 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 6.0 Hz, 2H), 5.24‒5.20 (m, 2H), 4.65‒4.56 (m, 1H), 4.39 (d, J = 15.2 Hz, 1H), 4.37‒4.31 (m, 1H), 4.28‒4.20 (m, 1H), 2.93 (d, J = 8.0 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.6, 173.1, 170.8, 167.1, 143.5, 135.7, 134.7, 132.8, 131.4, 129.7, 129.3, 128.7,



Page 20 of 34

127.7, 127.5, 126.6, 124.6 (q, 1JCF = ‒280.4 Hz), 123.7, 122.9, 109.5, 73.9, 73.0, 62.5, 60.4 (q, 2JCF = 32.7 Hz), 51.4, 44.6, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.69 ppm. HRMS (ESI): m/z calcd. for C30H24ClF3N3O4S2 [M + H]+ 646.0843, found 646.0835. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-3''-(4-bromophenyl)-2,4''-dioxo-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3na). Obtained as a light yellow solid (68.5 mg, 99% yield), mp 106‒108 ℃. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 14.8 min (minor), tR = 42.2 min (major); minor diastereoisomer: tR = 18.2 min (minor), tR = 11.7 min (major); 98:2 dr, 91% ee for the major diastereoisomer. [α]D20 = 145.6 (c 3.23, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.30‒7.18 (m, 4H), 7.13 (t, J = 7.2 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 6.0 Hz, 2H), 5.23‒5.19 (m, 2H), 4.63‒4.57 (m, 1H), 4.40‒4.31 (m, 2H), 4.27‒4.19 (m, 1H), 2.93 (d, J = 7.6 Hz, 1H), 1.28 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.5, 173.1, 170.7, 167.1, 143.5, 134.7, 133.3, 132.7, 131.4, 129.6, 128.7, 127.7, 127.5, 126.6, 124.5 (q, 1JCF = ‒280.4 Hz), 123.9, 123.7, 122.8, 109.5, 73.9, 73.1, 62.5, 60.4 (q, 2JCF = 32.8 Hz ), 51.4, 44.6, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.69 ppm. HRMS (ESI): m/z calcd. for C30H24BrF3N3O4S2 [M + H]+ 690.0338, found 690.0328. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-5-methoxy-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ab). Obtained as a light yellow solid (63.7 mg, 99% yield), mp 185‒188 ℃. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 95:5, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 32.0 min (major); minor diastereoisomer: tR = 13.9 min (minor), tR = 17.7 min (major); 98:2 dr, >99% ee for the major diastereoisomer. [α]D20 = 89.9 (c 1.50, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.45‒7.35 (m, 4H), 7.19‒7.11 (m, 5H), 6.82‒6.77 (m, 3H), 6.58 (d, J = 8.8 Hz, 1H), 5.22 (d, J = 15.6 Hz, 1H), 5.15 (d, J = 9.6 Hz, 1H), 4.65‒4.59 (m, 1H), 4.42‒4.33 (m, 2H), 4.28‒4.24 (m, 1H), 3.77 (s, 3H), 2.96 (d, J = 7.2 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.0, 172.8, 171.3, 167.4, 155.8, 136.6, 134.8, 134.5, 129.7, 129.5, 128.8, 128.0, 127.6, 127.3, 125.3, 124.5 (q, 1JCF = ‒280.4 Hz), 116.3,


Page 21 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


113.5, 110.2, 74.3, 72.7, 62.5, 60.8 (q, 2JCF = 32.6 Hz), 56.0, 51.6, 44.7, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.64 ppm. HRMS (ESI): m/z calcd. for C31H27F3N3O5S2 [M + H]+ 642.1339, found 642.1333. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-5-methyl-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ac). Obtained as a light yellow solid (61.8 mg, 99% yield), mp 170‒172 ℃. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 10.1 min (minor), tR = 13.2 min (major); minor diastereoisomer: tR = 6.9 min (minor), tR = 8.8 min (major); 99:1 dr, 93% ee for the major diastereoisomer. [α]D20 = 116.7 (c 1.42, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.56 (s, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.4 Hz, 2H), 7.18 (t, J = 7.0 Hz, 3H), 7.13‒7.06 (m, 3H), 6.71 (br s, 2H), 6.57 (d, J = 8.0 Hz, 1H), 5.23‒5.19 (m, 2H), 4.63‒4.57 (m, 1H, CH), 4.41‒4.33 (m, 2H), 4.29‒4.22 (m, 1H), 2.90 (d, J = 7.6 Hz, 1H), 2.30 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H) ppm.

13

C NMR (176 MHz,

CDCl3): δ 195.2, 173.2, 171.0, 167.2, 141.1, 134.9, 134.5, 132.5, 131.5, 129.4, 129.6, 129.4, 128.7, 128.0, 127.6, 127.4, 124.6 (q, 1JCF = ‒280.4 Hz), 123.8, 109.3, 74.0, 73.1, 62.4, 60.5 (q, 2JCF = 32.7 Hz), 51.4, 44.6, 21.2, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.70 ppm. HRMS (ESI): m/z calcd. for C31H27F3N3O4S2 [M + H]+ 626.1390, found 626.1393. (3S,3'R,4'S,5'S)-Ethyl 1-benzyl-5,7-dimethyl-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ad). Obtained as a light yellow solid (51.2 mg, 80% yield), mp 145‒148 ℃. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 10.9 min (minor), tR = 13.5 min (major); minor diastereoisomer: tR = 7.4 min (minor), tR = 11.9 min (major); 97:3 dr, 98% ee for the major diastereoisomer. [α]D20 = 139.4 (c 1.62, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H), 7.43‒7.38 (m, 3H), 7.15‒7.04 (m, 5H), 6.90 (s, 1H), 6.85 (d, J = 5.6 Hz, 2H), 5.23 (d, J = 16.8 Hz, 1H), 5.03 (d, J = 9.2 Hz, 1H), 4.94 (d, J = 16.8 Hz, 1H), 4.68‒4.62 (m, 1H), 4.38‒4.24 (m, 2H), 2.99 (d, J = 8.8 Hz, 1H), 2.30 (s, 3H), 2.18 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.3, 173.8, 171.9, 167.5, 138.9, 136.7, 135.6, 134.6, 132.6, 129.7, 129.4, 128.8, 128.0, 127.1, 125.7,



Page 22 of 34

125.5, 124.9, 124.5 (q, 1JCF = ‒280.2 Hz), 120.0, 73.9, 72.7, 62.5, 61.1 (q, 2JCF = 32.3 Hz), 52.1, 45.8, 20.9, 18.7, 14.2 ppm.

19



1-benzyl-5-fluoro-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ae). Obtained as a light yellow solid (61.8 mg, 98% yield), mp 91‒94 ℃. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 14.4 min (minor), tR = 12.1 min (major); minor diastereoisomer: tR = 10.4 min (minor), tR = 8.4 min (major); 95:5 dr, 80% ee for the major diastereoisomer. [α]D20 = 204.2 (c 0.63, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 1H), 7.47‒7.37 (m, 3H), 7.22‒7.12 (m, 5H), 6.99 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 4.4 Hz, 2H), 6.61 (q, J = 4.2 Hz, 1H), 5.23 (d, J = 16.0 Hz, 1H), 5.15 (d, J = 9.2 Hz, 1H), 4.64‒4.55 (m, 1H), 4.43‒4.25 (m, 3H), 2.92 (d, J = 7.2 Hz, 1H), 1.31 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.5, 173.1, 171.1, 167.2, 158.7 (d, 1JCF = 243.1 Hz), 139.5, 134.5 (d, 4JCF = 4.4 Hz), 129.8, 129.5, 128.9, 128.0, 127.8, 127.3, 125.7 (d, 3JCF = 7.9 Hz), 124.5 (q, 1JCF = ‒280.7 Hz), 117.7 (d, 2JCF = 19.4 Hz), 115.1 (d, 2JCF = 22.5 Hz), 110.2 (d, 3JCF = 7.7 Hz), 73.9, 72.5, 62.7, 60.7 (q, 2JCF = 33.1 Hz), 51.8, 44.8, 14.2 ppm.

19

F NMR (376 MHz, CDCl3): δ 71.56, 118.12 ppm. HRMS (ESI): m/z calcd. for


1-benzyl-5-chloro-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3af). Obtained as a light yellow solid (61.3 mg, 95% yield), mp 200‒203 ℃. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 5.3 min (minor), tR = 9.4 min (major); minor diastereoisomer: tR = 6.0 min (minor), tR = 7.5 min (major); 93:7 dr, > 99% ee for the major diastereoisomer. [α]D20 = 52.2 (c 1.37, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.46‒7.37 (m, 3H), 7.25‒7.12 (m, 6H), 6.79 (br s, 2H), 6.60 (d, J = 8.4 Hz, 1H), 5.21 (d, J = 16.0 Hz, 1H), 5.16 (d, J = 9.6 Hz, 1H), 4.64‒4.56 (m, 1H), 4.43‒4.23 (m, 3H), 2.91 (d, J = 6.8 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H) ppm.

13

C NMR (176 MHz, CDCl3): δ 194.4, 173.0, 171.0, 167.0, 142.0, 134.4, 134.3,


Page 23 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


131.2, 129.8, 129.5, 128.9, 128.3, 127.9, 127.8, 127.3, 127.2, 125.7, 124.5 (q, 1JCF = ‒280.6 Hz), 110.5, 73.7, 72.6, 62.7, 60.5 (q, 2JCF = 32.7 Hz), 51.7, 44.7, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.59 ppm. HRMS (ESI): m/z calcd. for C30H24ClF3N3O4S2 [M + H]+ 646.0843, found 646.0832. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-6-chloro-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ag). Obtained as a light yellow solid (58.9 mg, 91% yield), mp 181‒183 ℃. HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 12.4 min (minor), tR = 8.6 min (major); minor diastereoisomer: tR = 20.0 min (minor), tR = 6.7 min (major); 86:14 dr, 91% ee for the major diastereoisomer. [α]D20 = 40.5 (c 2.25, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.4 Hz, 1H), 7.47‒7.35 (m, 4H), 7.22‒7.15 (m, 4H), 7.04 (d, J = 8.4 Hz, 1H), 6.78 (br s, 2H), 6.67 (s, 1H), 5.24‒5.18 (m, 2H), 4.62‒4.55 (m, 1H), 4.40‒4.23 (m, 3H), 2.86 (d, J = 7.6 Hz, 1H), 1.30 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.6, 173.3, 170.9, 167.1, 144.8, 137.4, 134.4, 129.8, 129.5, 129.2, 129.0, 127.94, 127.90, 127.7, 127.3, 124.5 (q, 1JCF = 280.5 Hz), 123.3, 122.8, 122.2, 110.1, 73.4, 72.7, 62.6, 60.3 (q, 2JCF= 32.7 Hz), 51.7, 44.7, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.60 ppm. HRMS (ESI): m/z calcd. for C30H24ClF3N3O4S2 [M + H]+ 646.0843, found 646.0848. (3S,3'R,4'S,5'S)-Ethyl

1-benzyl-5-bromo-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ah). Obtained as a light yellow solid (66.3 mg, 96% yield), mp 205‒208 ℃. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 95: 5, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 16.8 min (minor), tR = 18.3 min (major); minor diastereoisomer: tR = 9.5 min (minor), tR = 13.1 min (major); 95:5 dr, 95% ee for the major diastereoisomer. [α]D20 = 10.6 (c 2.08, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.88 (s, 1H), 7.46‒7.36 (m, 4H), 7.21‒7.11 (m, 5H), 6.78 (br s, 2H), 6.55 (d, J = 8.4 Hz, 1H), 5.22‒5.15 (m, 2H), 4.60‒4.55 (m, 1H), 4.41‒4.23 (m, 3H), 2.91 (d, J = 7.2 Hz, 1H), 1.30 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.4, 172.9, 170.9, 167.0, 142.5, 134.4, 134.3, 134.1, 129.9, 129.7, 129.5, 128.9, 127.9, 127.8, 127.3, 125.9, 124.5 (q, 1JCF = 280.7 Hz), 115.4, 111.0, 73.7, 72.6, 62.6, 60.4 (q, 2JCF =



Page 24 of 34

32.9 Hz), 51.7, 44.7, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.69 ppm. HRMS (ESI): m/z calcd. for C30H24BrF3N3O4S2 [M + H]+ 690.0338, found 690.0346. (3S,3'R,4'S,5'S)-Ethyl

2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)dispiro[indoline-3,2'-

pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ai). Obtained as a light yellow solid (44.3 mg, 85% yield), mp 95‒98 ℃. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 9.4 min (minor), tR = 19.1 min (major); minor diastereoisomer: tR = 7.3 min (minor), tR = 6.4 min (major); 97:3 dr, 89% ee for the major diastereoisomer. [α]D20 = 133.8 (c 0.55, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.40 (s, 3H), 7.33 (t, J = 7.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 8.0 Hz, 3H), 5.24 (d, J = 9.6 Hz, 1H), 4.57‒4.52 (m, 1H), 4.40‒4.30 (m, 1H), 4.28‒4.20 (m, 1H), 2.79 (d, J = 6.8 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.0, 175.3, 170.8, 167.0, 141.4, 134.6, 131.5, 129.8, 129.5, 127.9, 127.2, 124.6 (q, 1JCF = 280.7 Hz), 123.6, 122.7, 110.2, 73.8, 73.4, 62.5, 60.0 (q, 1JCF = 32.5 Hz), 51.3, 14.2 ppm.

19

F NMR (376 MHz, CDCl3): δ 71.41 ppm. HRMS

(ESI): m/z calcd. for C23H19F3N3O4S2 [M + H]+ 522.0764, found 522.0759. (3S,3'R,4'S,5'S)-Ethyl

1-methyl-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)dispiro-

[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3aj). Obtained as a light yellow solid (49.3 mg, 92% yield), mp 160‒162 ℃. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 9.0 min (minor), tR = 36.1 min (major); minor diastereoisomer: tR = 5.2 min (minor), tR = 7.0 min (major); 99:1 dr, 89% ee for the major diastereoisomer. [α]D20 = 181.9 (c 2.11, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 7.6 Hz, 1H), 7.42 (s, 4H), 7.10 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.2 Hz, 3H), 5.26 (d, J = 9.6 Hz, 1H), 4.56 (br s, 1H), 4.39‒4.31 (m, 1H), 4.27‒4.19 (m, 1H), 3.11 (s, 3H), 2.86 (s, 1H), 1.28 (t, J = 7.2 Hz, 3H) ppm.

13

C NMR (176 MHz, CDCl3): δ 195.1, 173.4, 170.8, 167.0, 144.2, 134.6, 131.4, 129.8, 129.5,

127.8, 126.7, 124.6 (q, 1JCF = 280.6 Hz), 123.3, 122.6, 108.3, 73.5, 73.4, 62.5, 60.1 (q, 2JCF = 32.8 Hz), 51.4, 20.5, 14.2 ppm.

19


C24H21F3N3O4S2 [M + H]+ 536.0920, found 536.0904.


Page 25 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(3S,3'R,4'S,5'S)-Ethyl 1-allyl-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)dispiro[indoline3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3ak). Obtained as a light yellow solid (55.0 mg, 98% yield), mp 83‒86 ℃. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 8.2 min (minor), tR = 9.9 min (major); minor diastereoisomer: tR = 5.2 min (minor), tR = 6.8 min (major); 98:2 dr, 89% ee for the major diastereoisomer. [α]D20 = 180.3 (c 1.95, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.6 Hz, 1H), 7.42‒7.36 (m, 4H), 7.09 (t, J = 7.4 Hz, 1H), 6.84‒6.80 (m, 3H), 5.69‒5.60 (m, 1H), 5.19 (s, 1H), 5.15 (d, J = 9.2 Hz, 1H), 5.10 (d, J = 9.6 Hz, 1H), 4.61‒4.55 (m, 1H), 4.49 (dd, J1 = 16.4 Hz, J2 = 3.6 Hz, 1H), 4.39‒4.31 (m, 1H), 4.27‒4.19 (m, 1H), 4.00 (dd, J1 = 16.0 Hz, J2 = 6.0 Hz, 1H), 2.87 (d, J = 7.2 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 195.0, 172.9, 170.8, 167.1, 143.4, 134.6, 131.3, 130.8, 129.8, 129.4, 127.9, 126.6, 124.6 (q, 1JCF = 280.5 Hz), 123.6, 122.7, 118.2, 109.2, 73.8, 73.4, 62.5, 60.4 (q, 2JCF = 32.6 Hz), 51.2, 42.8, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.59 ppm. HRMS (ESI): m/z calcd. for C26H23F3N3O4S2 [M + H]+ 562.1077, found 562.1053. (3S,3'R,4'S,5'S)-Ethyl

1-(4-nitrobenzyl)-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3al). Obtained as a light yellow solid (53.9 mg, 82% yield), mp 110‒113 ℃. HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 11.1 min (minor), tR = 9.3 min (major); minor diastereoisomer: tR = 8.4 min (major); >99:1 dr, 90% ee for the major diastereoisomer. [α]D20 = 241.3 (c 2.36, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.35‒7.30 (m, 5H), 7.09 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 8.0 Hz, 3H), 5.38‒5.30 (m, 2H), 4.62‒4.56 (m, 1H), 4.43‒4.35 (m, 2H), 4.27‒4.19 (m, 1H), 2.92 (d, J = 7.2 Hz, 1H), 1.29 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.5, 173.7, 170.4, 166.7, 147.3, 143.0, 142.2, 134.3, 131.6, 129.9, 129.5, 128.5, 127.7, 127.2, 124.6 (q, 1JCF = 280.7 Hz), 123.9, 123.1, 123.0, 108.8, 73.7, 73.6, 62.5, 59.9 (q, 2JCF = 33.0 Hz), 50.8, 43.8, 14.2 ppm.

19

F NMR (376 MHz,

CDCl3): δ 71.66 ppm. HRMS (ESI): m/z calcd. for C30H24F3N4O6S2 [M + H]+ 657.1084, found 657.1100.



(3S,3'R,4'S,5'S)-Ethyl

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1-(4-bromobenzyl)-2,4''-dioxo-3''-phenyl-2''-thioxo-5'-(trifluoromethyl)-

dispiro[indoline-3,2'-pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (3am). Obtained as a light yellow solid (60.1 mg, 87% yield), mp 109‒112 ℃. HPLC (Daicel Chiralpak ADH, n-hexane/2propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): major diastereoisomer: tR = 13.2 min (minor), tR = 37.2 min (major); minor diastereoisomer: tR = 9.2 min (minor), tR = 11.3 min (major); 98:2 dr, 92% ee for the major diastereoisomer. [α]D20 = 199.3 (c 2.06, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 7.6 Hz, 2H), 7.07 (t, J = 8.4 Hz, 2H), 6.66‒6.61 (m, 3H), 5.29 (d, J = 9.6 Hz, 1H), 5.22 (d, J = 15.6 Hz, 1H), 4.61‒4.57 (m, 1H), 4.42‒4.34 (m, 1H), 4.27‒4.19 (m, 2H), 2.88 (br s, 1H), 1.29 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 194.7, 173.5, 170.5, 166.9, 143.3, 134.4, 133.8, 131.8, 131.5, 129.8, 129.5, 129.4, 127.8, 126.9, 124.6 (q, 1JCF = 280.6 Hz), 123.3, 122.9, 121.6, 109.2, 73.7, 73.4, 62.5, 60.1 (q, 2JCF = 32.9 Hz), 51.0, 44.0, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.68 ppm. HRMS (ESI): m/z calcd. for C30H24BrF3N3O4S2 [M + H]+ 690.0338, found 690.0337. Synthetic transformation of 3aa. To a solution of compound 3aa (61.2 mg, 0.10 mmol) in acetic acid (1.0 mL) was added chromium trioxide (30.0 mg, 0.30 mmol) in three portions over 30 mintutes at room temperature. The solution was stirred at 50 ℃ for 12 h. The mixture was treated with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts was washed by brine, dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by silica gel chromatography to yield the desired product 4. (3S,3'R,4'S,5'S)-Ethyl 1-benzyl-2,2'',4''-trioxo-3''-phenyl-5'-(trifluoromethyl)dispiro[indoline-3,2'pyrrolidine-3',5''-thiazolidine]-4'-carboxylate (4). Obtained as a light yellow solid (51.8 mg, 87% yield), mp 88‒91 ℃. [α]D20 = 95.8 (c 1.14, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.6 Hz, 1H), 7.39‒7.32 (m, 3H), 7.30‒7.22 (m, 3H), 7.19 (d, J = 6.8 Hz, 1H), 7.13 (t, J = 7.2 Hz, 2H), 7.06 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 7.6 Hz, 2H), 6.69 (d, J = 8.0 Hz, 1H), 5.32 (d, J = 9.6 Hz, 1H), 5.21 (d, J = 15.6 Hz, 1H), 4.63‒4.54 (m, 1H), 4.42 (d, J = 15.6 Hz, 1H), 4.38‒4.32 (m, 1H), 4.30‒4.23 (m, 1H), 2.87 (d, J = 7.6 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (176 MHz, CDCl3): δ 173.7, 169.1,


Page 27 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


167.1, 166.7, 143.7, 134.9, 132.2, 131.4, 129.4, 129.3, 128.7, 127.7, 127.5, 127.0, 126.9, 124.7 (q, 1JCF = 280.4 Hz), 123.7, 122.6, 109.5, 73.7, 71.9, 62.4, 60.2 (q, 2JCF = 32.7 Hz), 51.6, 44.6, 14.2 ppm. 19F NMR (376 MHz, CDCl3): δ 71.54 ppm. HRMS (ESI): m/z calcd. for C30H25F3N3O5S [M + H]+ 596.1462, found 596.1462.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.xxxxxx. Copies of 1H, 13C and 19F NMR spectra, X-ray crystallographic data of 3na (PDF) X-ray crystallographic data of 3na (CIF).

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We are grateful for financial support from National Natural Science Foundation of China (Grant No. 21272024). We also thank Analysis & Testing Center of Beijing Institute of Technology for the measurement of NMR and mass spectrometry.

REFERENCES (1) (a) Michael, J. P. Indolizidine and quinolizidine alkaloids. Nat. Prod. Rep., 2008, 25, 139‒165. (b) Vitaku, E.; Smith, D, T.; Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals: miniperspective. J. Med. Chem., 2014, 57, 10257‒10274.



Page 28 of 34

(2) For examples, see: (a) Marti, C.; Carreira, E. M. Construction of Spiro [pyrrolidine-3,3’-oxindoles]- Recent Applications to the Synthesis of Oxindole Alkaloids. Eur. J. Org. Chem., 2003, 2003, 2209‒2219. (b) Galliford, C. V.; Scheidt, K. A. Natürliche Pyrrolidinylspirooxindole als Vorlagen für die Entwicklung medizinischer Wirkstoffe. Angew. Chem., 2007, 119, 8902‒8912; Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents. Angew. Chem. Int. Ed., 2007, 46, 8748‒8758. (c) Badillo, J. J.; Hanhan, N. V.; Franz, A. K. Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery. Curr. Opin. Drug Discov. Dev., 2010, 13, 758‒776. (d) Zhou, F.; Liu, Y. L.; Zhou, J. Catalytic Asymmetric Synthesis of Oxindoles Bearing a Tetrasubstituted Stereocenter at the C-3 Position. Adv. Synth. Catal., 2010, 352, 1381‒1407. (e) Rios, R. Enantioselective methodologies for the synthesis of spiro compounds. Chem. Soc. Rev., 2012, 41, 1060‒1074. (f) Hong, L.; Wang, R. Recent Advances in Asymmetric Organocatalytic Construction of 3,3’-Spirocyclic Oxindoles. Adv. Synth. Catal., 2013, 355, 1023‒1052. (g) Liu, Y.; Wang, H.; Wan, J. Recent Advances in Diversity Oriented Synthesis through Isatin-based Multicomponent Reactions. Asian J. Org. Chem., 2013, 2, 374‒386. (h) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas III, C. F. Organocatalytic asymmetric assembly reactions: synthesis of spirooxindoles via organocascade strategies. ACS Catal., 2014, 4, 743‒762. (3) (a) Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. Total synthesis of spirotryprostatin A, leading to the discovery of some biologically promising analogues. J. Am. Chem. Soc., 1999, 121, 2147‒2155. (b) Boldi, A. M. Libraries from natural product-like scaffolds. Curr. Opin. Chem. Boil., 2004, 8, 281‒286. (c) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S. Structure-based design of potent non-peptide MDM2 inhibitors. J. Am. Chem. Soc., 2005, 127, 10130‒10131. (d) Shangary, S.; Qin, D.; McEachern, D.; Liu, M.; Miller, R. S.; Qiu, S.; Nikolovska-Coleska, Z.; Ding, K.; Wang, G.; Chen, J.; Bernard, D.; Zhang, J.; Lu, Y.; Gu, Q.; Shah, R. B.; Pienta, K. J.; Ling, X.; Kang, S.; Guo, M.; Sun, Y.; Yang, D.; Wang, S. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Nat. Acad. Sci., 2008, 105, 3933‒3938. (4) For examples on spirocyclic compounds, see: (a) Sannigrahi, M. Stereocontrolled synthesis of spirocyclics. Tetrahedron, 1999, 55, 9007‒9071. (b) Pradhan, R.; Patra, M.; Behera, A. K.; Mishra, B. K.; Behera, R. K. A


Page 29 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


synthon approach to spiro compounds. Tetrahedron, 2006, 62, 779‒828. (c) Kotha, S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Selected synthetic strategies to spirocyclics. Synthesis, 2009, 2009, 165‒193. (5) (a) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century. Angew. Chem.e Int. Ed., 2000, 39, 44‒122; Der stand der totalsynthese zu beginn des 21. jahrhunderts. Angew. Chem., 2000, 112, 46‒126. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Cascade reactions in total synthesis. Angew. Chem.e Int. Ed., 2006, 45,71347186; Kaskadenreaktionen in der Totalsynthese. Angew. Chem., 2006, 118, 7292‒7344. (c) Li, J. W. H.; Vederas, J. C. Drug discovery and natural products: end of an era or an endless frontier?. Science, 2009, 325, 161‒165. (d) Gaich, T.; Baran, P. S. Aiming for the ideal synthesis. J. Org. Chem., 2010, 75, 4657‒4673. (6) Alonso, C.; Martinez de Marigorta, E.; Rubiales, G.; Palacios, F. Carbon trifluoromethylation reactions of hydrocarbon derivatives and heteroarenes. Chem. Rev., 2015, 115, 1847‒1935. (7) For examples on organofluorine compounds, see: (a) Isanbor, C.; O’Hagan, D. Fluorine in medicinal chemistry: A review of anti-cancer agents. J. Fluorine Chem., 2006, 127, 303‒319. (b) Dal Pozzo, A.; Ni, M., Muzi, L.; de Castiglione, R.; Mondelli, R.; Mazzini, S.; Penco, S.; Pisano, C.; Castorina, M.; Giannini, G. Incorporation of the Unusual Cα-Fluoroalkylamino Acids into Cyclopeptides: Synthesis of Arginine-GlycineAspartate (RGD) Analogues and Study of Their Conformational and Biological Behavior. J. Med. Chem., 2006, 49, 1808‒1817. (c) Smits, R.; Cadicamo, C. D.; Burger, K.; Koksch, B. Synthetic strategies to αtrifluoromethyl and α-difluoromethyl substituted α-amino acids. Chem. Soc. Rev., 2008, 37, 1727‒1739. (d) O’Shea, P. D.; Chen, C. Y.; Gauvreau, D.; Gosselin, F.; Hughes, G.; Nadeau, C.; Volante, R. P. A practical enantioselective synthesis of Odanacatib, a potent cathepsin K inhibitor, via triflate displacement of an αtrifluoromethylbenzyl triflate. J. Org. Chem., 2009, 74, 1605‒1610. (e) Nie, J.; Guo, H. C.; Cahard, D.; Ma, J. A. Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates. Chem. Rev., 2010, 111, 455‒529. (f) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001‒2011). Chem. Rev., 2013, 114, 2432‒2506. (g) Cheng, G.; Wu, Q.; Shang, Z.; Liang, X.; Lin, X. Stereoselective Transformations of α-Trifluoromethylated Ketoximes to Optically Active Amines by Enzyme-Nanometal Cocatalysis:



Page 30 of 34

Synthesis of (S)-Inhibitor of Phenylethanolamine N-Methyltransferase. ChemCatChem, 2014, 6, 2129‒2133. (h) Yang, X.; Chen, Z.; Cai, Y.; Huang, Y. Y.; Shibata, N. An aza-Michael addition protocol to fluoroalkylated β-amino acid derivatives and enantiopure trifluoromethylated N-heterocycles. Green Chem., 2014, 16, 4530‒4534. (8) Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science, 2007, 317, 1881‒1886. (9) (a) Dolbier Jr, W. R. Fluorine chemistry at the millennium. J. Fluorine Chem., 2005, 126, 157‒163. (b) Kirk, K. L. Fluorination in medicinal chemistry: methods, strategies, and recent developments. Org. Process Res. Dev., 2008, 12, 305‒321. (c) Zhu, W.; Wang, J.; Wang, S.; Gu, Z.; Aceña, J. L.; Izawa, K.; Liu, H.; Soloshonok, V. A. Recent advances in the trifluoromethylation methodology and new CF3-containing drugs. J. Fluorine Chem., 2014, 167, 37‒54. (10)

(a) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of Fluorine and Fluorine-Containing Functional

Groups. Angew. Chem. Int. Ed., 2013, 52, 8214‒8264; Einführung von Fluor und fluorhaltigen funktionellen Gruppen. Angew. Chem., 2013, 125, 8372‒8423. (b) Besset, T.; Poisson, T.; Pannecoucke, X. Recent Progress in Direct Introduction of Fluorinated Groups on Alkenes and Alkynes by means of Cð H Bond Functionalization. Chem. Eur. J., 2014, 20, 16830‒16845. (c) Egami, H.; Sodeoka, M. Trifluoromethylation of alkenes with concomitant introduction of additional functional groups. Angew. Chem. Int. Ed., 2014, 53, 8294‒8308; Trifluormethylierung von Alkenen unter gleichzeitiger Einführung weiterer funktioneller Gruppen. Angew. Chem., 2014, 126, 8434‒8449. (d) Merino, E.; Nevado, C. Addition of CF3 across unsaturated moieties: a powerful functionalization tool. Chem. Soc. Rev., 2014, 43, 6598‒6608. (11)

(a) Brown, F. C. 4-Thiazolidinones. Chem. Rev., 1961, 61, 463‒521. (b) Lesyk, R. B.; Zimenkovsky, B. S.

4-Thiazolidones: centenarian history, current status and perspectives for modern organic and medicinal chemistry. Curr. Org. Chem., 2004, 8, 1547‒1577. (c) Mendgen, T.; Steuer, C.; Klein, C. D. Privileged scaffolds or promiscuous binders: a comparative study on rhodanines and related heterocycles in medicinal chemistry. J. Med. Chem., 2012, 55, 743‒753. (12)

For selected examples, see: (a) Singh, S. P.; Parmar, S. S.; Raman, K.; Stenberg, V. I. Chemistry and

biological activity of thiazolidinones. Chem. Rev., 1981, 81, 175‒203. (b) Nomura, M.; Kinoshita, S.; Satoh,


Page 31 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


H.; Maeda, T.; Murakami, K.; Tsunoda, M.; Miyachi, H.; Awano, K. (3-Substituted benzyl) thiazolidine-2, 4diones as structurally new antihyperglycemic agents. Bioorg. Med. Chem. Lett., 1999, 9, 533‒538. (c) Lugovskoy, A. A.; Degterev, A. I.; Fahmy, A. F.; Zhou, P.; Gross, J. D.; Yuan, J.; Wagner, G. A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors. J. Am. Chem. Soc., 2002, 124, 1234‒1240. (d) Soltero-Higgin, M.; Carlson, E. E.; Phillips, J. H.; Kiessling, L. L. Identification of inhibitors for UDP-galactopyranose mutase. J. Am. Chem. Soc., 2004, 126, 10532‒10533. (e) Carlson, E. E.; May, J. F.; Kiessling, L. L. Chemical probes of UDP-galactopyranose mutase. Chem. Boil., 2006, 13, 825‒837. (f) Murugan, R.; Anbazhagan, S.; Narayanan, S. S. Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3 + 2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives. Eur. J. Med. Chem., 2009, 44, 3272‒3279. (g) Tomasic, T.; Masic, L. P. Rhodanine as a privileged scaffold in drug discovery. Curr. Med. Chem., 2009, 16, 1596‒1629. (h) Ponnuchamy, S.; Sumesh, R. V.; Kumar, R. R. Regioselective synthesis of novel dispiro oxindole– pyrrolizine–thiazolidine-2,4-dione hybrids. Tetrahedron Lett., 2015, 56, 4374‒4376. (13)

For examples on chiral thiazolidinone derivatives, see: (a) Wu, W. B.; Huang, H. C.; Yuan, X. Q.; Zhu, K.

L.; Ye, J. X. Asymmetric construction of spirocyclohexanonerhodanines catalyzed by simple diamine derived from chiral tert-leucine. Chem. Comm., 2012, 48, 9180‒9182. (b) Zhu, K. L.; Huang, H. C.; Wu, W. B.; Wei, Y.; Ye, J. X. Aminocatalyzed asymmetric Diels-Alder reaction of 2,4-dienals and rhodanine/hydantoin derivatives. Chem. Comm., 2013, 49, 2157‒2159. (c) Han, B.; Huang, W.; Ren, W.; He, G.; Wang, J. H.; Peng, C. Asymmetric Synthesis of Cyclohexane-Fused Drug-Like Spirocyclic Scaffolds Containing Six Contiguous Stereogenic Centers via Organocatalytic Cascade Reactions. Adv. Synth. Catal., 2015, 357, 561‒568. (d) Yang, W. L.; Tang, F. F.; He, F. S.; Li, C. Y.; Yu, X.; Deng, W. P. Asymmetric Construction of Spirocyclic Pyrrolidine-thia(oxa)zolidinediones via N, O-Ligand/Cu(I) Catalyzed 1,3-Dipolar Cycloaddition of Azomethine Ylides with 5-Alkylidene Thia(oxa)zolidine-2,4-diones. Org. Lett., 2015, 17, 4822‒4825. (14)

For examples on N-2,2,2-trifluoroethylisatin ketimines, see: (a) Ma, M. X.; Zhu, Y. Y.; Sun, Q. T.; Li, X.

Y.; Su, J. H.; Zhao, L.; Zhao, Y. Y.; Qiu, S.; Yan, W. J.; Wang, K. R.; Wang, R. The asymmetric synthesis of CF3-containing spiro [pyrrolidin-3,2’oxindole] through the organocatalytic 1,3-dipolar cycloaddition reaction. Chem. Comm., 2015, 51, 8789‒8792. (b) Li, X. Y.; Su, J. H.; Liu, Z. R. J.; Zhu, Y. Y.; Dong, Z. H.; Qiu, S.;



Page 32 of 34

Wang, J. Y.; Lin, L.; Shen, Z. Q.; Yan, W. J. Wang, K. R.; Wang, K. Synthesis of Chiral αTrifluoromethylamines with 2,2,2-Trifluoroethylamine as a “Building Block”. Org. Lett., 2016, 18, 956‒959. (c) Ponce, A.; Alonso, I.; Adrio, J.; Carretero, J. C. Stereoselective Ag-Catalyzed 1,3-Dipolar Cycloaddition of Activated Trifluoromethyl-Substituted Azomethine Ylides. Chem. Eur. J., 2016, 22, 4952‒4959. (d) Gao, Y. N.; Shi, M. Enantioselective Synthesis of Isatin-Derived α-(Trifluoromethyl) imine Derivatives: Phosphine-Catalyzed γ-Addition of α-(Trifluoromethyl) imines and Allenoates. Eur. J. Org. Chem., 2017, 2017, 1552‒1560. (15)

For selected examples, see: (a) Yang, W.; Du, D. M. Cinchona-based squaramide-catalysed cascade aza-

Michael-Michael addition: enantioselective construction of functionalized spirooxindole tetrahydroquinolines. Chem. Comm., 2013, 49, 8842‒8844. (b) Li, J. H.; Feng, T. F.; Du, D. M. Construction of spirocyclopropanelinked heterocycles containing both pyrazolones and oxindoles through Michael/alkylation cascade reactions. J. Org. Chem., 2015, 80(22), 11369‒11377. (c) Liu, L.; Zhao, B. L.; Du, D. M. Organocatalytic Asymmetric Michael/Cyclization Cascade Reaction of 3-Isothiocyanato Oxindoles with Maleimides for the Efficient Construction of Pyrrolidonyl Spirooxindoles. Eur. J. Org. Chem., 2016, 2016, 4711‒4718. (d) Zhao, B. L.; Du, D. M. Squaramide-Catalyzed Enantioselective Cascade Approach to Bispirooxindoles with Multiple Stereocenters. Adv. Synth. Catal., 2016, 358, 3992‒3998. (e) Lin, Y.; Liu, L.; Du, D. M. Squaramidecatalyzed asymmetric Michael/cyclization cascade reaction of 3-isothiocyanato oxindoles with chalcones for synthesis of pyrrolidinyl spirooxindoles. Org. Chem. Fron., 2017, 4, 1229‒1238. (16)

CCDC 1843248 (for 3na) contain the supplementary crystallographic data for this paper. These

data can be obtained free of charge from The Cambridge Crystallographic Data Centre. (17)

(a) Martínez, J. I.; Villar, L.; Uria, U.; Carrillo, L.; Reyes, E.; Vicario, J. L. Bifunctional squaramide

catalysts with the same absolute chirality for the diastereodivergent access to densely functionalised cyclohexanes through enantioselective domino reactions. synthesis and mechanistic studies. Adv. Synth. Catal., 2014, 356, 3627‒3648. (b) Sun, Q.T.; Li, X. Y.; Su, J. H.; Zhao, L.; Ma, M. X.; Zhu, Y. Y.; Zhao, Y. Y.; Zhu, R. R.; Yan, W. J.; Wang, K. R.; Wang, R. The Squaramide-Catalyzed 1,3-Dipolar Cycloaddition of Nitroalkenes with N-2,2,2-Trifluoroethylisatin Ketimines: An Approach for the Synthesis of 5’Trifluoromethyl-spiro[pyrrolidine-3,2’-oxindoles]. Adv. Synth. Catal., 2015, 357, 3187‒3196. (c) Wang, Z.


Page 33 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


H.; Wu, Z. J.; Yue, D. F.; Hu, W. F.; Zhang, X. M.; Xu, X. Y.; Yuan, W. C. Organocatalytic asymmetric [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines with 3-alkenyl-5-arylfuran-2(3H)-ones. Chem. Comm., 2016, 52, 11708‒11711. (d) Guo, J.; Wong, M. W. Cinchona Alkaloid-Squaramide Catalyzed SulfaMichael Addition Reaction: Mode of Bifunctional Activation and Origin of Stereoinduction. J. Org. Chem., 2017, 82, 4362‒4368. (e) Grayson, M. N. Mechanism and Origins of Stereoselectivity in the Cinchona Thiourea-and Squaramide-Catalyzed Asymmetric Michael Addition of Nitroalkanes to Enones. J. Org. Chem., 2017, 82, 4396‒4401. (f) Huang, W. J.; Chen, Q.; Lin, N.; Long, X. W.; Pan, W. G.; Xiong, Y. S.; Weng, J.; Lu, G. Asymmetric synthesis of trifluoromethyl-substituted 3,3’-pyrrolidinyl-dispirooxindoles through organocatalytic 1,3-dipolar cycloaddition reactions. Org. Chem. Front., 2017, 4, 472‒482. (g) Zhi, Y.; Zhao, K.; von Essen, C.; Rissanen, K.; Enders, D. Thiourea-catalyzed domino Michael-Mannich [3+2] cycloadditions: A strategy for the asymmetric synthesis of 3,3’-pyrrolidinyl-dispirooxindoles. Synlett, 2017, 28, 2876‒2880. (h) Wang, P.; Gao, Y.; Zhao, Y.; Liu, W.; Wang, Y. Unveiling Mechanism of a QuinineSquaramide Catalyzed Enantioselective Aza-Friedel-Crafts Reaction between Cyclic Trifluoromethyl Ketimine and Naphthol: A DFT Study. J. Org. Chem., 2017, 82, 13109‒13114. (18)

(a) Shailendra, T.; Singh, K. P.; Akhilesh, K.; Poonam, P.; Ansari, N. F. Synthesis and pesticidal

activities of some 3,5-disubstituted furothiazole-2-thiones. J. Applicable. Chem., 2014, 3, 2372‒2377. (b) Jin, S.; Tagliazucchi, M.; Son, H. J.; Harris, R. D.; Aruda, K. O.; Weinberg, D. J.; Nepomnyashchii, A. B.; Farha, O. K.; Hupp, J. T.; Weiss, E. A. Enhancement of the yield of photoinduced charge separation in zinc porphyrin–quantum dot complexes by a bis (dithiocarbamate) linkage. J. Phys. Chem. C, 2015, 119, 5195‒5202. (c) Üngören, Ş. H.; Albayrak, S.; Günay, A.; Yurtseven, L.; Yurttaş, N. A new method for the preparation of 5-acylidene and 5-imino substituted rhodanine derivatives and their antioxidant and antimicrobial activities. Tetrahedron, 2015, 71, 4312‒4323. (19)

(a) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Squaramide-Catalyzed Enantioselective Michael Addition of

Diphenyl Phosphite to Nitroalkenes. Angew. Chem. Int. Ed. 2010, 49, 153‒156; Squaramide-Catalyzed Enantioselective Michael Addition of Diphenyl Phosphite to Nitroalkenes. Angew. Chem., 2010, 122, 157‒160. (b) Yang, W.; Du, D. M. Highly enantioselective Michael addition of nitroalkanes to chalcones using chiral squaramides as hydrogen bonding organocatalysts. Org. Lett., 2010, 12, 5450‒5453. (c) Yang,



Page 34 of 34

W.; Du, D. M. Chiral Squaramide-Catalyzed Highly Enantioselective Michael Addition of 2-Hydroxy-1,4naphthoquinones to Nitroalkenes. Adv. Synth. Catal., 2011, 353(8), 1241‒1246.


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