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Communication

Organocatalytic, Asymmetric [2+2+2] Annulation to Construct Six-Membered Spirocyclic Oxindoles with Six Continuous Stereogenic Centers

by
Zhi-Long Li
1,
Chao Liu
2,
Rui Tan
1,*,
Zhi-Ping Tong
1,* and
Yan-Kai Liu
2,*
1
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
2
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
*
Authors to whom correspondence should be addressed.
Catalysts 2016, 6(5), 65; https://doi.org/10.3390/catal6050065
Submission received: 17 March 2016 / Revised: 13 April 2016 / Accepted: 15 April 2016 / Published: 27 April 2016
(This article belongs to the Special Issue Metal-free Organocatalysis)
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Abstract

:
Lactols and cyclic hemiaminals were directly used in a one-pot organo/organo dual catalytic system induced [2+2+2] tandem reaction for the asymmetric construction of six-membered carbocycles. The enamine-based stereoselective Michael addition of lactols or cyclic hemiaminals to electron-deficient olefinic oxindole motifs provided chiral C4 components, which were further combined with triethylamine catalyzed Michael/Henry sequential reactions affording spirocyclic oxindole derivatives containing six continuous stereogenic centers with excellent enantioselectivities as a single diastereoisomer. All these desired products have versatile molecular complexity, which might have potential applications in synthetic organic chemistry and the pharmaceutical industry.

Graphical Abstract

1. Introduction

One-pot organocatalytic multicomponent reaction, which could meet the demands of atom economy and efficiency, has proven to be a promising approach for the preparation of chiral organic molecules with multistereogenic centers [1,2,3,4,5]. Over the past few years, the combination of dual catalytic systems into asymmetric one-pot tandem procedures has been paid much attention due to the fact that this could provide effective access to valuable chiral complex structures from simple precursors via sequential processes. Compared with the costly organo/metal dual catalytic system-induced one-pot sequential processes [6,7,8,9,10,11,12,13], organo/organo catalysis is more experimentally simple and environmentally friendly which could support the development of green and sustainable chemistry [14,15,16,17,18,19,20].
Six-membered carbocycles can be found in many nature products and bioactive molecules [21,22]. As a result, great efforts have been devoted towards the development of practical methods for the production of these types of compounds with diverse substitution patterns [23,24,25,26,27]. However, concerning both the number of total stereoisomers and molecular complexity, it is challenging to stereoselectively install six continuous stereogenic centers on a six-membered ring, especially one containing spirocyclic oxindole structures which might have potential bioactivity [28,29,30,31,32,33,34,35,36,37]. Among the reported approaches, the organocatalyzed [2+2+2] tandem cycloaddition has emerged as a pivotal strategy to construct fully substituted six-membered carbocycles (Scheme 1) [38,39,40].
Very recently, we and others independently reported research on the application of lactols or cyclic hemiaminals as nucleophiles under enamine activation to produce chiral substituted lactones, lactams, and other interesting heterocycles with excellent enantioselectivity and diastereoselectivity [41,42,43,44,45,46]. In an effort to expand our exploration on the application of lactols or cyclic hemiaminals, herein we would like to report an asymmetric [2+2+2] annulation under an organo/organo dual catalytic system to produce six-membered carbocycles with six continuous stereogenic centers including an all-carbon quaternary center and spirooxindole moiety in the product structure.

2. Results and Discussion

We first investigated the reaction of N-Boc-protected olefinic oxindole 1a and lactol 2a in the presence of commercially available chiral catalyst 3 and 4-NO2PhCOOH in CH3CN as the solvent at room temperature. After the enamine-based Michael addition step was completed, the β-nitrostyrene 4a was then directly added to the crude reaction mixture and N,N-diisopropylethylamine (DIPEA) was used as the base catalyst to promote the sequential Michael/Henry cascade additions. To our gratification, this organo/organo dual catalytic system trigged [2+2+2] tandem reaction proceeded smoothly, leading to fully substituted spirocyclic six-membered carbocycles 5a in 81% yield with high enantioselectivity as a single diastereoisomer (Table 1, entry 1). Similar results were attained with other acid additives (Table 1, entries 2–4). Interestingly, the reaction gave better stereocontrolled results when the less sterically hindered base, triethylamine (TEA), was used (Table 1, entry 5). Moreover, the inorganic base (K2CO3) could also catalyze the reaction and gave excellent enantioselectivity, albeit in lower yield (Table 1, entry 6). After screening a variety of solvents, EtOH with 5% H2O was found to be the best solvent system (Table 1, entries 7–11). To have a more efficient process, the catalyst loading was decreased to 5 mol %. Notably, both the isolated yield and enantioselectivity of this elegant [2+2+2] cyclization reaction were maintained (Table 1, entry 12).
With the optimized conditions in hand (Table 1, entry 11), we next explored the substrate scope and limitations of this organo/organo dual catalytic system induced one-pot Michael/Michael/Henry tandem reaction. As shown in Scheme 2, various olefinic oxindole 1, lactol 2, and nitroolefin 4 were subjected to this asymmetric [2+2+2] annulation. Concerning the scope of nitroolefin 4, good yields (71%–88%) and excellent enantioselectivities (93%–99%) were obtained irrespective of substituent positions and electronic properties changed on the aromatic ring (5a–i). Heteroaromatic groups, such as furan, thiophene, and indole, could also be used as the substituent of the nitroolefin 4 leading to the desired products with excellent enantioselectivity (5j–l). In the case of olefinic oxindole 1, high reactivity had been observed regardless of the substituents on the aromatic groups (5m–r). Furthermore, various substituted lactol 2 proved to be suitable substrates, the expected spirocyclic products 5s–v were obtained in high yields and excellent stereoselectivities. Additionally, the ester moiety has no effect on the reaction process (5w). It should be noted that not only lactol but also cyclic hemiaminal could be used and thus lead to the formation of 5x with a Tos-protected amino group in the structure.
Moreover, the one-pot [2+2+2] cyclization between olefinic oxindole 1a, lactol 2a and cinnamaldehyde 6 was also investigated under slightly modified conditions. It was pleasing that the cascade reaction proceeded well and provided the desired product 7 in good yield with excellent stereoselectivity (Scheme 3) [38].
Unfortunately, we finally could not obtain any single crystal of product 5 or 7, which is suitable for X-ray crystallographic analysis, while we obtained a single crystal of racemate 5g which could provide the relative configuration of all the substituents on the ring system. Accordingly, as shown in Figure 1, we could propose the absolute configuration of both adduct 5g and its enantiomer 5g’ [47].
The detailed process of this one-pot organo/organo dual catalytic system-induced [2+2+2] annulation is depicted in Scheme 4 to rationalize the proposed stereochemistry of the products 5g. According to our previously developed enamine-based asymmetric Michael reaction of lactol 2a, the (S)-diphenylprolinol TMS ether 3 showed the same catalytic behavior, as in the asymmetric Michael reaction of aliphatic aldehydes, for the stereoselectivity control of the reaction process [41]. Thus, in the first step of this one-pot process, reaction of 3 with the lactol 2a affords the enamine A, which allows for si-face attack of the olefinic oxindole 1a, leading to formation of lactol B with (R,R)-configured stereocenters. This should be consistent with the observations of the earlier studies [33,38,40]. The key intermediate lactol B containing a lactol moiety is found as an equilibrium mixture with the corresponding hydroxyaldehyde C. Subsequently, the second Michael addition was conducted between the hydroxyaldehyde C and β-nitrostyrene 4g in the presence of TEA, which occurs from Si-face attack followed by the Henry reaction providing the desired product 5g as a single diastereoisomer, and obviously, the high stereoselectivity can be attributed to the directing effect of the primary chiral substituted groups in the structure. Therefore, the structure and stereochemistry of 5g could be determined based on the relative configuration from the single-crystal X-ray analysis of racemate 5g and combined with several known activation modes in the reaction of olefinic oxindole 1a and aliphatic aldehydes driven by (S)-diphenylprolinol TMS ether 3 [33,38,40].

3. Materials and Methods

3.1. General Information

Reagents and solvents were purchased from commercial suppliers and used as received, without further purification. Chromatographic purification of products was accomplished using force-flow chromatography (FC) on silica gel (200–400 mesh). For thin layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm) were used, using UV light as the visualizing agent and an acidic mixture of ceric ammonium molybdate or basic aqueous potassium permanganate (KMnO4) as stain developing solutions. 1H NMR spectra were obtained with a Bruker Avance 500 MHz spectrometer. Chemical shifts were reported in δ (ppm) units relative to tetramethylsilane (TMS) as the internal standard. 13C NMR spectra were obtained at 125 MHz; chemical shifts were reported in ppm relative to TMS with the solvent resonance as the internal standard. Infrared spectra were obtained with a Bruker ALPHA-P spectrometer or a Perkin Elmer Spectrum One spectrometer. High resolution mass spectra (electron spray ionization) were obtained with a Bruker APEX IV Fourier-Transform mass spectrometer. Enantiomeric excesses (ee) were determined by chiral HPLC analysis using an Agilent 1200 LC instrument with a Daicel Chiralpak IA, IB or IC column and i-PrOH/n-hexane as the eluent was used. HPLC traces were compared with racemic samples prepared via mixing two enantiomeric final products, equally, obtained from (S) and (R) catalysts, respectively. (S) and (R)-Diphenylprolinol silyl ethers 3 are commercially available from Daicel chiral Technologies. All the cyclic hemiaminals, lactols and N-Boc-protected olefinic oxindole were synthesized according to literature procedures.

3.2. General Procedure for the One-Pot, [2+2+2] Tandem Reaction

To a mixture of 3 (0.005 mmol, 0.05 equiv) and p-nitrobenzoic acid (0.005 mmol, 0.05 equiv) in 0.4 mL EtOH (with 5% H2O) was added olefinic oxindole 1 (0.1 mmol, 1 equiv), lactol 2 (0.12 mmol, 1.2 equiv) subsequently. The reaction was stirred at room temperature for 3 h, after which nitroolefin 4 was added followed by the addition of TEA (0.04 mmol 0.4 equiv). The reaction was kept in 25 °C for another 12 h. The product 5 was isolated by chromatography.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5a): 88% yield; [α] D 25 = +52.6 (c = 1.0 in CHCl3); 98% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.86 min, tminor = 9.11 min]; 1H NMR (500 MHz, CDCl3) δ 7.48 (dd, J = 7.3, 1.2 Hz, 1H), 7.40 (dd, J = 7.9, 0.9 Hz, 1H), 7.22–7.12 (m, 4H), 7.04–6.84 (m, 6H), 6.71–6.58 (m, 1H), 6.03 (dd, J = 12.3, 2.9 Hz, 1H), 4.40 (s, 1H), 4.13 (d, J = 12.3 Hz, 1H), 3.92–3.83 (m, 2H), 3.66 (d, J = 11.9 Hz, 1H), 3.40–3.34 (m, 1H), 3.08–3.02 (m, 1H), 2.46 (dd, J = 13.7, 4.4 Hz, 1H), 1.55 (s, 9H), 0.87 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.83, 171.38, 153.74, 148.43, 139.34, 133.02, 131.73, 129.03, 128.34, 127.86, 127.57, 124.39, 123.83, 122.83, 121.62, 115.82, 114.75, 85.94, 84.23, 68.24, 61.03, 54.68, 51.06, 46.62, 39.50, 29.42, 28.04, 13.62. ESI-HRMS: calcd. for C34H35N2O9 [M − H]− 615.2343, found 615.2340.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-6-(4-fluorophenyl)-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxospiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5b): 84% yield; [α] D 25 = +21.5 (c = 1.0 in CHCl3); 97% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.39 min, tminor = 8.38 min]; 1H NMR (500 MHz, CD3OD) δ 7.62 (d, J = 7.2 Hz, 1H), 7.39–7.35 (m, 1H), 7.29–7.19 (m, 2H), 7.14–7.04 (m, 2H), 6.84–6.52 (m, 5H), 5.87 (dd, J = 12.2, 2.7 Hz, 1H), 4.37 (s, 1H), 4.17 (d, J = 12.2 Hz, 1H), 3.79–3.71 (m, 2H), 3.58 (d, J = 12.2 Hz, 1H), 3.52–3.45 (m, 1H), 2.85–2.78 (m, 1H), 2.61 (dd, J = 13.4, 4.4 Hz, 1H), 1.55 (s, 8H), 0.84 (t, J = 7.1 Hz, 3H).13C NMR (125 MHz, CD3OD) δ 175.42, 171.43, 162.95, 161.33, 155.38, 148.48, 139.28, 131.03, 130.31, 128.87, 127.93, 127.58, 124.66, 124.49, 123.33, 119.41, 114.71, 114.38, 86.90, 84.36, 68.61, 60.64, 54.83, 51.35, 45.49, 38.12, 30.25, 26.93, 12.66. ESI-HRMS: calcd. for C34H34FN2O9 [M − H]− 633.2248, found 633.2243.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-2-(4-bromophenyl)-4-hydroxy-5-(2-hydroxybenzyl)-3-nitro-2’-oxospiro[cyclohexane-1,3’-indoline]-1’,6-dicarboxylate (5c): 86% yield; [α] D 25 = +65.7(c = 1.0 in CHCl3); 97% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.50 min, tminor = 9.20 min]; 1H NMR (500 MHz, CD3OD) δ 7.64–7.59 (m, 1H), 7.37 (dd, J = 7.7, 1.1 Hz, 1H), 7.30–7.21 (m, 2H), 7.18–6.95 (m, 4H), 6.79 (dd, J = 13.7, 7.4 Hz, 2H), 6.64–6.31 (m, 1H), 5.86 (dd, J = 12.1, 2.8 Hz, 1H), 4.38 (s, 1H), 4.15 (d, J = 12.1 Hz, 1H), 3.79–3.71 (m, 2H), 3.58 (d, J = 12.2 Hz, 1H), 3.53–3.44 (m, 1H), 2.85–2.78 (m, 1H), 2.62 (dd, J = 13.4, 4.4 Hz, 1H), 1.55 (s, 7H), 0.84 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CD3OD) δ 175.37, 171.41, 163.55, 155.39, 148.39, 139.28, 133.69, 131.03, 130.62, 128.97, 127.80, 127.59, 124.65, 124.54, 123.35, 121.31, 119.41, 114.71, 114.47, 86.64, 84.44, 68.62, 60.66, 54.71, 51.26, 45.72, 38.13, 30.26, 26.94, 12.66. ESI-HRMS: calcd. for C34H34BrN2O9 [M − H]− 693.1448, found 693.1451.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxybenzyl)-6-(4-methoxyphenyl)-5-nitro-2’-oxospiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5d): 75% yield; [α] D 25 = +56.3 (c = 1.0 in CHCl3); 95% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 5.76 min, tminor = 12.08 min]; 1H NMR (500 MHz, CDCl3) δ 7.47–7.42 (m, 2H), 7.22–7.12 (m, 4H), 6.93 (dd, J = 10.7, 4.1 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.57–6.40 (m, 3H), 5.98 (dd, J = 12.3, 2.7 Hz, 1H), 4.37 (s, 1H), 4.10–4.02 (m, 2H), 3.92–3.82 (m, 2H), 3.62 (s, 3H), 3.38–3.29 (m, 1H), 3.07–2.99 (m, 1H), 2.45 (dd, J = 13.7, 4.4 Hz, 1H), 1.57 (s, 8H), 0.87 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.91, 171.29, 158.97, 153.79, 148.45, 139.40, 131.71, 129.00, 128.35, 127.70, 124.75, 124.37, 123.79, 122.73, 121.63, 115.91, 114.87, 113.33, 86.17, 84.18, 68.08, 61.05, 54.98, 54.73, 51.07, 45.98, 39.39, 28.06, 13.62. ESI-HRMS: calcd. for C35H37N2O10 [M − H]− 645.2448, found 645.2450.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-6-(4-cyanophenyl)-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxospiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5e): 75% yield; [α] D 25 = +83.2 (c = 1.0 in CHCl3); 99% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 10.29 min, tminor = 19.55 min]; 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J = 7.0 Hz, 1H), 7.48–7.18 (m, 6H), 7.15–7.05 (m, 2H), 6.80 (dd, J = 13.9, 7.5 Hz, 2H), 5.94 (dd, J = 12.1, 2.8 Hz, 1H), 4.43 (s, 1H), 4.28 (d, J = 12.1 Hz, 1H), 3.80–3.70 (m, 2H), 3.60 (d, J = 12.1 Hz, 1H), 3.53–3.45 (m, 1H), 2.84–2.79 (m, 1H), 2.63 (dd, J = 13.4, 4.4 Hz, 1H), 1.55 (s, 9H), 0.84 (t, J = 7.1 Hz, 3H).13C NMR (125 MHz, CD3OD) δ 175.00, 171.27, 163.55, 155.39, 148.35, 140.46, 139.16, 131.03, 129.15, 127.62, 127.39, 124.64, 124.61, 123.47, 119.43, 117.80, 114.72, 114.42, 111.26, 86.42, 84.57, 68.64, 60.72, 54.69, 51.41, 46.24, 38.14, 30.24, 26.93, 12.66. ESI-HRMS: calcd. For C35H34N3O9 [M − H]− 640.2295, found 640.2291.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxo-6-(p-tolyl)spiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5f): 75% yield; [α] D 25 = +59.7 (c = 1.0 in CHCl3); 95% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.92 min, tminor = 9.40 min]; 1H NMR (500 MHz, CD3OD) δ 7.60 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.28–7.17 (m, 2H), 7.14–7.04 (m, 2H), 6.85–6.67 (m, 4H), 5.90–5.84 (m, 1H), 4.35 (s, 1H), 4.11 (d, J = 12.2 Hz, 1H), 3.79–3.69 (m, 2H), 3.57 (d, J = 12.1 Hz, 1H), 3.53–3.45 (m, 1H), 2.82 (dd, J = 13.4, 10.1 Hz, 1H), 2.60 (dd, J = 13.4, 4.4 Hz, 1H), 2.12 (s, 3H), 1.54 (s, 8H), 0.83 (t, J = 7.1 Hz, 3H).13C NMR (125 MHz, CD3OD) δ 175.48, 171.40, 155.24, 148.43, 139.24, 137.05, 130.91, 128.55, 128.11, 128.02, 127.44, 124.59, 124.22, 123.16, 119.30, 114.60, 114.26, 86.86, 84.05, 68.50, 60.47, 54.74, 51.30, 45.72, 38.05, 30.14, 26.85, 19.50, 12.55. ESI-HRMS: calcd. For C35H37N2O9 [M − H]− 629.2499, found 629.2498.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-6-(2-chlorophenyl)-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxospiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5g): 71% yield; [α] D 25 = +27.8 (c = 1.0 in CHCl3); 96% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.83 min, tminor = 10.62 min]; 1H NMR (500 MHz, CD3OD) δ 7.68–7.64 (m, 1H), 7.34 (dd, J = 12.0, 4.8 Hz, 2H), 7.20–7.01 (m, 7H), 6.80 (dd, J = 13.2, 7.2 Hz, 2H), 5.83 (dd, J = 12.0, 2.7 Hz, 1H), 5.01 (d, J = 12.0 Hz, 1H), 4.38 (s, 1H), 3.78–3.69 (m, 2H), 3.62 (d, J = 12.1 Hz, 1H), 3.58–3.51 (m, 1H), 2.86–2.81 (m, 1H), 2.61 (dd, J = 13.4, 4.3 Hz, 1H), 1.59 (s, 9H), 0.83 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CD3OD) δ 175.83, 171.35, 163.55, 155.37, 148.61, 138.93, 135.87, 132.98, 131.03, 129.64, 128.88, 128.69, 127.57, 126.97, 126.39, 125.14, 124.71, 123.77, 119.42, 114.71, 113.72, 87.64, 84.43, 68.68, 60.63, 54.60, 51.89, 40.53, 38.13, 30.23, 27.00, 12.64. ESI-HRMS: calcd. for C34H34ClN2O9 [M − H]− 649.1953, found 649.1957.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxybenzyl)-6-(3-methoxyphenyl)-5-nitro-2’-oxospiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5h): 79% yield; [α] D 25 = +57.2 (c = 1.0 in CHCl3); 93% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.33 min, tminor = 7.09 min]; 1H NMR (500 MHz, CDCl3) δ 7.46 (t, J = 8.3 Hz, 2H), 7.23–7.10 (m, 4H), 6.98–6.80 (m, 3H), 6.57 (d, J = 8.2 Hz, 1H), 6.38 (s, 1H), 6.00 (d, J = 12.3 Hz, 1H), 4.38 (s, 1H), 4.14–4.07 (m, 1H), 3.92–3.81 (m, 2H), 3.65 (d, J = 11.9 Hz, 1H), 3.58–3.42 (m, 3H), 3.36 (t, J = 10.5 Hz, 1H), 3.04 (t, J = 12.8 Hz, 1H), 2.46 (dd, J = 13.6, 3.8 Hz, 1H), 1.55 (s, 8H), 0.90–0.84 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 174.69, 171.27, 153.67, 148.47, 139.52, 134.40, 131.73, 129.07, 128.81, 128.36, 127.68, 124.29, 123.79, 122.76, 121.70, 115.84, 114.88, 85.91, 84.23, 68.20, 61.08, 54.91, 54.60, 51.06, 46.65, 39.43, 29.38, 27.97, 13.62. ESI-HRMS: calcd. for C35H37N2O10 [M − H]− 645.2448, found 645.24544.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxybenzyl)-6-(naphthalen-2-yl)-5-nitro-2’-oxospiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5i): 72% yield; [α] D 25 = +109.8 (c = 1.0 in CHCl3); 97% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 5.93 min, tminor = 9.89 min]; 1H NMR (500 MHz, CDCl3) δ 7.68–7.51 (m, 3H), 7.40–7.27 (m, 3H), 7.24–7.09 (m, 4H), 6.96 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.77–6.56 (m, 1H), 6.30 (s, 1H), 6.21–6.13 (m, 1H), 4.44 (s, 1H), 4.30 (d, J = 12.2 Hz, 1H), 4.06 (s, 1H), 3.94–3.81 (m, 2H), 3.71 (d, J = 11.9 Hz, 1H), 3.43 (t, J = 10.5 Hz, 1H), 3.07 (t, J = 12.8 Hz, 1H), 2.49 (dd, J = 13.7, 4.1 Hz, 1H), 1.39 (s, 8H), 0.90–0.85 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 174.82, 171.26, 153.69, 148.26, 139.35, 132.73, 132.64, 131.75, 129.10, 128.38, 127.97, 127.52, 127.31, 126.08, 125.87, 124.38, 123.81, 122.82, 121.73, 115.87, 114.82, 86.18, 84.16, 68.26, 61.09, 54.77, 51.21, 41.95, 39.48, 29.42, 27.87, 13.62. ESI-HRMS: calcd. for C38H37N2O9 [M − H]− 665.2499, found 665.2494.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-6-(furan-2-yl)-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2'-oxospiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5j): 81% yield; [α] D 25 = +42.7 (c = 1.0 in CHCl3); 97% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 9.20 min, tminor = 11.41 min]; 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 7.7 Hz, 1H), 7.45–7.41 (m, 1H), 7.28–7.19 (m, 2H), 7.16–7.11 (m, 2H), 7.00 (d, J = 1.0 Hz, 1H), 6.93 (dd, J = 15.4, 8.0 Hz, 1H), 6.86–6.81 (m, 1H), 6.00 (dd, J = 3.2, 1.8 Hz, 1H), 5.89 (dd, J = 12.1, 2.9 Hz, 1H), 5.72 (d, J = 3.3 Hz, 1H), 4.37 (s, 1H), 4.30 (d, J = 12.1 Hz, 1H), 3.93–3.83 (m, 2H), 3.56 (d, J = 11.9 Hz, 1H), 3.33–3.24 (m, 1H), 3.05–2.97 (m, 1H), 2.42 (dd, J = 13.6, 4.4 Hz, 1H), 1.59 (s, 8H), 0.88 (q, J = 6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.40, 171.13, 153.59, 148.71, 148.24, 142.04, 139.57, 131.76, 129.19, 128.34, 127.73, 124.60, 123.76, 122.79, 121.72, 115.73, 114.86, 110.12, 108.17, 85.06, 84.31, 67.94, 61.12, 53.76, 50.91, 41.10, 39.40, 29.25, 28.05, 13.63. ESI-HRMS: calcd. for C32H33N2O10 [M − H]− 605.2135, found 605.2136.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxo-6-(thiophen-2-yl)spiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5k): 81% yield; [α] D 25 = +46.6 (c = 1.0 in CHCl3); 96% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 5.15 min, tminor = 8.72 min]; 1H NMR (500 MHz, CDCl3) δ 7.54–7.50 (m, 1H), 7.45 (dd, J = 8.3, 4.9 Hz, 1H), 7.24 (dd, J = 5.6, 3.4 Hz, 2H), 7.14 (t, J = 6.7 Hz, 2H), 6.93 (dd, J = 13.5, 6.2 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.71–6.65 (m, 2H), 5.93 (dd, J = 12.0, 2.7 Hz, 1H), 4.40–4.34 (m, 2H), 3.93–3.83 (m, 2H), 3.61 (d, J = 11.9 Hz, 1H), 3.35–3.27 (m, 1H), 3.05–2.98 (m, 1H), 2.43 (dd, J = 13.6, 4.4 Hz, 1H), 1.57 (s, 9H), 0.88 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.78, 171.19, 153.64, 148.55, 139.72, 135.62, 131.74, 129.32, 128.37, 127.84, 126.13, 125.63, 125.23, 124.68, 123.73, 122.71, 121.69, 115.76, 114.96, 87.16, 84.32, 68.11, 61.13, 54.99, 51.06, 42.04, 39.34, 29.29, 28.04, 13.63. ESI-HRMS: calcd. for C32H33N2O9S [M − H]− 621.1907, found 621.1909.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-2-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)-4-hydroxy-5-(2-hydroxybenzyl)-3-nitro-2’-oxospiro[cyclohexane-1,3’-indoline]-1’,6-dicarboxylate (5l): 99% yield; [α] D 25 = +53.7 (c = 1.0 in CHCl3); 92% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.46 min, tminor = 8.30 min]; 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 9.1 Hz, 1H), 7.15 (dd, J = 12.1, 7.6 Hz, 2H), 7.09 (t, J = 7.5 Hz, 2H), 7.04–6.92 (m, 3H), 6.83 (d, J = 7.9 Hz, 1H), 6.31 (s, 1H), 5.90 (d, J = 12.2 Hz, 1H), 4.52 (d, J = 12.2 Hz, 1H), 4.36 (s, 1H), 4.06 (d, J = 6.9 Hz, 1H), 3.92–3.81 (m, 2H), 3.68 (d, J = 11.9 Hz, 1H), 3.33 (t, J = 9.9 Hz, 1H), 3.06 (t, J = 12.8 Hz, 1H), 2.45 (dd, J = 13.6, 3.9 Hz, 1H), 1.60 (d, J = 2.5 Hz, 15H), 0.88 (t, J = 7.1 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 175.29, 171.20, 153.59, 149.22, 148.69, 139.31, 131.75, 130.00, 129.19, 128.37, 127.50, 124.36, 124.31, 123.79, 123.30, 122.86, 122.06, 121.73, 118.65, 115.79, 114.87, 114.75, 114.58, 87.64, 84.34, 83.95, 68.01, 61.10, 54.67, 51.58, 39.42, 36.67, 29.27, 28.10, 28.01, 13.61. ESI-HRMS: calcd. for C41H44N3O11 [M − H]− 754.2976, found 754.2977.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-5’-bromo-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5m): 77% yield; [α] D 25 = +33.8 (c = 1.0 in CHCl3); 96% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 5.27 min, tminor = 10.20 min]; 1H NMR (500 MHz, CDCl3) δ 7.61 (s, 1H), 7.31 (q, J = 8.7 Hz, 2H), 7.16 (t, J = 7.2 Hz, 2H), 7.08–6.93 (m, 4H), 6.84 (d, J = 8.2 Hz, 1H), 6.30 (s, 1H), 5.97 (dd, J = 12.2, 2.0 Hz, 1H), 4.38 (s, 1H), 4.08 (d, J = 12.1 Hz, 1H), 3.99–3.84 (m, 2H), 3.61 (d, J = 11.9 Hz, 1H), 3.33 (dd, J = 11.6, 9.2 Hz, 1H), 3.03 (dd, J = 24.0, 11.7 Hz, 1H), 2.47 (dd, J = 13.6, 3.9 Hz, 1H), 1.55 (s, 8H), 0.94–0.86 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 173.91, 171.20, 153.61, 148.19, 138.51, 132.60, 132.01, 131.76, 129.89, 128.44, 128.09, 128.07, 125.88, 123.67, 121.76, 85.70, 84.59, 68.08, 61.21, 54.72, 50.82, 46.58, 39.49, 29.36, 28.01, 13.69. ESI-HRMS: calcd. for C34H34BrN2O9 [M − H]− 693.1448, found 693.1446.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-5’-chloro-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5n): 82% yield; [α] D 25 = +103.8 (c = 1.0 in CHCl3); 98% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 5.99 min, tminor = 11.37 min]; 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 1.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.16 (t, J = 8.0 Hz, 3H), 7.08–6.92 (m, 4H), 6.84 (d, J = 7.8 Hz, 1H), 6.29 (s, 1H), 5.98 (dd, J = 12.2, 2.2 Hz, 1H), 4.37 (d, J = 13.9 Hz, 1H), 4.09 (d, J = 12.5 Hz, 2H), 3.97–3.85 (m, 2H), 3.62 (d, J = 11.9 Hz, 1H), 3.38–3.30 (m, 1H), 3.04 (t, J = 12.8 Hz, 1H), 1.55 (s, 8H), 0.92 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.05, 171.18, 153.62, 137.99, 132.63, 131.75, 129.88, 129.56, 129.09, 128.43, 128.07, 123.67, 123.02, 121.75, 116.11, 115.82, 85.73, 84.57, 68.09, 61.20, 54.77, 50.83, 46.57, 39.49, 29.37, 28.02, 13.68. ESI-HRMS: calcd. for C34H34ClN2O9 [M − H]− 649.1953, found 649.1957.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxybenzyl)-5’-methoxy-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5o): 65% yield; [α] D 25 = +88.8 (c = 1.0 in CHCl3); 92% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 5.45 min, tminor = 15.19 min]; 1H NMR (500 MHz, CDCl3) δ 7.26 (d, J = 2.5 Hz, 1H), 7.15 (t, J = 8.1 Hz, 2H), 7.05–6.91 (m, 5H), 6.85 (d, J = 7.8 Hz, 1H), 6.38 (s, 1H), 6.02 (dd, J = 12.3, 2.2 Hz, 1H), 4.38 (s, 1H), 4.11–4.04 (m, 2H), 3.64 (d, J = 11.9 Hz, 1H), 3.40–3.30 (m, 1H), 3.04 (t, J = 12.8 Hz, 1H), 2.47 (dd, J = 13.7, 4.2 Hz, 1H), 2.39 (s, 3H), 1.54 (s, 7H), 0.87 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.90, 171.25, 153.73, 148.46, 137.00, 134.04, 132.94, 131.74, 129.53, 128.36, 127.85, 127.45, 123.81, 123.24, 121.68, 115.87, 114.56, 85.98, 84.00, 68.18, 61.02, 54.66, 51.05, 46.68, 39.41, 29.42, 28.05, 21.12, 13.61.. ESI-HRMS: calcd. for C35H37N2O10 [M − H]− 645.2448, found 645.2448.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-5’-fluoro-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5p): 65% yield; [α] D 25 = +47.8 (c = 1.0 in CHCl3); 94% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 5.31 min, tminor = 11.33 min]; 1H NMR (500 MHz, CDCl3) δ 7.41 (dd, J = 8.9, 4.4 Hz, 1H), 7.21 (dd, J = 7.5, 2.3 Hz, 1H), 7.16 (t, J = 7.4 Hz, 2H), 7.07–6.93 (m, 4H), 6.90–6.82 (m, 2H), 6.30 (s, 1H), 5.99 (dd, J = 12.2, 2.4 Hz, 1H), 4.38 (s, 1H), 4.08 (dd, J = 12.5, 5.1 Hz, 2H), 3.96–3.85 (m, 2H), 3.60 (d, J = 11.9 Hz, 1H), 3.35 (td, J = 11.9, 2.8 Hz, 1H), 3.08–3.00 (m, 1H), 2.46 (dd, J = 13.7, 4.3 Hz, 1H), 1.55 (s, 8H), 0.92 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 173.80, 171.22, 153.59, 147.88, 144.77, 144.37, 132.40, 131.76, 129.50, 128.49, 128.32, 128.23, 125.37, 123.58, 121.80, 118.39, 115.69, 115.00, 85.50, 68.04, 65.90, 61.40, 54.68, 50.75, 46.46, 39.67, 29.37, 27.98, 13.77. ESI-HRMS: calcd. for C34H34FN2O9 [M − H]− 633.2248, found 633.2243.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxybenzyl)-5,5’-dinitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5q): 39% yield; [α] D 25 = +136.5 (c = 1.0 in CHCl3); 98% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 6.39 min, tminor = 15.73 min]; 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 9.0, 2.1 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.17 (t, J = 7.5 Hz, 2H), 7.10–6.93 (m, 4H), 6.84 (d, J = 7.9 Hz, 1H), 5.94 (dd, J = 12.2, 2.5 Hz, 1H), 4.41 (s, 1H), 4.18 (d, J = 12.2 Hz, 2H), 3.90 (q, J = 7.1 Hz, 2H), 3.73 (t, J = 11.1 Hz, 1H), 3.34 (td, J = 11.8, 2.7 Hz, 1H), 3.07 (t, J = 12.8 Hz, 1H), 2.48 (dd, J = 13.6, 4.3 Hz, 1H), 1.58 (s, 9H), 0.91 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.34, 171.16, 160.75, 158.81, 153.62, 148.35, 135.39, 132.68, 131.75, 129.57, 129.51, 128.42, 128.07, 128.03, 123.68, 121.76, 116.32, 116.25, 115.82, 115.76, 115.58, 110.37, 110.17, 85.75, 84.43, 68.09, 61.21, 54.90, 50.90, 46.60, 39.51, 29.35, 28.03, 13.68. ESI-HRMS: calcd. for C34H34N3O11 [M − H]− 660.2193, found 660.2195.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-7’-bromo-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5r): 71% yield; [α] D 25 = +21.3 (c = 1.0 in CHCl3); 98% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.60 min, tminor = 10.12 min]; 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.16 (t, J = 6.9 Hz, 2H), 7.10–6.93 (m, 5H), 6.83 (d, J = 8.2 Hz, 1H), 6.09 (s, 1H), 6.04 (dd, J = 12.2, 2.2 Hz, 1H), 4.37 (s, 1H), 4.14 (d, J = 12.2 Hz, 1H), 4.01–3.85 (m, 3H), 3.58 (d, J = 11.9 Hz, 1H), 3.27 (dd, J = 11.9, 9.4 Hz, 1H), 3.01 (t, J = 12.8 Hz, 1H), 2.44 (dd, J = 13.7, 4.1 Hz, 1H), 1.56 (s, 8H), 0.96–0.90 (m, 3H).13C NMR (125 MHz, CDCl3) δ 174.54, 170.50, 153.60, 150.83, 146.72, 138.28, 133.79, 132.48, 131.74, 131.16, 128.42, 128.14, 125.25, 123.65, 122.14, 121.77, 115.87, 106.21, 85.77, 85.15, 68.00, 61.40, 55.68, 51.28, 46.38, 39.38, 29.27, 27.66, 13.61. ESI-HRMS: calcd. for C34H34BrN2O9 [M − H]− 693.1448, found 693.1449.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-3-(5-fluoro-2-hydroxybenzyl)-4-hydroxy-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5s): 81% yield; [α] D 25 = +51.2 (c = 1.0 in CHCl3); 97% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.53 min, tminor = 7.64 min]; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.1 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.23–7.14 (m, 2H), 7.06–6.77 (m, 7H), 6.65 (s, 1H), 6.05 (dd, J = 12.3, 2.0 Hz, 1H), 4.39 (s, 1H), 4.14–4.04 (m, 2H), 3.92–3.81 (m, 2H), 3.65 (d, J = 11.9 Hz, 1H), 3.41–3.32 (m, 1H), 3.02 (t, J = 12.7 Hz, 1H), 2.43 (dd, J = 13.6, 4.2 Hz, 1H), 1.55 (s, 8H), 0.86 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.79, 171.22, 158.28, 156.37, 149.92, 149.91, 148.40, 139.33, 132.77, 129.10, 127.95, 127.90, 127.44, 125.52, 125.46, 124.42, 122.79, 117.78, 117.60, 116.86, 116.79, 114.79, 114.60, 85.91, 84.34, 68.16, 61.19, 54.63, 50.94, 46.68, 39.20, 29.67, 28.03, 13.58. ESI-HRMS: calcd. for C34H34FN2O9 [M − H]− 633.2248, found 633.2245.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-3-(4-chloro-2-hydroxybenzyl)-4-hydroxy-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5t): 63% yield; [α] D 25 = +33.9 (c = 1.0 in CHCl3); 92% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.36 min, tminor = 7.11 min]; 1H NMR (500 MHz, CDCl3) δ 7.47 (t, J = 8.8 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.23–7.15 (m, 2H), 7.10–6.85 (m, 7H), 6.06–6.00 (m, 1H), 4.38 (d, J = 21.5 Hz, 1H), 4.16–4.03 (m, 2H), 3.93–3.79 (m, 2H), 3.65 (d, J = 11.9 Hz, 1H), 3.36 (td, J = 11.8, 2.8 Hz, 1H), 3.06–2.96 (m, 1H), 2.45 (dd, J = 13.7, 4.3 Hz, 1H), 1.55 (s, 8H), 0.86 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 175.04, 171.39, 154.83, 148.37, 139.26, 133.16, 132.83, 132.43, 129.11, 127.93, 127.48, 124.49, 122.85, 122.63, 121.45, 116.27, 114.80, 85.92, 84.48, 68.18, 61.22, 54.70, 50.99, 46.65, 39.20, 29.14, 28.02, 13.59. ESI-HRMS: calcd. for C34H34ClN2O9 [M − H]− 649.1953, found 649.1951.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxy-5-methoxybenzyl)-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5u): 73% yield; [α] D 25 = +71.4 (c = 1.0 in CHCl3); 99% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 6.91 min, tminor = 13.76 min]; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.22–7.13 (m, 2H), 7.06–6.88 (m, 4H), 6.78 (d, J = 9.2 Hz, 1H), 6.70 (d, J = 7.0 Hz, 2H), 6.12 (s, 1H), 6.02 (dt, J = 11.8, 5.9 Hz, 1H), 4.39 (s, 1H), 4.20 (s, 1H), 4.11 (d, J = 12.3 Hz, 1H), 3.91–3.83 (m, 2H), 3.79 (s, 3H), 3.65 (d, J = 11.9 Hz, 1H), 3.37 (td, J = 11.7, 3.4 Hz, 1H), 3.03 (t, J = 12.8 Hz, 1H), 2.42 (dd, J = 13.6, 4.4 Hz, 1H), 1.56 (s, 8H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.79, 171.30, 154.30, 148.41, 147.48, 139.40, 132.94, 129.04, 127.88, 127.55, 124.74, 124.35, 122.76, 116.69, 116.28, 114.77, 113.92, 85.89, 84.17, 68.24, 61.06, 55.83, 54.63, 51.00, 46.64, 39.45, 29.72, 28.04, 13.63.ESI-HRMS: calcd. for C35H37N2O10 [M − H]− 645.2448, found 645.2450.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxy-5-methylbenzyl)-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5v): 77% yield; [α] D 25 = +71.8 (c = 1.0 in CHCl3); 99% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 4.77 min, tminor = 8.59 min]; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.23–7.13 (m, 2H), 7.06–6.86 (m, 5H), 6.73 (d, J = 8.0 Hz, 1H), 6.10 (s, 1H), 6.03 (dd, J = 12.3, 2.2 Hz, 1H), 4.38 (s, 1H), 4.11 (d, J = 12.4 Hz, 2H), 3.91–3.84 (m, 2H), 3.64 (d, J = 11.9 Hz, 1H), 3.38–3.29 (m, 1H), 3.01 (t, J = 12.8 Hz, 1H), 2.40 (dd, J = 13.6, 4.2 Hz, 1H), 2.28 (s, 3H), 1.56 (s, 8H), 0.87 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.79, 171.30, 154.30, 148.41, 147.48, 139.40, 132.94, 129.04, 127.88, 127.55, 124.74, 124.35, 122.76, 116.69, 116.28, 114.77, 113.92, 85.89, 84.17, 68.24, 61.06, 55.83, 54.63, 51.00, 46.64, 39.45, 29.72, 28.04, 13.63. ESI-HRMS: calcd. for C35H37N2O9 [M − H]− 629.2499, found 629.2495.
di-tert-butyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-hydroxybenzyl)-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3’-indoline]-1’,2-dicarboxylate (5w): 73% yield; [α] D 25 = +48.8 (c = 1.0 in CHCl3); 98% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 3.84 min, tminor = 8.05 min]; 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.24–7.12 (m, 4H), 7.04–6.91 (m, 4H), 6.86–6.80 (m, 2H), 6.03 (dd, J = 12.3, 2.5 Hz, 1H), 4.38 (s, 1H), 4.18–4.09 (m, 2H), 3.51 (d, J = 11.9 Hz, 1H), 3.35–3.27 (m, 1H), 3.04 (t, J = 12.8 Hz, 1H), 2.49 (dd, J = 13.7, 4.0 Hz, 1H), 1.55 (s, 9H), 1.11 (d, J = 8.4 Hz, 9H). 13C NMR (125 MHz, CDCl3) δ 174.65, 170.20, 153.86, 148.49, 139.42, 133.09, 131.72, 128.93, 128.29, 127.83, 127.72, 124.31, 124.01, 123.03, 121.53, 115.82, 114.65, 85.97, 84.06, 81.98, 68.16, 54.74, 51.92, 46.67, 39.50, 29.29, 28.04, 27.30. ESI-HRMS: calcd. for C36H39N2O9 [M − H]− 643.2656, found 643.2651.
1’-(tert-butyl)2-ethyl(1S,2R,3R,4R,5S,6R)-4-hydroxy-3-(2-((4-methylphenyl)sulfonamido)ethyl)-5-nitro-2’-oxo-6-phenylspiro[cyclohexane-1,3'-indoline]-1’,2-dicarboxylate (5x): 47% yield; [α] D 25 = +32.6 (c = 1.0 in CHCl3); 93% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 11.21 min, tminor = 8.98 min]; 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.43–7.40 (m, 1H), 7.38–7.30 (m, 3H), 7.19–7.11 (m, 2H), 7.07–6.92 (m, 3H), 6.07 (dd, J = 12.3, 2.2 Hz, 1H), 4.89 (t, J = 6.0 Hz, 1H), 4.58 (s, 1H), 4.05 (d, J = 12.3 Hz, 1H), 3.80–3.66 (m, 2H), 3.49 (d, J = 12.0 Hz, 1H), 3.29 (d, J = 3.0 Hz, 1H), 3.16 (t, J = 10.0 Hz, 1H), 3.10–2.97 (m, 2H), 2.43 (s, 3H), 1.97–1.81 (m, 1H), 1.55 (s, 8H), 0.76 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.76, 170.94, 148.31, 143.70, 139.27, 136.32, 132.56, 129.86, 129.04, 128.00, 127.89, 127.28, 127.18, 124.33, 122.83, 114.73, 86.40, 84.19, 68.15, 61.04, 54.40, 50.49, 46.67, 40.41, 35.37, 29.04, 28.04, 21.53, 13.46. ESI-HRMS: calcd. for C36H40N3O10S [M − H]− 706.2434, found 706.2437.

3.3. One-Pot, Three-Component Tandem Reaction to Access Spirocyclic Oxindole

To a mixture of 3 (0.02 mmol, 0.2 equiv) and p-nitrobenzoic acid (0.02 mmol, 0.2 equiv) in acetonitrile (0.2 mL) was added olefinic oxindole 1a (0.1 mmol, 1 equiv), lactol 2a (0.12 mmol, 1.2 equiv) and α,β-unsaturated aldehyde 6 (0.12 mmol, 1.2 equiv) in one portion. The reaction was stirred at 25 °C for 24 h. After completion, the mixture was directly subjected to column chromatography using (EtOAc/petroleum ether = 1:5) as eluent to give the product 7 for NMR and chiral HPLC analysis.
(7): 57% yield; [α] D 25 = −61.1 (c = 1.0 in CHCl3); 99% ee, determined by chiral HPLC analysis [Daicel Chiralcel IC, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 201 nm, tmajor = 13.04 min, tminor = 9.19 min]; 1H NMR (500 MHz, CDCl3) δ 9.40 (s, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 7.5, 1.3 Hz, 1H), 7.24–7.16 (m, 3H), 6.98–6.92 (m, 2H), 6.80 (t, J = 11.6 Hz, 2H), 6.74–6.70 (m, 1H), 6.33 (d, J = 6.0 Hz, 1H), 5.70 (d, J = 5.9 Hz, 1H), 5.50 (d, J = 7.1 Hz, 1H), 3.89–3.75 (m, 4H), 3.34 (dd, J = 14.2, 4.2 Hz, 1H), 3.10 (d, J = 10.9 Hz, 1H), 2.95 (dd, J = 14.2, 5.6 Hz, 1H), 1.64 (s, 8H), 0.82 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 192.49, 174.58, 172.21, 155.12, 154.63, 149.30, 139.39, 138.13, 135.73, 133.40, 132.45, 128.86, 128.78, 126.75, 125.24, 123.19, 122.52, 120.50, 116.79, 114.40, 84.53, 61.81, 50.55, 46.75, 44.08, 38.47, 31.59, 28.12, 13.21. ESI-HRMS: calcd. for C35H35ClNO7 [M + H]+ 616.2102, found 616.2104.

4. Conclusions

In summary, we have reported a one-pot organo/organo dual catalytic system-induced [2+2+2] tandem reaction for the asymmetric synthesis of six-membered carbocycles with excellent enantioselectivities as a single diastereoisomer. The process enables the formation of a series of spiro oxindolic carbocyclic derivatives with versatile molecular complexity, which might have potential bioactivity. We believe that this asymmetric organo/organo dual catalytic system-induced one-pot strategy may enable further application of lactol or cyclic hemiaminal in the synthesis of structural diversification of carbocycles and heterocycles. Additional results will be reported in due course.

Supplementary Materials

The supplementary materials are available online at www.mdpi.com/2073-4344 /6/5/65/s1.

Acknowledgments

We thank the National Nature Science Foundation of China (NO. 21302156, 81473337, 81274184), NSFC-Shandong Joint Fund for Marine Science Research Centers (NO. U1406402), Opening subject of state key laboratory of pharmaceutical biotechnology (KF-GN-201404) and Ocean University of China (OUC) for generous financial support.

Author Contributions

Zhi-Long Li and Yan-Kai Liu conceived and designed the experiments. Zhi-Long Li and Chao Liu performed the experiments and analyzed the data. Zhi-Long Li, Rui Tan, Zhi-Ping Tong and Yan-Kai Liu wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 06 00065 sch001 1024
Scheme 1. [2+2+2] tandem reaction to synthesize six-membered carbocycles with six continuous stereogenic centers.
Scheme 1. [2+2+2] tandem reaction to synthesize six-membered carbocycles with six continuous stereogenic centers.
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Catalysts 06 00065 sch002 1024
Scheme 2. Substrate scope for the [2+2+2] tandem reaction.
Scheme 2. Substrate scope for the [2+2+2] tandem reaction.
Catalysts 06 00065 sch002
Catalysts 06 00065 sch003 1024
Scheme 3. One-pot, three-component tandem reaction to access spirocyclic oxindole.
Scheme 3. One-pot, three-component tandem reaction to access spirocyclic oxindole.
Catalysts 06 00065 sch003
Catalysts 06 00065 sch004 1024
Scheme 4. The detailed process of the one-pot, three-component [2+2+2] tandem reaction.
Scheme 4. The detailed process of the one-pot, three-component [2+2+2] tandem reaction.
Catalysts 06 00065 sch004
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Figure 1. X-ray crystal structure of racemate 5g and the hydrogen atoms (except those of the chiral centers) are omitted for clarity.
Figure 1. X-ray crystal structure of racemate 5g and the hydrogen atoms (except those of the chiral centers) are omitted for clarity.
Catalysts 06 00065 g001
Table
Table 1. Screening studies for the [2+2+2] annulation to synthesize six-membered carbocycles a.
Table 1. Screening studies for the [2+2+2] annulation to synthesize six-membered carbocycles a.
Catalysts 06 00065 i001
EntrySolventAcidBaset [h]Yield (%) bEe (%) c
1CH3CN4-NO2PhCOOHDIPEA128193
2CH3CNPhCOOHDIPEA167693
3CH3CN4-MeOPhCOOHDIPEA167993
4CH3CN2-FPhCOOHDIPEA128193
5CH3CN4-NO2PhCOOHTEA128497
6CH3CN4-NO2PhCOOHK2CO367797
7Toluene4-NO2PhCOOHTEA248893
8CH2Cl24-NO2PhCOOHTEA247597
9THF4-NO2PhCOOHTEA367597
10EtOH4-NO2PhCOOHTEA27595
11 dEtOH4-NO2PhCOOHTEA18297
12 eEtOH4-NO2PhCOOHTEA38898
Notes: a Unless noted otherwise, reactions were carried out with 1a (0.1 mmol), 2a (0.12 mmol), 3 (0.02 mmol) and acid (0.02 mmol) in 0.4 mL of solvent at room temperature. After full conversion of the first step, 4a (0.12 mmol) and base (0.04 mmol) were added to react for another 12 h. b Yield of isolated 5a. c Enantiomeric excess (ee) was determined by HPLC analysis on a chiral stationary phase. dr > 20:1. d 5% H2O was added. e 5 mol% 3 was used. THF = tetrahydrofuran; TMS = trimethylsilyl.

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MDPI and ACS Style

Li, Z.-L.; Liu, C.; Tan, R.; Tong, Z.-P.; Liu, Y.-K. Organocatalytic, Asymmetric [2+2+2] Annulation to Construct Six-Membered Spirocyclic Oxindoles with Six Continuous Stereogenic Centers. Catalysts 2016, 6, 65. https://doi.org/10.3390/catal6050065

AMA Style

Li Z-L, Liu C, Tan R, Tong Z-P, Liu Y-K. Organocatalytic, Asymmetric [2+2+2] Annulation to Construct Six-Membered Spirocyclic Oxindoles with Six Continuous Stereogenic Centers. Catalysts. 2016; 6(5):65. https://doi.org/10.3390/catal6050065

Chicago/Turabian Style

Li, Zhi-Long, Chao Liu, Rui Tan, Zhi-Ping Tong, and Yan-Kai Liu. 2016. "Organocatalytic, Asymmetric [2+2+2] Annulation to Construct Six-Membered Spirocyclic Oxindoles with Six Continuous Stereogenic Centers" Catalysts 6, no. 5: 65. https://doi.org/10.3390/catal6050065

APA Style

Li, Z. -L., Liu, C., Tan, R., Tong, Z. -P., & Liu, Y. -K. (2016). Organocatalytic, Asymmetric [2+2+2] Annulation to Construct Six-Membered Spirocyclic Oxindoles with Six Continuous Stereogenic Centers. Catalysts, 6(5), 65. https://doi.org/10.3390/catal6050065

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