Asymmetric [3+ 2] Cycloaddition Reaction of Isatin-Derived MBH

Jul 2, 2018 - A highly regio- and stereoselective [3 + 2] cycloaddition reaction for constructing a novel 3,3'-cyclopentenyldispirooxindoles incorpora...
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Cite This: J. Org. Chem. 2018, 83, 10465−10475

Asymmetric [3 + 2] Cycloaddition Reaction of Isatin-Derived MBH Carbonates with 3‑Methyleneoxindoles: Enantioselective Synthesis of 3,3′-Cyclopentenyldispirooxindoles Incorporating Two Adjacent Quaternary Spirostereocenters Yu Chen,† Bao-Dong Cui,*,† Yi Wang,† Wen-Yong Han,† Nan-Wei Wan,† Mei Bai,† Wei-Cheng Yuan,‡ and Yong-Zheng Chen*,† Downloaded via UNIV OF SUNDERLAND on September 7, 2018 at 08:50:42 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Generic Drug Research Center of Guizhou Province, School of Pharmacy, Zunyi Medial University, Zunyi 563000, China National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China

‡

S Supporting Information *

ABSTRACT: A highly regio- and stereoselective [3 + 2] cycloaddition reaction for constructing novel 3,3′cyclopentenyldispirooxindoles incorporating two adjacent quaternary spirostereocenters is reported. Under the mild conditions, the asymmetric annulation of isatin-derived MBH carbonates with 3-methyleneoxindoles involving a chiral tertiary amine catalyst provides the corresponding dispirooxindole frameworks with an extraordinary level of enantioselective control. Further synthetic utility of this method was demonstrated by the gram-scale experiment and simple transformation of the obtained product. Moreover, a plausible mechanism for this annulation reaction was also proposed on the basis of the control experiments.

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INTRODUCTION Spirooxindoles have emerged as a fascinating framework that defines the typical structural core of many pharmaceuticals and bioactive natural products.1−5 Among these, spirooxindoles, characterized by containing two adjacent quaternary spirostereocenters distribute in several biologically active molecules (Figure 1).4,5 Particularly, dispirooxindoles fused to a fivemembered ring always exhibit prominent bioactivities, probably due to their unique well-defined three-dimensional architectures.5 Therefore, great attentions have been concentrated on the development of creative methods for the construction of such dispirosystems.6−8 However, most of the approaches were focused on the synthesis of these compounds in their racemic form,6 and the enantioselective routes to access this type of chiral dispirooxindoles are still limited, mainly ascribed to the great challenge in building such structurally rigid architectures incorporating two adjacent quaternary spirostereocenters.7,8 Thus, in order to further enrich the structural diversity of chiral dispirooxindole © 2018 American Chemical Society

derivatives, a new efficient and alternative asymmetric strategy toward the construction of such chiral architectures fused to other ring systems is still highly desirable. Recently, the chiral Lewis base catalyzed asymmetric [3 + 2] cycloaddition reaction of Morita−Baylis−Hillman carbonates have become a simple and powerful strategy to access structurally various and functionalized spirocyclic carbo- and heterocycles.7a,9−11 In this realm, isatin-derived MBH carbonates, which are a particular type of three-carbon synthon, have demonstrated their great potential in the construction of optically active spirocyclic cyclopentene/pyrrolidine/dihydrothiophene oxindole derivatives by reacting with electrondeficient CC, CN, or CS double bonds.7a,11 In these reactions, isatin-derived MBH carbonates are inclined to undergo a nucleophilic addition by the chiral Lewis base catalyst and transformed into a zwitterion, and sequentially, the Received: June 14, 2018 Published: July 2, 2018 10465

DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475

Article

The Journal of Organic Chemistry

Figure 1. Representative pharmaceutical active dispirooxindoles with two adjacent quaternary spirostereocenters.

Scheme 1. Reactivity of Isatin-Derived MBH Carbonates and Synthetic Design for Construction of 3,3′Cyclopentenyldispirooxindole Derivatives

asymmetric [3 + 2] annulation of zwitterion with the electrondeficient double bonds takes place via a α/γ-regioselectivity to generate different functionalized spirooxindoles (Scheme 1). In addition, we noticed that 3-methyleneoxindoles are a type of highly reactive acceptors and have been utilized in several organocatalytic Michael-type reactions12 and D−A reactions to build up a spirooxindole moiety.13 In this context, we envisioned that a new type of dispirooxindole skeletons incorporating two adjacent quaternary spirostereocenters could be constructed through a [3 + 2] annulation between isatin-derived MBH carbonates and 3methyleneoxindoles controlled by a suitable chiral Lewis base catalyst. In the synthetic strategy, the nucleophilic α-attack of zwitterion in situ generated from isatin-derived MBH carbonates to the CC double bond of 3-methyleneoxindoles followed by intramolecular cyclization is preferable, giving the final α-regioselective dispirooxindole isomers (Scheme 1). As a continuation of our studies on the development of creative methodologies for the construction of structurally diverse spirooxindoles,14 herein, we present a highly regio- and stereoselective strategy catalyzed by a chiral tertiary amine for construction of 3,3′-cyclopentenyldispirooxindole skeletons incorporating two adjacent quaternary spirostereocenters through a [3 + 2] annulation of isatin-derived MBH carbonates with 3-methyleneoxindoles, giving the chiral dispirooxindole

derivatives in moderate to excellent yields with overall excellent diastereo- and enantioselectivities (up to 91% yield, >99:1 dr, and >99% ee).

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RESULTS AND DISCUSSION Our study was initiated with the model reaction of isatinderived MBH carbonate 1a and 3-methyleneoxindole 2a under the catalysis of PPh3. Excitingly, the reaction proceeded smoothly in CH2Cl2 at 25 °C for 7 h, giving the αregioselective and isomerized product 3a in 90% yield with 50:50 dr (Table 1, entry 1). But the expected product 4 was not detected. Inspired by this success, the asymmetric version with chiral phosphine catalysts was next explored. (R,R)-DIOP 5a could efficiently catalyze the same cyclization reaction. The chiral product 3a was provided in 90% yield with 77:23 dr and 55% ee (entry 2). Pleasingly, very excellent enantioselectivity was obtained using (R,R)-DIPAMP 5b despite the diastereoselectivity was very poor (entry 3). However, no desired product 3a was detected with the catalysis of 5c−f (entries 4− 7). Subsequently, we investigated some tertiary amine catalysts. The achiral DABCO showed prominent catalytic activity, delivering 3a with excellent diastereoselectivity (entry 8). Further examination of the chiral tertiary amine catalyst indicated that quinidine-derived β-isocupreidine 5h could efficiently catalyze the reaction and give the title product 3a in 10466

DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475

Article

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

entry

catalyst

2

solvent

3/yieldb (%)

drc

eed (%)

1 2e 3e 4 5 6 7 8 9 10 11 12 13 14 15 16f 17f,g

PPh3 5a 5b 5c 5d 5e 5f DABCO 5g 5h 5h 5h 5h 5h 5h 5h 5h

2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2b 2b 2b 2b 2b 2b

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 toluene CH3CN THF CH2Cl2 CH2Cl2

3a/90 3a/90 3a/91 3a/trace 3a/trace 3a/trace 3a/trace 3a/95 3a/trace 3a/99 3b/80 3b/77 3b/69 3b/73 3b/57 3b/85 3b/89

50:50 77:23 65:35 − − − − 97:3 − 50:50 97:3 97:3 97:3 97:3 46:54 97:3 97:3

− 55 >99 − − − − − − >99 >99 >99 >99 >99 >99 >99 >99

Unless otherwise noted, the reactions were performed with 1a (0.12 mmol, 41.6 mg), 2 (0.1 mmol), Cat (10 mol %) in 2.0 mL of solvent at 25 °C for the specified time. bIsolated yields of 3. cDetermined by chiral HPLC analysis. dEnantiomeric excess for major diastereoisomers determined by chiral HPLC analysis. eThe reaction was performed for 30 h. fThe reaction was performed with 20 mol % of 5h for 5 h. gThe ratio of 1a and 2b was 1.5:1. a

high yield and very excellent enantioselectivity with exception of the poor diastereoselectivity (entry 10). In contrast, both good yield and excellent stereoselectivity were obtained with the COPh- substituted 3-methyleneoxindole 2b (entry 11). The following solvent screening revealed that no better reaction results were produced in other solvent including CHCl3, toluene, CH3CN and THF (entries 12−15). In addition, increasing the catalyst load could accelerate the reaction rate and also improve the production of 3b (entry 16). Finally, changing the ratio of 1a and 2b from 1.2:1 to 1.5:1 was further beneficial for the generation of compound 3b (entry 17). With the established reaction conditions in hand (Table 1, entry 17), we first explored the substrate scope of the reaction with regard to isatin-derived MBH carbonates 1 (Table 2). Generally, regardless of the electronic property and position of substituents on the phenyl ring of MBH carbonates (1b−f), all reactions proceeded smoothly and led to the production of chiral 3,3′-cyclopentenyldispirooxindoles 3c−g in good yields with overall excellent diastereo- and enantioselectivities

(entries 2−6). Exceptionally, substrate 1g with 7-trifluoromethyl group just provided lower enantioselectivity of dispirooxindole 3h (entry 7). Next, effect of various N1 substituents of isatin-derived MBH carbonates was investigated, and the corresponding chiral 3,3′-cyclopentenyldispirooxindoles 3i−k were afforded in 53−85% yileds with up to >99:1 dr and >99% ee (entries 8−10). The absolute configuration of major stereoisomer of optically active 3b was assigned to be (C1R, C4R, C5S) by single crystal X-ray analysis.15 The following further substrate scope exploration was carried out by the asymmetric [3 + 2] annulation reaction of isatin-derived MBH carbonate 1a with 3-methyleneoxindoles containing different substituents on the aromatic ring of oxindole framework or benzoyl (Table 3). It was found that N1-Et substituted 3-methyleneoxindole 2c showed good reaction activity and generated compound 3l in 90% yield with 99% ee but lower dr (entry 1). In contrast, 3methyleneoxindoles with other N1-substituents, including n Pr-, Ph-, and Bn-, showed moderate reaction activity, but 10467

DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475

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The Journal of Organic Chemistry Table 2. Substrate Scope of Isatin-Derived MBH Carbonates 1a

entry 1 2 3 4 5 6 7 8 9 10

1 1

R R1 R1 R1 R1 R1 R1 R1 R1 R1

= = = = = = = = = =

2

H, R = Me (1a) 5-Me, R2 = Me (1b) 5-OMe, R2 = Me (1c) 5-F, R2 = Me (1d) 6-Br, R2 = Me (1e) 7-F, R2 = Me (1f) 7-CF3, R2 = Me (1g) H, R2 = nPr (1h) H, R2 = Ph (1i) H, R2 = Bn (1j)

Scheme 2. Gram-Scale Experiment and Chemical Transformation of Compound 3b

3/yieldb (%)

drc

eed (%)

3b/89 3c/70 3d/85 3e/84 3f/77 3g/78 3h/89 3i/53 3j/85 3k/62

97:3 >99:1 97:3 96:4 97:3 98:2 >99:1 97:3 >99:1 98:2

>99 99 99 >99 98 99 87 89 98 >99

In order to illustrate the mechanism of this asymmetric [3 + 2] cycloaddition reaction, two control experiments were performed (Scheme 3). On the one hand, although the methyl protecting chiral tertiary amine 5i also could promoted the reaction of isatin-derived MBH carbonate 1a with 3methyleneoxindole 2b, it delivered the title product 3b with lower yield and very poor enantioselectivity, indicating that the hydrogen bonding interaction of the free hydroxyl with acceptor probablly existed and was crucial for both the acceleration and stereocontrol of this asymmetric annulation [Scheme 3, (1)]. On the other hand, the D-labeled 3methyleneoxindole 2b delivered D-3b and 3b with 1:1.5 ratio, which was determined by 1H NMR analysis [Scheme 3, (2)]. This result demonstrated that migration of proton occurred in this annulation process, and it also provided the proof for no detection of the expected product 4 from the opposite angle. According to the above control experiments, a plausible catalytic cycle for this α-regio- and stereoselective cycloaddition reaction process is presented. As depicted in Scheme 4, the initial displacement of carbonate moiety by the chiral tertiary amine via an addition−elimination step and followed by deprotonation generate ylide (II). Then the ylide (II) undergo a nucleophilic α-attack and the subsequent intramolecular conjugate addition with 3-methyleneoxindoles 2 activated via the hydrogen bonding interaction of the free hydroxyl in 5h with carbonyl group delivers the spirocyclic zwitterion intermediate (III). Finally, the 1,3-H shift followed by elimination of the chiral tertiary amine completes the catalytic cycle, yielding the target products 3 and the free catalyst. However, the formation of γ-regioselective isomers was unfavorable due to a serious steric hindrance from the interaction of oxindole skeleton with the resulting ammonium salt encountered in the crucial addition−elimination step.

a

Unless otherwise noted, the reactions were performed with 1 (0.3 mmol), 2b (0.2 mmol, 52.7 mg), 5h (20 mol %, 12.4 mg) in 4.0 mL of CH2Cl2 at 25 °C for 5 h. bIsolated yields of 3. cDetermined by chiral HPLC analysis. dEnantiomeric excess for major diastereoisomers determined by chiral HPLC analysis.

providing the corresponding products 3m−o with overall excellent diastereo- and enantioselectivities (entries 2−4). In particular, substrate 2g with the electron-withdrawing Bocgroup at the N1 position only gave 26% yield of 3p despite the reaction time was prolonged to 24 h (entry 5). Subsequently, the investigation of substituents on the phenyl ring of oxindole framework disclosed that the electronic property and position of substituents had a remarkable impact on the reaction activity but little influence in the stereoselectivity. These differences were reflected by the reaction results that the electron-rich substrates could offer lower yields than the substrates with electron-withdrawing substituents (entries 6 and 7 vs 8−10), and that the C5-substituted 3-methyleneoxindoles furnished higher yields than the C7-substituted substrates (entries 6−10 vs 11 and 12). Furthermore, the reaction results also demonstrated that 3-methyleneoxindole substrates with introduction on the phenyl ring of benzoyl generally revealed inferior reaction activity regardless of the electronic property of the substituents (entries 13−17). Notablely, the bulky 2-naphthyl substituted substrate 2t was also applicable to this reaction and gave rise to the corresponding chiral 3,3′-cyclopentenyldispirooxindole 3c′ in 47% yield with 96:4 dr and 85% ee (entry 18). Finally, the analogue of 3-methyleneoxindole 2u also participated well in this asymmetric annulation reaction, leading to the production of title compound 3d′ in acceptable yield with nearly optically purity (entry 19). The potential synthetic utility of this method was illustrated by the scale-up experiment and a simple chemical transformation of the obtained product 3b. First, the 10-fold scaleup reaction of 3 mmol of 1a with 4.5 mmol of 2b proceeded smoothly and provided compound 3b in 70% yield with no obvious change in the diastero- and enantioselectivity [Scheme 2, (1)]. Moreover, the palladium-mediated hydrogenation of carbonyl in 3b afforded compound 5 in 42% yield with 84:16 dr and >99% ee [Scheme 2, (2)].

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CONCLUSION In conclusion, we have developed a highly regio- and stereoselective [3 + 2] cycloaddition reaction of isatin-derived MBH carbonates with 3-methyleneoxindoles, successfully achieving the enantioselective construction of 3,3′-cyclopentenyldispirooxindole derivatives incorporating two adjacent quaternary spirostereocenters. With β-isocupreidine as the nucleophilic catalyst, this straightforward annulation process afforded the corresponding products with generally excellent stereoselectivities (up to >99:1 dr and >99% ee) under the 10468

DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475

Article

The Journal of Organic Chemistry Table 3. Substrate Scope of 3-Methyleneoxindoles 2a

a

Unless otherwise noted, the reactions were performed with 1a (0.3 mmol, 104.1 mg), 2 (0.2 mmol), 5h (20 mol %, 12.4 mg) in 4.0 mL of CH2Cl2 at 25 °C for 5 h. bIsolated yields of 3. cDetermined by chiral HPLC analysis. dEnantiomeric excess for major diastereoisomers determined by chiral HPLC analysis. eThe reaction was performed for 24 h. fReactions were performed for 7 h. gThe reaction was performed for 44 h. employed as the internal standard (CDCl3 at 7.26 ppm). Data are reported as the follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet), coupling constants (Hz) and integration. 13C NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl3 at 77.16 ppm). General Procedure for the Synthesis of Compounds 3. In a 5 mL of flame-dried vial with a stir bar, the mixture of isatin-derived MBH carbonates 1 (0.3 mmol, 1.5 equiv), 3-methyleneoxindoles 2 (0.2 mmol), catalyst 5h (0.04 mmol, 12.4 mg) in 4.0 mL of CH2Cl2 was stirred at 25 °C for the specified time. After completion of the reaction indicated by TLC, the mixture was directly purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1−3:1) to afford the compounds 3. Compound 3b. Light yellow solid; 87.7 mg, 89% yield; 97:3 dr, >99% ee; [α]D25 = −101.0 (c 1.00, CHCl3); mp 230.1−231.2 °C. The

mild reaction conditions. The gram-scale experiment and chemical transformation of compound 3b further demonstrated the synthetic utility of this protocol. Moreover, a proposed mechanism for this annulation reaction was depicted on the basis of the control experiments.

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EXPERIMENTAL SECTION

Reagents were purchased from commercial sources and were directly used unless otherwise noted. Catalysts 5a−h were purchased from commercial sources [Daicel Chiral Technologies (China) Co., Ltd.]. Substrates 1 were prepared according to the known method.11f Substrates 2 were prepared according to the known method.16 1H NMR and 13C NMR (400 and 100 MHz, respectively) spectra were recorded in CDCl3. 1H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance 10469

DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475

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The Journal of Organic Chemistry Scheme 3. Control Experiments

Scheme 4. Proposed Catalytic Cycle for the Asymmetric [3 + 2] Cycloaddition Reaction

ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 10.5 min). 1H NMR (400 MHz, CDCl3) δ 2.98 (3H, s), 3.05−3.06 (3H, m), 3.62−3.63 (3H, m), 4.98 (1H, d, J = 2.0 Hz), 6.55 (2H, dd, J = 7.7 Hz, 2.5 Hz), 6.79 (1H, t, J = 7.6 Hz), 6.94 (1H, t, J = 7.6 Hz), 7.09 (1H, td, J = 7.7 Hz, 1.3 Hz), 7.15−7.18 (2H, m), 7.23−7.24 (1H, m), 7.43−7.50 (3H, m), 7.53−7.57 (1H, m), 7.97 (2H, d, J = 8.3 Hz); 13C NMR (100 MHz, CDCl3) δ 25.9, 26.4, 52.5, 56.0, 62.3, 66.6, 107.9, 108.0, 122.4, 122.5, 124.1, 124.6, 125.1, 125.2, 128.7, 129.3, 129.4, 129.9, 133.2, 137.2, 143.0, 144.4, 144.7, 145.0, 169.9, 175.0, 176.3, 191.4. HRMS (ESI-TOF) calcd. for C30H25N2O5 [M + H]+ 493.1758, found 493.1758. Compound 3c. Red solid; 70.9 mg, 70% yield; >99:1 dr, 99% ee; [α]D25 = −40.7 (c 0.50, CHCl3); mp 218.7−220.3 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 7.8 min, tminor = 11.2 min). 1H NMR (400 MHz, CDCl3) δ 2.28 (3H, s), 2.97 (3H, s), 3.08 (3H, s), 3.64 (3H, s), 4.97 (1H, s), 6.45 (1H, d, J = 7.9 Hz), 6.56 (1H, d, J = 7.8 Hz), 6.80 (1H, t, J = 7.6 Hz), 6.96 (1H, d, J = 7.8 Hz), 7.10 (1H, t, J = 7.7 Hz), 7.16 (1H, d, J = 1.2 Hz), 7.25 (1H, s), 7.32 (1H, s), 7.47 (2H, t, J = 7.5 Hz), 7.56 (1H, t, J = 7.3 Hz), 7.99 (2H, d, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 21.2,

25.9, 26.4, 52.6, 55.9, 62.3, 66.5, 107.6, 108.0, 122.5, 124.6, 124.8, 125.1, 125.2, 128.7, 129.2, 129.6, 129.9, 131.9, 133.2, 137.2, 142.0, 142.9, 144.6, 145.1, 170.0, 174.9, 176.2, 191.4. HRMS (ESI-TOF) calcd. for C31H27N2O5 [M + H]+ 507.1914, found 507.1918. Compound 3d. Light yellow solid; 88.8 mg, 85% yield; 97:3 dr, 99% ee; [α]D25 = −75.3 (c 1.00, CHCl3); mp 123.7−125.5 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/ 70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 14.3 min, tminor = 19.8 min). 1H NMR (400 MHz, CDCl3) δ 2.96 (3H, s), 3.08 (3H, s), 3.62 (3H, s), 3.72 (3H, s), 4.96 (1H, d, J = 1.7 Hz), 6.45 (1H, d, J = 8.5 Hz), 6.56 (1H, d, J = 7.8 Hz), 6.69 (1H, dd, J = 8.4 Hz, 2.3 Hz), 6.78 (1H, t, J = 7.6 Hz), 7.09 (1H, t, J = 7.6 Hz), 7.14 (2H, dd, J = 5.5 Hz, 2.1 Hz), 7.24 (1H, d, J = 2.1 Hz), 7.44 (2H, t, J = 7.5 Hz), 7.54 (1H, t, J = 7.3 Hz), 7.97 (2H, d, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 26.0, 26.4, 52,5, 55.9, 56.1, 62.5, 66.5, 108.0, 108.3, 114.3, 122.5, 124.6, 125.1, 126.4, 128.6, 129.3, 129.8, 133.2, 137.2, 137.8, 143.0, 144.7, 144.9, 155.8, 169.9, 174.9, 175.9, 191.3. HRMS (ESI-TOF) calcd. for C31H27N2O6 [M + H]+ 523.1864, found 523.1866. Compound 3e. Light yellow solid; 85.8 mg, 84% yield; 96:4 dr, >99% ee; [α]D25 = −144.6 (c 1.00, CHCl3); mp 197.2−199.1 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 10470

DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475

Article

The Journal of Organic Chemistry 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 13.3 min). 1H NMR (400 MHz, CDCl3) δ 2.99 (3H, s), 3.12 (3H, s), 3.65 (3H, s), 4.95−4.97 (1H, m), 6.50 (1H, dd, J = 8.5 Hz, 4.2 Hz), 6.60 (1H, d, J = 7.8 Hz), 6.81 (1H, t, J = 7.6 Hz), 6.88 (1H, td, J = 8.8 Hz, 2.3 Hz), 7.10−7.19 (2H, m), 7.25 (1H, d, J = 5.5 Hz), 7.30 (1H, dd, J = 8.5 Hz, 2.2 Hz), 7.47 (2H, t, J = 7.6 Hz), 7.57 (1H, t, J = 7.3 Hz), 7.97 (2H, d, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3) δ 26.1, 26.5, 52.6, 56.2, 62.3, 66.5, 108.1, 108.4 (1C, d, J = 8.1 Hz), 112.5 (1C, d, J = 25.9 Hz), 115.6 (1C, d, J = 23.4 Hz), 122.7, 124.6, 124.9, 127.0 (1C, d, J = 8.4 Hz), 128.7, 129.5, 129.9, 133.3, 137.1, 140.4, 143.0, 144.6, 144.7, 159.1 (1C, d, J = 239.0 Hz), 169.8, 174.7, 176.0, 191.2. HRMS (ESI-TOF) calcd. for C30H24FN2O5 [M + H]+ 511.1664, found 511.1665. Compound 3f. Red solid; 88.0 mg, 77% yield; 97:3 dr, 98% ee; [α]D25 = −31.2 (c 0.50, CHCl3); mp 123.3−125.1 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 13.5 min, tminor = 15.3 min). 1H NMR (400 MHz, CDCl3) δ 3.03 (3H, s), 3.15 (3H, s), 3.70 (3H, s), 5.01 (1H, d, J = 1.4 Hz), 6.67 (1H, d, J = 7.8 Hz), 6.78 (1H, s), 6.86 (1H, t, J = 7.6 Hz), 7.13 (1H, d, J = 8.0 Hz), 7.18−7.20 (2H, m), 7.29 (1H, d, J = 4.8 Hz), 7.41 (1H, d, J = 8.1 Hz), 7.51 (2H, t, J = 7.6 Hz), 7.61 (1H, t, J = 7.2 Hz), 8.01 (2H, d, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 26.1, 26.5, 52.7, 56.1, 61.8, 66.3, 108.3, 111.6, 122.7, 123.2, 124.3, 124.5, 124.9, 125.3, 125.5, 128.7, 129.5, 129.8, 133.3, 137.1, 143.0, 144.6, 144.7, 145.8, 169.8, 174.8, 176.2, 191.2. HRMS (ESI-TOF) calcd. for C30H24BrN2O5 [M + H]+ 571.0863, found 571.0865. Compound 3g. Light brown solid; 79.6 mg, 78% yield; 98:2 dr, 99% ee; [α]D25 = −95.1 (c 1.00, CHCl3); mp 225.3−227.1 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/ 70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 8.5 min, tminor = 20.8 min). 1H NMR (400 MHz, CDCl3) δ 3.07 (3H, s), 3.21 (3H, d, J = 2.2 Hz), 3.66 (3H, s), 4.97 (1H, d, J = 1.5 Hz), 6.60 (1H, d, J = 7.8 Hz), 6.83 (1H, t, J = 7.6 Hz), 6.87−6.93 (2H, m), 7.13−7.16 (2H, m), 7.24 (1H, d, J = 6.8 Hz), 7.30 (1H, d, J = 7.8 Hz), 7.46 (2H, t, J = 7.5 Hz), 7.56 (1H, t, J = 7.4 Hz), 7.97 (2H, d, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 26.4, 28.4, 52.6, 56.3, 62.3, 66.6, 108.2, 117.4 (1C, d, J = 19.0 Hz), 120.1 (1C, d, J = 3.2 Hz), 122.7, 122.9 (1C, d, J = 6.4 Hz), 124.6, 124.9, 128.2 (1C, d, J = 3.3 Hz), 128.7, 129.6, 129.8, 131.1 (1C, d, J = 8.3 Hz), 133.3, 137.1, 142.9, 144.5, 144.7, 147.3 (1C, d, J = 241.7 Hz), 169.8, 174.8, 176.0, 191.2. HRMS (ESI-TOF) calcd. for C30H24FN2O5 [M + H]+ 511.1664, found 511.1672. Compound 3h. Light yellow solid; 99.7 mg, 89% yield; >99:1 dr, 87% ee; [α]D25 = −110.0 (c 1.00, CHCl3); mp 125.8−127.1 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 6.6 min, tminor = 13.3 min). 1H NMR (400 MHz, CDCl3) δ 3.06 (3H, s), 3.21 (3H, s), 3.67 (3H, s), 5.00 (1H, s), 6.60 (1H, d, J = 7.8 Hz), 6.84 (1H, t, J = 7.6 Hz), 7.05 (1H, t, J = 7.9 Hz), 7.13−7.20 (3H, m), 7.49 (3H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.72 (1H, d, J = 7.6 Hz), 7.99 (2H, d J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 26.4, 28.6 (1C, q, J = 6.5 Hz), 52.7, 56.0, 60.7, 108.3, 112.2 (1C, q, J = 3.3 Hz), 121.6, 122.8, 124.3, 124.5, 124.7, 127.3 (1C, q, J = 6.0 Hz), 127.4, 127.8, 128.7, 129.6, 129.8, 133.4, 137.0, 142.4, 142.6, 144.4, 144.6, 169.7, 174.6, 177.2, 191.1. HRMS (ESI-TOF) calcd. for C31H24F3N2O5 [M + H]+ 561.1632, found 561.1639. Compound 3i. Light red solid; 55.2 mg, 53% yield; 97:3 dr, 89% ee; [α]D25 = −147.3 (c 1.00, CHCl3); mp 105.5−107.3 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/ 70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 7.3 min, tminor = 14.0 min). 1H NMR (400 MHz, CDCl3) δ 0.84 (3H, t, J = 7.3 Hz), 1.53 (2H, q, J = 7.4 Hz), 3.08 (3H, s), 3.46 (2H, t, J = 7.5 Hz), 3.63 (3H, s), 4.99 (1H, d, J = 1.8 Hz), 6.59 (2H, t, J = 8.9 Hz), 6.80 (1H, t, J = 7.6 Hz), 6.95 (1H, t, J = 7.6 Hz), 7.11 (1H, t, J = 7.8 Hz), 7.16−7.19 (2H, m), 7.29 (1H, d, J = 7.6 Hz), 7.47 (2H, t, J = 7.7 Hz), 7.52−7.60 (2H, m), 8.00 (2H, d, J = 8.2 Hz); 13C NMR (100 MHz, CDCl3) δ 11.6, 20.7, 26.4, 41.8, 52.5, 56.2, 62.0, 66.6, 108.0, 108.2, 122.2, 122.6, 124.3, 124.9, 125.2, 125.4, 128.7, 129.2, 129.3, 129.9, 133.2, 137.2, 143.0, 144.2, 144.7, 145.0, 169.8, 175.1, 176.1,

191.4. HRMS (ESI-TOF) calcd. for C32H29N2O5 [M + H]+ 521.2071, found 521.2080. Compound 3j. Light red solid; 94.3 mg, 85% yield; >99:1 dr, 98% ee; [α]D25 = −153.0 (c 1.00, CHCl3); mp 128.7−129.6 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/ 70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 6.8 min, tminor = 11.5 min). 1H NMR (400 MHz, CDCl3) δ 3.13 (3H, s), 3.72 (3H, s), 5.10 (1H, d, J = 2.0 Hz), 6.44 (1H, d, J = 7.8 Hz), 6.65 (1H, d, J = 7.8 Hz), 6.84 (1H, t, J = 7.6 Hz), 7.00 (1H, t, J = 7.6 Hz), 7.09−7.12 (3H, m), 7.17−7.21 (2H, m), 7.30 (1H, d, J = 7.5 Hz), 7.37−7.49 (5H, m), 7.54−7.60 (2H, m), 7.99 (2H, d, J = 8.3 Hz); 13C NMR (100 MHz, CDCl3) δ 26.4, 52.6, 56.5, 62.2, 66.7, 108.1, 109.2, 122.7, 122.8, 124.3, 124.9, 125.1, 125.2, 127.1, 128.5, 128.6, 129.2, 129.4, 129.7, 129.9, 133.2, 134.2, 137.2, 142.9, 144.7, 144.8, 169.9, 174.9, 175.9, 191.4. HRMS (ESI-TOF) calcd. for C35H27N2O5 [M + H]+ 555.1914, found 555.1911. Compound 3k. Light red solid; 70.5 mg, 62% yield; 98:2 dr, >99% ee; [α]D25 = −71.2 (c 1.00, CHCl3); mp 193.7−195.6 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 15.7 min). 1H NMR (400 MHz, CDCl3) δ 3.11 (3H, s), 3.62 (3H, s), 4.70 (1H, d, J = 16.0 Hz), 4.83 (1H, d, J = 16.0 Hz), 5.04 (1H, s), 6.42 (1H, d, J = 7.7 Hz), 6.64 (1H, d, J = 7.7 Hz), 6.76 (1H, t, J = 7.5 Hz), 6.94−6.98 (3H, m), 7.08 (1H, t, J = 7.6 Hz), 7.15−7.20 (5H, m), 7.30 (1H, d, J = 7.4 Hz), 7.49 (2H, t, J = 7.3 Hz), 7.56−7.60 (2H, m), 8.01 (2H, d, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 26.5, 43.8, 52.6, 56.6, 62.2, 66.7, 108.2, 109.2, 110.1, 122.5, 123.0, 124.4, 125.1, 125.3, 125.4, 127.2, 127.4, 128.7, 129.2, 129.3, 129.9, 133.2, 135.3, 137.2, 143.0, 143.9, 144.8, 144.9, 169.8, 175.1, 176.4, 191.3. HRMS (ESI-TOF) calcd. for C36H29N2O5 [M + H]+ 569.2071, found 569.2075. Compound 3l. Light red solid; 91.2 mg, 90% yield; 86:14 dr, 99% ee; [α]D25 = −130.7 (c 1.00, CHCl3); mp 79.5−81.3 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 9.8 min, tminor = 22.9 min). 1H NMR (400 MHz, CDCl3) δ 1.07 (3H, t, J = 7.2 Hz), 3.02 (3H, s), 3.49−3.57 (1H, m), 3.65 (3H, s), 3.77−3.86 (1H, m), 5.01 (1H, s), 6.58−6.61 (2H, m), 6.80 (1H, t, J = 7.6 Hz), 6.97 (1H, t, J = 7.6 Hz), 7.11 (1H, t, J = 7.7 Hz), 7.16−7.21 (2H, m), 7.29 (1H, d, J = 7.6 Hz), 7.47 (2H, t, J = 7.5 Hz), 7.54−7.59 (2H, m), 8.00 (2H, d, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 12.49, 25.93, 34.94, 52.54, 56.12, 62.21, 66.29, 76.84, 77.16, 77.48, 107.97, 108.14, 122.34, 122.50, 124.53, 124.84, 125.25, 125.46, 128.65, 129.26, 129.90, 133.19, 137.28, 143.20, 143.93, 144.44, 144.71, 169.96, 174.62, 176.39, 191.37. HRMS (ESI-TOF) calcd. for C31H27N2O5 [M + H]+ 507.1914, found 507.1919. Compound 3m. Yellow solid; 79.1 mg, 76% yield; 97:3 dr, >99% ee; [α]D25 = −116.5 (c 1.00, CHCl3); mp 105.9−107.8 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/ 70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 9.4 min). 1H NMR (400 MHz, CDCl3) δ 0.85 (3H, t, J = 7.4 Hz), 1.51− 1.59 (2H, m), 3.02 (3H, s), 3.43−3.51 (1H, m), 3.61−3.70 (4H, m), 5.01 (1H, d, J = 2.2 Hz), 6.60 (2H, dd, J = 7.8 Hz, 2.7 Hz), 6.80 (1H, t, J = 7.6 Hz), 6.96 (1H, t, J = 7.6 Hz), 7.10 (1H, t, J = 7.7 Hz), 7.15 (1H, d, J = 2.2 Hz), 7.19 (1H, t, J = 7.8 Hz), 7.29 (1H, d, J = 7.6 Hz), 7.48 (2H, t, J = 7.7 Hz), 7.53−7.58 (2H, m), 8.00 (2H, d, J = 7.2 Hz); 13 C NMR (100 MHz, CDCl3) δ 11.5, 20.9, 25.9, 42.0, 52.5, 56.1, 62.1, 66.2, 107.9, 108.3, 122.2, 122.5, 124.5, 124.7, 125.2, 125.3, 128.6, 129.2, 129.3, 129.9, 133.1, 137.2, 143.2, 144.4, 144.5, 144.6, 169.9, 174.9, 176.4, 191.3. HRMS (ESI-TOF) calcd. for C32H29N2O5 [M + H]+ 521.2071, found 521.2076. Compound 3n. Light red solid; 79.9 mg, 72% yield; >99:1 dr, >99% ee; [α]D25 = −24.1 (c 1.00, CHCl3); mp 140.3−142.1 °C. The ee was determined by HPLC (Chiralpak OD-H, i-PrOH/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 23.3 min). 1H NMR (400 MHz, CDCl3) δ 3.12 (3H, s), 3.73 (3H, s), 5.07 (1H, s), 5.36 (1H, s), 6.48 (1H, d, J = 7.9 Hz), 6.72 (1H, d, J = 7.8 Hz), 6.91 (1H, t, J = 7.6 Hz), 7.04−7.11 (2H, m), 7.24 (1H, s), 7.31−7.35 (2H, m), 7.41 (1H, d, J = 7.6 Hz), 7.45−7.48 (1H, m), 7.53−7.61 (5H, m), 7.65−7.68 (1H, m), 8.12 (2H, d, J = 7.8 Hz); 13C 10471

DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475

Article

The Journal of Organic Chemistry NMR (100 MHz, CDCl3) δ 26.0, 52.6, 56.0, 62.4, 66.9, 108.1, 109.3, 122.6, 122.9, 124.7, 124.8, 124.9, 125.3, 127.4, 128.5, 128.7, 129.2, 129.5, 129.7, 129.9, 133.3, 134.4, 137.2, 143.2, 144.5, 144.8, 145.2, 170.0, 174.6, 176.3, 191.3. HRMS (ESI-TOF) calcd. for C35H27N2O5 [M + H]+ 555.1914, found 555.1915. Compound 3o. Light red solid; 79.6 mg, 70% yield; >99:1 dr, >99% ee; [α]D25 = −117.1 (c 1.00, CHCl3); mp 101.7−103.0 °C. The ee was determined by HPLC (Chiralpak OD-H, i-PrOH/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 30.7 min). 1H NMR (400 MHz, CDCl3) δ 3.04 (3H, s), 3.66 (3H, s), 4.74 (1H, d, J = 16.2 Hz), 5.02 (1H, d, J = 16.9 Hz), 5.04 (1H, s), 6.36 (1H, d, J = 7.8 Hz), 6.66 (1H, d, J = 7.8 Hz), 6.79 (1H, t, J = 7.6 Hz), 6.91−7.00 (4H, m), 7.18−7.26 (5H, m), 7.33 (1H, d, J = 7.5 Hz), 7.48−7.54 (3H, m), 7.59 (1H, t, J = 7.3 Hz), 8.02 (2H, d, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 26.0, 44.1, 52.6, 56.3, 62.2, 66.6, 108.2, 109.4, 122.7, 122.9, 124.3, 125.5, 126.9, 127.3, 128.6, 128.7, 129.3, 129.3, 129.9, 133.3, 139.3, 137.3, 143.4, 144.2, 144.6, 144.8, 169.9, 175.3, 176.5, 191.4, HRMS (ESI-TOF) calcd. for C36H29N2O5 [M + H]+ 569.2071, found 569.2077. Compound 3p. Light yellow solid; 30.1 mg, 26% yield; >99:1 dr, 83% ee; [α]D25 = −100.3 (c 1.00, CHCl3); mp 163.1−165.0 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 22.0 min, tminor = 44.8 min). 1H NMR (400 MHz, CDCl3) δ 1.61 (9H, s), 2.97 (3H, s), 3.66 (3H, s), 4.89 (1H, s), 6.60 (1H, d, J = 7.8 Hz), 6.90−6.99 (2H, m), 7.15 (1H, t, J = 7.9 Hz), 7.20−7.24 (2H, m), 7.29 (1H, d, J = 7.6 Hz), 7.45−7.51 (3H, m), 7.58−7.62 (2H, m), 7.99 (2H, d, J = 8.2 Hz); 13C NMR (100 MHz, CDCl3) δ 26.0, 28.2, 52.7, 55.9, 63.1, 67.0, 84.2, 108.2, 114.9, 122.6, 124.0, 124.1, 124.3, 124.4, 124.5, 128.8, 129.5, 129.7, 129.9, 133.4, 136.9, 140.6, 142.5, 144.4, 145.5, 148.7, 169.7, 173.5, 175.6, 190.9. HRMS (ESI-TOF) calcd. for C34H31N2O7 [M + H]+ 579.2126, found 579.2131. Compound 3q. Light yellow solid; 62.8 mg, 62% yield; 96:4 dr, 95% ee; [α]D25 = −98.8 (c 1.00, CHCl3); mp 167.1−168.3 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/ 70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 8.6 min, tminor = 18.0 min). 1H NMR (400 MHz, CDCl3) δ 2.15 (3H, s), 3.01 (3H, s), 3.06 (3H, s), 3.66 (3H, s), 5.00 (1H, d, J = 1.9 Hz), 6.46 (1H, d, J = 7.9 Hz), 6.58 (1H, d, J = 7.8 Hz), 6.91 (1H, d, J = 7.8 Hz), 6.96 (1H, t, J = 7.6 Hz), 7.09 (1H, s), 7.17−7.20 (2H, m), 7.49 (3H, t, J = 7.2 Hz), 7.59 (1H, t, J = 7.3 Hz), 8.00 (2H, d, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 21.2, 25.9, 26.5, 52.6, 55.9, 62.4, 66.7, 107.7, 107.9, 122.4, 124.1, 125.1, 125.3, 128.7, 129.3, 129.6, 129.9, 132.0, 133.2, 137.3, 142.3, 143.0, 144.4, 145.2, 170.0, 174.9, 176.3, 191.4. HRMS (ESI-TOF) calcd. for C31H26N2O5 [M + H]+ 507.1914, found 507.1917. Compound 3r. Light yellow solid; 57.5 mg, 55% yield; 96:4 dr, >99% ee; [α]D25 = −58.6 (c 1.00, CHCl3); mp 113.7−114.9 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 12.7 min). 1H NMR (400 MHz, CDCl3) δ 3.05 (3H, s), 3.06 (3H, s), 3.62 (3H, s), 3.65 (3H, s), 5.01 (1H, s), 6.48 (1H, d, J = 8.4 Hz), 6.61 (1H, d, J = 7.7 Hz), 6.65 (1H, dd, J = 8.4 Hz, 1.9 Hz), 6.95−6.99 (2H, m), 7.17−7.21 (2H, m), 7.46−7.53 (3H, m), 7.58 (1H, t, J = 7.2 Hz), 8.00 (2H, d, J = 7.7 Hz); 13C NMR (100 MHz, CDCl3) δ 26.0, 26.5, 52.5, 55.8, 56.2, 62.3, 66.8, 108.0, 108.3, 111.7, 114.0, 122.5, 124.3, 125.2, 126.4, 128.7, 129.3, 129.9, 133.2, 137.3, 138.3, 143.0, 144.4, 145.1, 155.8, 169.9, 174.7, 176.3, 191.3. HRMS (ESI-TOF) calcd. for C31H26N2O6 [M + H]+ 523.1864, found 523.1866. Compound 3s. Light yellow solid; 92.9 mg, 91% yield; 98:2 dr, 98% ee; [α]D25 = −112.3 (c 1.00, CHCl3); mp 209.8−210.3 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 12.4 min, tminor = 20.8 min). 1H NMR (400 MHz, CDCl3) δ 3.06 (3H, s), 3.08 (3H, s), 3.65 (3H, s), 5.01 (1H, d, J = 1.5 Hz), 6.51 (1H, dd, J = 8.5 Hz, 4.1 Hz), 6.63 (1H, d, J = 7.8 Hz), 6.83 (1H, td, J = 8.8 Hz, J = 2.3 Hz), 6.98 (1H, t, J = 7.6 Hz), 7.08 (1H, dd, J = 8.5 Hz, J = 2.2 Hz), 7.19−7.23 (2H, m), 7.47−7.51 (3H, m), 7.59 (1H, t, J = 7.4 Hz), 7.99 (2H, d, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3) δ 26.0, 26.6, 52.6, 56.2, 62.1, 66.5, 108.1, 108.4 (1C, d, J = 8.2 Hz),

112.8 (1C, d, J = 25.9 Hz), 115.5 (1C, d, J = 23.4 Hz), 122.6, 124.2, 124.9, 126.9 (1C, d, J = 8.4 Hz), 128.7, 129.5, 129.8, 133.4, 137.0, 140.7, 142.7, 144.3, 145.4, 159.1 (1C, d, J = 238.8 Hz), 169.7, 174.8, 176.0, 191.2. HRMS (ESI-TOF) calcd. for C30H24FN2O5 [M + H]+ 511.1664, found 511.1669. Compound 3t. Light yellow solid; 76.9 mg, 73% yield; 97:3 dr, 97% ee; [α]D25 = −35.8 (c 1.00, CHCl3); mp 119.7−121.9 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 10/ 90, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 41.4 min, tminor = 60.0 min). 1H NMR (400 MHz, CDCl3) δ 3.06 (3H, s), 3.07 (3H, s), 3.66 (3H, s), 4.99 (1H, s), 6.51 (1H, d, J = 8.3 Hz), 6.62 (1H, d, J = 7.8 Hz), 6.97 (1H, t, J = 7.6 Hz), 7.10 (1H, d, J = 8.2 Hz), 7.20−7.23 (2H, m), 7.28 (1H, s), 7.46−7.52 (3H, m), 7.60 (1H, t, J = 7.2 Hz), 7.98 (2H, d, J = 7.7 Hz); 13C NMR (100 MHz, CDCl3) δ 26.0, 26.6, 52.7, 56.0, 62.2, 66.5, 108.2, 108.9, 122.6, 124.1, 124.9, 125.0, 126.9, 128.0, 128.8, 129.3, 129.5, 129.9, 133.4, 137.1, 142.6, 143.4, 144.4, 145.7, 169.7, 174.6, 176.0, 191.2. HRMS (ESITOF) calcd. for C30H24ClN2O5 [M + H]+ 527.1368, found 527.1375. Compound 3u. Light yellow solid; 99.4 mg, 87% yield; >99:1 dr, 98% ee; [α]D25 = 4.5 (c 1.00, CHCl3); mp 134.6−136.5 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/ 70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 12.9 min, tminor = 18.7 min). 1H NMR (400 MHz, CDCl3) δ 2.92 (6H, s), 3.51 (3H, s), 4.83 (1H, s), 6.31 (1H, d, J = 8.3 Hz), 6.47 (1H, d, J = 7.8 Hz), 6.82 (1H, t, J = 7.6 Hz), 7.04−7.11 (4H, m), 7.30−7.37 (3H, m), 7.44−7.48 (1H, m), 7.84 (2H, d, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 25.9, 26.5, 52.6, 55.8, 62.1, 66.4, 108.1, 109.4, 115.2, 122.5, 124.0, 124.8, 127.2, 127.6, 128.7, 129.5, 129.8, 132.2, 133.4, 137.0, 142.5, 143.8, 144.3, 145.7, 169.7, 174.4, 176.0, 191.1. HRMS (ESI-TOF) calcd. for C30H24BrN2O5 [M + H]+ 571.0863, found 571.0875. Compound 3v. Light yellow solid; 45.9 mg, 45% yield; 96:4 dr, 95% ee; [α]D25 = −64.8 (c 1.00, CHCl3); mp 192.4−193.3 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/ 70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 10.0 min, tminor = 15.1 min). 1H NMR (400 MHz, CDCl3) δ 3.01 (3H, s), 3.30 (3H, s), 3.65 (3H, s), 4.99 (1H, s), 6.63 (1H, d, J = 7.8 Hz), 6.72−6.77 (1H, m), 6.82−6.87 (1H, m), 7.00 (1H, t, J = 7.6 Hz), 7.08 (1H, d, J = 7.5 Hz), 7.18 (1H, s), 7.23 (1H, d, J = 7.8 Hz), 7.48−7.51 (3H, m), 7.59 (1H, t, J = 7.3 Hz), 7.99 (2H, d, J = 7.9 Hz); 13 C NMR (100 MHz, CDCl3) δ 26.0, 29.0, 52.6, 56.0, 62.3, 66.6, 108.1, 117.4 (1C, d, J = 19.1 Hz), 120.5, 122.7, 123.3 (1C, d, J = 6.5 Hz), 124.1, 124.9, 128.1 (1C, d, J = 3.6 Hz), 128.7, 129.6, 129.9, 133.4, 137.1, 142.8, 144.4, 145.3, 147.3 (1C, d, J = 241.7 Hz), 169.8, 174.7, 176.1, 191.3. HRMS (ESI-TOF) calcd. for C30H24FN2O5 [M + H]+ 511.1664, found 511.1673. Compound 3w. White solid; 49.1 mg, 43% yield; 98:2 dr, 95% ee; [α]D25 = −108.1 (c 1.00, CHCl3); mp 248.3−250.1 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 10.2 min, tminor = 18.6 min). 1H NMR (400 MHz, CDCl3) δ 2.99 (3H, s), 3.45 (3H, s), 3.63 (3H, s), 4.96 (1H, d, J = 2.0 Hz), 6.61−6.66 (2H, m), 6.99 (1H, t, J = 7.6 Hz), 7.16−7.17 (1H, m), 7.19−7.24 (3H, m), 7.43−7.49 (3H, m), 7.56−7.60 (1H, m), 7.96−7.98 (2H, m); 13C NMR (100 MHz, CDCl3) δ 26.0, 30.2, 52.6, 56.1, 62.6, 66.1, 102.2, 108.3, 122.7, 123.6, 123.7, 124.1, 124.8, 128.4, 128.8, 129.7, 129.8, 133.4, 135.1, 137.1, 142.0, 142.7, 144.3, 145.4, 169.8, 175.6, 176.0, 191.2. HRMS (ESI-TOF) calcd. for C30H24BrN2O5 [M + H]+ 571.0863, found 571.0867. Compound 3x. Red solid; 36.5 mg, 36% yield; >99:1 dr, 95% ee; [α]D25 = −31.2 (c 0.50, CHCl3); mp 247.1−249.0 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 18.3 min, tminor = 26.0 min). 1H NMR (400 MHz, CDCl3) δ 2.40 (3H, s), 2.99 (3H, s), 3.07 (3H, s), 3.63 (3H, s), 4.98 (1H, d, J = 2.1 Hz), 6.56 (2H, dd, J = 7.7 Hz, 4.2 Hz), 6.79 (1H, t, J = 7.6 Hz), 6.95 (1H, t, J = 7.6 Hz), 7.10 (1H, t, J = 7.8 Hz), 7.12−7.13 (1H, m), 7.17 (1H, t, J = 7.7 Hz), 7.24−7.27 (3H, m), 7.50 (1H, d, J = 7.5 Hz), 7.89 (2H, d, J = 8.1 Hz); 13C NMR (100 MHz, CDCl3) δ 21.9, 25.9, 26.4, 52.5, 56.0, 62.2, 66.6, 107.9, 108.0, 122.4, 122.5, 124.1, 124.6, 125.2, 125.3, 10472

DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475

Article

The Journal of Organic Chemistry

108.0, 108.1, 121.4, 121.5, 122.3, 122.4, 122.6, 122.7, 124.1, 124.2, 125.1, 125.2, 125.3, 125.6, 125.8, 126.2, 129.3, 129.4, 129.5, 134.7, 135.4, 144.1, 144.2, 144.3, 144.4, 145.4, 147.7, 150.3, 150.4, 160.8, 163.0, 168.1, 169.7, 174.6, 174.7, 175.7, 175.8. HRMS (ESI-TOF) calcd. for C34H27N2O5 [M + H]+ 543.1914, found 543.1923. Compound 3d′. Light yellow solid; 47.7 mg, 47% yield; >99:1 dr, >99% ee; [α]D25 = 130.5 (c 1.00, CHCl3); mp 175.8−176.7 °C. The ee was determined by HPLC (Chiralpak OD-H, i-PrOH/hexane = 8/ 92, flow rate 0.8 mL/min, λ = 254 nm, major diastereomer: tmajor = 25.8 min). 1H NMR (400 MHz, CDCl3) δ 1.95 (3H, s), 2.08 (3H, s), 2.93 (3H, s), 3.62 (3H, s), 4.77 (1H, d, J = 2.0 Hz), 6.56 (1H, d, J = 7.8 Hz), 6.61 (1H, d, J = 7.9 Hz), 6.79 (1H, d, J = 7.9 Hz), 7.04 (1H, t, J = 7.6 Hz), 7.21−7.25 (1H, m), 7.29−7.30 (1H, m), 7.44 (1H, d, J = 7.6 Hz), 7.51 (3H, t, J = 7.7 Hz), 7.59−7.63 (1H, m), 8.01 (1H, d, J = 8.2 Hz); 13C NMR (100 MHz, CDCl3) δ 14.5, 19.3, 26.1, 52.6, 54.7, 62.2, 68.9, 108.0, 117.6, 120.9, 122.9, 124.1, 124.3, 126.3, 129.0, 129.7, 129.8, 130.9, 133.5, 133.9, 135.7, 140.0, 144.4, 145.9, 152.4, 169.6, 174.3, 176.2, 190.0. HRMS (ESI-TOF) calcd. for C31H26NO6 [M + H]+ 508.1757, found 508.1759. Isotope Tracer Experiments of Deuterium. In a 5 mL of flamedried vial with a stir bar, the mixture of isatin-derived MBH carbonate 1a (0.3 mmol, 104.1 mg, 1.5 equiv), deuterium substituted 3methyleneoxindole 2b (0.2 mmol, 52.9 mg), catalyst 5h (0.04 mmol, 12.4 mg) in 4.0 mL of dry CH2Cl2 was stirred at 25 °C for 5 h. After completion of the reaction indicated by TLC, the mixture was directly purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1−3:1) to afford a mixture of D-3b and 3b. The structure of D-3b was assigned by the 1H NMR and HRMS analysis. The ratio of D-3b and 3b was determined by the 1H NMR analysis. The 1H NMR and HRMS spectra of the mixture of D-3b and 3b were listed in Supporting Information.17 Chemical Transformation of Product 3b to Compound 5. A mixture of 3b (98.5 mg, 0.2 mmol) and 10% Pd/C (10 mg) in MeOH (6 mL) was stirred vigorously under the atmosphere of hydrogen at room temperature for 15 h. Then, the mixture was filtered through a Celite plug, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1/1) to furnish the compound 5 as a light yellow solid (41.5 mg, 42% yield). Compound 5. Light yellow solid; 41.5 mg, 42% yield; 84:16 dr, >99% ee; [α]D25 = −221.3 (c 1.00, CHCl3); mp 109.9−120.0 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 8.9 min). 1H NMR (400 MHz, CDCl3) δ (major) 2.39 (d, J = 1.1 Hz, 3H), 2.85 (s, 2H), 2.97 (d, J = 1.0 Hz, 3H), 3.60 (d, J = 1.1 Hz, 3H), 4.86 (s, 1H), 4.96 (s, 1H), 6.30 (d, J = 7.7 Hz, 1H), 6.50 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 7.8 Hz, 2H), 6.82−6.86 (m, 2H), 6.89−6.93 (m, 1H), 7.04−7.16 (m, 4H), 7.34 (d, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ (major) 25.5, 25.9, 52.2, 55.0, 63.7, 66.6, 72.6, 107.7, 107.8, 122.2, 122.3, 124.2, 124.3, 125.9, 126.1, 127.7, 127.8, 127.9, 128.0, 128.9, 129.3, 132.6, 138.8, 144.1, 144.5, 145.6, 171.4, 174.5, 176.7. HRMS (ESI-TOF) calcd. for C30H26N2O5Na [M + Na]+ 517.1734, found 517.1740.

129.2, 129.3, 129.4, 130.0, 134.7, 143.1, 144.1, 144.3, 144.4, 144.7, 170.0, 175.1, 176.3, 191.0. HRMS (ESI-TOF) calcd. for C31H27N2O5 [M + H]+ 507.1914, found 507.1921. Compound 3y. White solid; 51.0 mg, 49% yield; 97:3 dr, >99% ee; [α]D25 = −106.8 (c 1.00, CHCl3); mp 219.1−220.5 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 12.6 min). 1H NMR (400 MHz, CDCl3) δ 2.36 (3H, s), 2.38 (3H, s), 3.00 (3H, d, J = 1.0 Hz), 3.06 (3H, d, J = 1.0 Hz), 3.61 (3H, d, J = 0.9 Hz), 4.95 (1H, s), 6.57 (2H, d, J = 7.8 Hz), 6.85 (1H, t, J = 7.6 Hz), 6.96 (1H, t, J = 7.6 Hz), 7.01−7.03 (2H, m), 7.12 (2H, t, J = 7.6 Hz), 7.18 (1H, t, J = 7.7 Hz), 7.32 (1H, d, J = 7.6 Hz), 7.49 (1H, d, J = 7.6 Hz), 7.87 (1H, d, J = 7.7 Hz); 13C NMR (100 MHz, CDCl3) δ 20.6, 21.6, 25.9, 26.4, 52.5, 55.8, 62.5, 66.2, 107.9, 108.0, 122.4, 122.5, 124.1, 124.6, 125.3, 125.5, 126.3, 129.2, 129.3, 131.7, 132.3, 134.5, 138.7, 142.0, 144.4, 144.6, 144.9, 145.5, 169.9, 175.0, 176.3, 193.0. HRMS (ESI-TOF) calcd. for C32H29N2O5 [M + H]+ 521.2071, found 521.2076. Compound 3z. Light yellow solid; 70.5 mg, 69% yield; >99:1 dr, >99% ee; [α]D25 = −90.5 (c 1.00, CHCl3); mp 232.3−233.9 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 11.5 min). 1H NMR (400 MHz, CDCl3) δ 3.03 (3H, s), 3.10 (3H, d, J = 0.7 Hz), 3.67 (3H, s), 5.03 (1H, d, J = 1.7 Hz), 6.60 (2H, dd, J = 7.7 Hz, J = 2.6 Hz), 6.84 (1H, t, J = 7.6 Hz), 6.99 (1H, t, J = 7.6 Hz), 7.12−7.23 (5H, m), 7.28 (1H, s), 7.52 (1H, d, J = 7.6 Hz), 8.05 (2H, dd, J = 8.1 Hz, 5.7 Hz); 13C NMR (100 MHz, CDCl3) δ 25.9, 26.4, 52.6, 56.0, 62.2, 66.5, 108.1 (1C, d, J = 4.4 Hz), 115.9 (1C, d, J = 21.8 Hz), 122.5, 122.6, 124.1, 124.5, 125.0, 125.1, 129.3, 129.4, 132.4, 132.5, 133.6, 142.8, 144.4, 144.7, 144.8, 166.0 (1C, d, J = 253.5 Hz), 169.9, 174.9, 176.3, 189.9. HRMS (ESI-TOF) calcd. for C30H24FN2O5 [M + H]+ 511.1664, found 511.1672. Compound 3a′. White solid; 73.8 mg, 70% yield; 97:3 dr, >99% ee; [α]D25 = −99.1 (c 1.00, CHCl3); mp 231.4−233.1 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 15.6 min). 1H NMR (400 MHz, CDCl3) δ 3.00 (3H, s), 3.07 (3H, s), 3.64 (3H, s), 4.99 (1H, d, J = 2.0 Hz), 6.56−6.58 (2H, m), 6.81 (1H, t, J = 7.6 Hz), 6.95 (1H, t, J = 7.6 Hz), 7.09−7.14 (2H, m), 7.18 (1H, t, J = 7.7 Hz), 7.23 (1H, d, J = 7.9 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.48 (1H, d, J = 7.6 Hz), 7.93 (2H, d, J = 8.3 Hz); 13C NMR (100 MHz, CDCl3) δ 26.0, 26.4, 52.6, 56.0, 62.3, 66.5, 108.0, 108.1, 122.5, 122.6, 124.1, 124.5, 125.0, 125.1, 129.1, 129.4, 131.3, 135.6, 139.8, 142.8, 144.4, 144.7, 145.2, 169.8, 174.9, 176.3, 190.2. HRMS (ESI-TOF) calcd. for C30H24ClN2O5 [M + H]+ 527.1368, found 527.1375. Compound 3b′. White solid; 57.1 mg, 50% yield; 97:3 dr, >99% ee; [α]D25 = −31.2 (c 1.00, CHCl3); mp 233.2−234.5 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 18.0 min). 1H NMR (400 MHz, CDCl3) δ 2.99 (3H, s), 3.05 (3H, s), 3.63 (3H, s), 4.99 (1H, s), 6.56 (2H, dd, J = 7.6 Hz, J = 2.7 Hz), 6.80 (1H, t, J = 7.6 Hz), 6.95 (1H, t, J = 7.6 Hz), 7.08−7.19 (3H, m), 7.23 (1H, d, J = 7.9 Hz), 7.48 (1H, d, J = 7.5 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.2 Hz); 13C NMR (100 MHz, CDCl3) δ 25.9, 26.4, 52.6, 56.0, 62.2, 66.5, 108.0, 108.1, 122.4, 122.5, 124.0, 124.5, 124.9, 125.0, 128.4, 129.4, 131.3, 132.0, 135.9, 142.7, 144.3, 144.7, 145.2, 169.7, 174.8, 176.2, 190.3. HRMS (ESI-TOF) calcd. for C30H24BrN2O5 [M + H]+ 571.0870, found 571.0863. Compound 3c′. Light yellow solid; 51.0 mg, 47% yield; 96:4 dr, 85% ee; [α]D25 = −4.8 (c 0.50, CHCl3); mp 232.8−234.1 °C. The ee was determined by HPLC (Chiralpak AD-H, i-PrOH/hexane = 30/ 70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 20.3 min, tminor = 40.3 min). 1H NMR (400 MHz, CDCl3) δ 3.04 (3H, s), 3.11 (3H, s), 3.67 (3H, s), 5.04 (1H, d, J = 2.0 Hz), 6.60 (2H, dd, J = 7.7 Hz, J = 2.7 Hz), 6.82 (1H, t, J = 7.6 Hz), 6.98 (1H, t, J = 7.6 Hz), 7.12 (1H, t, J = 7.7 Hz), 7.20 (1H, t, J = 7.7 Hz), 7.24− 7.25 (1H, m), 7.33 (1H, d, J = 7.5 Hz), 7.53−7.56 (1H, m), 7.57− 7.63 (2H, m), 7.85−7.90 (2H, m), 7.92−7.95 (1H, m), 8.10 (1H, d, J = 7.5 Hz), 8.65 (1H, s); 13C NMR (100 MHz, CDCl3) δ 25.8, 25.9, 26.3, 26.4, 51.9, 52.6, 55.4, 55.6, 62.9, 63.0, 65.9, 66.1, 107.8, 107.9,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01506. Crystal data (CIF) 1 H, 13C NMR spectra of new compounds 3 and 5, 1H NMR and HRMS spectra of mixture of D-3b and 3b, single crystal X-ray crystallography data for chiral 3b (PDF)

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Corresponding Authors

*E-mail: [email protected]. 10473

DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475

Article

The Journal of Organic Chemistry *E-mail: [email protected].

Thennarasu, S. Lewis Acid Catalyzed Unprecedented [3 + 2] Cycloaddition Yields 3,3′-Pyrrolidinyldispirooxindoles Containing Four Contiguous Chiral Stereocenters with Two Contiguous Quaternary Spirostereocenters. Org. Lett. 2014, 16, 3732−3735. (b) Han, Y.-Y.; Chen, W.-B.; Han, W.-Y.; Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-C. Highly Efficient and Stereoselective Construction of Dispiro-[oxazolidine-2-thione]bisoxindoles and Dispiro[imidazolidine-2-thione]bisoxindoles. Org. Lett. 2012, 14, 490−493. (c) Xiao, J.-A.; Zhang, H.-G.; Liang, S.; Ren, J.-W.; Yang, H.; Chen, X.-Q. Synthesis of Pyrrolo(spiro-[2.3′]-oxindole)-spiro-[4.3″]-oxindole via 1,3-Dipolar Cycloaddition of Azomethine Ylides with 3Acetonylideneoxindole. J. Org. Chem. 2013, 78, 11577−11583. (d) Lanka, S.; Thennarasu, S.; Perumal, P. T. StoichiometryControlled Cycloaddition of Azomethine Ylide with Dipolarophiles: Chemoselective and Regioselective Synthesis of Bis- and TrisSpirooxindole Derivatives. Tetrahedron Lett. 2014, 55, 2585−2588. (e) Dandia, A.; Jain, A. K.; Laxkar, A. K.; Bhati, D. S. Synthesis and Stereochemical Investigation of Highly Functionalized Novel Dispirobisoxindole Derivatives via [3 + 2] Cycloaddition Reaction in Ionic Liquid. Tetrahedron 2013, 69, 2062−2069. (f) Liu, J.; Sun, H.; Liu, X.; Ouyang, L.; Kang, T.; Xie, Y.; Wang, X. Direct Construction of Novel Exo′-Selective Spiropyrrolidine Bisoxindoles via a Three-Component 1,3-Dipolar Cycloaddition Reaction. Tetrahedron Lett. 2012, 53, 2336−2340. (g) Jain, R.; Sharma, K.; Kumar, D. Ionic Liquid Mediated 1,3-Dipolar Cycloaddition of Azomethine Ylides: A Facile and Green Synthesis of Novel Dispiro Heterocycles. Tetrahedron Lett. 2012, 53, 1993−1997. (7) For the asymmetric synthesis of chiral 3,3′-pyrrolidinyldispirooxindoles, see: (a) He, Q.; Du, W.; Chen, Y.-C. Asymmetric Synthesis of Trifluoromethyl-Substituted 3,3′-Pyrrolidinyl-Dispirooxindoles through Organocatalytic 1,3-Dipolar Cycloaddition Reactions. Adv. Synth. Catal. 2017, 359, 3782−3719. (b) 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. (c) Zhao, K.; Zhi, Y.; Li, X.; Puttreddy, R.; Rissanen, K.; Enders, D. Asymmetric Synthesis of 3,3′-Pyrrolidinyl-Dispirooxindoles via a One-pot Organocatalytic Mannich/Deprotection/Aza-Michael Sequence. Chem. Chem. Commun. 2016, 52, 2249−2252. (d) Dai, W.; Jiang, X.-L.; Wu, Q.; Shi, F.; Tu, S.-J. Diastereo- and Enantioselective Construction of 3,3′-Pyrrolidinyldispirooxindole Framework via Catalytic Asymmetric 1,3-Dipolar Cycloadditions. J. Org. Chem. 2015, 80, 5737−5744. (8) Liu, Y.-L.; Wang, X.; Zhao, Y.-L.; Zhu, F.; Zeng, X.-P.; Chen, L.; Wang, C.-H.; Zhao, X.-L.; Zhou, J. One-Pot Tandem Approach to Spirocyclic Oxindoles Featuring Adjacent Spiro-Stereocenters. Angew. Chem., Int. Ed. 2013, 52, 13735−13739. (9) Shi, M.; Xu, Y.-M. Catalytic, Asymmetric Baylis-Hillman Reaction of Imines with Methyl Vinyl Ketone and Methyl Acrylate. Angew. Chem., Int. Ed. 2002, 41, 4507−4510. (10) For reviews, see: (a) Wei, Y.; Shi, M. Recent Advances in Organocatalytic Asymmetric Morita-Baylis-Hillman/aza-Morita-Baylis-Hillman Reactions. Chem. Rev. 2013, 113, 6659−6690. (b) Liu, T.Y.; Xie, M.; Chen, Y.-C. Organocatalytic Asymmetric Transformations of Modified Morita-Baylis-Hillman Adducts. Chem. Soc. Rev. 2012, 41, 4101−4112. (c) Rios, R. Organocatalytic Enantioselective Methodologies Using Morita-Baylis-Hillman Carbonates and Acetates. Catal. Sci. Technol. 2012, 2, 267−268. (d) Xie, P.; Huang, Y. Morita-BaylisHillman Adduct Derivatives (Mbhads): Versatile Reactivity in Lewis Base-Promoted Annulation. Org. Biomol. Chem. 2015, 13, 8578− 8595. (11) For selected examples, see: (a) Peng, J.; Huang, X.; Jiang, L.; Cui, H.-L.; Chen, Y.-C. Tertiary Amine-Catalyzed Chemoselective and Asymmetric [3 + 2] Annulation of Morita-Baylis-Hillman Carbonates of Isatins with Propargyl Sulfones. Org. Lett. 2011, 13, 4584−4587. (b) Wang, Y.; Liu, L.; Zhang, T.; Zhong, N.-J.; Wang, D.; Chen, Y.-J. Diastereo- and Enantioselective [3 + 2] Cycloaddition Reaction of Morita-Baylis-Hillman Carbonates of Isatins with N-

ORCID

Bao-Dong Cui: 0000-0001-5693-5188 Wen-Yong Han: 0000-0001-6236-4238 Nan-Wei Wan: 0000-0003-3561-8380 Wei-Cheng Yuan: 0000-0003-4850-8981 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the financial support from National Nature Science Foundation of China (21662049), Science and Technology Department of Guizhou Province (QKHJC-2016-1421, QKHRC-2016-4029), National First-Rate Construction Discipline of Guizhou Province (Pharmacy) (YLXKJS-YX-04) and Program for Outstanding Youth of Zunyi Medical University (17zy-005).

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DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475

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DOI: 10.1021/acs.joc.8b01506 J. Org. Chem. 2018, 83, 10465−10475