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Article

PyBox–La(OTf)3-Catalyzed Enantioselective Diels–Alder Cycloadditions of 2-Alkenoylpyridines with Cyclopentadiene

by
Hao Wei
1,
Yujie Zhang
1,
Sanlin Jin
1,
Ying Yu
2,*,
Ning Chen
1,
Jiaxi Xu
1 and
Zhanhui Yang
1,*
1
Department of Organic Chemistry, College of Chemistry, Beijing University of Chemical Technology, Beijing 100029, China
2
China United Test & Certification Co., Ltd., Beijing 100088, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(13), 2978; https://doi.org/10.3390/molecules29132978
Submission received: 7 May 2024 / Revised: 19 June 2024 / Accepted: 19 June 2024 / Published: 22 June 2024
(This article belongs to the Special Issue Current Development of Asymmetric Catalysis and Synthesis)
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Versions Notes

Abstract

:
The PyBox–La(OTf)3-catalyzed enantioselective Diels–Alder cycloaddition of 2-alk-2-enoylpyridines with cyclopentadiene is realized, producing enantiopure disubstituted norbornenes, which possess four contiguous stereocenters and are biologically relevant structures in up to 92:8 dr and 99:1 er.

1. Introduction

Enantioenriched norbornene scaffolds with multiple stereocenters are prevalent motifs in many pharmaceutically relevant and naturally occurring compounds (Figure 1) [1,2,3,4,5,6]. Therefore, the construction of such scaffolds constitutes an intriguing topic in the synthetic community. The catalytic asymmetric Diels–Alder cycloadditions of auxiliary-substituted alkenes with cyclopentadienes provide a straightforward and atom-economical access to the norbornene scaffolds, and are anticipated to produce good levels of chirality transfer and diastereocontrol by virtue of interactions between auxiliary groups and chiral catalysts [7]. In this regard, alkenoyl pyridines, which can chelate their pyridinyl nitrogen and carbonyl oxygen atoms to the metal center of a chiral catalyst, are demonstrated as robust dienophiles to undergo asymmetric Diels–Alder cycloadditions with cyclopentadienes, even in aqueous media (Scheme 1). Documented catalysts and ligands that are applicable to this useful type of reaction include Engberts’s chiral amino acid–Cu(II) system (74% ee) [8], Pedro’s chiral bis(oxazoline)–Cu(II) system (19% ee) [9], Lin and Feng’s N,N’-dioxide–Ni(II) system (up to 95:5 dr and 96% ee) [10] and Ollevier’s chiral bipyridine diol–Fe(III) system (up to 93:7 dr and 84% ee) [11]. In addition, numerous chiral artificial metalloenzymes and DNA-modified catalysts were also developed [12,13,14,15,16,17]. In spite of the above advances, new alternative catalytic systems are still in demand for effecting high levels of diastereo- and enantiocontrol, a purpose that was hitherto only satisfied by Lin and Feng’s N,N’-dioxide–Ni(II) catalysts [10].
The past decades have witnessed fruitful advancements on rare earth-catalyzed asymmetric Diels–Alder cycloadditions [18], which encouraged us to provide a rare-earth protocol for enantiocontrol. The key factor that underlies this protocol is the choice of a chiral ligand. Our previous research with didentate pyridyl imidazolines [19,20,21,22] led us to consider similar chirally modified nitrogen ligands. Considering the special coordination numbers of rare earth salts, we designed and synthesized several tridentate chiral nitrogen ligands and evaluated their chirality transfer ability in the rare earth-catalyzed Diels–Alder cycloadditions between 2-alk-2-enoylpyridines and cyclopentadiene. We eventually found that the combination of chiral pyridine-2,6-bisoxazolines and La(OTf)3 displays the best results in terms of diastereo- and enantiocontrol, producing enantioenriched norbornenes in good yields and enantiopurities (Scheme 1b).

2. Results and Discussion

We first optimized the reaction conditions using (E)-styrenoyl pyridine (1a) and cyclopentadiene (2A) as the model substrates. The selected attempts on ligand screening are listed in Table 1 (for more details, see Tables S1 and S2 in the Supplementary Materials). Pyridine-2,6-bisimidazoline ligands PyBim-1 and PyBim-2 produced 3aA in 84:16 and 75:25 er, respectively [23,24,25]. In contrast, 3aA was produced in 94:6 and 68:32 er values when the respective pyridine-2,6-bisoxazoline ligands PyBox-1 and PyBox-2 were used. The reaction with 1,10-phenanthroline-2-oxazoline (PhenOx) delivered 3aA as a nearly racemic mixture. Apparently, PyBox-1 produced the best result in terms of enantioselectivity. It deserves mention that similar ligands were also employed by Desimoni’s group in 2002 in the Diels–Alder exo-cycloadditions between alkenoyl-1,3-oxazolidin-2-ones and cyclopentadiene [26]. With this ligand, other lanthanum(III) salts such as LaCl3 and La(BF4)3 were evaluated, but nearly no enantioselectivity was observed. Thus, from the conditions listed in Table 1, entry 3 was selected as the optimal one.
With the optimal conditions at hand, a number of dienophiles, that is, 2-alk-2-enoylpyridines 1a–r, were reacted with cyclopentadiene. The results regarding enantio- and diastereoselectivities (endo/exo) are summarized in Figure 2. 2-Alk-2-enoylpyridines bearing electronically diverse aryl substituents were first screened. In addition to (E)-styrenoylpyridine (1a), the halogen-substituted dienophiles 1b–1h all productively gave desired products 3bA–3hA in 80–98 yields, 64:36–89:11 drs, and most importantly, 87:13–95.5:4.5 ers. The highest enantioselectivity (95.5:4.5 er) was observed in the reaction producing 3cA. Strongly electron-withdrawing cyano-substituted dienophile 1i, as well as those with electron-donating alkyl and methoxy substituents, produced desired products 3iA–3lA in 87:13–93:7 ers with varying diastereoselectivities and yields. Dienophiles with heteroaryls and fused aryls were also amenable, and the corresponding products were procured in 81:19 to 90:10 er. The alkyl-substituted 2-alk-2-enoylpyridines 1p–1r were also tested under the optimal conditions. Dienophiles 1p and 1q with more steric hindrance delivered products 3pA and 3qA in excellent 99:1 and 95:5 ers, respectively, whilst dienophile 1r with less steric cyclopropyl only afforded moderate enantioselectivity of 77:23. Acyclic dienes were also examined. 2,3-Dimethylbuta-1,3-diene (2B) afforded 3aB at a 45% yield with 82:18 er and >20:1 dr. However, other attempted dienes, including 2-methylbuta-1,3-diene (2C), cyclohexa-1,3-diene (2D) and furan (2E), did not react with 1a.
Mechanistic studies were performed (Scheme 2). Mixing PyBox-1 with La(OTf)3 afforded a stable complex 4 (Scheme 2a). The complex can even be prepared in a decagram scale at a 91% yield. In the presence of 10 mol% of 4, the cycloaddition of 1a and 2A produced 3aA at a 91% yield, 91.5:8.5 er and 89:11 dr, a result almost identical with that obtained with separately added PyBox-1 and La(OTf)3. In the control experiment (Scheme 2b), the reaction of E-chalcone (1s) with cyclopentadiene (2A) did not yield the desired product 3sA, highlighting the essence of the pyridine auxiliary and nitrogen coordination to the metal center. Based on the above results, a plausible enantiocontrol model is proposed (Scheme 2c). Ligand exchange between A and substrate 1a afforded chiral complex B. The C2-asymmetry created a chiral pocket that allowed cyclopentadiene to approach the dienophile from the southwest upper face of B. A π-stacking interaction between the pyridinyl ring and the upward phenyl ring in proximity to the nitrogen atom was proposed to stabilize the transition state TS [27]. Once product 3a was formed, it was still coordinated with the rare earth metal. Ligand exchange between C and 1a ultimately produced 3aA and opened a new catalytic cycle.
The PyBox-La(OTf)3-catalyzed cycloaddition is featured with good scalability (Scheme 3a). In the gram-scale reaction, 3aA was obtained in 93.5:6.5 er, 86:14 dr with a 98% yield. The obtained difunctionalized norbornene 3aA possesses two reactive chemical handles to undergo further manipulations (Scheme 3b). Epoxidation of the endocyclic C=C bond yielded epoxide 5, with two new stereocenters generated at a 73% yield, leaving the electron-rich pyridine nitrogen intact. The facial selectivity was assigned according to the empirical rule proposed by Brown and coworkers [27]. Grignard addition to the carboxyl group led to a tertiary alcohol 6 at a 92% yield, whereas the NaBH4 reduction produced a secondary alcohol 7 at a 93% yield. However, the ozonolysis of 3aA led to complex mixtures with all the starting material consumed.

3. Materials and Methods

3.1. Materials and Instruments

Unless otherwise noted, all materials were purchased from commercial suppliers. Dichloromethane (DCM) and dichloroethane (DCE) were refluxed over CaH2; tetrahydrofuran (THF) and toluene (PhMe) were refluxed over lithium aluminum hydride. The solvents were freshly distilled prior to use. Column chromatography was performed on silica gel (normal phase, 200–300 mesh) from Anhui Liangchen Silicon Material Co., Ltd. (Lu’An, China), with petroleum ether (PE, bp. 60–90 °C) and ethyl acetate (EA) as eluent. Reactions were monitored using thin-layer chromatography (TLC) on GF254 silica gel plates (0.2 mm) from Anhui Liangchen Silicon Material Co., Ltd. The plates were visualized via UV light using other TLC stains (1% potassium permanganate in water; 10 g of iodine absorbed on 30 g of silica gel). 1H and 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer, usually in CDCl3 as an internal standard, and the chemical shifts (δ) were reported in parts per million (ppm). Multiplicities are indicated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), m (multiplet) and b (broad). Coupling constants (J) are reported in Hertz (Hz). HRMS measurements were carried out on an Agilent LC/MSD TOF mass spectrometer. The enantiomeric excesses were determined via HPLC analysis using Agilent Technologies 1260 Infinity equipment, and the employed chiral stationary phase column are specified in the individual experiment by comparing the enantiomeric samples with the appropriate racemic mixtures.
Substrate 1a–r were prepared according to Caggiano’s study [28]. The nuclear magnetic spectra of 1a to 1c, 1e to 1p and 1r are in agreement with the predecessors. PyBim-2 [23], and PhenOx-1 [29] were prepared according to published procedures.

3.2. General Procedure for Reduction of 2-Alkenoylpyridines

To a solution of ketone (5 mmol) and aldehyde (5.5 mmol) in ethanol (15mL), aqueous sodium hydroxide solution (5 mL, 2.5 M) was added dropwise at 0 °C. The reaction mixture was further stirred at room temperature until the completion of reaction (detected by TLC). Then, the reaction mixture was filtered and washed with ethanol–water solution (1/1, v/v) and dried. The precipitate was recrystallized in methanol to obtain pure unsaturated ketone products.

3.2.1. (E)-3-(2,3-Difluorophenyl)-1-(pyridin-2-yl)prop-2-en-1-one (1d)

Yellow solid, 1.018 g, yield 83%, Rf = 0.5 (PE/EA = 5:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.75 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.38 (d, J = 16.3 Hz, 1H), 8.19 (dt, J = 7.8, 1.1 Hz, 1H), 8.04 (d, J = 16.3 Hz, 1H), 7.89 (td, J = 7.7, 1.7 Hz, 1H), 7.52 (dddd, J = 15.1, 7.5, 4.5, 1.5 Hz, 2H), 7.23–7.09 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 189.2, 153.8, 148.9, 137.0, 135.5, 127.1, 125.5 (d, J = 8.7 Hz), 124.3 (d, J = 5.6 Hz), 124.2 (t, J = 5.8, 11.4 Hz), 123.8, 123.0, 118.7 (d, J = 17.3 Hz), 118.6. 19F NMR (376 MHz, CDCl3) δ −137.72, −139.62. HRMS (ESI): m/z [M+H]+ calculated for C14H10F2NO+ 246.0725, found 246.0732.

3.2.2. (E)-3-Cyclopentyl-1-(pyridin-2-yl)prop-2-en-1-one (1q)

Colorless oil, 532.6 mg, yield 53%, Rf = 0.65 (PE/EA = 5:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.70 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.12 (dt, J = 7.9, 1.1 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.59 (dd, J = 15.6, 1.1 Hz, 1H), 7.45 (ddd, J = 7.5, 4.8, 1.3 Hz, 1H), 7.22 (dd, J = 15.6, 8.2 Hz, 1H), 2.77 (h, J = 8.1, 7.6 Hz, 1H), 1.96–1.87 (m, 2H), 1.75–1.48 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 189.6, 154.6, 154.2, 148.7, 136.8, 126.6, 122.8, 122.4, 43.5, 32.6, 25.4. HRMS (ESI): m/z [M+H]+ calculated for C13H16NO+ 202.1226, found 202.1234.

3.3. General Procedure for Reduction of PyBim-1 and PyBox

Molecules 29 02978 i002
This was prepared according to Beller’s procedure, with slight modification [24]. The 1H and 13C NMR spectra are in agreement with those reported [24]. Procedure: To an oven-dried round-bottom flask equipped with a magnetic stirring bar was added 2,6-pyridinedicarbonitrile (2.6 g, 20 mmol), sodium methoxide (108 mg, 2 mmol), and methanol (40 mL). The mixture was stirred at ambient temperature. After 12 h, the solution was transferred to an oven-dried flask and then quenched with acetic acid (0.24 mL). The solvent was evaporated under reduced pressure to obtain product S1 (>99% yield).
To an oven-dried round-bottom flask equipped with a magnetic stirring bar was added S1 and (1S, 2S)-1,2-diphenylethane-1,2-diamine (8.53 g, 40 mmol). The flask was sealed immediately with a rubber stopper and protected with a nitrogen balloon by evacuation-backfill operations (repeated three times). Dry dichloromethane (DCM, 60 mL) was injected to the flask via a syringe, and the reaction mixture was kept at 43 °C for 48 h. The solvent was evaporated under reduced pressure, and the crude mixture was subjected to column chromatography (PE:EA:Et3N = 20:10:1) on silica gel to afford the corresponding crude product. Final purification by recrystallization from ethyl acetate and petroleum ether afforded PyBim-1 in 98% yield (10.17 g) as a white solid.
Molecules 29 02978 i003
This was prepared according to Fokin’s procedure, with slight modification [30]. The 1H and 13C NMR spectrum and data are in agreement with those reported. Procedure: To an oven-dried round-bottom flask equipped with a magnetic stirring bar was added 2,6-pyridinedicarbonitrile (5.2 g, 40 mmol), sodium methoxide (216 mg, 4 mmol), and methanol (80 mL). The reaction mixture was stirred at ambient temperature. After 12 h, the solution was transferred to an oven-dried flask and quenched with acetic acid (0.48 mL); the solvent was evaporated under reduced pressure to obtain product S1 (>99% yield). To an oven-dried round-bottom flask equipped with a magnetic stirring bar was added S1 and (1S, 2R)-2-amino-1,2-diphenylethan-1-ol (17.06 g, 80 mmol). The flask was sealed immediately with a rubber stopper and protected with a nitrogen balloon by evacuation-backfill operations (repeated three times). Dry DCM (120 mL) was injected to the flask via a syringe, and the reaction mixtures was kept at 43 °C. After 48 h, the solvent was evaporated, and the remaining mixture was solidified by MeOH and washed with MeOH and EA to obtain PyBox-1 (17.069 g, 82%) as a white solid.
Molecules 29 02978 i004
Procedure: To an oven-dried round-bottom flask equipped with a magnetic stirring bar was successively added PyBox-1 (7.5 g, 14.4 mmol) and La(OTf)3 (7.03 g, 12 mmol). The flask was sealed immediately with a rubber stopper and protected with a nitrogen balloon by evacuation-backfill operations (repeated three times). A mixture of DCM and toluene (v/v = 4:1) (120 mL) was injected to the tube via a syringe, and the mixture was stirred for about 24 h. The solvent was evaporated under reduced pressure. The crude mixture was washed with Et2O to obtain the product (12.085 g, 91%) as a white solid.

3.4. General Procedure for Reduction of Chiral Product 3

Molecules 29 02978 i005
General Procedure: To an oven-dried reaction tube equipped with a magnetic stirring bar was added 2-alkenoyl pyridines 1 (0.1 mmol, 1.0 equiv), La(OTf)3 (5.9 mg, 0.01 mmol) and ligand PyBox-1 (6.3 mg, 0.012 mmol). The tube was sealed immediately with a rubber stopper and protected with a nitrogen balloon by evacuation-backfill operations (repeated three times). Dry Et2O (1 mL) was injected to the tube via a syringe. The resultant mixture was stirred for about 1 h, followed by addition of cyclopentadiene (2A) (33 μL, 0.4 mmol, 4.0 equiv) or 2,3-dimethylbuta-2,3-diene (2B) (90 μL, 0.4 mmol, 4.0 equiv) via a microsyringe. The mixture was stirred at 25 °C for 48 h. The solvent was evaporated under reduced pressure, and the crude mixture was subjected to column chromatography on silica gel to afford the corresponding products.

3.4.1. ((1R,2S,3S,4S)-3-Phenylbicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3aA)

Colorless oil, 25 mg, yield 91%, Rf = 0.5 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.76–8.60 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.42 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 7.36–7.06 (m, 6H), 6.49 (dd, J = 5.6, 3.2 Hz, 1H), 5.82 (dd, J = 5.6, 2.8 Hz, 1H), 4.53 (dd, J = 5.2, 3.4 Hz, 1H), 3.54 (s, 1H), 3.46 (d, J = 4.8 Hz, 1H), 3.09 (s, 1H), 2.07 (d, J = 8.4 Hz, 1H), 1.61 (dd, J = 8.4, 2.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 201.0, 153.5, 148.8, 144.6, 139.3, 136.7, 132.8, 128.3, 127.6, 126.8, 125.7, 122.1, 54.2, 49.3, 48.7, 48.2, 45.5.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 97:3, 0.65 mL/min, T = 15 °C): tR1 (major) = 17.172 min, tR2 (minor) = 12.070 min; dr: 89:11; er: 94:6.
[α]20D = +135.7 (c = 1.0, CHCl3).

3.4.2. ((1R,2S,3S,4S)-3-(2-Fluorophenyl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3bA)

Colorless oil, 28 mg, yield 96%, Rf = 0.55 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.66 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.05 (dt, J = 7.9, 1.1 Hz, 1H), 7.82 (td, J = 7.7, 1.8 Hz, 1H), 7.48–7.40 (m, 2H), 7.19–7.08 (m, 2H), 6.94 (ddd, J = 10.5, 7.9, 1.5 Hz, 1H), 6.48 (dd, J = 5.7, 3.2 Hz, 1H), 5.88 (dd, J = 5.6, 2.8 Hz, 1H), 4.53 (dd, J = 5.1, 3.5 Hz, 1H), 3.53 (d, J = 5.0 Hz, 1H), 3.49 (s, 1H), 3.19 (d, J = 2.1 Hz, 1H), 1.97 (d, J = 8.5 Hz, 1H), 1.62 (dd, J = 8.5, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 200.2,160.2 (d, J = 246 Hz), 153.5, 148.8, 138.3, 136.8, 133.3, 131.8, 127.2 (d, J = 9.3 Hz), 126.8, 123.8 (d, J = 2.8 Hz), 122.2, 115.2 (d, J = 22.7 Hz), 52.5, 48.5, 48.1, 47.6, 39.2. 19F NMR (376 MHz, CDCl3) δ −139.01. HRMS (ESI): m/z [M+H]+ calculated for C19H17FNO+ 294.1289, found 294.1288.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 97:3, 0.65 mL/min, T = 15 °C): tR1 (major) = 14.393 min, tR2 (minor) = 13.080 min; dr: 65:35; er: 87:13.
[α]20D = +81.4 (c = 1.7, CHCl3).

3.4.3. ((1R,2S,3S,4S)-3-(4-Fluorophenyl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3cA)

Colorless oil, 27 mg, yield 92%, Rf = 0.55 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.6 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.82 (td, J = 7.7, 1.8 Hz, 1H), 7.46 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 7.30–7.21 (m, 2H), 7.01–6.85 (m, 2H), 6.48 (dd, J = 5.7, 3.2 Hz, 1H), 5.83 (dd, J = 5.6, 2.8 Hz, 1H), 4.46 (dd, J = 5.2, 3.4 Hz, 1H), 3.54 (s, 1H), 3.42 (d, J = 4.7 Hz, 1H), 3.07–3.01 (dd, J = 1.2 Hz, 1H), 2.03 (d, J = 8.5 Hz, 1H), 1.62 (dd, J = 8.5, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 201.0, 160.2, 153.5, 148.9, 140.2, 139.3, 136.8, 132.9, 129.0, 128.9 (d, J = 7.8 Hz), 126.9, 122.2, 115.1 (d, J = 21.0 Hz), 54.5, 49.4, 48.7, 48.1, 44.9. 19F NMR (376 MHz, CDCl3) δ −117.84.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 97:3, 0.65 mL/min, T = 15 °C): tR1 (major) = 14.534 min, tR2 (minor) = 11.045 min; dr: 89:11; er:95.5:4.5.
[α]20D = +127.6 (c = 2.3, CHCl3).

3.4.4. ((1R,2S,3S,4S)-3-(2,3-Difluorophenyl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3dA)

Colorless oil, 27 mg, yield 87%, Rf = 0.5 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.66 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.05 (dt, J = 7.9, 1.1 Hz, 1H), 7.83 (td, J = 7.7, 1.8 Hz, 1H), 7.46 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 7.17 (ddd, J = 7.0, 4.6, 2.0 Hz, 1H), 7.04–6.93 (m, 2H), 6.47 (dd, J = 5.6, 3.2 Hz, 1H), 5.89 (dd, J = 5.6, 2.8 Hz, 1H), 4.51 (dd, J = 5.1, 3.5 Hz, 1H), 3.55 (d, J = 5.2 Hz, 1H), 3.51 (s, 1H), 3.17 (d, J = 1.7 Hz, 1H), 1.95 (d, J = 8.6 Hz, 1H), 1.63 (dd, J = 8.6, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 199.8, 153.3, 148.8, 138.2, 136.9, 134.5 (d, J = 10.7 Hz), 133.5, 127.0, 123.6 (t, J = 5.8, 11.9 Hz), 122.3, 121.9 (d, J = 2.7 Hz), 114.6 (d, J = 5.0 Hz), 52.6, 48.5, 48.2, 47.8, 39.1. 19F NMR (376 MHz, CDCl3) δ −111.33, 116.03. HRMS (ESI): m/z [M+H]+ calculated for C19H16F2NO+ 312.1194, found 312.1199.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 97:3, 0.65 mL/min, T = 15 °C): tR1 (major) = 16.212 min, tR2 (minor) = 11.443 min; dr: 86:14; er: 90:10.
[α]20D = +93.5 (c = 2.1, CHCl3).

3.4.5. ((1S,2R,3R,4R)-3-(3-Chlorophenyl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3eA)

Colorless oil, 25 mg, yield 81%, Rf = 0.5 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.3 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.83 (td, J = 7.7, 1.8 Hz, 1H), 7.46 (ddd, J = 7.6, 4.7, 1.3 Hz, 1H), 7.30–7.07 (m, 4H), 6.47 (dd, J = 5.7, 3.2 Hz, 1H), 5.83 (dd, J = 5.6, 2.8 Hz, 1H), 4.46 (dd, J = 5.2, 3.4 Hz, 1H), 3.56 (s, 1H), 3.42 (d, J = 4.2 Hz, 1H), 3.07 (d, J = 1.8 Hz, 1H), 2.03 (d, J = 8.5 Hz, 1H), 1.63 (dd, J = 8.6, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 200.7, 153.4, 148.9, 146.8, 139.2, 136.9, 134.2, 133.0, 129.6, 127.6, 127.0, 126.0, 122.2, 54.4, 49.1, 48.7, 48.2, 45.3.
HPLC (Daicel Chiralpak AD-H, nhexane/iPrOH = 99.5:0.5, 0.5 mL/min, T = 12 °C): tR1 (major) = 36.171 min, tR2 (minor) = 38.433 min; dr: 89:11; er: 92:8.
[α]20D = +112.8 (c = 1.6, CHCl3).

3.4.6. ((1R,2S,3S,4S)-3-(4-Chlorophenyl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3fA)

Colorless oil, 30 mg, yield 98%, Rf = 0.5 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.8 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.85 (td, J = 7.7, 1.8 Hz, 1H), 7.48 (ddd, J = 7.5, 4.7, 1.3 Hz, 1H), 7.26 (m, 4H), 6.50 (dd, J = 5.7, 3.2 Hz, 1H), 5.85 (dd, J = 5.6, 2.8 Hz, 1H), 4.48 (dd, J = 5.2, 3.4 Hz, 1H), 3.57 (s, 1H), 3.43 (dd, J = 5.2, 1.8 Hz, 1H), 3.07 (d, J = 1.7 Hz, 1H), 2.03 (d, J = 8.5 Hz, 1H), 1.64 (dd, J = 8.5, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 200.9, 153.4, 148.9, 143.1, 139.2, 136.8, 133.0, 131.5, 128.9, 128.4, 127.0, 122.2, 54.4, 49.2, 48.7, 48.1, 45.0.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 97:3, 0.65 mL/min, T = 15 °C): tR1 (maJor) = 14.238 min, tR2 (minor) = 10.897 min; dr: 88:12; er: 92:8.
[α]20D = +104.4 (c = 1.4, CHCl3).

3.4.7. ((1R,2S,3S,4S)-3-(2-Bromophenyl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3gA)

Colorless oil, 28 mg, yield 80%, Rf = 0.5 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.53 (ddd, J = 11.1, 8.0, 1.6 Hz, 2H), 7.44 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 7.32–7.25 (m, 1H), 7.05 (td, J = 7.7, 1.7 Hz, 1H), 6.53 (dd, J = 5.6, 3.2 Hz, 1H), 5.90 (dd, J = 5.6, 2.8 Hz, 1H), 4.68 (dd, J = 5.1, 3.5 Hz, 1H), 3.60 (d, J = 3.5 Hz, 1H), 3.48 (s, 1H), 3.06 (dd, J = 3.3, 1.7 Hz, 1H), 1.99 (d, J = 8.5 Hz, 1H), 1.59 (dd, J = 8.5, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 200.3, 153.6 148.8, 143.4, 138.5, 136.8, 133.6, 133.1, 127.9, 127.4, 127.2, 126.8, 126.3, 122.2, 51.2, 49.9, 48.4, 47.7, 46.3.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 99:1, 0.65 mL/min, T = 15 °C): tR1 (major) = 18.929 min, tR2 (minor) = 17.916 min; dr: 64:36; er: 88:12.
[α]20D = +61.9 (c = 2.3, CHCl3).

3.4.8. ((1R,2S,3S,4S)-3-(4-Bromophenyl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3hA)

Colorless oil, 30 mg, yield 85%, Rf = 0.5 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.67 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.00 (dt, J = 7.9, 1.1 Hz, 1H), 7.82 (td, J = 7.7, 1.8 Hz, 1H), 7.46 (ddd, J = 7.5, 4.7, 1.3 Hz, 1H), 7.41–7.35 (m, 2H), 7.21–7.15 (m, 2H), 6.47 (dd, J = 5.6, 3.2 Hz, 1H), 5.83 (dd, J = 5.7, 2.8 Hz, 1H), 4.46 (dd, J = 5.2, 3.4 Hz, 1H), 3.55 (s, 1H), 3.39 (d, J = 4.6 Hz, 1H), 3.04 (d, J = 2.2 Hz, 1H), 2.01 (d, J = 8.6 Hz, 1H), 1.62 (dd, J = 8.6, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 200.8, 153.4, 148.8, 143.7, 139.2, 136.9, 133.0, 131.3, 129.4, 127.0, 122.2, 119.5, 54.4, 49.2, 48.7, 48.1, 45.1.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 97:3, 0.65 mL/min, T = 15 °C): tR1 (major) = 15.277 min, tR2 (minor) = 11.426 min; dr: 88.5:11.5; er: 88:12.
[α]20D = +90.2 (c = 2.3, CHCl3).

3.4.9. 4-((1S,2S,3S,4R)-3-Picolinoylbicyclo[2.2.1]hept-5-en-2-yl)benzonitrile (3iA)

Colorless oil, 25 mg, yield 84%, Rf = 0.6 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.5 Hz, 1H), 8.01 (d, J = 7.6 Hz 1H), 7.88–7.82 (m, 1H), 7.60–7.54 (m, 2H), 7.48 (ddd, J = 7.6, 4.0, 2.8 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 6.48 (dd, J = 5.7, 3.2 Hz, 1H), 5.86 (dd, J = 5.6, 2.8 Hz, 1H), 4.45 (dd, J = 5.3, 3.4 Hz, 1H), 3.59 (s, 1H), 3.49 (d, J = 4.8 Hz, 1H), 3.10 (dd, J = 3.3, 1.6 Hz, 1H), 1.99 (d, J = 8.6 Hz, 1H), 1.65 (dd, J = 8.6, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 200.4, 153.2, 150.5, 148.9, 139.0, 136.9, 133.3, 132.2, 128.4, 127.1, 122.3, 119.0, 109.6, 54.5, 48.8, 48.7, 48.2, 45.8.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 97:3, 0.65 mL/min, T = 13 °C): tR1 (major) = 34.765 min, tR2 (minor) = 40.230 min; dr: 73.5:26.5; er:87:13.
[α]20D = +79.6 (c = 2.0, CHCl3).

3.4.10. Pyridin-2-yl((1R,2S,3S,4S)-3-(p-tolyl)bicyclo[2.2.1]hept-5-en-2-yl)methanone (3jA)

Colorless oil, 26 mg, yield 91%, Rf = 0.6 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.0 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.80 (td, J = 7.7, 1.8 Hz, 1H), 7.44 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 6.48 (dd, J = 5.6, 3.2 Hz, 1H), 5.81 (dd, J = 5.6, 2.8 Hz, 1H), 4.52 (dd, J = 5.2, 3.4 Hz, 1H), 3.53 (s, 1H), 3.41 (d, J = 4.8 Hz, 1H), 3.05 (s, 1H), 2.30 (s, 3H), 2.06 (d, J = 8.4 Hz, 1H), 1.59 (dd, J = 8.5, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 201.2, 153.6, 148.8, 141.5, 139.4, 136.8, 135.2, 132.7, 129.0, 127.5, 126.8, 122.1, 54.1, 49.6, 48.7, 48.2, 45.2, 20.9.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 97:3, 0.65 mL/min, T = 12 °C): tR1 (major) = 16.212 min, tR2 (minor) = 11.443 min; dr: 86:14; er: 93:7.
[α]20D = +111.6 (c = 2.3, CHCl3).

3.4.11. ((1R,2S,3S,4S)-3-(3,5-Dimethylphenyl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3kA)

Colorless oil, 24 mg, yield 86%, Rf = 0.6 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.6 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.81 (td, J = 7.7, 1.7 Hz, 1H), 7.44 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 6.94 (s, 2H), 6.81 (s, 1H), 6.48 (dd, J = 5.7, 3.2 Hz, 1H), 5.80 (dd, J = 5.6, 2.8 Hz, 1H), 4.49 (dd, J = 5.2, 3.4 Hz, 1H), 3.54 (s, 1H), 3.38 (d, J = 4.9 Hz, 1H), 3.05 (s, 1H), 2.27 (s, 6H), 2.09 (d, J = 8.4 Hz, 1H), 1.60 (dd, J = 8.5, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 201.1, 153.6, 148.8, 144.5, 139.5, 137.8, 136.8, 132.7, 127.5, 126.8, 125.5, 122.2, 54.2, 49.5, 48.7, 48.3, 45.3, 21.4. HRMS (ESI): m/z [M+H]+ calculated for C21H22NO+ 304.1696, found 304.1692.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 97:3, 0.65 mL/min, T = 11 °C): tR1 (major) = 25.518 min, tR2 (minor) = 9.663 min; dr: 90:10; er: 89:11.
[α]20D = +111.8 (c = 1.9, CHCl3).

3.4.12. ((1R,2S,3S,4S)-3-(4-Methoxyphenyl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3lA)

Colorless oil, 21 mg, yield 68%, Rf = 0.4 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.68 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.00 (dt, J = 7.8, 1.1 Hz, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.44 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 7.26–7.22 (m, 2H), 6.86–6.80 (m, 2H), 6.48 (dd, J = 5.7, 3.2 Hz, 1H), 5.81 (dd, J = 5.7, 2.8 Hz, 1H), 4.49 (dd, J = 5.2, 3.4 Hz, 1H), 3.77 (s, 3H), 3.53 (s, 1H), 3.38 (d, J = 4.4 Hz, 1H), 3.05–3.00 (m, 1H), 2.08–2.03 (m, 1H), 1.60 (dd, J = 8.5, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 201.2, 157.7, 153.6, 148.8, 139.4, 136.8, 132.7, 128.5, 126.8, 122.1, 113.7, 55.2, 54.2, 49.6, 48.7, 48.1, 44.9.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 99:1, 0.65 mL/min, T = 12 °C): tR1 (major) = 40.987 min, tR2 (minor) = 22.953 min; dr: 90:10; er: 89:11.
[α]20D = +91.5 (c = 2.2, CHCl3).

3.4.13. ((1R,2S,3S,4S)-3-(Naphthalen-2-yl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3mA)

Colorless oil, 29 mg, yield 89%, Rf = 0.65 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 4.5 Hz, 1H), 8.16–8.11 (m, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.83 (td, J = 7.5, 1.7 Hz, 2H), 7.73 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.50–7.41 (m, 4H), 6.66 (dd, J = 5.7, 3.2 Hz, 1H), 5.96 (dd, J = 5.6, 2.8 Hz, 1H), 4.73 (dd, J = 5.1, 3.5 Hz, 1H), 4.10 (d, J = 4.9 Hz, 1H), 3.57 (s, 1H), 3.24 (s, 1H), 2.23 (d, J = 8.4 Hz, 1H), 1.72 (dd, J = 8.5, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 201.2, 153.5, 148.8, 140.7, 139.0, 136.8, 133.8, 133.4, 132.7, 128.6, 126.9, 126.6, 125.9, 125.4, 125.3, 124.3, 123.0, 122.2, 52.7, 49.9, 48.8, 48.5, 41.6. HRMS (ESI): m/z [M+H]+ calculated for C23H20NO+ 326.1539, found 326.1543.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 98:2, 0.65 mL/min, T = 15 °C): tR1 (major) = 25.574 min, tR2 (minor) = 12.468 min; dr: 92:2; er: 81:19.
[α]20D = +92.6 (c = 1.2, CHCl3).

3.4.14. Pyridin-2-yl((1R,2S,3S,4S)-3-(thiophen-2-yl)bicyclo[2.2.1]hept-5-en-2-yl)methanone (3nA)

Colorless oil, 22 mg, yield 78%, Rf = 0.4 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.70 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.00 (dt, J = 7.8, 1.1 Hz, 1H), 7.82 (td, J = 7.7, 1.8 Hz, 1H), 7.46 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 7.14–7.08 (m, 1H), 6.93–6.88 (m, 2H), 6.45 (dd, J = 5.7, 3.2 Hz, 1H), 5.80 (dd, J = 5.6, 2.8 Hz, 1H), 4.57 (dd, J = 4.9, 3.4 Hz, 1H), 3.63 (dd, J = 4.9, 1.7 Hz, 1H), 3.55 (s, 1H), 3.06 (s, 1H), 2.11 (d, J = 8.7 Hz, 1H), 1.64 (dd, J = 8.7, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 200.4, 153.4, 148.9, 138.6, 136.8, 132.7, 126.9, 126.6, 123.7, 122.9, 122.2, 55.7, 51.5, 48.6, 48.5, 41.6.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 99:1, 0.65 mL/min, T = 17 °C): tR1 (major) = 20.617 min, tR2 (minor) = 16.158 min; dr: 76:24; er: 89:11.
[α]20D = +125.6 (c = 1.4, CHCl3).

3.4.15. ((1R,2S,3S,4S)-3-(Benzo[b]thiophen-2-yl)bicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3oA)

Colorless oil, 32 mg, yield 97%, Rf = 0.4 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.6 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.76–7.71 (m, 1H), 7.64 (dd, J = 7.6, 1.4 Hz, 1H), 7.45 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 7.29–7.21 (m, 2H), 7.13 (s, 1H), 6.48 (dd, J = 5.7, 3.2 Hz, 1H), 5.84 (dd, J = 5.7, 2.8 Hz, 1H), 4.67 (dd, J = 5.0, 3.4 Hz, 1H), 3.69 (d, J = 5.1 Hz, 1H), 3.59 (s, 1H), 3.18 (s, 1H), 2.14 (d, J = 8.7 Hz, 1H), 1.67 (dd, J = 8.7, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 200.2, 153.3, 149.8, 148.9, 140.0, 139.0, 138.6, 136.8, 132.9, 127.0, 124.1, 123.5, 122.8, 122.2, 122.0, 120.0, 55.1, 51.0, 48.7, 48.6, 42.3. HRMS (ESI): m/z [M+H]+ calculated for C21H18NOS+ 332.1104, found 332.1110.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 97:3, 0.65 mL/min, T = 11 °C): tR1 (major) = 28.571 min, tR2 (minor) = 14.914 min; dr: 84.5:15.5; er: 90:10.
[α]20D = +109.6 (c = 2.3, CHCl3).

3.4.16. ((1R,2S,3S,4S)-3-Cyclohexylbicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3pA)

Colorless oil, 21 mg, yield 78%, Rf = 0.6 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.75–8.71 (m, 1H), 7.98 (dt, J = 7.8, 1.2 Hz, 1H), 7.83 (dd, J = 7.7, 1.8 Hz, 1H), 7.46 (ddd, J = 7.6, 4.8, 1.4 Hz, 1H), 6.33 (dd, J = 5.7, 3.3 Hz, 1H), 5.68 (dd, J = 5.6, 2.8 Hz, 1H), 4.12 (dd, J = 5.0, 3.4 Hz, 1H), 3.30 (s, 1H), 2.91 (d, J = 2.3 Hz, 1H), 2.02–1.94 (m, 1H), 1.80 (ddd, J = 10.3, 5.0, 1.7 Hz, 1H), 1.77–1.71 (m, 2H), 1.63–1.56 (m, 3H), 1.47–1.43 (m, 1H), 1.24–1.07 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 201.8, 153.6, 148.8, 139.3, 136.8, 131.7, 126.7, 122.2, 51.4, 48.5, 48.1, 47.8, 44.6, 42.3, 32.9, 32.5, 26.6, 26.5, 26.3.
HPLC (Daicel Chiralpak AD-H, nhexane/iPrOH = 99:1, 0.8 mL/min, T = 12 °C): tR1 (major) = 10.062 min, tR2 (minor) = 8.462 min; dr: 82:18; er: 99:1.
[α]20D = +70.2 (c = 2.8, CHCl3).

3.4.17. ((1R,2S,3S,4S)-3-Cyclopentylbicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3qA)

Colorless oil, 22 mg, yield 82%, Rf = 0.6 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 4.7 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.47 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 6.36 (dd, J = 5.7, 3.2 Hz, 1H), 5.68 (dd, J = 5.7, 2.8 Hz, 1H), 4.14–4.09 (m, 1H), 3.33 (s, 1H), 2.80–2.73 (m, 1H), 1.97–1.39 (m, 12H), 1.33–1.00 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 201.9, 153.8, 148.8, 139.2, 136.8, 131.4, 126.7, 122.1, 52.3, 48.4, 48.2, 47.5, 47.1, 45.6, 32.4, 32.2, 25.3, 25.0. HRMS (ESI): m/z [M+H]+ calculated for C18H22NO+ 268.1696, found 268.1700.
HPLC (Daicel Chiralpak AD-H, nhexane/iPrOH = 99:1, 0.5 mL/min, T = 16 °C): tR1 (major) = 13.391 min, tR2 (minor) = 14.348 min; dr: 82:18; er: 94.5:5.5.
[α]20D = +99.4 (c = 3.7, CHCl3).

3.4.18. ((1R,2S,3S,4S)-3-Cyclopropylbicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanone (3rA)

Colorless oil, 18 mg, yield 75%, Rf = 0.55 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.72 (dt, J = 4.8, 1.2 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.46 (ddd, J = 7.5, 4.8, 1.3 Hz, 1H), 6.29 (dd, J = 5.7, 3.2 Hz, 1H), 5.66 (dd, J = 5.7, 2.8 Hz, 1H), 4.21–4.16 (m, 1H), 3.37 (s, 1H), 2.80 (s, 1H), 1.91 (d, J = 8.4 Hz, 1H), 1.53 (dd, J = 8.5, 1.9 Hz, 1H), 1.41 (dd, J = 4.8, 2.5 Hz, 1H), 0.76 (dddd, J = 12.8, 9.8, 8.0, 4.9 Hz, 1H), 0.49–0.36 (m, 2H), 0.22 (dq, J = 9.3, 4.8 Hz, 1H), 0.06–0.00 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 201.7, 153.8, 148.8, 139.0, 136.8, 131.8, 126.7, 122.1, 53.5, 48.6, 48.1, 48.0, 47.2, 15.9, 5.0, 4.4. HRMS (ESI): m/z [M+H]+ calculated for C16H18NO+ 240.1383, found 240.1389.
HPLC (Daicel Chiralpak AD-H, nhexane/iPrOH = 99.5:0.5, 0.5 mL/min, T = 18 °C): tR1 (major) = 15.321 min, tR2 (minor) = 16.065 min; dr: 87.5:12.5; er: 77:23.
[α]20D = +46.2 (c = 3.8, CHCl3).

3.4.19. ((1S,2S)-4,5-Dimethyl-1,2,3,6-tetrahydro-[1,1’-biphenyl]-2-yl)(pyridin-2-yl)methanone (3aB)

Colorless oil, 13 mg, yield 45%, Rf = 0.75 (PE/EA = 5:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.66 (dt, J = 4.9, 1.3 Hz, 1H), 7.78–7.73 (m, 1H), 7.68 (td, J = 7.6, 1.7 Hz, 1H), 7.38 (ddd, J = 7.4, 4.8, 1.4 Hz, 1H), 7.23–7.17 (m, 2H), 7.11 (dd, J = 8.4, 6.8 Hz, 2H), 7.06–6.99 (m, 1H), 4.74 (ddd, J = 11.6, 10.2, 5.7 Hz, 1H), 3.26 (ddd, J = 11.5, 9.9, 6.5 Hz, 1H), 2.36–2.20 (m, 4H), 1.67 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 204.7, 153.3, 148.7, 144.9, 136.7, 128.1, 127.5, 126.8, 125.9, 125.5, 124.2, 122.0, 45.3, 43.1, 41.2, 36.4, 18.7. HRMS (ESI): m/z [M+H]+ calculated for C20H22NO+ 292.1696, found 292.1697.
HPLC (Daicel Chiralpak OD-H, nhexane/iPrOH = 98:2, 1.0 mL/min, T = 14 °C): tR1 (major) = 7.349 min, tR2 (minor) = 6.717 min; dr: >20:1; er: 82:18.
[α]20D = −21.5 (c = 0.2, CHCl3).

3.5. Synthesis and Characterization of Product 5

Molecules 29 02978 i006
Procedure: To an oven-dried reaction tube equipped with a magnetic stirring bar was added 3aA (55 mg, 0.2 mmol), m-CPBA (53 mg, 0.24 mmol) and DCM (2 mL). The reaction was stirred at ambient temperature for 5 h. After completion of the reaction, as monitored using TLC, the mixture was washed with NaHCO3 solution and dried over MgSO4. After removal of the solvent in vacuo, the reaction mixture was purified via column chromatography on silica gel with PE and EA as eluent to afford product 5.

((1R,2R,4S,5S,6R,7S)-7-Phenyl-3-oxatricyclo[3.2.1.02,4]octan-6-yl)(pyridin-2-yl)methanone (5)

Colorless oil, 42 mg, yield 73%, Rf = 0.3 (PE/EA = 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.69 (dt, J = 4.8, 1.2 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.88 (td, J = 7.7, 1.7 Hz, 1H), 7.50 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 7.32–7.27 (m, 4H), 7.24–7.16 (m, 1H), 4.47 (dd, J = 5.6, 3.8 Hz, 1H), 3.70 (d, J = 5.1 Hz, 1H), 3.47 (dd, J = 3.7, 1.4 Hz, 1H), 3.28–3.24 (m, 1H), 3.02 (d, J = 3.3 Hz, 1H), 2.85 (d, J = 1.7 Hz, 1H), 1.66–1.57 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 200.6, 153.2, 149.0, 143.9, 137.0, 128.5, 128.2, 128.1, 126.1, 122.2, 57.4, 51.8, 50.0, 43.3, 43.2, 42.8, 26.7. HRMS (ESI): m/z [M+H]+ calculated for C19H18NO2+ 292.1332, found 292.1337.

3.6. Synthesis and Characterization of Product 6

Molecules 29 02978 i007
To an oven-dried reaction tube equipped with a magnetic stirring bar was added 3aA (55 mg, 0.2 mmol). The tube was sealed immediately with a rubber stopper and protected with a nitrogen balloon by evacuation-backfill operations repeated three times. Dry THF (1 mL) and (4-chlorophenyl) magnesium bromide (58 μL, 1.2 equiv) was injected to the tube via a syringe at −78 °C. The mixture was stirred at 25 °C overnight. Water (3.0 mL) was added dropwise, and the mixture was dried over sodium sulfate and filtered. After removal of the solvent in vacuo, the reaction mixture was purified using column chromatography on silica gel with PE and EA as eluent to afford product 6.

(4-Chlorophenyl)((1R,2S,3S,4S)-3-phenylbicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanol (6)

Colorless oil, 91 mg, yield 92%, Rf = 0.35 (PE/EA = 5:1, v/v). It is a mixture of three diastereoisomers; only the characteristic signals in 1H NMR are provided. 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, chloroform-d) δ 8.50 (d, J = 4.5 Hz, 1H), 8.34 (d, J = 4.6 Hz, 1H), 8.24 (d, J = 4.7 Hz, 1H). HRMS (ESI): m/z [M+H]+ calculated for C25H23ClNO+ 388.1463, found 388.1465.

3.7. Synthesis and Characterization of Product 7

Molecules 29 02978 i008
Procedure: To an oven-dried reaction tube equipped with a magnetic stirring bar was added 3aA (55 mg, 0.2 mmol) and NaBH4 (53 mg, 0.24 mmol) in CH3OH-DCM (v/v = 2:1) (3 mL) at 0 °C. The reaction was stirred at ambient temperature overnight. Water (3.0 mL) was added dropwise, and the mixture was dried over sodium sulfate and filtered. After removal of the solvent in vacuo, the reaction mixture was purified using column chromatography on silica gel with PE and EA as eluent to afford product 7.

(S)-((1R,2S,3S,4S)-3-Phenylbicyclo[2.2.1]hept-5-en-2-yl)(pyridin-2-yl)methanol (7)

Colorless oil, 51.5 mg, yield 93%, Rf = 0.5 (PE/EA = 2:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 4.6 Hz, 1H), 7.43 (td, J = 7.7, 1.8 Hz, 1H), 7.14–6.97 (m, 5H), 6.86 (dd, J = 6.8, 1.9 Hz, 2H), 6.44 (dd, J = 5.7, 3.1 Hz, 1H), 6.36 (dd, J = 5.6, 2.9 Hz, 1H), 4.26 (d, J = 9.3 Hz, 1H), 3.61 (s, 1H), 3.22 (s, 1H), 2.76 (s, 1H), 2.58 (ddd, J = 9.0, 5.4, 3.3 Hz, 1H), 2.35 (d, J = 5.0 Hz, 1H), 1.74 (d, J = 8.7 Hz, 1H), 1.52 (dd, J = 8.7, 1.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 161.8, 148.6, 144.1, 138.4, 136.3, 135.0, 127.9, 127.4, 125.5, 122.4, 121.4, 54.2, 50.6, 47.7, 46.4, 44.8. HRMS (ESI): m/z [M+H]+ calculated for C19H20NO+ 278.1539, found 278.1535.

4. Conclusions

We have identified a chiral PyBox–La(OTf)3 complex for catalyzing enantioselective Diels–Alder cycloadditions of 2-alk-2-enoylpyridines with cyclopentadiene. The asymmetric reactions proceeded efficiently, displaying good levels of diastereo- and enantiocontrol (up to 92:8 dr and 99:1 er). Enantiopure disubstituted norbornenes, which possess four contiguous stereocenters and are biologically relevant structures, are produced conveniently in this way. Further manipulations of these structures were also demonstrated, yielding the more densely functionalized norbornene derivatives. We hope our catalytic protocol could benefit the synthetic and medicinal chemists who are associated with enantioenriched norbornenes.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29132978/s1, Further results of reaction condition optimization, copies of 1H NMR, 13C NMR, 19F NMR and HPLC spectra of products and are included in the supporting information.

Author Contributions

Conceptualization, Z.Y.; Methodology, Z.Y.; Validation, H.W.; Formal analysis, H.W.; Investigation, H.W., Y.Z. and S.J.; Resources, Y.Y., J.X. and Z.Y.; Data curation, H.W.; Writing—original draft, Z.Y.; Writing—review & editing, H.W., N.C. and J.X.; Visualization, H.W.; Supervision, J.X. and Z.Y.; Project administration, Z.Y.; Funding acquisition, Y.Y., J.X. and Z.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the National Key Research and Development Program of China (no. 2022YFF0709803).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

Author Ying Yu was employed by the company China United Test & Certification Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Molecules 29 02978 g001
Figure 1. Representative bioactive compunds.
Figure 1. Representative bioactive compunds.
Molecules 29 02978 g001
Molecules 29 02978 sch001
Scheme 1. Previous work (a) and our work (b) on the asymmetric Diels–Alder cycloadditions of 2-alk-2-enoylpyridines with cyclopentadiene.
Scheme 1. Previous work (a) and our work (b) on the asymmetric Diels–Alder cycloadditions of 2-alk-2-enoylpyridines with cyclopentadiene.
Molecules 29 02978 sch001
Molecules 29 02978 g002
Figure 2. Scope of substrates.
Figure 2. Scope of substrates.
Molecules 29 02978 g002
Molecules 29 02978 sch002
Scheme 2. Proposed mechanism.
Scheme 2. Proposed mechanism.
Molecules 29 02978 sch002
Molecules 29 02978 sch003
Scheme 3. Gram-scale reaction and product derivatization.
Scheme 3. Gram-scale reaction and product derivatization.
Molecules 29 02978 sch003
Table 1. Selected optimization of the reaction conditions.
Table 1. Selected optimization of the reaction conditions.
Molecules 29 02978 i001
EntryCatalyst Ligand Yield a (%) Er bDr b
1La(OTf)3PyBim-15484:1651:49
2La(OTf)3PyBim-26785.5:14.579.5:20.5
3La(OTf)3PyBox-19194:688:12
4La(OTf)3PyBox-29568:3289:11
5La(OTf)3PhenOx-18758:4286.5:13.5
6LaCl3PyBox-14851.5:48.584:16
7La(BF4)3PyBox-17151:4989:11
a Isolated yields on column chromatography. b Enantioselective and diastereoselective ratios obtained by chiral HPLC. dr = endo:exo ratios.
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MDPI and ACS Style

Wei, H.; Zhang, Y.; Jin, S.; Yu, Y.; Chen, N.; Xu, J.; Yang, Z. PyBox–La(OTf)3-Catalyzed Enantioselective Diels–Alder Cycloadditions of 2-Alkenoylpyridines with Cyclopentadiene. Molecules 2024, 29, 2978. https://doi.org/10.3390/molecules29132978

AMA Style

Wei H, Zhang Y, Jin S, Yu Y, Chen N, Xu J, Yang Z. PyBox–La(OTf)3-Catalyzed Enantioselective Diels–Alder Cycloadditions of 2-Alkenoylpyridines with Cyclopentadiene. Molecules. 2024; 29(13):2978. https://doi.org/10.3390/molecules29132978

Chicago/Turabian Style

Wei, Hao, Yujie Zhang, Sanlin Jin, Ying Yu, Ning Chen, Jiaxi Xu, and Zhanhui Yang. 2024. "PyBox–La(OTf)3-Catalyzed Enantioselective Diels–Alder Cycloadditions of 2-Alkenoylpyridines with Cyclopentadiene" Molecules 29, no. 13: 2978. https://doi.org/10.3390/molecules29132978

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