Diastereoselective Synthesis of Morphan Derivatives by Michael and

Jan 2, 2018 - A general and concise method was developed for the synthesis of highly functionalized morphans 3–4 by the Michael and hetero-Michael ...
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Article Cite This: ACS Omega 2018, 3, 8−21

Diastereoselective Synthesis of Morphan Derivatives by Michael and Hetero-Michael Addition of 1,1-Enediamines to Quinone Monoketals Xing-Mei Hu, Da-Yun Luo, Quan-Xing Zi, Jun Lin,* and Sheng-Jiao Yan* Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, P. R. China S Supporting Information *

ABSTRACT: A general and concise method was developed for the synthesis of highly functionalized morphans 3−4 by the Michael and hetero-Michael addition reaction of different types of quinone monoketals 1 and 1,1-enediamines 2 in ethanol or 1,4-dioxane at reflux. This method is suitable for the efficient parallel syntheses of N-containing heterocycles. A library of highly functional morphan derivatives was easily constructed using the Michael/hetero-Michael reaction.

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have a wide range of biological activities, such as antitumor,36 herbicide, pesticide,37 antianxiety,38 antileishmanial,39 and antibacterial.40 However, acyclic EDAMs have not been considered for many years. Seldom literature reports have shown that EDAMs serve as bisnucleophiles (α-carbon and N as nucleophilic sites) and react with biselectrophiles to produce fused heterocyclic compounds.41 To date, to the best of our knowledge, incorporation of the two nucleophilic sites (α-C and N) through the Michael and hetero-Michael addition of EDAMs to form bridged-ring frame compounds has not been reported. Our group recently obtained the bridged-ring frame morphans with an immunosuppressive activity based on cyclic EDAM building blocks.42a To get molecularly diverse morphans and further investigate more active immunosuppressants,42b we designed and synthesized novel target compounds morphans by the Michael/hetero-Michael addition reaction of EDAMs through the two reaction sites (α-C and N).

INTRODUCTION Morphan (2-azabicyclo[3.3.1]nonane) derivatives are becoming more and more important in medicine1,2 and are a common structural motif in many biologically active natural products and pharmacologically active molecules, such as the immunosuppressant FR9014834,3 daphniphyllum alkaloids (cytotoxic agents),4 opioid agonists (e.g., compound A),5 opioid receptor antagonists (e.g., morphine,6 compound B,7 naloxone,8 naltrexone,9 TENA,10 GNTI,11 ANTI,12 BNTI,13 and C-CAM14), and madangamines15 (Figure 1).16 Morphan derivatives have been studied based on their broad spectrum of biological activities. Although many methods have been developed for the synthesis of morphan derivatives by organic or pharmaceutical chemists for many years,17−21 these approaches usually require metal catalysts under strict anhydrous conditions or multistep syntheses. Consequently, it is desirable and important to develop concise, highly regioselective, and environmentally friendly methods for building up a highly substituted morphan derivative library. Quinone monoketals can be easily obtained from phenols in a single step22 and are widely used for the synthesis of various structurally complex molecules.23,24 Though quinone monoketals contain two unsaturated CC bonds, they usually undergo 1,4-nucleophilic addition.25,26 Their reaction via double Michael addition is very seldom.27 Cyclic 1,1-enediamines (EDAMs) are a fascinating and versatile building block28 that is widely used to synthesize various fused heterocyclic compounds including quinolones,29 isoquinolin-1-imines,30 indoles,31 indolin-2-ones,32 isocoumarins,33 pyridines,34 and pyrroles.35 Many of these compounds © 2018 American Chemical Society

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RESULTS AND DISCUSSION Here, we report a novel synthesis method to produce morphan derivatives 3 and 4 by refluxing the mixture of quinone monoketals 1 and EDAMs 2 in ethanol or 1,4-dioxane, promoted by cesium carbonate (Scheme 1). The target compounds were obtained in good yields (58−90%). Received: October 9, 2017 Accepted: December 19, 2017 Published: January 2, 2018 8

DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21

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Figure 1. Biologically active morphans and targeted compounds.

Scheme 1. Strategy for the Michael/Hetero-Michael Addition Synthesis of Morphans 3 and 4

Table 1. Optimized Conditions for the Synthesis of 3aa

entry

solvent

base

T (°C)

time (h)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

1,4-dioxane EtOH acetonitrile 1,4-dioxane toluene acetone EtOH THF 1,4-dioxane EtOH acetonitrile THF 1,4-dioxane toluene acetonitrile 1,4-dioxane t-BuOH EtOH EtOH EtOH

− Et3N Et3N Et3N Et3N K2CO3 K2CO3 K2CO3 K2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 t-BuOK t-BuOK t-BuOK DIPEA DBU DABCO

reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux

12 12 12 12 12 12 12 12 12 6 6 6 6 6 6 6 6 12 12 12

n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r. 90 78 n.r. 89 n.r. complex complex complex n.r. n.r. n.r.

a

Reaction conditions: 1a (1.1 mmol), 2a (1.0 mmol), promoter (2.0 mmol), and solvent (15 mL). bIsolated yield based on EDAM 2a (n.r. = no reaction).

14). As a result, with ethanol as the solvent, the reaction can proceed smoothly to give the target product 3a in a 90% yield. A stronger alkali, t-BuOK, was used in aprotic solvents (acetonitrile and 1,4-dioxane) and protic solvents (t-BuOH). The results showed that the reaction becomes more complex and cannot achieve a positive result as the alkaline is too strong (Table 1, entries 15−17). Other organic alkalis including N,Ndiisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO) could not promote the reaction smoothly even under the optimal solvent ethanol (Table 1, entries 18−20). The results

First, we evaluated the Michael/hetero-Michael addition reaction of quinone monoketals 1 and EDAMs 2. The mixture (1a/2a = 1.1:1) was treated under various conditions (Table 1, entries 1−20). The results demonstrated that the reaction could not proceed at reflux in 1,4-dioxane under withoutadditive conditions (Table 1, entry 1). Et3N and K2CO3 were selected as promoters to test the reaction under different solvents (ethanol, acetonitrile, 1,4-dioxane, and toluene) and reflux conditions. The result is still negative (Table 1, entries 2−9). Then, Cs2CO3 (2.0 equiv) was charged into the different solvents and refluxed for 6 h (Table 1, entries 10− 9

DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21

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ACS Omega Table 2. Michael/Hetero-Michael Addition for the Synthesis of Morphan Derivatives 3a,b

a

Reagents and conditions: 1 (1.1 mmol), 2 (1.0 mmol), Cs2CO3 (2.0 mmol), and EtOH (15.0 mL). bIsolated yield based on 2.

EDAMs usually produce the target compounds in lower yields (Table 2, 3b vs 3d; 3k vs 3l; and 3n vs 3p). In addition, sterically hindered quinone monoketals can greatly decrease the yields (Table 2, 3s−3x). It must be noted that the Michael/hetero-Michael addition reaction has very high regioselectivity and diastereoselectivity. As a result, only the target product 3 was obtained in the form of compounds 3a−3c′ (no diastereoisomers of 3a−3c′ were detected) (Table 2). To further explore the sterically hindered EDAMs, N,N-bissubstituted EDAMs 2 have been used as substrates to react with quinone monoketals 1a in EtOH (Table 3, entries 1−2).

demonstrate that the optimal reaction conditions for the synthesis of morphan derivatives were ethanol or 1,4-dioxane as the solvent and Cs2CO3 as the promoter under reflux for 6 h in a 89−90% yield (Table 1, entries 10 vs 13). Encouraged by this result, we explored the scope and limitations of the double Michael reactions involving different quinone monoketals 1 with various EDAMs 2 (Table 2, 3a− 3c′) in ethanol. The results showed that the electronwithdrawing group (F and Cl)-substituted N-benzyl EDAM can achieve higher yield than the electron-donating group (Me and MeO) EDAM (Table 2, 3a vs 3c; 3f vs 3h). The Nphenyl-ethyl EDAM follows the same rule. Longer chain 10

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ACS Omega Table 3. Michael/Hetero-Michael Addition for the Synthesis of Morphan Derivatives 4a,b

entry

1

n

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1e 1f

1 1 1 1 1 1 2 2 2 2 2 2 2 2 3 1 1 1 2

R Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Et CH2CH2O Me Me

R1

R2

R3

R′

4

yieldb [%]

OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OEt

H H H H H H H H H H H H H H H H H Me H

H H H H H H H H H H H H H H H H H H Me

4-FC6H4 4-MeOC6H4 4-FC6H4 4-MeOC6H4 2,4-FC6H3 3,4-FC6H3 4-FC6H4 3-FC6H4 2-FC6H4 4-ClC6H4 3-ClC6H4 2-ClC6H4 C 6H 5 4-MeC6H4 C 6H 5 C 6H 5 H C 6H 5 C 6H 5

4a 4b 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q

80c 76c 88d 80d 89d 88d 88d 84d 86d 83d 83d 81d 78d 75d 71d 65d 78d n.r.d n.r.d

OMe OMe

a

Reaction conditions: 1 (1.1 mmol), 2 (1.0 mmol), and Cs2CO3 (2.0 mmol). bIsolated yield based on 2. cEtOH (15.0 mL). d1,4-Dioxane (15.0 mL).

To achieve the molecular diversity of the products, N,Oacetal (5a) and N,S-acetal (5b),43 which have different structures, were applied as substrates to react with quinone monoketals 1a−1b to synthesize the products 6a−6c in good to excellent yields (71−85%) (Table 4). To confirm the structure of the morphan derivatives, 3b, 3e, 3u, and 4a were selected as the representative compounds and were characterized by X-ray crystallography, as shown in Figure 2 (CCDC 1546771 and CCDC 1546772) and Figure 3 (CCDC 1578670 and CCDC 1546773) (see the Supporting Information). A proposed mechanism of the base-promoted Michael/ hetero-Michael addition reaction is shown in Scheme 2. Initially, the quinone monoketals 1 react with EDAMs 2 via Michael addition to form the intermediate 7. Then, intermediate compound 8 is obtained from intermediate 7 by imine−enamine tautomerization. Finally, intermediate 8 is followed by intramolecular hetero-Michael addition to produce compounds 3−4.

As a result, we can get only moderate yields (76−80%). As 1,4dioxane replaces EtOH as the solvent under the same conditions (Table 3, entries 3−4), we find that the reaction can get higher yields (80−88%). We believe that the sterically hindered EDAMs make the reaction difficult at lower temperature (at reflux in EtOH) compared with at higher temperature (at reflux in 1,4-dioxane). Consequently, different sterically hindered N,N-bis-substituted EDAMs 2 are used as substrates to react with various quinone monoketals in 1,4dioxane for the synthesis of 4a−4o (Table 3, entries 3−17). Generally, EDAMs with electron-withdrawing groups (F and Cl) often can obtain higher yields than electron-donating group EDAMs (Table 3, entries 3 vs 4; 10 vs 13−14). Longer chain EDAMs get the target compounds in lower yields (Table 3, entries 13 vs 15). The mixture of sterically hindered quinone monoketals (1e and 1f) and EDAMs 2 was refluxed in ethanol under the same conditions (Table 3, entries 18−19). The results demonstrated that the steric hindrance effects on quinone monoketals 1 cannot make the reaction proceed smoothly.

Table 4. Michael/Hetero-Michael Addition for the Synthesis of Morphan Derivatives 6a,b

a

Reagents and conditions: 1 (1.1 mmol), 5 (1.0 mmol), Cs2CO3 (2.0 mmol), and 1,4-dioxane (15.0 mL). bIsolated yield based on 5. 11

DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21

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Figure 2. ORTEP diagrams of 3b (left) and 3e (right); ellipsoids are drawn at the 30% probability level.

Figure 3. ORTEP diagrams of 3u (left) and 4a (right); ellipsoids are drawn at the 30% probability level.

Scheme 2. Mechanism Hypotheses for the Synthesis of Target Compounds 3−4

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CONCLUSIONS We developed a procedure for the simple synthesis of a variety of potentially biologically active morphan derivatives based on the Michael/hetero-Michael addition reaction. Accordingly, a molecularly diverse morphan library was rapidly constructed in one-pot in good yields by simply refluxing a reaction mixture of quinone monoketals and EDAMs in an environmentally friendly solvent (ethanol) or 1,4-dioxane, promoted by Cs2CO3.

determined on an XT-4A melting point apparatus and are uncorrected. High-resolution mass spectrometry (HRMS) was performed on an Agilent LC/Msd TOF instrument. X-ray diffraction was obtained by APEX DUO. All chemicals and solvents were used as received without further purification unless otherwise stated. All chemicals were purchased from Adamas-beta. Column chromatography was performed on silica gel (Qingdao, 200−300 mesh). Compounds 1 were prepared according to the literature.44,45 Compounds 2 were prepared according to the literature.46 General Procedure for the Synthesis of Compounds 3. Quinone monoketals 1 (1.1 mmol), EDAMs 2 (1.0 mmol), Cs2CO3 (2.0 mmol), and ethanol (15 mL) were charged into a 25 mL round-bottom flask. The mixture was kept at reflux for about 6 h and monitored by TLC until the quinone monoketal 1 substrate was completely consumed. After the reaction was completed, the reaction system was cooled to room temperature. The reaction mixture was poured into 25 mL of water and 50 mL of ethyl acetate for extraction and separation. Then,

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EXPERIMENTAL SECTION General Methods. All compounds were fully characterized by spectroscopic data. NMR spectra were recorded on a Bruker DRX300, DRX400, or DRX500, chemical shifts (δ) are expressed in ppm, J values are given in Hz, and deuterated DMSO-d6 or CDCl3 was used as the solvent. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using a KBr pellet. The reactions were monitored by thin-layer chromatography (TLC) using silica gel GF254. The melting points were 12

DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21

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COCH2), 2.83−2.89 (m, 3H, COCH2 CHN, CH2Ar), 3.17 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.44−3.49 (m, 2H, CH2N), 3.69−3.73 (m, 1H, CH), 3.94−3.98 (m, 1H, CHN), 7.22− 7.24 (m, 1H, ArH), 7.29−7.36 (m, 2H, ArH), 7.37−7.41 (m, 1H, ArH), 8.06 (br, 1H, NH), 10.70 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 33.9, 37.3, 41.4, 42.3, 46.2, 48.7, 48.9, 50.6, 96.4, 107.1, 127.0, 128.1, 129.2, 130.7, 133.5, 141.3, 153.5, 208.4; HRMS (EI+): m/z calcd for C18H23ClN3O5 [M + H]+, 396.1321; found, 396.1323. (1R,5R)-9,9-Diethoxy-3-((4-fluorobenzyl)amino)-4-nitro-2azabicyclo[3.3.1]non-3-en-7-one (3f). Yellow liquid; mp 130.0 °C; IR (KBr): 3416, 3258, 1719, 1619, 1563, 1344, 1057, 755 cm−1; 1H NMR (500 MHz, CDCl3): δ = 1.02−1.04 (m, 3H, CH3CH2O), 1.18−1.20 (m, 3H, CH3CH2O), 2.40− 2.44 (m, 1H, COCH2), 2.56−2.57 (m, 2H, COCH2, COCH2CHN), 2.71−2.75 (m, 1H, COCH2CHN), 3.33− 3.43 (m, 2H, CH2O), 3.52−3.59 (m, 2H, CH2O), 3.72−3.76 (m, 1H, CH), 4.04−4.08 (m, 1H, CHN), 4.33−4.44 (m, 2H, CH2N), 6.89−6.92 (m, 2H, ArH), 7.06−7.09 (m, 2H, ArH), 8.32 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 10.3, 10.4, 33.5, 36.3, 39.8, 41.0, 46.8, 51.9, 51.9, 91.2, 104.3, 111.0 (d, J = 21.3 Hz), 124.1 (d, J = 21.3 Hz), 126.5, 149.0, 158.6 (d, J = 245.0 Hz), 203.8; HRMS (EI+): m/z calcd for C19H25FN3O5 [M + H]+, 394.1773; found, 394.1773. (1R,5R)-3-(Benzylamino)-9,9-diethoxy-4-nitro-2azabicyclo[3.3.1]non-3-en-7-one (3g). White solid; mp 172.0 °C; IR (KBr): 3417, 3250, 1720, 1616, 1567, 1348, 1092, 757 cm−1; 1H NMR (500 MHz, CDCl3): δ = 1.06−1.09 (m, 3H, CH3CH2O), 1.20−1.23 (m, 3H, CH3CH2O), 2.20−2.23 (m, 1H, COCH2), 2.36−2.39 (m, H, COCH2CHN), 2.68−2.72 (m, 1H, COCH2), 2.82−2.86 (m, 1H, COCH2CHN), 3.33− 3.37 (m, 2H, CH3CH2), 3.61−3.71 (m, 2H, CH3CH2), 3.71− 3.73 (m, 1H, CH), 3.91 (s, 1H, CHN), 4.52−4.55 (m, 2H, CH2N), 7.23−7.25 (m, 2H, ArH), 7.28−7.31 (m, 1H, ArH), 7.35−7.38 (m, 2H, ArH), 8.06 (br, 1H, NH), 11.035 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 15.5, 15.5, 38.2, 41.5, 44.3, 46.3, 51.4, 56.5, 56.7, 96.2, 107.5, 127.2, 127.9, 129.0, 137.2, 153.8, 208.4; HRMS (EI+): m/z calcd for C19H26N3O5 [M + H]+, 376.1867; found, 376.1872. (1R,5R)-9,9-Diethoxy-3-((4-methoxybenzyl)amino)-4nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3h). Yellow solid; mp 116.3 °C; IR (KBr): 3416, 3251, 1719, 1614, 1561, 1345, 1056, 755 cm−1; 1H NMR (500 MHz, CDCl3): δ = 1.05−1.08 (m, 3H, CH3CH2O), 1.20−1.23 (m, 3H, CH3CH2O), 2.22− 2.35 (m, 1H, COCH2), 2.36−2.39 (m, 1H, COCH2CHN), 2.68−2.72 (m, 1H, COCH 2 ), 2.83−2.87 (m, 1H, COCH2CHN), 3.33−3.38 (m, 1H, CH3CH2O), 3.45−3.48 (m, 1H, CH3CH2O), 3.63−3.70 (m, 2H, CH3CH2O), 3.70− 3.71 (m, H, CH), 3.74 (s, 3H, CH3O), 3.90−3.94 (m, 1H, CHN), 4.42−4.45 (m, 2H, CH2N), 6.91−6.94 (m, 2H, ArH), 7.19−7.21 (m, 2H, ArH), 8.06 (br, 1H, NH), 10.96 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 15.5, 15.5, 38.2, 41.5, 44.0, 46.3, 51.4, 55.6, 55.6, 56.5, 56.7, 96.2, 107.5, 114.5, 128.8, 153.6, 159.2, 208.4; HRMS (EI + ): m/z calcd for C20H27N3NaO6 [M + Na]+, 428.1792; found, 428.1796. (1R,5R)-9,9-Diethoxy-3-((4-fluorophenethyl)amino)-4nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3i). White solid; mp 181.3 °C; IR (KBr): 3421, 3188, 1719, 1619, 1511, 1382, 1079, 756 cm−1; 1H NMR (500 MHz, CDCl3): δ = 1.08−1.11 (m, 3H, CH 3 CH 2 O), 1.21−1.24 (m, 3H, CH3CH2O), 2.26−2.36 (m, 2H, COCH2, COCH2CHN), 2.67−2.71 (m, 1H, COCH2), 2.83−2.85 (m, 2H, CH2Ar), 2.87−2.88 (m, 1H, COCH2CHN), 3.43−3.50 (m, 4H, CH2N,

the crude product was concentrated by distillation under reduced pressure, purified by column chromatography (petroleum ether/ethyl acetate = 1:2), and produced a series of compounds 3 in a 58−90% yield. (1R,5R)-3-((4-Fluorobenzyl)amino)-9,9-dimethoxy-4nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3a). Yellow solid; mp 130.3 °C; IR (KBr): 3424, 1720, 1619, 1563, 1381, 1223, 1057, 755 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.19− 2.22 (m, 1H, COCH2), 2.35−2.38 (m, 1H, COCH2CHN), 2.67−2.71 (m, 1H, COCH 2 ), 2.81−2.85 (m, 1H, COCH2CHN), 3.12 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.70−3.74 (m, 1H, CH), 3.90−3.94 (m, 1H, CHN), 4.48− 4.51 (m, 2H, CH2N), 7.20−7.32 (m, 4H, ArH), 8.08 (br, 1H, NH), 10.97 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 37.4, 41.4, 43.8, 46.2, 48.6, 48.9, 50.6, 96.4, 107.3, 115.9 (d, J = 21.3 Hz), 129.5 (d, J = 7.5 Hz), 133.3, 153.7, 162.0 (d, J = 241.3 Hz), 208.3; 19F NMR (467 MHz, DMSO-d6): δ = −115.2; HRMS (EI+): m/z calcd for C17H21FN3O5 [M + H]+, 366.1460; found, 366.1460. (1R,5R)-3-(Benzylamino)-9,9-dimethoxy-4-nitro-2azabicyclo[3.3.1]non-3-en-7-one (3b). Yellow solid; mp 256.5−257.5 °C; IR (KBr): 3423, 3254, 1720, 1621, 1562, 1386, 1267, 1053, 741 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.22−2.25 (m, 1H, COCH2), 2.39−2.41 (m, 1H, COCH2CHN), 2.50−2.51 (m, 1H, COCH2), 2.69−2.70 (m, 1H, COCH2CHN), 3.14 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 3.74−3.76 (m, 1H, CH), 3.92−3.96 (m, 1H, CHN), 4.52− 4.57 (m, 2H, CH2N), 7.26−7.41 (m, 5H, ArH), 8.13 (br, 1H, NH2), 11.01 (br, 1H, NH2); 13C NMR (125 MHz, DMSOd6): δ = 37.4, 41.4, 44.5, 46.2, 48.7, 48.9, 50.7, 96.5, 107.3, 127.4, 127.9, 129.1, 137.0, 153.7, 208.3; HRMS (EI+): m/z calcd for C17H22N3O5 [M + H]+, 348.1554; found, 348.1556. (1R,5R)-9,9-Dimethoxy-4-nitro-3-(phenethylamino)-2azabicyclo[3.3.1]non-3-en-7-one (3c). Yellow solid; mp 182.6 °C; IR (KBr): 3440, 1720, 1621, 1561, 1384, 1252, 1027, 754 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.24−2.27 (m, 1H, COCH2), 2.36−2.39 (m, 1H, COCH2CHN), 2.68−2.72 (m, 1H, COCH2), 2.83−2.87 (m, 1H, COCH2CHN), 3.15 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.73−3.74 (m, 1H, CH), 3.98−4.02 (m, 1H, CHN), 6.94−6.96 (m, 2H, ArH), 7.22− 7.24 (m, 2H, ArH), 8.09 (br, 1H, NH), 10.92 (br, 1H, NH); 13 C NMR (125 MHz, DMSO-d6): δ = 37.4, 41.4, 44.2, 46.2, 48.7, 48.9, 50.7, 55.6, 96.5, 107.3, 114.6, 128.8, 129.0, 153.5, 159.2, 208.3; HRMS (EI+): m/z calcd for C18H24N3O6 [M + H]+, 378.1660; found, 378.1659. (1R,5R)-9,9-Dimethoxy-4-nitro-3-(phenethylamino)-2azabicyclo[3.3.1]non-3-en-7-one (3d). White solid; mp 186.4 °C; IR (KBr): 3430, 1721, 1621, 1564, 1345, 1287, 1034, 754 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.27−2.36 (m, 2H, COCH2, COCH2CHN), 2.66−2.67 (m, 1H, COCH2), 2.82−2.87 (m, 3H, COCH2CHN, CH2Ar), 3.16 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.44−3.46 (m, 2H, CH2N), 3.70−3.71 (m, 1H, CH), 3.92−3.96 (m, 1H, CHN), 7.23− 7.33 (m, 5H, ArH), 8.03 (br, 1H, NH), 10.69 (br, 1H, NH); 13 C NMR (125 MHz, DMSO-d6): δ = 34.8, 37.7, 41.9, 43.2, 46.7, 49.1, 49.3, 51.1, 96.9, 107.5, 127.4, 129.3, 129.7, 139.2, 153.9, 208.7; HRMS (EI+): m/z calcd for C18H24N3O5 [M + H]+, 326.1710; found, 326.1713. (1R,5R)-3-((3-Chlorophenethyl)amino)-9,9-dimethoxy-4nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3e). White solid; mp 202.8−203.3 °C; IR (KBr): 3423, 1721, 1621, 1570, 1344, 1288, 754 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.28− 2.37 (m, 2H, COCH2, COCH2CHN), 2.67−2.71 (m, 1H, 13

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CH2O), 4.49−4.50 (m, 2H, CH2N), 7.21−7.24 (m, 2H, ArH), 7.32−7.35 (m, 2H, ArH), 8.19 (br, H, NH), 10.95 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 40.5, 42.6, 44.0, 47.3, 53.8, 65.4, 65.8, 103.6, 107.3, 115.9 (d, J = 21.3 Hz), 129.8 (d, J = 8.9 Hz), 133.3 (d, J = 2.5 Hz), 153.1, 162.0 (d, J = 242.5 Hz), 208.0; 19F NMR (467 MHz, DMSO-d6): δ = −115.0; HRMS (EI+): m/z calcd for C17H19FN3O5 [M + H]+, 364.1303; found, 364.1305. (1R,5R)-3-(Benzylamino)-4-nitro-2-azaspiro[bicyclo[3.3.1]nonane-9,2′-[1,3]dioxolan]-3-en-7-one (3n). Yellow solid; mp 237.3−237.8 °C; IR (KBr): 3419, 3250, 1720, 1619, 1558, 1381, 1254, 1053, 754 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.17−2.21 (m, 1H, COCH2), 2.36−2.43 (m, 1H, COCH 2 CHN), 2.81−2.90 (m, 2H, COCH 2 , COCH2CHN), 3.39−3.43 (m, 1H, CH), 3.60−3.64 (m, 1H, CHN), 3.93−4.01 (m, 2H, CH2O), 4.07−4.09 (m, 2H, CH2O), 4.43−4.44 (m, 2H, CH2N), 7.20−7.33 (m, 5H, ArH), 8.12 (br, 1H, NH), 10.90 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 40.4, 42.7, 44.7, 47.3, 53.8, 65.4, 65.8, 103.7, 107.3, 127.6, 128.1, 129.2, 137.0, 153.3, 207.9; HRMS (EI+): m/z calcd for C17H19N3O5 [M + H]+, 346.1397; found, 346.1398. (1R,5R)-3-((3-Chlorophenethyl)amino)-4-nitro-2-azaspiro[bicyclo[3.3.1]nonane-9,2′-[1,3]dioxolan]-3-en-7-one (3o). Yellow solid; mp 188.8 °C; IR (KBr): 3442, 3253, 1723, 1623, 1564, 1393, 1258, 1065, 754 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 3.31−3.43 (m, 2H, COCH2, COCH2CHN), 2.83−2.91 (m, 3H, COCH2, CH2Ar), 2.91−2.98 (m, 1H, COCH2CHN), 3.41−3.50 (m, 3H, CH2N, CH2O), 3.68−3.72 (m, 1H, CH), 4.00−4.07 (m, 2H, CH2O), 4.12−4.19 (m, 2H, CH2O, CHN), 7.23−7.40 (m, 4H, ArH), 8.09−8.10 (m, 1H, NH), 10.67−10.70 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 33.9, 40.2, 42.4, 42.7, 47.3, 53.7, 65.3, 65.8, 103.7, 107.1, 127.0, 128.1, 129.2, 130.7, 133.5, 141.3, 153.1, 208.0; HRMS (EI+): m/z calcd for C18H21ClN3O5 [M + H]+, 394.1164; found, 394.1164. (1R,5R)-4-Nitro-3-(phenethylamino)-2-azaspiro[bicyclo[3.3.1]nonane-9,2′-[1,3]dioxolan]-3-en-7-one (3p). Yellow solid; mp 221.8−222.3 °C; IR (KBr): 3430, 3026, 1718, 1622, 1563, 1342, 1281, 1068, 754 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.31−2.34 (m, 1H, COCH2), 2.40−2.43 (m, 1H, COCH2CHN), 2.85−2.91 (m, 3H, COCH2, CH2Ar), 2.94−2.98 (m, 1H, COCH2CHN), 3.40−4.49 (m, 3H, CH2N, CH), 3.67−3.71 (m, 1H, CHN), 4.00−4.07 (m, 2H, CH2O), 4.12−4.17 (m, 2H, CH2O), 7.23−7.34 (m, 5H, ArH), 8.09 (br, 1H, NH), 10.68 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 34.4, 42.7, 42.8, 47.3, 53.7, 65.3, 65.7, 103.7, 107.1, 127.0, 128.9, 129.3, 138.7, 153.1, 208.0; HRMS (EI+): m/z calcd for C18H22N3O5 [M + H]+, 360.1554; found, 360.1554. (1R,5R,9R)-3-((4-Fluorobenzyl)amino)-9-methoxy-9-methyl-4-nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3q). Yellow solid; mp 137.1 °C; IR (KBr): 3444, 1717, 1620, 1570, 1512, 1383, 1225, 1061, 754 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 1.60 (s, 3H, CH3), 2.20−2.24 (m, 1H, COCH2), 2.36−2.40 (m, 1H, COCH2CHN), 2.75−2.80 (m, 1H, COCH2), 2.86−2.91 (m, 1H, COCH2CHN), 3.06−3.10 (m, 3H, OCH3), 3.49−3.53 (m, 1H, CH), 3.78−3.82 (m, 1H, CHN), 4.47−4.50 (m, 2H, CH2N), 7.19−7.23 (m, 2H, ArH), 7.29−7.32 (m, 2H, ArH), 7.98 (br, 1H, NH), 11.07 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 18.0, 40.2, 42.1, 43.6, 46.7, 49.3, 53.7, 71.5, 108.0, 115.8 (d, J = 21.4 Hz), 129.5 (d, J = 8.1 Hz), 133.5 (d, J = 2.8 Hz), 153.9, 161.9 (d, J =

CH2O), 3.61−3.65 (m, 4H, CH2O), 3.66−3.70 (m, 1H, CH), 3.92−3.96 (m, 1H, CHN), 7.12−7.15 (m, 2H, ArH), 7.28− 7.31 (m, 2H, ArH), 8.05 (br, 1H, NH), 10.70 (br, 1H, NH); 13 C NMR (125 MHz, CDCl3): δ = 15.5, 15.6, 33.5, 38.1, 41.5, 42.6, 46.4, 51.4, 56.5, 56.7, 96.2, 107.4, 115.6 (d, J = 21.3 Hz), 131.1 (d, J = 7.5 Hz), 134.9 (d, J = 2.5 Hz), 153.5, 161.5 (d, J = 240.0 Hz), 208.4; 13F NMR (467 MHz, CDCl3): δ = −116.0; HRMS (EI+): m/z calcd for C20H27FN3O5 [M + H]+, 408.1929; found, 408.1934. (1R,5R)-3-((3-Chlorophenethyl)amino)-9,9-diethoxy-4nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3j). Yellow solid; mp 144.4 °C; IR (KBr): 3420, 3155, 1717, 1625, 1572, 1345, 1067, 756 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 1.07− 1.10 (m, 3H, CH3CH2O), 1.19−1.22 (m, 3H, CH3CH2O), 2.35−2.38 (m, 1H, COCH2), 2.53−2.62 (m, 2H, COCH2, COCH2CHN), 2.75−2.83 (m, 3H, COCH2CHN, CH2Ar), 3.39−3.49 (m, 4H, CH2N, CH2O), 3.56−3.60 (m, 2H, CH2O), 3.79−3.83 (m, 1H, CH), 3.91−3.95 (m, 1H, CHN), 7.03−7.05 (m, 1H, ArH), 7.09−7.20 (m, 3H, ArH), 7.96 (br, 1H, NH), 10.89 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 15.2, 15.2, 34.3, 37.9, 41.1, 42.4, 46.0, 51.6, 56.5, 56.6, 96.0, 108.1, 127.0, 127.2, 128.7, 130.1, 134.2, 140.0, 153.6, 208.3; HRMS (EI+): m/z calcd for C20H27ClN3O5 [M + H]+, 424.1634; found, 424.1637. (1R,5R)-9,9-Diethoxy-4-nitro-3-(phenethylamino)-2azabicyclo[3.3.1]non-3-en-7-one (3k). Yellow solid; mp 216.5−217.0 °C; IR (KBr): 3441, 3146, 1717, 1627, 1569, 1345, 1066, 755 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 1.09−1.12 (m, 3H, CH 3 CH 2 O), 1.21−1.24 (m, 3H, CH3CH2O), 2.27−2.37 (m, 2H, COCH2, COCH2 CHN), 2.68−2.71 (m, 1H, COCH 2 ), 2.84−2.89 (m, 3H, COCH2CHN, CH2Ar), 3.45−3.51 (m, 4H, CH2O, CH2O), 3.61−3.65 (m, 2H, CH2N), 3.67−3.71 (m, 1H, CH), 3.93− 3.97 (m, 1H, CHN), 7.22−7.33 (m, 5H, ArH), 8.07 (br, 1H, NH), 10.71 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 15.5, 15.6, 34.4, 38.1, 41.5, 42.6, 46.4, 51.4, 56.5, 56.7, 96.2, 107.4, 126.9, 128.9, 129.2, 138.8, 153.5, 208.4; HRMS (EI+): m/z calcd for C20H28N3O5 [M + H]+, 390.2023; found, 390.2025. (1R,5R)-9,9-Diethoxy-4-nitro-3-((3-phenylpropyl)amino)2-azabicyclo[3.3.1]non-3-en-7-one (3l). Yellow solid; mp 79.7 °C; IR (KBr): 3420, 1719, 1622, 1564, 1344, 1075, 753 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 1.07−1.09 (m, 3H, CH3CH2O), 1.19−1.24 (m, 3H, CH3CH2O), 1.82−1.87 (m, 2H, CH2CH2N), 2.25−2.28 (m, 1H, COCH2), 2.49−2.50 (m, 2H, CH2Ar), 2.59−2.62 (m, 1H, COCH2), 2.68−2.72 (m, 1H, COCH2), 2.85−2.89 (m, 1H, COCH2CHN), 3.20−3.23 (m, 2H, CH2N), 3.45−3.50 (m, 2H, CH2O), 3.51−3.70 (m, 2H, CH2O), 3.69−3.73 (m, 1H, CH), 3.92−3.96 (m, 1H, CHN), 7.17−7.21 (m, 3H, ArH), 7.26−7.31 (m, 3H, ArH), 8.00 (br, 1H, NH), 10.81 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 15.3, 15.5, 30.2, 32.5, 38.2, 41.5, 46.4, 51.4, 56.5, 56.7, 96.2, 107.5, 126.4, 128.7, 128.9, 128.9, 141.4, 153.7, 208.4; HRMS (EI+): m/z calcd for C21H30N3O5 [M + H]+, 404.2180; found, 404.2185. (1R,5R)-3-((4-Fluorobenzyl)amino)-4-nitro-2-azaspiro[bicyclo[3.3.1]nonane-9,2′-[1,3]dioxolan]-3-en-7-one (3m). White solid; mp 258.5−259.5 °C; IR (KBr): 3429, 1726, 1629, 1567, 1339, 1056, 755 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.24−2.27 (m, 1H, COCH2), 2.42−2.4 (m, 1H, COCH 2 CHN), 2.88−2.98 (m, 2H, COCH 2 , COCH2CHN), 3.45−3.49 (m, 1H, CH), 3.67−3.71 (m, 1H, CHN), 4.00−4.08 (m, 2H, CH2O), 4.15−7.4.17 (m, 2H, 14

DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21

Article

ACS Omega 241.8 Hz), 208.6; HRMS (EI+): m/z calcd for C17H21FN3O4 [M + H]+, 350.1511; found, 350.1513. (1R,5R,9R)-3-(Benzylamino)-9-methoxy-9-methyl-4-nitro2-azabicyclo[3.3.1]non-3-en-7-one (3r). Yellow solid; mp 126.9 °C; IR (KBr): 3260, 1718, 1620, 1564, 1433, 1346, 1200, 1059, 741 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 1.59−1.63 (s, 3H, CH3), 2.21−2.42 (m, 2H, COCH2, COCH2CHN), 2.80−2.91 (m, 2H, COCH2, COCH2CHN), 3.06−3.10 (m, 3H, OCH3), 3.51−3.53 (m, 1H, CH), 3.79− 3.83 (m, 1H, CHN), 4.50−4.52 (m, 2H, CH2N), 7.25−7.40 (m, 5H, ArH), 8.01 (br, 1H, NH), 11.11 (br, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ = 19.0, 40.2, 42.2, 44.4, 46.7, 49.3, 53.7, 71.5, 108.0, 127.8 (d, J = 10.2 Hz), 129.1, 137.2, 154.0, 208.6; HRMS (EI+): m/z calcd for C17H22N3O4 [M + H]+, 332.1605; found, 332.1606. (1R,5R,8S)-9,9-Dimethoxy-3-((4-methoxybenzyl)amino)8-methyl-4-nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3s). White solid; mp 254.8−255.8 °C; IR (KBr): 3421, 3243, 1720, 1614, 1554, 1398, 1275, 1036, 756 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 0.74−0.76 (m, 3H, CH3), 2.35−2.38 (m, 1H, COCH2), 2.68−2.71 (m, 1H, COCH2), 2.83−2.85 (m, 1H, COCH), 3.17 (s, 3H, OCH3), 3.36 (m, 3H, OCH3), 3.73−3.74 (m, 1H, CH), 3.75−3.79 (m, 1H, CHN), 4.54− 4.55 (m, 2H, CH2N), 7.21−7.23 (m, 2H, ArH), 7.29−7.32 (m, 1H, ArH), 7.36−7.39 (m, 1H, ArH), 7.92 (br, 1H, NH), 11.05 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 10.9, 38.4, 41.2, 44.4, 46.1, 48.7, 49.0, 55.4, 56.2, 96.9, 107.3, 127.3 (d, J = 16.3 Hz), 127.9, 129.1, 137.1, 153.9, 209.6; HRMS (EI+): m/z calcd for C19H26N3O6 [M + H]+, 392.1816; found, 392.1817. (1R,5R,8S)-9,9-Dimethoxy-3-((4-methoxyphenethyl)amino)-8-methyl-4-nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3t). Yellow solid; mp 171.3 °C; IR (KBr): 3445, 1717, 1623, 1563, 1514, 1349, 1247, 1081, 758 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 0.96−0.97 (s, 3H, CH3), 2.33−2.37 (m, 1H, COCH2), 2.69−2.70 (m, 2H, COCH2), 2.78−2.81 (m, 2H, CH2Ar), 2.85−2.88 (m, 1H, COCH), 3.17 (s, 3H, CH3O), 3.36 (s, 3H, CH3O), 3.71−3.74 (m, 2H, CH), 3.80−3.84 (m, 2H, CHN), 6.87−6.89 (m, 2H, ArH), 7.17−7.18 (m, 2H, ArH), 7.93 (br, 1H, NH), 10.70 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 11.2, 33.5, 38.3, 41.2, 43.0, 46.1, 48.7, 49.0, 55.5, 56.3, 96.8, 107.2, 114.3, 130.2, 130.6, 153.7, 158.5, 209.8; HRMS (EI+): m/z calcd for C20H28N3O6 [M + H]+, 406.1973; found, 406.1969. (1R,5R,8S)-9,9-Dimethoxy-8-methyl-4-nitro-3-(phenethylamino)-2-azabicyclo[3.3.1]non-3-en-7-one (3u). White solid; mp 241.5−242.0 °C; IR (KBr): 3425, 3260, 1718, 1623, 1563, 1348, 1274, 1079, 756 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 0.96−0.97 (s, 3H, CH3), 2.32−2.33 (m, 1H, COCH2), 2.68−2.72 (m, 1H, COCH2), 2.84−2.86 (m, 2H, ArCH2), 2.89−2.91 (m, 1H, COCH), 3.17 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 3.45−3.48 (m, 2H, CH2N), 3.71 (s, 1H, CH), 3.80 (s, 1H, CHN), 7.22−7.33 (m, 5H, ArH), 7.93 (br, 1H, NH), 10.71 (br, 1H, NH); 13C NMR (125 MHz, DMSOd6): δ = 11.2, 34.4, 38.2, 41.2, 42.8, 46.1, 48.7, 49.0, 56.3, 96.8, 107.2, 127.0, 128.9, 129.2, 138.8, 153.7, 209.8; HRMS (EI+): m/z calcd for C19H26N3O5 [M + H]+, 376.1867; found, 376.1869. (1R,5R)-3-((4-Fluorophenethyl)amino)-9,9-dimethoxy-1methyl-4-nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3v). Yellow solid; mp 241.5−242.0 °C; IR (KBr): 3424, 3267, 1721, 1623, 1552, 1509, 1395, 1270, 1067, 756 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 1.35−1.39 (m, 3H, CH3), 2.21−2.28

(m, 2H, COCH2), 2.72−2.76 (m, 1H, COCH2CHN), 2.85− 2.88 (m, 3H, COCH2CHN, CH2Ar), 3.27 (s, 3H, OCH3), 3.45 (s, 3H, OCH3), 3.45−3.51 (m, 2H, CH2N), 3.84−3.88 (m, 1H, CH), 3.89−3.90 (m, 1H, CHN), 7.11−7.15 (m, 2H, ArH), 7.30 (br, 2H, ArH), 7.57 (br, 1H, NH), 10.71 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 21.6, 33.5, 37.3, 42.0, 42.8, 50.9, 51.2, 53.5, 61.8, 97.0, 107.0, 115.6 (d, J = 20.0 Hz), 131.1 (d, J = 8.8 Hz), 134.9 (d, J = 2.5 Hz), 153.0, 161.5 (d, J = 240.0 Hz), 208.0; HRMS (EI+): m/z calcd for C19H25FN3O5 [M + H]+, 394.1773; found, 394.1772. (1R,5R)-9,9-Dimethoxy-1-methyl-3-((4-methylphenethyl)amino)-4-nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3w). Yellow solid; mp 233.5−234.0 °C; IR (KBr): 3440, 3276, 1718, 1625, 1560, 1513, 1359, 1060, 756 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 1.24−1.28 (m, 3H, CH3), 2.21−2.24 (m, 4H, CH3, COCH2), 2.50−2.53 (m, 1H, COCH2CHN), 2.63−2.67 (m, 2H, COCH2, COCH2CHN), 2.74−2.77 (m, 2H, CH2Ar), 3.24 (s, 3H, OCH3), 3.38−3.42 (m, 2H, CH2N), 3.39−3.43 (m, 1H, CH), 3.40 (s, 3H, OCH3), 3.98−3.99 (m, 1H, CHN), 5.99 (br, 1H, NH), 6.98−7.03 (m, 4H, ArH), 10.83 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 21.1, 21.8, 34.5, 37.1, 41.7, 43.1, 50.8, 51.2, 53.1, 61.6, 96.9, 107.6, 128.6, 129.7, 134.9, 136.4, 153.1, 207.9; HRMS (EI+): m/z calcd for C20H28N3O5 [M + H]+, 390.2023; found, 390.2024. (1R,5R)-9,9-Dimethoxy-3-((4-methoxyphenethyl)amino)1-methyl-4-nitro-2-azabicyclo-[3.3.1]non-3-en-7-one (3x). Yellow solid; mp 216.2−216.7 °C; IR (KBr): 3424, 3278, 1718, 1625, 1556, 1514, 1360, 1245, 1074, 757 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 1.36−1.40 (m, 3H, CH3), 2.21−2.28 (m, 2H, COCH 2 ), 2.72−2.73 (m, 1H, COCH2CHN), 2.76−2.81 (m, 2H, CH2Ar), 2.85−2.88 (m, 1H, COCH2CHN), 3.25−3.29 (m, 3H, CH3O), 3.45−3.46 (m, 3H, CH3O), 3.41−3.45 (m, 1H, CH), 3.71−3.75 (m, 3H, CH3O), 3.88−3.90 (m, 1H, CHN), 6.86−6.88 (m, 2H, ArH), 7.04 (br, 1H, NH), 7.17−7.19 (m, 2H, ArH), 10.70 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 21.6, 33.5, 37.3, 42.0, 43.1, 50.9, 51.2, 53.5, 55.5, 61.8, 97.0, 107.0, 114.3, 130.3, 130.6, 153.0, 158.5, 208.1; HRMS (EI+): m/z calcd for C20H28N3O6 [M + H]+, 406.1973; found, 406.1978. (1R,5R)-3-((4-Chlorophenyl)amino)-9,9-dimethoxy-4nitro-2-azabicyclo[3.3.1]non-3-en-7-one (3y). Yellow solid; mp > 300 °C; IR (KBr): 3415, 1706, 1618, 1561, 1372, 1296, 1079, 760 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.22− 2.25 (m, 1H, COCH2), 2.32−2.35 (m, 1H, COCH2), 2.65− 2.68 (m, 1H, COCH2CH), 2.74−2.77 (m, 1H, COCH2CH), 3.12 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 3.70−43.71 (m, 1H, CH), 3.81−3.85 (m, 1H, CHN), 7.22−7.24 (m, 2H, ArH), 7.46−7.48 (m, 2H, ArH), 7.89 (br, 1H, NH), 12.02 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 37.4, 41.5, 45.9, 48.8, 49.0, 50.9, 96.4, 108.0, 127.8, 130.3, 131.8, 134.4, 152.6, 208.3; HRMS (EI+): m/z calcd for C16H18ClN3NaO5 [M + Na]+, 390.0827; found, 390.0833. (1R,5R)-Ethyl 9,9-Dimethoxy-3-(methylamino)-7-oxo-2azabicyclo[3.3.1]non-3-ene-4-carboxylate (3z). White solid; mp 184.2 °C; IR (KBr): 3432, 2977, 1638, 1542, 1450, 1320, 1158, 1065, 779 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 1.10−1.13 (m, 3H, CH3CH2O), 2.17−2.20 (m, 1H, COCH2), 2.34−2.37 (m, 1H, COCH 2 ), 2.58−2.61 (m, 1H, COCH2CHN), 2.63−2.66 (m, 1H, COCH2CHN), 2.87 (s, 3H, OCH3), 3.14 (s, 3H, CH3NH), 3.17−3.21 (m, 1H, CH), 3.32 (s, 3H, OCH3), 3.73−3.77 (m, 1H, CHN), 3.89−3.98 (m, 2H, CH2O), 7.33 (br, 2H, NH, NHCH3); 13C NMR (125 15

DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21

Article

ACS Omega MHz, DMSO-d6): δ = 15.4, 34.7, 35.9, 43.0, 45.7, 48.5, 48.6, 57.6, 59.4, 72.5, 97.1, 157.9, 168.3, 210.0; HRMS (EI+): m/z calcd for C14H22NaN2O4 [M + Na]+, 321.1421; found, 321.1422. (1R,5R)-Ethyl 9,9-Diethoxy-3-(methylamino)-7-oxo-2azabicyclo[3.3.1]non-3-ene-4-carboxylate (3a′). White solid; mp 156.6 °C; IR (KBr): 3472, 2974, 1640, 1537, 1441, 1320, 1164, 1069, 776 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 1.08−1.14 (m, 6H, CH3CH2O, CH3CH2O), 1.18−1.21 (m, 3H, CH3CH2O), 2.18−2.21 (m, 1H, COCH2), 2.32−2.35 (m, 1H, COCH 2 ), 2.58−2.65 (m, 1H, COCH2CHN), 2.67−2.68 (m, 1H, COCH2CH), 2.87 (s, 3H, CH3NH), 3.29−3.33 (m, 1H, CH), 3.45−3.48 (m, 2H, CH3CH2O), 3.55−3.59 (m, 2H, CH3CH2O), 3.73 (m, 1H, CHN), 3.89−3.99 (m, 2H, CH3CH2O), 7.35 (br, 2H, NH, NHCH3); 13C NMR (125 MHz, DMSO-d6): δ = 15.4, 15.6, 15.7, 35.6, 36.0, 43.2, 45.8, 56.2, 56.3, 57.6, 60.2, 72.8, 96.9, 158.0, 168.3, 210.0; HRMS (EI+): m/z calcd for C16H27N2O5 [M + H]+, 327.1914; found, 327.1918. (1R,5R)-Ethyl 3-Amino-9,9-dimethoxy-7-oxo-2azabicyclo[3.3.1]non-3-ene-4-carboxylate (3b′). Yellow solid; mp 170.5 °C; IR (KBr): 3414, 2959, 1638, 1537, 1372, 1086, 755 cm−1; 1H NMR (500 MHz, CDCl3): δ = 1.21−1.24 (m, 3H, CH3CH2O), 2.31−2.35 (m, 1H, COCH2), 2.42−2.45 (m, 1H, COCH 2 ), 2.70−2.77 (m, 2H, COCH2CHN), 3.28 (s, 3H, OCH3), 3.34−3.38 (m, 1H, CH), 3.38 (s, 3H, OCH3), 3.77−3.81 (m, 1H, CHN), 4.00− 4.10 (m, 2H, CH2O), 5.57−5.58 (m, 1H, NH), 6.36 (br, 2H, NH2); 13C NMR (125 MHz, CDCl3): δ = 14.7, 34.4, 44.9, 46.7, 48.5, 48.6, 50.8, 58.4, 73.6, 97.3, 156.5, 169.1, 211.7; HRMS (EI+): m/z calcd for C13H19N2O5 [M − H]−, 283.1299; found, 283.1303. (1R,5R)-Ethyl 3-Amino-9,9-diethoxy-7-oxo-2-azabicyclo[3.3.1]non-3-ene-4-carboxylate (3c′). Yellow liquid; IR (KBr): 3413, 2976, 1639, 1538, 1372, 1083, 780 cm−1; 1H NMR (500 MHz, CDCl3): δ = 1.18−1.28 (m, 12H, CH3CH2O, CH3CH2O, CH3), 2.33−2.36 (m, 1H, COCH2), 2.45−2.48 (m, 1H, COCH 2 ), 2.73−2.80 (m, 2H, COCH2CHN), 3.34−3.38 (m, 1H, CH), 3.53−3.62 (m, 4H, CH2O, CH3CH2O), 3.75−3.79 (m, 1H, CHN), 4.01−4.12 (m, 2H, CH3CH2O), 4.93 (br, 1H, NH), 6.15 (br, 2H, NH2); 13C NMR (125 MHz, CDCl3): δ = 14.8, 15.3, 15.3, 29.7, 35.0, 45.0, 46.9, 52.0, 56.4, 56.4, 58.5, 97.1, 156.0, 169.4, 211.8; HRMS (EI+): m/z calcd for C15H24N2NaO5 [M + Na]+, 335.1577; found, 335.1578. General Procedure for the Synthesis of Compounds 4. Quinone monoketals 1 (1.1 mmol), EDAMs 2 (1.0 mmol), Cs2CO3 (2.0 mmol), and 1,4-dioxane (15 mL) were charged into a 25 mL round-bottom flask. The mixture was kept at reflux for about 6 h and monitored by TLC until the quinone monoketal 1 substrate was completely consumed. After the reaction was completed, the reaction system was cooled to room temperature. The reaction mixture was poured into 25 mL of water and 50 mL of ethyl acetate for extraction and separation. Then, the crude product was concentrated by distillation under reduced pressure, purified by column chromatography (petroleum ether/ethyl acetate = 2:1), and produced a series of compounds 4 in a 65−89% yield. (1R,5R)-2-(4-Fluorobenzyl)-3-((4-fluorobenzyl)amino)-9,9dimethoxy-4-nitro-2-azabicyclo[3.3.1]non-3-en-7-one (4a). Yellow solid; mp 158.6 °C; IR (KBr): 3409, 1714, 1585, 1511, 1474, 1358, 1223, 1087, 716 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.48−2.51 (m, 2H, COCH2), 2.75−2.78 (m,

2H, COCH2CHN), 3.12 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 3.79−3.80 (m, 1H, CH), 3.32−3.36 (m, 1H, CHN), 4.43− 4.44 (m, 2H, CH2N), 4.76−4.78 (m, 2H, CH2N), 6.93−7.08 (m, 6H, ArH), 7.17−7.20 (m, 4H, ArH), 7.24−7.28 (m, 2H, ArH), 7.40−7.43 (m, 2H, ArH), 11.54 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 37.2, 41.2, 44.0, 48.8, 49.0, 49.1, 56.0, 59.4, 96.2, 111.2, 116.0, 116.1, 129.2 (d, J = 7.5 Hz), 129.7 (d, J = 7.5 Hz), 133.3 (d, J = 202.5 Hz), 133.3 (d, J = 202.5 Hz), 158.7, 162.1 (d, J = 242.5 Hz), 162.5 (d, J = 242.5 Hz), 207.4; 19F NMR (467 MHz, CDCl3): δ = −114.9, −114.5; HRMS (EI+): m/z calcd for C24H26FN3O5 [M + H]+, 474.1835; found, 474.1836. (1R,5R)-9,9-Dimethoxy-2-(4-methoxybenzyl)-3-((4methoxybenzyl)amino)-4-nitro-2-aza-bicyclo[3.3.1]non-3en-7-one (4b). Yellow solid; mp 74.8 °C; IR (KBr): 3421, 1717, 1613, 1513, 1461, 1351, 1250, 1094, 820 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.42−2.46 (m, 1H, COCH2), 2.54−2.56 (m, 1H, COCH 2 ), 2.75−2.78 (m, 2H, COCH2CHN), 3.18 (s, 3H, OCH3), 3.22 (s, 3H, OCH3), 3.52−3.53 (m, 1H, CH), 3.71 (s, 3H, CH3OAr), 3.75 (s, 3H, CH3OAr), 3.95−3.96 (m, 1H, CHN), 4.28−4.29 (m, 1H, CH2N), 4.34−4.36 (m, 1H, CH2N), 4.47−4.49 (m, 2H, CH2N), 6.76−6.78 (m, 2H, ArH), 6.85−6.87 (m, 2H, ArH), 6.96−6.97 (m, 2H, ArH), 7.13−7.20 (m, 2H, ArH), 11.62 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 36.8, 41.0, 44.0, 48.7, 49.1, 49.3, 55.3, 55.4, 57.2, 58.2, 96.4, 111.3, 111.4, 114.6, 126.7, 127.9, 128.0, 128.8, 159.4, 159.5, 159.7, 207.1; HRMS (EI+): m/z calcd for C26H32N3O7 [M + H]+, 498.2235; found, 498.2239. (1R,5R)-2-(2,4-Difluorobenzyl)-3-((2,4-difluorobenzyl)amino)-9,9-dimethoxy-4-nitro-2-azabicyclo[3.3.1]non-3-en7-one (4c). Yellow solid; mp 197.1 °C; IR (KBr): 3420, 1716, 1620, 1505, 1431, 1365, 1280, 1032, 773 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.46−2.49 (m, 1H, COCH2), 2.60−2.65 (m, 1H, COCH 2 CH), 2.73−2.77 (m, 2H, COCH 2 , COCH2CH), 3.15 (s, 3H, OCH3), 3.21 (s, 3H, OCH3), 3.51−3.55 (m, 1H, CH), 3.86−3.90 (m, 1H, CHN), 4.29− 4.35 (m, 2H, CH2N), 4.42−4.46 (m, 1H, CH2N), 4.67−4.71 (m, 1H, CH2N), 6.67−6.71 (m, 1H, ArH), 6.77−6.82 (m, 2H, ArH), 6.86−6.89 (m, 1H, ArH), 7.11−7.16 (m, 1H, ArH), 7.32−7.36 (m, 1H, ArH), 11.19 (m, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 36.6, 40.9, 43.7, 43.9, 48.7, 48.9, 51.8, 58.2, 96.1, 104.1−104.2 (m), 104.3−104.4 (m), 104.5−104.7 (m), 111.7−111.8 (m), 111.8, 111.8−112.0 (m), 118.4 (d, J = 17.5 Hz), 119.9 (d, J = 17.5 Hz), 129.1 (d, J = 13.8 Hz), 129.9 (d, J = 15.0 Hz), 159.4−159.8 (m), 160.1, 161.4−161.9 (m), 163.8−163.9 (m), 206.6; 19F NMR (467 MHz, CDCl3): δ = −113.9 (d, J = 4.7 Hz), −112.4 (d, J = 4.7 Hz), −109.3 (d, J = 4.7 Hz), −109.2 (d, J = 4.7 Hz); HRMS (EI+): m/z calcd for C24H24F4N3O5 [M + H]+, 510.1647; found, 510.1647. (1R,5R)-2-(3,4-Difluorobenzyl)-3-((3,4-difluorobenzyl)amino)-9,9-dimethoxy-4-nitro-2-azabicyclo[3.3.1]non-3-en7-one (4d). Yellow solid; mp 178.2 °C; IR (KBr): 3420, 1720, 1581, 1519, 1434, 1347, 1298, 1039, 780 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.45−2.51 (m, 1H, COCH2), 2.75− 2.80 (m, 2H, COCH2CH), 3.13 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 3.77−3.81 (m, 1H, CH), 3.87−3.91 (m, 2H, CHN), 4.41−4.42 (m, 2H, CH2N), 4.69−4.80 (m, 2H, CH2N), 6.97− 7.01 (m, 1H, ArH), 7.17−7.20 (m, 2H, ArH), 7.38−7.49 (m, 3H, ArH), 11.34 (br, 1H, NH); 13C NMR (125 MHz, DMSOd6): δ = 37.1, 41.2, 44.0, 48.4, 49.0, 49.1, 55.7, 59.6, 96.1, 111.4, 116.4−116.5 (m), 116.6−116.7 (m), 118.2, 118.3, 123.9, 124.3−124.4 (m), 134.1, 135.8, 148.2−148.4, 148.8− 16

DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21

Article

ACS Omega 149.0, 150.2−150.4, 150.8−151.0, 158.8, 207.3; 19F NMR (467 MHz, DMSO-d6): δ = −140.3 (d, J = 23.4 Hz), −140.3 (d, J = 23.4 Hz), −138.0 (d, J = 18.7 Hz), −138.0 (d, J = 23.4 Hz); HRMS (EI+): m/z calcd for C24H24F4N3O5 [M + H]+, 510.1647; found, 510.1648. (1R,5R)-2-(4-Fluorophenethyl)-3-((4-fluorophenethyl)amino)-9,9-dimethoxy-4-nitro-2-azabicyclo[3.3.1]non-3-en7-one (4e). Yellow solid; mp 140.8 °C; IR (KBr): 3419, 1713, 1618, 1579, 1468, 1351, 1229, 1066, 760 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 2.44−2.51 (m, 2H, COCH2), 2.71− 2.75 (m, 1H, COCH2CH), 2.84−2.89 (m, 1H, COCH2CH), 2.91−2.96 (m, 2H, CH2Ar), 3.01−3.04 (m, 2H, CH2Ar), 3.18 (s, 3H, OCH3), 3.36 (s, 3H, OCH3), 3.46−3.50 (m, 1H, CH), 3.58−3.68 (m, 2H, CH2N), 3.69−4.13 (m, 2H, CH2N), 4.11− 4.15 (m, 2H, CHN), 7.12−7.19 (m, 4H, ArH), 7.28−7.40 (m, 3H, ArH), 7.42−7.43 (m, 1H, ArH), 11.08 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 27.3, 29.5, 37.2, 41.0, 44.8, 46.5, 49.1, 54.0, 58.7, 96.1, 110.8, 115.6−115.8 (m), 124.7− 124.8 (m), 125.0−125.1 (m), 129.3−129.4 (m), 131.4−131.8 (m), 159.0, 161.1 (d, J = 241.3 Hz), 161.2 (d, J = 242.5 Hz), 207.5; 19F NMR (467 MHz, DMSO-d6): δ = −118.4, −118.3; HRMS (EI+): m/z calcd for C26H30F2N3O5 [M + H]+, 502.2148; found, 502.2149. (1R,5R)-2-(3-Fluorophenethyl)-3-((3-fluorophenethyl)amino)-9,9-dimethoxy-4-nitro-2-azabicyclo[3.3.1]non-3-en7-one (4f). Yellow solid; mp 65.2 °C; IR (KBr): 3420, 2924, 1716, 1590, 1452, 1352, 1091, 782 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.33−2.36 (m, 1H, COCH2), 2.64−2.70 (m, 3H, COCH2, COCH2CH), 2.82−2.90 (m, 4H, CH2Ar), 3.14 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 3.36−3.39 (m, 1H, CH2N), 3.45−3.48 (m, 3H, CH2N, CH2N), 3.59−3.63 (m, 1H, CH), 3.79−3.83 (m, 1H, CHN), 6.76−6.93 (m, 6H, ArH), 7.19− 7.23 (m, 2H, ArH), 11.07 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 34.2, 36.2, 36.6, 40.8, 44.7, 48.7, 48.8, 49.0, 55.9, 59.1, 95.9, 111.2, 114.0−114.1 (m), 114.1−114.2 (m), 115.4, 115.5, 124.1−124.2 (m), 124.4, 130.4−130.5, 130.5−130.6, 139.5−139.6, 139.8−139.9, 159.6, 162.0, 164.0, 206.9; 19F NMR (467 MHz, CDCl3): δ = −112.6, −112.2; HRMS (EI+): m/z calcd for C26H30F2N3O5 [M + H]+, 502.2148; found, 502.2149. (1R,5R)-2-(2-Fluorophenethyl)-3-((2-fluorophenethyl)amino)-9,9-dimethoxy-4-nitro-2-azabicyclo[3.3.1]non-3-en7-one (4g). Yellow solid; mp 61.0 °C; IR (KBr): 3424, 1714, 1580, 1493, 1458, 1351, 1229, 1068, 759 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.38−2.41 (m, 1H, COCH2), 2.73−2.76 (m, 3H, COCH2, COCH2CHN), 2.94−2.98 (m, 4H, CH2Ar, CH2Ar), 3.17 (s, 3H, OCH3), 3.33 (m, 3H, OCH3), 3.46−3.52 (m, 3H, CH2N, CH2N), 3.63−3.66 (m, 1H, CH2N), 3.70− 3.74 (m, 1H, CH), 3.82−3.86 (m, 1H, CHN), 6.98−7.07 (m, 4H, ArH), 7.12−7.23 (m, 4H, ArH), 11.16 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 28.2, 30.5, 36.6, 40.7, 44.7, 47.1, 48.7, 48.9, 54.9, 58.8, 95.9, 111.1, 115.5, 115.7, 123.8, 124.0, 124.5, 124.6, 129.0, 129.2, 131.3, 131.3, 159.6, 161.1 (d, J = 243.8 Hz), 161.1 (d, J = 243.8 Hz), 206.9; HRMS (EI+): m/z calcd for C26H30F2N3O5 [M + H]+, 502.2148; found, 502.2149. (1R,5R)-2-(4-Chlorophenethyl)-3-((4-chlorophenethyl)amino)-9,9-dimethoxy-4-nitro-2-azabicyclo[3.3.1]non-3-en7-one (4h). Yellow solid; mp 168.5 °C; IR (KBr): 3414, 1717, 1589, 1494, 1355, 1039, 775 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.33−2.36 (m, 1H, COCH2), 2.64−2.65 (m, 1H, COCH2CH), 2.69−2.71 (m, 2H, COCH2, COCH2CH), 2.81−2.88 (m, 4H, CH2Ar), 3.13 (s, 3H, OCH3), 3.28 (s,

3H, OCH3), 3.33−3.37 (m, 1H, CH2N), 3.41−3.47 (m, 1H, CH2N), 3.56−3.60 (m, 1H, CH), 3.79−3.83 (m, 1H, CHN), 6.98−6.99 (m, 2H, ArH), 7.06−7.08 (m, 2H, ArH), 7.20−7.22 (m, 4H, ArH), 11.05 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 33.9, 35.8, 36.6, 40.8, 44.8, 48.7, 49.0, 49.0, 56.0, 59.2, 95.9, 111.1, 129.0, 129.1, 129.8, 130.0, 133.2, 133.1, 135.5, 135.9, 159.6, 206.8; HRMS (EI+): m/z calcd for C26H30Cl2N3O5 [M + H]+, 534.1557; found, 534.1561. (1R,5R)-2-(3-Chlorophenethyl)-3-((3-chlorophenethyl)amino)-9,9-dimethoxy-4-nitro-2-azabicyclo[3.3.1]non-3-en7-one (4i). Yellow solid; mp 74.5 °C; IR (KBr):3422, 1716, 1599, 1465, 1351, 1075, 782 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.38−2.42 (m, 1H, COCH2), 2.71−2.77 (m, 3H, COCH2, COCH2CHN), 2.87−2.95 (m, 4H, CH2Ar, CH2Ar), 3.20 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.41−3.44 (m, 1H, CH2N), 3.51−3.55 (m, 2H, CH2N), 3.67−3.71 (m, 1H, CH2N), 3.67−3.71 (m, 1H, CH), 3.86−3.87 (m, 1H, CHN), 7.00−7.24 (m, 8H, ArH), 11.13 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 34.1, 36.1, 36.6, 40.8, 44.7, 48.7, 48.8, 49.0, 55.8, 59.1, 95.9, 111.2, 126.7, 127.0, 127.3, 127.4, 128.6, 128.6, 130.2, 130.3, 134.5, 134.7, 139.1, 139.5, 159.6, 206.9; HRMS (EI+): m/z calcd for C26H30Cl2N3O5 [M + H]+, 534.1557; found, 534.1559. (1R,5R)-2-(2-Chlorophenethyl)-3-((2-chlorophenethyl)amino)-9,9-dimethoxy-4-nitro-2-azabicyclo[3.3.1]non-3-en7-one (4j). Yellow solid; mp 124.1 °C; IR (KBr): 3422, 1715, 1575, 1465, 1349, 1094, 759 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.44−2.51 (m, 2H, COCH2), 2.72−2.76 (m, 1H, COCH2CHN), 2.87−2.91 (m, 1H, COCH2CHN), 3.00−3.03 (m, 2H, CH2Ar), 3.09−3.12 (m, 2H, CH2Ar), 3.19 (s, 3H, OCH3), 3.37 (s, 3H, OCH3), 3.43−3.47 (m, 1H, CH2N), 3.54−3.61 (m, 2H, CH2N), 3.68−3.69 (m, 1H, CH), 3.72− 3.75 (m, 1H, CH2N), 4.11−4.15 (m, 1H, CHN), 7.25−7.32 (m, 4H, ArH), 7.35−7.36 (m, 1H, ArH), 7.39−7.41 (m, 1H, ArH), 7.44−7.48 (m, 1H, ArH), 11.06 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 31.4, 34.1, 37.2, 41.0, 44.9, 46.5, 49.1, 49.2, 54.1, 58.4, 96.1, 110.9, 127.8, 128.0, 129.2, 129.2, 129.9, 131.4, 131.8, 133.5, 133.6, 135.6, 135.7, 137.4, 159.2, 207.3; HRMS (EI+): m/z calcd for C26H30Cl2N3O5 [M + H]+, 534.1557; found, 534.1557. (1R,5R)-9,9-Dimethoxy-4-nitro-2-phenethyl-3-(phenethylamino)-2-azabicyclo[3.3.1]non-3-en-7-one (4k). Yellow liquid; IR (KBr): 3421, 1716, 1587, 1455, 1352, 1262, 1069, 700 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.29−2.32 (m, 1H, COCH2), 2.59−2.67 (m, 3H, COCH2, COCH2CH), 2.79−2.85 (m, 4H, CH2Ar, CH2Ar), 3.09 (s, 3H, OCH3), 3.22 (s, 3H, OCH3), 3.36−3.50 (m, 4H, CH2N), 3.59−3.63 (m, 1H, CH), 3.76−3.80 (m, 1H, CHN), 7.02−7.04 (m, 2H, ArH), 7.10−7.20 (m, 8H, ArH), 11.15 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 34.6, 36.5, 36.7, 40.8, 44.7, 48.7, 48.9, 49.1, 56.2, 59.0, 95.9, 111.0, 127.0, 127.2, 128.5, 128.7, 128.8, 129.0, 137.1, 137.5, 159.6, 207.1; HRMS (EI+): m/z calcd for C26H32N3O5 [M + H]+, 466.2336; found, 466.2339. (1R,5R)-9,9-Dimethoxy-2-(4-methylphenethyl)-3-((4methylphenethyl)amino)-4-nitro-2-azabicyclo[3.3.1]non-3en-7-one (4l). Yellow liquid; IR (KBr): 3472, 1717, 1591, 1461, 1350, 1261, 1092, 716 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.24 (s, 6H, CH3Ar), 2.29−2.32 (m, 1H, COCH2), 2.59−2.61 (m, 1H, COCH2), 2.68−2.71 (m, 1H, COCH2CH), 2.80−2.86 (m, 4H, CH2Ar, CH2Ar), 3.12 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 3.38−3.54 (m, 4H, CH2N, CH2N), 3.54−3.55 (m, 1H, CH), 3.80−3.81 (m, 1H, CHN), 17

DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21

Article

ACS Omega 6.93−7.05 (m, 8H, ArH), 11.15 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 21.1, 21.1, 34.2, 36.1, 36.6, 40.8, 44.7, 48.7, 49.0, 49.3, 56.5, 58.9, 96.1, 111.0, 128.4, 128.6, 129.5, 129.5, 129.6, 129.6, 133.9, 134.4, 136.7, 136.9, 159.6, 207.0; HRMS (EI+): m/z calcd for C28H36N3O5 [M + H]+, 494.2649; found, 494.2651. (1R,5R)-9,9-Dimethoxy-4-nitro-2-(3-phenylpropyl)-3-((3phenylpropyl)amino)-2-azabicyclo[3.3.1]non-3-en-7-one (4m). Yellow solid; mp 163.8 °C; IR (KBr): 3417, 1716, 1603, 1561, 1453, 1350, 1201, 1054, 752 cm−1; 1H NMR (500 MHz, DMSO): δ = 1.68−1.74 (m, 3H, CH2CH2N, COCH2), 1.93− 1.97 (m, 1H, COCH2), 2.34−2.37 (m, 1H, COCH2CH), 2.47−2.58 (m, 6H, CH2Ar, CH2Ar, CH2CH2N), 2.71−2.75 (m, 2H, CH2N), 2.83−2.87 (m, 2H, CH2N), 2.93−2.97 (m, 1H, COCH2CH), 2.85−2.89 (m, 1H, CH2Ar), 3.16 (s, 3H, OCH3), 3.31 (s, 3H, OCH3), 3.68−3.72 (m, 1H, CH), 3.98− 4.02 (m, 1H, CHN), 7.12−7.30 (m, 10H, ArH), 11.19 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 29.6, 31.7, 32.1, 32.3, 37.4, 41.0, 44.9, 45.7, 49.1, 53.2, 58.7, 96.1, 110.4, 126.5, 128.8, 128.8, 128.8, 128.9, 128.9, 128.9, 128.9, 141.1 (d, J = 20.0 Hz), 158.8, 207.6; HRMS (EI+): m/z calcd for C28H36N3O5 [M + H]+, 494.2649; found, 494.2652. (1R,5R)-2-Benzyl-3-(benzylamino)-9,9-diethoxy-4-nitro-2azabicyclo[3.3.1]non-3-en-7-one (4n). Yellow liquid; IR (KBr): 3423, 1716, 1592, 1453, 1351, 1075, 733 cm−1; 1H NMR (500 MHz, CDCl3): δ = 1.11−1.14 (m, 6H, CH3CH2O, CH3CH2O), 2.46−2.50 (m, 1H, COCH2), 2.56−2.57 (m, 1H, COCH2CHN), 2.78−2.80 (m, 2H, COCH2, COCH2CHN), 3.29−3.33 (m, 1H, CH2O), 3.44−3.48 (m, 2H, CH2O), 3.55− 3.56 (m, 1H, CH2O), 3.97−3.98 (m, 1H, CH2O), 4.30−4.36 (m, 2H, CH2N), 4.46−4.50 (m, 1H, CH), 4.48−4.52 (m, 1H, CHN), 6.98−7.73 (m, 10H, ArH), 11.78 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 15.1, 15.2, 37.5, 41.1, 43.9, 49.5, 56.7, 56.9, 57.4, 59.5, 96.0, 111.5, 126.4, 126.6, 128.0, 128.2, 129.0, 129.2, 135.2, 136.8, 159.8, 207.3; HRMS (EI+): m/z calcd for C26H32N3O5 [M + H]+, 466.2336; found, 466.2341. (1R,5R)-2-(4-Methoxybenzyl)-3-((4-methoxybenzyl)amino)-4-nitro-2-azaspiro[bicyclo[3.3.1]nonane-9,2′-[1,3]dioxolan]-3-en-7-one (4o). Yellow solid; mp 164.1 °C; IR (KBr): 3417, 1719, 1614, 1547, 1355, 1276, 1028, 712 cm−1; 1 H NMR (400 MHz, DMSO-d6): δ = 2.50−2.62 (m, 2H, COCH 2 , COCH 2 CH), 2.85−2.93 (m, 2H, COCH 2 , COCH2CH), 3.38−3.42 (m, 1H, CH2O), 3.54−3.58 (m, 1H, CH2O), 3.74 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.00− 4.11 (m, 3H, CH2O, CH2N), 4.42−4.43 (m, 2H, CH2N), 4.62−4.76 (s, 2H, CH, CHN), 6.90−6.92 (m, 2H, ArH), 6.98−7.00 (m, 2H, ArH), 7.10−7.12 (m, 2H, ArH), 7.30−7.32 (m, 2H, ArH), 11.8 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 40.6, 40.8, 42.1, 49.4, 55.4, 55.6, 56.4, 59.7, 65.4, 65.7, 103.4, 111.1, 114.7, 114.7, 128.0, 128.9, 129.1, 129.7, 158.7, 159.3, 159.3, 207.0; HRMS (EI+): m/z calcd for C26H30N3O7 [M + H]+, 496.2078; found, 496.2078. (5R,9R)-10-Benzoyl-11,11-dimethoxy-2,3,5,6,8,9-hexahydro-7H-5,9-methanooxazolo[3,2-a]azocin-7-one (6a). Yellow liquid; IR (KBr): 3415, 2959, 1714, 1528, 1405, 1285, 1113, 1070, 745 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.54−2.57 (m, 2H, COCH 2 ), 2.76−2.80 (m, 1H, COCH2CHN), 2.87−2.91 (m, 1H, COCH2CHN), 3.30 (s, 3H, CH3O), 3.39−3.41 (m, 1H, CH), 3.44 (s, 3H, CH3O), 3.55−3.60 (m, 1H, CHN), 3.83−3.87 (m, 2H, CH2N), 4.16− 4.23 (m, 2H, CH2O), 7.27−7.32 (m, 3H, ArH), 7.36−7.38 (m, 2H, ArH); 13C NMR (125 MHz, CDCl3): δ = 34.6, 42.6, 44.7,

46.6, 49.0, 49.0, 55.7, 67.6, 87.4, 97.9, 127.3, 127.5, 129.0, 143.2, 162.1, 190.0, 209.2; HRMS (EI+): m/z calcd for C19H22NO5 [M + H]+, 344.1492; found, 344.1488. (5R,9R)-10-Benzoyl-11,11-diethoxy-2,3,5,6,8,9-hexahydro7H-5,9-methanooxazolo[3,2-a]azocin-7-one (6b). Yellow solid; mp 199.4 °C; IR (KBr): 3416, 2974, 1719, 1542, 1454, 1226, 1116, 1070, 745 cm−1; 1H NMR (500 MHz, DMSO-d6): δ = 1.12−1.15 (m, 3H, C3CH2O), 1.23−1.26 (m, 3H, C3CH2O), 2.20−2.23 (m, 1H, COCH2), 2.52−2.55 (m, 1H, COCH2), 2.74−2.82 (m, 2H, COCH2CHN), 3.41−3.45 (m, 1H, CH), 3.48−3.57 (m, 3H, CH2N, C3CH2O), 3.62− 3.70 (m, 3H, C3CH2O), 3.09−4.13 (m, 1H, CHN), 4.18−4.23 (m, 2H, CH2O), 7.20−7.22 (m, 2H, ArH), 7.27−7.34 (m, 3H, ArH); 13C NMR (125 MHz, DMSO-d6): δ = 15.7, 15.8, 35.7, 42.8, 45.1, 46.3, 55.4, 56.6, 56.9, 68.4, 86.8, 97.9, 127.7, 127.7, 129.2, 144.0, 162.3, 188.3, 209.4; HRMS (EI+): m/z calcd for C21H26NO5 [M + H]+, 372.1805; found, 372.1802. (5R,9R)-10-Benzoyl-11,11-dimethoxy-2,3,5,6,8,9-hexahydro-7H-5,9-methanothiazolo[3,2-a]azocin-7-one (6c). Yellow liquid; IR (KBr): 3440, 2956, 1715, 1593, 1496, 1407, 1246, 1115, 1061, 750 cm−1; 1H NMR (500 MHz, CDCl3): δ = 2.20−2.23 (m, 1H, COCH2), 2.45−2.49 (m, 1H, COCH2), 2.58−2.64 (m, 2H, COCH2CHN), 2.92−2.98 (m, 2H, CH2S), 3.16 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 3.27−3.31 (m, 1H, CH), 3.46−3.49 (m, 1H, CH2N), 3.62−3.65 (m, 1H, CH2N), 3.79−3.83 (m, 1H, CHN), 7.24−7.29 (m, 5H, ArH); 13C NMR (125 MHz, CDCl3): δ = 27.9, 36.4, 41.7, 45.5, 48.8, 48.9, 53.0, 57.0, 97.5, 102.0, 126.4, 128.2, 129.0, 141.3, 161.3, 190.7, 208.4; HRMS (EI+): m/z calcd for C19H22NO4S [M + H]+, 360.1264; found, 360.1265.

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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/acsomega.7b01493.

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Spectroscopic and analytical data and the original copy of 1H and 13C NMR spectra of all new compounds (PDF) X-ray crystallographic data of compound 3b (CCDC 1546771) (CIF) X-ray crystallographic data of compound 3e (CCDC 1546772) (CIF) X-ray crystallographic data of compound 3u (CCDC 1578670) (CIF) X-ray crystallographic data of compound 4a (CCDC 1546773) (CIF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Phone/Fax: +86 87165031633 (J.L.). *E-mail: [email protected]. Phone/Fax: +86 87165031633 (S.-J.Y.). ORCID

Jun Lin: 0000-0002-2087-6013 Sheng-Jiao Yan: 0000-0002-7430-4096 Notes

The authors declare no competing financial interest. 18

DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21

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ACS Omega

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ACKNOWLEDGMENTS This work was supported by the Program for Changjiang Scholars and Innovative Research Team in University (no. IRT17R94), the National Natural Science Foundation of China (nos. 21662042, 21362042, 81760621, and U1202221), the Natural Science Foundation of Yunnan Province (2017FA003), the Reserve Talent Foundation of Yunnan Province for Middle-aged and Young Academic and Technical Leaders (no. 2012HB001), Donglu Scholars of Yunnan University, Excellent Young Talents, Yunnan University, and High-Level Talents Introduction Plan of Yunnan Province.

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DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21

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DOI: 10.1021/acsomega.7b01493 ACS Omega 2018, 3, 8−21