Total Synthesis of (±)-Cermizine B - The Journal of Organic

A practical synthesis of (±)-cermizine B was achieved. The nine-step synthesis mainly comprised two uninterrupted Michael additions including a highl...
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Article Cite This: J. Org. Chem. 2017, 82, 11110-11116

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Total Synthesis of (±)-Cermizine B Xin Shi,†,‡ Zhen-Tao Deng,†,‡ Yu Zhu,†,‡ Ying Bao,†,‡ Li-Dong Shao,*,† and Qin-Shi Zhao*,† †

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People’s Republic of China ‡ University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China S Supporting Information *

ABSTRACT: A practical synthesis of (±)-cermizine B was achieved. The nine-step synthesis mainly comprised two uninterrupted Michael additions including a highly diastereoselective 1,4-addition of 2-picoline to methyl 4-methyl-6oxocyclohex-1-ene-1-carboxylate, Krapcho decarboxylation, a double reductive amination that resulted in ring closure and dearomatization of pyridine in 24% overall yield.

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INTRODUCTION Lycopodium alkaloids1 include a cornucopia of structurally complex natural products. Owing to both their synthetically challenging polycyclic skeletons and extensive biological activities, a great number of total syntheses of Lycopodium alkaloids have been reported.2 Among the Lycopodium alkaloids, tricyclic phlegmarine-type alkaloids contain the core framework embedded throughout the Lycopodium alkaloids and exhibit various biologically important activities3 (Figure 1).

Scheme 1. Biogenetic Relationship of Lycopodium Alkaloids

5,7-disubstituted decahydroquinoline ring and a C16N2 tricyclic skeleton1,7 and exhibits promising cytotoxicity against murine lymphoma L1210 cells (IC50 = 5.5 μg/mL).6 In 2014, Bradshaw et al. reported the first total synthesis of (−)-cermizine B via the development of an organocatalyzed tandem cyclization to access 5-oxodecahydroquinoline bearing three stereogenic centers in a one-pot manner and by utilizing an uninterrupted eight-step reaction sequence on the gramscale.2a Most recently, the Amat group reported the total synthesis of cermizine B, taking advantage of stereoconvergent cyclocondensation reactions of phenylglycinol with cyclohexanone-based δ-keto esters to access 5-oxodecahydroquinoline.2b Herein we report a practical synthesis of (±)-cermizine B through the orderly combination of methyl 4-methyl-6oxocyclohex-1-ene-1-carboxylate (3d), 2-picoline, and acrolein.

Figure 1. Representative phlegmarine-type Lycopodium alkaloids.

Biogenetically, the phlegmarine-type tricyclic skeleton can be used as a platform to access other classes of Lycopodium alkaloids (Scheme 1).3c,4 Therefore, the importance of phlegmarine-type alkaloids have attracted the interests of organic chemists and resulted in several total syntheses of these structurally unique phlegmarine alkaloids.2a−c,3b,5 Cermizine B is a phlegmarine-type alkaloid that belongs to the Lycopodium family,1 which was isolated from the club moss Lycopodium cernuum and L. chinense in 2004 by Kobayashi and co-workers.6 This compound is structurally characterized by a © 2017 American Chemical Society

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RESULTS AND DISCUSSION In the retrosynthetic analysis (Scheme 2), we reasoned that the dearomatization/methylation of 13 would provide (±)-cermizine B. Intermediate 13 can be accessed from bicyclic 6a−c via Received: August 16, 2017 Published: October 3, 2017 11110

DOI: 10.1021/acs.joc.7b02073 J. Org. Chem. 2017, 82, 11110−11116

Article

The Journal of Organic Chemistry

electron-rich groups such as 3a [R1 = (CH2)2CN] and 3b [R1 = (CH2)3N3]. In this pattern, deprotonated 2-picoline tended to attack the carbonyl group, resulting in 1,2-addition instead of 1,4-addition. Moreover, when R 1 is larger, such as (CH2)3NHPhth (3c), neither 1,2- nor 1,4-addition proceeded at all. However, highly effective stereochemically controlled 1,4additions with appropriate yields have been reported in the literature2c,d,8 when R1 is an electron-withdrawing group. Thus, β-ketoester 3d8a−c and 3e were chosen as the conjugate addition substrate. Therefore, the Michael addition of 3d and 3e to the organocopper reagent in situ derived from 2-picoline resulted in desired 1,4-addition products 4d and 4e as a ∼4:1 mixture of enol and keto tautomers in excellent yields (Table 2, entries 1−4).

Scheme 2. Retrosynthetic Analysis of (±)-Cermizine B

cyclization/amination. Bicyclic 6a−c can be obtained from Michael additions of 2-picoline to the corresponding enones 3a−c. Consequently, the model 1,4-addition of 2-picoline to 5methyl-2-cyclohexen-1-one (3) was performed (Scheme 3). As a result, the 1,4-addition product 6 was obtained with the dr values of 6.4:1 and 2.2:1 in the presence of CuI and CuBr· Me2S, respectively (Table 1, entries 1 and 2).

Table 2. 1,4-Addition Attempts with Enones 3d and 3e

Scheme 3. Model 1,4-Addition of 2-Picoline to 3

Table 1. 1,4-Addition Attempts with Enones 3a−c

a

a

Isolated yield. bDetermined by 1H NMR.

To introduce the α-C3 unit effectively, the cascade Michael− Michael/SN2 reactions were tested by using 3 and 3d as substrates, acrylonitrile and methyl acrylate as the second Michael receptors, or allyl bromide as the second electrophile (Table 3). To our disappointment, only the 1,4-addition products (6 or 4d) were obtained, likely due to the low reactivity of newly formed enolate intermediate during the reaction. Thus, the retrosynthesis was revised as shown in Scheme 4. Bicyclic 6a/6e can be obtained from two continuous Michael additions which include a diastereoselective conjugate addition of lithiated methylpyridines to enone. After optimization of the 1,4-addition by varying the quantities of 2-picoline and the copper(I) salts, the dr value and the yield of this 1,4-addition were improved to 32:1 and 95%, respectively, as evidenced by 1H NMR analysis (Table 4, entry 3). Consequently, the synthesis was started from 4d. Initial attempts to perform the addition of 4d to acrylonitrile using either DBU or Triton B as the catalyst failed. When Bu4NOH was used as the catalyst, the Michael addition of 4d proceeded smoothly to deliver the desired product 5a in 87% yield (brsm).9 The methyl formate group was removed using standard Krapcho conditions to give α,β-disubstituted ketone

Isolated yield. bDetermined by 1H NMR.

Based on the successful model reaction, the 1,4-additions of α-substituted enones 3a−c were tested for their reactivity with 2-picoline (Table 1, entries 3−8). Unfortunately, these substrates led to either 1,2-addition products (entries 3−6) or no reaction (entries 7 and 8). We proposed that the inert 1,4-addition of electron-rich nucleophile 2-picoline to αsubstituted 5-methyl-2-cyclohexen-1-one occurred when the α-position of cyclohexenone was substituted with flexible and 11111

DOI: 10.1021/acs.joc.7b02073 J. Org. Chem. 2017, 82, 11110−11116

Article

The Journal of Organic Chemistry Table 3. Cascade Michael−Michael/SN2 Attempts

Table 4. Optimization of the Conjugate Addition

entry

2-picoline (equiv)

CuX (equiv)

dra

yieldb (%)

1 2 3 4 5 6 7 8 9

4 2 2 2 2 4 2 2 2

CuI (2.0) CuI (2.0) CuI (2.5) CuI (3.5) CuI (5.0) CuBr·Me2S (2.0) CuBr·Me2S (2.0) CuBr·Me2S (2.5) CuCN (2.5)

3:1 8.1:1 32:1 5.5:1 1.1:1 2.2:1 6.8:1 17.2:1 1:2.5

87 84 95 83 87 82 92 84 87

a b

Determined by 1H NMR analysis (see Supporting Information). Isolated yield.

Scheme 5. Synthesis of (±)-Cermizine B

a

Conditions: enone (1 equiv), 2-picoline (4 equiv), n-BuLi (4 equiv), CuI (2 equiv), allyl-R2 (1.5 equiv); bIsolated yield.

6a in 75% yield.10 Transformation of the nitrile group of 6a to an amine by Pd-catalyzed hydrogenation was unsuccessful. Then 6a was treated with Boc2O/NiCl2/NaBH411 followed by Dess−Martin oxidation to furnish N-Boc 10 in 74% yield over two steps. Cyclization of 10 was performed using 2 N HCl which was followed by the addition of NaBH4 in the reaction, and the newly formed secondary amine was directly protected with p-TsCl to give the tricyclic intermediate 13 in 79% yield over two steps. The 1H and 13C NMR spectroscopy results for 13 were consistent with those reported by the Bradshaw group.8c Next, dearomatization of the pyridine ring was accomplished with PtO2 in AcOH under a H2 atmosphere (balloon) followed by treatment with ClCO2Me to give compound 12 in 75% yield over two steps as a 1:1 epimer of C5. Finally, 12 was converted to (±)-cermizine B in 85% yield by the reduction of methyl formate and removal of the Ts protection in one step using LiAlH42a (Scheme 5). Given that NH4OAc was used together with NaBH4, the glutaraldehyde could be converted to a piperidine ring in a onepot reaction.12 We planned to optimize the synthesis route by replacing acrylonitrile with acrolein in the secondary Michael addition of compound 4d. Although aldehyde 5b was readily prepared by applying the Bu4NF catalyst, the methyl formate

could not be removed under various Krapcho conditions (Scheme 6). As we reasoned that 5b was unstable in the presence of the nucleophile (LiCl/DMF) and even under nearly neutral conditions (NH4OAc/toluene), we revised this substrate. Encouraged by the mild dealkoxycarbonylation reactions,13 we changed methyl formate to allyl formate in 5b. Fortunately, the methyl group of 4d was smoothly replaced with an allyl group by heating with an excess of allyl alcohol in the presence of a catalytic amount of DMAP.14 Subsequently, exposure of the intermediate allyl formate to acrolein under a

Scheme 4. Revised Retrosynthetic Analysis of (±)-Cermizine B

11112

DOI: 10.1021/acs.joc.7b02073 J. Org. Chem. 2017, 82, 11110−11116

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The Journal of Organic Chemistry

2.2 Hz, 1H), 3.16 (d, J = 14.5 Hz, 1H), 2.87 (d, J = 14.5 Hz, 1H), 2.70−2.49 (m, 3H), 2.29 (dd, J = 13.8, 5.9 Hz, 1H), 2.17 (dt, J = 17.5, 4.6 Hz, 1H), 1.88−1.75 (m, 1H), 1.73−1.63 (m, 1H), 1.48 (d, J = 12.3 Hz, 1H), 1.30 (t, J = 12.9 Hz, 1H), 0.85 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 159.4, 148.6, 139.6, 137.2, 125.9, 124.8, 121.9, 120.43, 74.8, 44.3 (2C), 34.2, 27.4, 27.2, 22.1, 18.1. HRMS (ESI-TOF) m/z: [M − H]− Calcd for C16H19N2O 255.1503; found 255.1502. (5R)-2-(3-Azidopropyl)-5-methyl-1-(pyridin-2-ylmethyl)cyclohex2-en-1-ol (3b−12). Data for 3b−12. 1H NMR (600 MHz, CDCl3) δ 8.51 (d, J = 4.8 Hz, 1H), 7.64 (td, J = 7.7, 1.7 Hz, 1H), 7.19 (t, J = 5.9 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.01 (s, 1H), 5.45−5.42 (m, 1H), 3.36−3.25 (m, 2H), 3.21 (d, J = 14.4 Hz, 1H), 2.87 (d, J = 14.4 Hz, 1H), 2.34−2.28 (m, 1H), 2.16−2.10 (m, 1H), 1.88−1.73 (m, 3H), 1.65 (s, 2H), 1.51 (d, J = 12.8 Hz, 1H), 1.30 (t, J = 12.9 Hz, 1H), 0.85 (d, J = 6.5 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 159.7, 148.5, 136.9, 124.6, 123.1, 121.6, 74.5, 61.5, 51.5, 44.4 (2C), 34.3, 28.4, 27.3, 26.9, 22.1. HRMS (ESI-TOF) m/z: [M − H]− Calcd for C16H21N4O 255.1721; found 285.1722. Determination of the dr Value of Enolate 4d. To a solution of 4d (0.2 mmol) in DCM (2 mL) was added triethylamine (0.3 mmol) followed by TBSOTf (0.24 mmol) at 0 °C, Then the cold bath was removed, and the reaction was stirred at rt for 2 h. H2O was added, and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with EA (3 × 3 mL), and the combined organics were then washed with brine (3 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure. The crude material was purified via flash chromatography. The corresponding dr value of enolate 4d was determined by 1H NMR (for details, see Supporting Information). General Procedure of Table 3. A solution of n-BuLi in hexanes (2.5 M, 0.48 mL) was added to a stirred solution of 2-picoline (1.2 mmol) in THF (4 mL) at 0 °C, and the resultant dark red solution was stirred for 30 min. The reaction was cooled to −35 °C, and CuI (0.6 mmol) was added. The reaction was stirred for 2 h at which time it was cooled to −78 °C. A solution of enone (0.3 mmol) in THF (0.5 mL) was then added over 3 min. After the reaction was stirred for 5 h at −78 °C, allyl-R2 (0.45 mmol) was added and warmed naturally to room temperature overnight. Aqueous NH3/NH4Cl (2.5 mL) was added, the cold bath was removed, and after warming to room temperature the mixture was transferred to a separatory funnel containing H2O (3 mL) and the layers were separated. The aqueous layer was extracted with EA (3 × 3 mL), and the combined organics were then washed with aq NH3/NH4Cl (pH ∼ 9, 2 × 2.5 mL), brine (3 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure. The crude material was purified via flash chromatography. Methyl (4R*,6S*)-2-Hydroxy-4-methyl-6-(pyridin-2-ylmethyl)cyclohex-1-ene-1-carboxylate (4d). A solution of n-BuLi in hexanes (2.5 M, 2.4 mL) was added to a stirred solution of 2-picoline (558 mg, 6 mmol) in THF (30 mL) at 0 °C, and the resultant dark red solution was stirred for 30 min. The reaction was cooled to −35 °C, and CuI (1.428 g, 7.5 mmol) was added. The reaction was stirred for 2 h at which time it was cooled to −78 °C. A solution of 3d (504 mg, 3 mmol, 55% purity8a,16) in THF (1 mL) was then added over 3 min, and the reaction was stirred for 5 h at −78 °C. Aqueous NH3/NH4Cl (7.5 mL) was added, the cold bath was removed, and after warming to room temperature the mixture was transferred to a separatory funnel containing H2O (10 mL) and the layers were separated. The aqueous layer was extracted with EA (3 × 10 mL), and the combined organics were then washed with aq NH3/NH4Cl (pH ∼ 9, 2 × 7.5 mL) and brine (10 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure. The crude material was purified via flash chromatography, eluting with PE/EA (3:1) to afford 410 mg (95%) of 4d as a yellow oil as a single diastereomer but as a mixture (∼4:1 in CDCl3) of enol and keto tautomers. 1H NMR (400 MHz, CDCl3) δ 12.39 (s, 1H), 8.53 (d, J = 4.4 Hz, 1H), 7.58 (td, J = 7.6, 1.7 Hz, 1H), 7.10 (dd, J = 15.9, 7.3 Hz, 2H), 3.70 (s, 3H), 3.07 (d, J = 10.1 Hz, 2H), 2.65 (dd, J = 14.2, 11.1 Hz, 1H), 2.37 (dd, J = 18.3, 4.6 Hz, 1H), 2.06 (s, 1H), 1.89 (dd, J = 18.2, 11.2 Hz, 1H), 1.49 (d, J = 13.3 Hz, 1H), 1.15−1.04 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 206.3, 173.2, 172.9, 170.0, 161.3, 159.0, 149.5, 149.2, 136.4,

Scheme 6. Optimized Synthesis of (±)-Cermizine B

catalytic amount of Bu4NF led to 5e in 67% yield.15 As expected, a mild dealkoxycarbonylation reaction of 5e proceeded smoothly using Pd(OAc)2/PPh3 to yield 6e.13 Next, the double reductive amination was induced by NH4OAc/NaBH4, resulting in ring closure. The resulting mixture was treated with p-TsCl to provide 13 in 60% yield over three steps.

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CONCLUSION A practical total synthesis of (±)-cermizine B was successfully accomplished in 24% overall yield using a process requiring only seven steps from methyl 4-methyl-6-oxocyclohex-1-ene-1carboxylate (3d). Two routes of the synthesis directly accessed the crucial intermediate 13. The yield and dr value of the key Michael addition of 2-picoline to 3d were optimized to 95% and 32:1, respectively. This synthesis will benefit the syntheses of other phlegmarine alkaloids and ring-fused Lycopodium alkaloids.

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EXPERIMENTAL SECTION

General Experimental Procedures. All NMR spectra were recorded with Bruker AVANCE III 400 and 600 MHz (1H NMR) spectrometers (100 and 150 MHz for 13C NMR) in CDCl3 and MeOD: chemical shifts (δ) are given in ppm and coupling constants (J) in hertz (Hz). The solvent signals were used as references (CDCl3: δC = 77.0 ppm and MeOD: δC = 49.0 ppm; CDCl3: δH = 7.26 ppm and MeOD: δH = 4.87 ppm). High-resolution mass spectra were recorded on an Agilent 6540 Q-Tof (ESIMS). All reactions were carried out under an atmosphere of argon and dry conditions and were monitored by analytical thin-layer chromatography (TLC), which was visualized by ultraviolet light (254 nm). All solvents were obtained from commercial sources and were purified according to standard procedures. General Procedure of Tables 1 and 2. A solution of n-BuLi in hexanes (2.5 M, 0.48 mL) was added to a stirred solution of 2-picoline (1.2 mmol) in THF (4 mL) at 0 °C, and the resultant dark red solution was stirred for 30 min. The reaction was cooled to −35 °C, and CuX (0.6 mmol) was added. The reaction was stirred for 2 h at which time it was cooled to −78 °C. A solution of enone (0.3 mmol) in THF (0.5 mL) was then added over 3 min, and the reaction was stirred for 5 h at −78 °C. Aqueous NH3/NH4Cl (2.5 mL) was added, the cold bath was removed, and after warming to room temperature the mixture was transferred to a separatory funnel containing H2O (3 mL) and the layers were separated. The aqueous layer was extracted with EA (3 × 3 mL), and the combined organics were then washed with aq NH3/NH4Cl (pH ∼ 9, 2 × 2.5 mL) and brine (3 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure. The crude material was purified via flash chromatography. 3-((4R)-6-Hydroxy-4-methyl-6-(pyridin-2-ylmethyl)cyclohex-1-en1-yl)propanenitrile (3a−12). Data for 3a−12. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 4.3 Hz, 1H), 7.65 (td, J = 7.7, 1.6 Hz, 1H), 7.20 (t, J = 5.2 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.23 (s, 1H), 5.56 (d, J = 11113

DOI: 10.1021/acs.joc.7b02073 J. Org. Chem. 2017, 82, 11110−11116

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The Journal of Organic Chemistry

HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H33N2O3 361.2486; found 361.2482. (4aS*,5S*,7R*,8aR*)-7-Methyl-5-(pyridin-2-ylmethyl)-1-tosyldecahydroquinoline (13). To a stirred solution of 10 (72 mg, 0.20 mmol) in MeOH (1 mL) was added HCl (2 M, 1.5 mL) at room temperature. After being stirred at room temperature 24 h, the reaction mixture was concentrated, including high vacuum pumping. To a stirred solution of the above crude product in MeOH (4 mL) at 0 °C and was added NaBH4 (31 mg, 0.8 mmol) in small portions over 10 min. After being stirred at room temperature for 2 h, the reaction mixture was quenched with aq NH4Cl (2 mL) and then extracted with CH2Cl2 and, sequentially, water and brine. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was used in next step without further purification. To a stirred solution of the above crude product (40 mg) in CH2Cl2 (2 mL) at 0 °C was added Et3N (33.4 μL, 0.24 mmol), followed by TsCl (40 mg, 0.21 mmol). After being stirred at room temperature for 8 h, the reaction mixture was concentrated and chromatographed to yield 13 (63 mg, 79% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.1 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.57 (td, J = 7.6, 1.6 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.11 (dd, J = 6.9, 5.2 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 4.32−4.18 (m, 1H), 3.69 (d, J = 12.1 Hz, 1H), 2.95 (td, J = 13.3, 2.4 Hz, 1H), 2.84 (qd, J = 13.5, 8.0 Hz, 2H), 2.40 (s, 3H), 2.10 (d, J = 4.6 Hz, 1H), 1.88−1.74 (m, 1H), 1.65 (dd, J = 13.0, 3.6 Hz, 1H), 1.55−1.40 (m, 4H), 1.32−1.16 (m, 3H), 1.13 (dd, J = 12.5, 4.6 Hz, 1H), 0.84 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 160.7, 149.5, 142.7, 138.8, 136.2, 129.5 (2C), 126.8 (2C), 123.6, 121.1, 51.7, 41.4, 40.5, 40.3, 37.8, 32.9, 32.6, 26.8, 25.1, 24.8, 22.4, 21.5. IR (KBr) 3441, 2925, 1591, 1470, 1332, 1174, 1151, 1091, 1003, 756, 585. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H31N2O2S 399.2101; found 399.2106. Methyl (S*)-2-(((4aS*,5S*,7R*,8aR*)-7-Methyl-1-tosyldecahydroquinolin-5-yl)methyl)piperidine-1-carboxylate (12). To a stirred solution of 13 (56 mg, 0.141 mmol) in AcOH (1 mL) was added PtO2 (20% w/w, 11.2 mg) at rt. The resulting mixture was evacuated and backfilled with hydrogen three times and then stirred under an atmosphere of H2 for 16 h. The mixture was diluted with CH2Cl2 (5 mL) before it was filtered through a pad of Celite and washed through with CH2Cl2. The filtered solution was washed with 2 N NaOH, dried, and concentrated in vacuo to give the epimeric mixture of piperidines (not shown) as a colorless oil which was used in the next step without further purification. To a stirred solution of the above mixture (0.141 mmol) in CH2Cl2 (1 mL) was added triethylamine (98 μL, 0.7 mmol), followed by methyl chloroformate (0.1 mL, 0.42 mmol). After 24 h, the reaction was quenched by the addition of 2 N HCl (3 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were dried and concentrated in vacuo. Purification by chromatography (PE/EA = 6:1) gave epi-12 (24 mg, 37%) as a colorless oil, followed by 12 (25 mg, 38%) as a colorless oil. Data for 12: 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 4.22−3.91 (m, 3H), 3.74 (d, J = 6.8 Hz, 1H), 3.58 (s, 2H), 2.94 (td, J = 13.4, 2.3 Hz, 1H), 2.74 (s, 1H), 2.42 (s, 3H), 1.66−1.16 (m, 20H), 0.85 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 156.1, 142.8, 138.7, 129.5 (2C), 126.9 (2C), 53.4, 52.2, 51.8, 48.6, 40.5 (2C), 38.8, 36.2, 32.9 (2C), 29.7, 27.2, 25.5, 25.3, 25.0, 22.4, 21.5, 18.9. IR (KBr) 3432, 2942, 1687, 1448, 1152, 1089, 749. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H38N2O4SNa 485.2444; found 485.2450. Data for epi-12. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 4.29 (s, 1H), 4.20−4.09 (m, 1H), 3.97 (s, 1H), 3.68 (s, 3H), 3.64 (d, J = 14.0 Hz, 1H), 2.92 (td, J = 13.1, 2.3 Hz, 1H), 2.73 (t, J = 12.8 Hz, 1H), 2.42 (s, 3H), 1.78−1.23 (m, 18H), 1.08 (td, J = 13.7, 4.4 Hz, 1H), 0.86 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 156.3, 142.8, 138.8, 129.6 (2C), 127.0 (2C), 53.4, 52.5, 52.0, 49.0, 40.4, 39.0, 36.6, 33.0, 32.7, 32.2, 29.1, 26.8, 25.6, 25.3, 25.0, 22.5, 21.5, 19.1. IR (KBr) 3442, 2929, 1695, 1450, 1153, 1091, 1005, 755, 685. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H38N2O4SNa 485.2444; found 485.2442. (±)-Cermizine B. To a stirred solution of the carbamate 12 (50 mg, 0.108 mmol) in THF (10 mL) was added LiAlH4 (41 mg, 1.08

136.1, 123.7, 123.4, 121.5, 121.0, 101.4, 61.0, 52.3, 51.5, 48.0, 43.4, 42.1, 37.9, 37.6, 34.8, 34.1, 33.5, 29.5, 23.2, 21.9, 20.7. IR (film) 2954, 1744, 1714, 1650, 1440, 1268, 1217, 1090, 1042. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H20NO3 262.1438; found 262.1443. Methyl (1R*,4R*,6S*)-1-(2-Cyanoethyl)-4-methyl-2-oxo-6-(pyridin-2-ylmethyl)cyclohexane-1-carboxylate (5a). To a stirred solution of 4d (336 mg, 1.29 mmol) in CH3CN (6.5 mL) at 0 °C was added acrylonitrile (85 μL, 1.29 mmol), followed by Bu4NOH·30H2O (51.5 mg, 0.064 mmol). After being stirred at room temperature for an addition 3 h, the reaction mixture was concentrated and chromatographed to yield 4d (57.2 mg, 17% yield), followed by 5a (283 mg, 70% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.5 Hz, 1H), 7.59 (td, J = 7.6, 1.7 Hz, 1H), 7.12 (t, J = 6.6 Hz, 2H), 3.77 (s, 3H), 3.09 (dd, J = 14.0, 2.8 Hz, 1H), 2.92−2.71 (m, 3H), 2.60−2.39 (m, 3H), 2.32−2.25 (m, 1H), 2.24−2.17 (m, 1H), 2.13 (ddd, J = 13.5, 10.6, 5.1 Hz, 1H), 1.96 (td, J = 12.5, 5.1 Hz, 1H), 1.40 (d, J = 13.1 Hz, 1H), 0.82 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 206.8, 170.5, 159.7, 149.7, 136.4, 123.8, 121.5, 119.7, 62.9, 52.5, 46.5, 39.4, 39.1, 33.1, 28.7, 28.0, 19.5, 13.0. IR (film) 2957, 2932, 2248, 1713, 1591, 1437, 1220, 1087, 1053, 754. HRMS (ESI-TOF) m/ z: [M + H]+ Calcd for C18H23N2O3 315.1703; found 315.1709. 3-((1S*,4R*,6S*)-4-Methyl-2-oxo-6-(pyridin-2-ylmethyl)cyclohexyl)propanenitrile (6a). To a solution of 5a (1.043g, 3.32 mmol) in DMF (6.65 mL) was added LiCl (352 mg, 8.3 mmol). The reaction mixture was stirred at 110 °C for 36 h. After the substrate vanished, the reaction mixture was concentrated, including high vacuum pumping, and then the mixture was transferred to a separatory funnel containing H2O (10 mL) and the layers were separated. The aqueous layer was extracted with EA (5 × 6 mL), and the combined organics were then washed brine (10 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure. The crude material was purified via flash chromatography, eluting with PE/EA (2:1) to afford 6a (640 mg, 75%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 4.4 Hz, 1H), 7.56 (td, J = 7.6, 1.5 Hz, 1H), 7.09 (dd, J = 7.0, 5.4 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 2.86−2.80 (m, 1H), 2.79− 2.63 (m, 2H), 2.48−2.28 (m, 4H), 2.26−2.09 (m, 2H), 2.05 (t, J = 12.8 Hz, 1H), 1.59−1.51 (m, 2H), 1.49 (dd, J = 11.9, 3.7 Hz, 1H), 0.94 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 211.1, 159.7, 149.6, 136.4, 123.5, 121.4, 119.6, 52.1, 50.3, 41.3, 37.1, 36.1, 30.1, 22.9, 22.3, 15.6. IR (film) 2955, 2928, 2245, 1708, 1590, 1435, 757. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H21N2O 257.1648; found 257.1650. tert-Butyl (3-((1S*,4R*,6S*)-4-Methyl-2-oxo-6-(pyridin-2ylmethyl)cyclohexyl)propyl)carbamate (N-Boc-10). To a solution of 6a (246 mg, 0.961 mmol) in MeOH (7.5 mL) were added NiCl2· 6H2O (22.84 mg, 0.0961 mmol) and Boc2O (441 μL, 1.922 mmol) under an inert atmosphere. Then the mixture was cooled to 0 °C, and NaBH4 (254.5 mg, 6.727 mmol) was added in small portions over 30 min. The reaction was warmed to room temperature afterward and stirred for 24 h. Then the solution was filtered over Celite, the solvent was evaporated under reduced pressure, and the resulting crude product was used in next step without further purification. To a stirred solution of the above crude product in CH2Cl2 (9.6 mL) was added NaHCO3 (252 mg, 2.883 mmol) at 0 °C for 5 min, and then DMP (848.3 mg, 1.922 mmol) was added. The resulting mixture was stirred at rt for 3 h. The reaction was quenched by aq Na2S2O3 (3 mL) and then extracted with CH2Cl2 and, sequentially, water and brine. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was chromatographed to yield 10 (255 mg, 74% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 6.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 4.68 (s, 1H), 3.16−2.97 (m, 2H), 2.77 (d, J = 9.9 Hz, 2H), 2.55 (d, J = 6.0 Hz, 1H), 2.41 (dd, J = 12.7, 2.9 Hz, 1H), 2.34 (t, J = 13.6 Hz, 1H), 2.27−2.12 (m, 2H), 2.01 (t, J = 12.4 Hz, 1H), 1.88−1.74 (m, 1H), 1.55 (d, J = 14.0 Hz, 1H), 1.44 (s, 1H), 1.41 (s, 9H), 1.35−1.20 (m, 2H), 0.93 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 212.5, 160.3, 156.0, 149.4, 136.3, 123.5, 121.2, 78.9, 53.4, 50.2, 41.2, 40.3, 36.7, 36.0, 30.1, 28.4 (3C), 27.8, 23.4, 22.2. IR (KBr) 3389, 2929, 1710, 1520, 1366, 1250, 1172, 757. 11114

DOI: 10.1021/acs.joc.7b02073 J. Org. Chem. 2017, 82, 11110−11116

Article

The Journal of Organic Chemistry mmol) at 0 °C. The resulting mixture was stirred at rt overnight. The reaction was quenched by the careful addition of water (0.05 mL), 15% aq NaOH (0.05 mL), and a second portion of water (0.15 mL). The mixture was then diluted with CH2Cl2 before it was filtered through a pad of Celite and washed through with CH2Cl2. The filtrate was concentrated in vacuo, and the product was purified by column chromatography (PE/Detn = 4/1) to give (±)-cermizine B (24 mg, 85%) as a colorless oil. 1H NMR (400 MHz, MeOD) δ 3.13−3.03 (m, 1H), 2.77 (td, J = 12.6, 2.8 Hz, 1H), 2.69−2.61 (m, 1H), 2.25 (s, 3H), 2.16 (td, J = 11.5, 4.2 Hz, 1H), 2.00−1.85 (m, 2H), 1.81−1.50 (m, 11H), 1.43−1.10 (m, 9H), 0.93 (d, J = 6.0 Hz, 3H). 13C NMR (100 MHz, MeOD) δ 64.0, 57.9, 51.7, 43.1, 42.1, 40.5, 38.6, 37.0, 34.8, 33.9, 32.0, 28.1, 27.8, 26.7, 26.3, 25.0, 23.1. IR (KBr) 3425, 2928, 2857, 2778, 1632, 1459, 1027. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H33N2 265.2638; found 265.2642. Allyl (1R*,4R*,6S*)-4-Methyl-2-oxo-1-(3-oxopropyl)-6-(pyridin-2ylmethyl)cyclohexane-1-carboxylate (5e). To a stirred solution of 4d (344 mg, 1.318 mmol) in toluene (15 mL) at rt and was added allyl alcohol (538 μL, 7.91 mmol), followed by DMAP (241.5 mg, 1.977 mmol). After being refluxed at 117 °C for 3 days, the reaction mixture was concentrated and the resulting crude product was used in next step without further purification. A solution of the above crude product in THF (3.5 mL) was cooled to −78 °C, and Bu4NF (93 μL, 1 M) was added, followed by acrolein (88 μL, 1.318 mmol). The reaction mixture was warmed naturally to room temperature and stirred for 4 h. After the substrate vanished, the reaction mixture was concentrated and purified via flash chromatography, eluting with PE/EA (2:1) to afford 5e (303 mg, 67% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 8.52 (d, J = 4.2 Hz, 1H), 7.57 (td, J = 7.7, 1.7 Hz, 1H), 7.11 (t, J = 6.1 Hz, 2H), 6.00−5.82 (m, 1H), 5.38−5.24 (m, 2H), 4.65−4.61 (m, 1H), 3.11 (dd, J = 13.9, 2.8 Hz, 1H), 2.88−2.69 (m, 3H), 2.66−2.46 (m, 3H), 2.32− 2.16 (m, 2H), 2.15−2.04 (m, 1H), 1.99−1.90 (m, 2H), 1.38 (d, J = 13.8 Hz, 1H), 0.83 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 207.4, 201.5, 170.6, 160.1, 149.5, 136.3, 131.3, 123.8, 121.4, 119.5, 65.9, 63.0, 46.6, 39.4, 39.3 (2C), 33.0, 28.5, 24.1, 19.8. IR (KBr) 3435, 2929, 1715, 1594, 1437, 1197, 993, 755. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H26NO4 344.1856; found 344.1858. 7-Methyl-1-(4-methylsulfonyl)-5-(pyridin-2-ylmethyl)decahydroquinoline (13) (from 5e). To a stirred solution of 5e (380 mg, 1.11 mmol) in CH3CN/H2O (25 mL, v/v, 9/1) at rt were added Et3N (185.2 μL, 1.332 mmol) and PPh3 (58.23 mg, 0.222 mmol), followed by Pd(OAc)2 (24.92 mg, 0.111 mmol). After being stirred at room temperature for 3 h, the reaction mixture was quenched with aq NH4Cl, concentrated, and then used in next step without further purification. To a solution of the above crude product in methanol (3 mL) cooled to 0 °C were successively added NaBH4 (85 mg, 2.22 mmol) and a solution of NH4OAc (86 mg, 1.11 mmol) in methanol (1.2 mL). After stirring for 24 h at room temperature, the mixture was concentrated in vacuo, and a 10% aqueous solution of NaOH was added and was followed by CH2Cl2 extractions. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was used in next step without further purification. To a stirred solution of the above crude product in CH2Cl2 (12 mL) at 0 °C was added Et3N (232 μL, 1.665 mmol), followed by pTsCl (278 mg, 1.46 mmol). After being stirred at room temperature for 8 h, the reaction mixture was concentrated and chromatographed to yield 13 (263 mg, 60% yield) as a colorless oil. Methyl (1R*,4R*,6S*)-4-Methyl-2-oxo-1-(3-oxopropyl)-6-(pyridin-2-ylmethyl)cyclohexane-1-carboxylate (5b). A solution of 4d (52 mg, 0.2 mmol) in THF (1 mL) was cooled to −78 °C, and Bu4NF (12 μL, 1 M) was added, followed by acrolein (13.4 μL, 0.2 mmol). The reaction mixture was warmed naturally to room temperature and stirred for 6 h. After the substrate vanished, the reaction mixture was concentrated and purified via flash chromatography, eluting with PE/ EA (3:1) to afford 4d (9 mg, 17% yield) as a yellow oil, followed by 5b (33.5 mg, 53% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 8.52 (d, J = 3.5 Hz, 1H), 7.58 (td, J = 7.7, 1.7 Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 3.73 (s, 3H), 3.10 (dd, J = 13.9, 2.8 Hz, 1H),

2.87−2.77 (m, 2H), 2.76−2.67 (m, 1H), 2.65−2.42 (m, 3H), 2.30− 2.24 (m, 1H), 2.20 (dd, J = 14.2, 3.4 Hz, 1H), 2.15−2.05 (m, 1H), 1.97−1.88 (m, 1H), 1.38 (d, J = 13.8 Hz, 1H), 0.84 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 207.5, 201.5, 171.4, 160.1, 149.5, 136.3, 123.8, 121.4, 63.0, 52.2, 46.6, 39.4, 39.3, 39.3, 33.0, 28.5, 24.1, 19.8. IR (film) 2955, 1743, 1713, 1590, 1436, 1236, 1149, 753. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H24NO4 318.1700; found 318.1695.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02073. Copies of 1H NMR and 13C NMR for all synthetic compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Li-Dong Shao: 0000-0003-4799-6784 Qin-Shi Zhao: 0000-0002-1249-2917 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank professors Yu-Rong Yang and Jun Deng from Kunming Institute of Botany for helpful discussion on the synthesis. This work was financially supported by the National Natural Science Foundation of China (U1502223, 81603000) and the National Basic Research Program (973 program no. 2011CB915503) of China.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02073 J. Org. Chem. 2017, 82, 11110−11116