General and Catalytic Enantioselective Approach to Isopavine

Oct 30, 2017 - A concise, versatile, and catalytic enantioselective approach to natural and non-natural isopavine alkaloids has been developed. The sy...
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General and Catalytic Enantioselective Approach to Isopavine Alkaloids Lingyu Sun,† Da Li,† Xiaowei Zhou,† Dongxu Zhang,† Jin Wang,† Zhongjing He,‡ Ru Jiang,*,† and Weiping Chen*,† †

School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi’an 710032, P.R. China Medical School, Xi’an Peihua University, 2 Baisha Road, Xi’an 710000, P.R. China

‡

S Supporting Information *

ABSTRACT: A concise, versatile, and catalytic enantioselective approach to natural and non-natural isopavine alkaloids has been developed. The synthesis takes advantage of catalytic asymmetric reaction to construct the pivotal stereogenic center in a highly enantioselective way (95−98% ee), and features use of intramolecular Pictet−Spengler reaction to build the core tetracyclic skeleton in a rapid and stereoselective fashion.

I

Scheme 1. Known Approaches to Isopavine Alkaloids

sopavine alkaloids 1 (Figure 1), originally isolated from plants of the Papaveraceae family, have a characteristic

Figure 1. Representative natural isopavine alkaloids.

amination and reduction of a hydroxyl ester (Scheme 1D).8 However, relatively few asymmetric total syntheses of these natural products have been reported. Syntheses of enantiomerically pure or enriched isopavine alkaloids have traditionally resorted to optical resolution, or starting with naturally occurring compounds, or utilizing chiral auxiliaries (Scheme 1A).9−13 Hanessian reported enantioselective synthesis of nonnatural isopavines by highly stereocontrolled, diastereoselective [1,2]-Stevens rearrangements of chiral quaternary salts (Scheme 1C).14 To the best of our knowledge, there is only one example where the enantioselective synthesis of the natural isopavine is accomplished by utilizing a catalytic asymmetric reaction. Stoltz reported the enantioselective total synthesis of (−)-amurensinine by using a catalytic oxidative kinetic resolution of secondary alcohols as a key step (Scheme 1D).8c In view of the pharmacological importance of the isopavines, and the paucity of methods to access enantiopure analogues,

tetracyclic tetrahydroisoquinoline core structure consisting of a doubly benzannulated azabicyclo[3.2.2]nonane.1,2 Both isopavines and non-natural analogues have been shown to possess interesting pharmacological activities for treatment of nerve system disorders like Alzheimer’s, Parkinson’s disease, Huntington’s chorea, amyotrophic lateral sclerosis and Down’s syndrome,3a−c as well as potent opioid receptor binding activity.3d During the past half century, the interesting structures and potential medicinal applications of the isopavines have promoted the interest of a number of research groups, and several elegant syntheses have been developed. A traditional approach to the synthesis of isopavine alkaloids is achieved by intramolecular double cyclization of (α-aryl-α-benzylmethyl) amino acetaldehyde dialkyl acetals, proceeding first to 1-benzyl4-hydroxy-1,2,3,4-tetrahydroisoquinolines, followed by a second cyclization (Scheme 1A).3a,4,5 Another three methods have also been developed: (i) one-step ring expansion-ring closure of an aziridinium iodide (Scheme 1B),6 (ii) [1,2]-Stevens rearrangements of a quaternary salt (Scheme 1C),7 and (iii) © 2017 American Chemical Society

Received: September 21, 2017 Published: October 30, 2017 12899

DOI: 10.1021/acs.joc.7b02385 J. Org. Chem. 2017, 82, 12899−12907

Note

The Journal of Organic Chemistry

In a key step of the synthesis, enantioselective addition of arylboronic acids 5 to β-nitrostyrenes 4, two catalytic systems, the tert-butanesulfinylphosphine-Rh catalyst developed by Liao and Zhang’s i-Pr-IsoQuinox-Pd catalyst, were tested.19,21 It was found that Zhang’s catalyst gave better results than Liao’s in our case (Table 1). Following Zhang’s procedure, β-nitrostyrenes 4 reacted with arylboronic acids 524 to afford the desired addition products 3aa−3ac in high yield (77−85%) and excellent enantioselectivity (95−98% ee) (Scheme 4).

herein, we report a simple, efficient, general and catalytic enantioselective approach to isopavine alkaloids. Our retrosynthetic strategy for the synthesis of isopavine alkaloids 1 commences with the disconnection of both C−N and C−C bonds on the bridgehead, exposing amino aldehyde dimethyl acetals 2 as a synthetic intermediate (Scheme 2). We reasoned Scheme 2. Retrosynthesis of Isopavine Alkaloids

Scheme 4. Catalytic Enantioselective Synthesis of Nitroacetals 3

that the intramolecular Pictet−Spengler reaction15 of 2 could form the isopavine alkaloids. Amino aldehyde dimethyl acetals 2 could be accessed from nitro compound 3, which could be produced enantioselectively from readily available β-nitroolefins 4 and arylboronic acids 5 by the application of the Rh- or Pdcatalyzed asymmetric addition of arylboronic acids to nitrostyrenes.16−21 We began our efforts toward isopavine alkaloids with the preparation of β-nitrostyrenes 4 (Scheme 3). The readily

In another key step of the synthesis, the intramolecular Pictet−Spengler reaction, we first envisioned that the nitroacetals 3 might be transformed into the demethylated isopavines 7 in a single step via reduction/hydrolysis/ intramolecular Pictet−Spengler reaction cascade using zinc dust and an acid (Scheme 5), since an acid catalyzes all these Scheme 5. Attempts Toward Synthesis of Demethylated Isopavines 7

Scheme 3. Synthesis of β-Nitrostyrenes 4

available 2-(2,2-dimethoxyethyl) benzaldehydes 6a−c22 were used as starting materials. Thus, according to Wünsch’s procedure,23 Henry reaction of aldehydes 6a−c with nitromethane proceeded in the presence of KOH to give the nitroaldol products, which were dehydrated by reaction with methanesulfonyl chloride and an excess of triethylamine, giving the β-nitrostyrenes 4a−c in 72−77% yields. Table 1. Asymmetric Addition of Arylboronic Acid 5 to β-Nitrostyrene 4

entry a

1 2b

precatalyst

solvent

yield (%)

ee (%)a

[Rh(C2H4)2Cl]2/L1 Pd(TFA)2/L2

EtOH MeOH

79 84

86 97

a

Reaction conditions: 4 (0.25 mmol), 5 (0.5 mmol), [Rh(C2H4)2Cl]2 (0.005 mmol), L1 (0.012 mmol), Et3N (50 mol%), EtOH (1.0 mL). bReaction conditions: 4 (0.2 mmol), 5 (0.3 mmol), Pd(TFA)2 (0.01 mmol), L2 (0.015 mmol), MeOH (1.0 mL). cDetermined by chiral HPLC analysis using Chiralcel AD-H column, hexane/i-propanol = 70:30. 12900

DOI: 10.1021/acs.joc.7b02385 J. Org. Chem. 2017, 82, 12899−12907

Note

The Journal of Organic Chemistry Scheme 6. Completion of the Total Synthesis of Isopavine Alkaloids

natural and non-natural isopavines were determined by HPLC to be >95% (see SI). In summary, we have developed a simple, efficient, general, and catalytic enantioselective approach to isopavine alkaloids. The synthesis takes advantage of catalytic asymmetric reaction to construct the pivotal stereogenic center in a highly enantioselective way, and features use of intramolecular Pictet−Spengler reaction to build the core tetracyclic skeleton in a rapid and stereoselective fashion. In this manner, a wide variety of natural and non-natural isopavines can be simply and efficiently synthesized in five or six steps from readily available 2-(2,2-dimethoxyethyl)benzaldehydes with >95% ee and >21.4% overall yields.

three reactions. Unfortunately, this transformation was unsuccessful under various conditions. Wünsch reported the one-pot Zn/HCl reductive cyclization of the similar racemic nitroacetals provided 3-benzazepines with poor to medium yields.23 We thought the cyclization of aminoacetals 2 would be feasible. Thus, the chemoselective reduction of nitroacetals 3 by sodium borohydride in the presence of NiCl2.6H2O25 afforded the expected aminoacetals 2 in 81−88% yield. However, the acid-catalyzed cyclization of aminoacetals 2 via hydrolysis/ intramolecular Pictet−Spengler cascade using different Lewis acids, such as trifluoroacetic acid, HCl, p-toluenesulfonic acid, sulfuric acid, ZnCl2, and BF3−OEt2, failed again. It is well-known that carbamates are more reactive than the corresponding free amines in the Pictet-Spengler reaction.26 Thus, the aminoacetals 2 were acylated with alkylchloroformate, in the presence of Et3N, to furnish the corresponding carbamates 8 in excellent yields (94−96%) (Scheme 6). Gratifyingly, when the carbamates 8 were refluxed with pTsOH in CH2Cl2 for 48 h, the carbamoyl isopavines 9 were successfully obtained in 64−71% yields. Finally, reduction of 9 with LiAlH4 afforded (−)-amurensinine 1b, (−)-reframidine 1c, (−)-O-methylthal-isopavine 1e, (−)-reframine 1f, benzylated (−)-thalidicine 1′d, non-natural isopavine 1′a, and 1′g in 71−78% yield. The 1′d, 1′a, and 1′g were debenzylated by Pd−C-catalyzed hydrogenolysis to give natural (−)-thalidicine 1d, and non-natural isopavines(−)-1a and(−)-1g in excellent yield (96−98%) (Scheme 6). 1H NMR and 13C NMR spectra of the synthetic natural (−)-amurensinine 1b,8a,12 (−)-reframidine 1c,4a,6b (−)-thalidicine 1d,27 (−)-O-methylthalisopavine 1e,4a,28,11,12 and (−)-reframine 1f4a,7,29 match with the data reported in literature. Notably, melting point and specific optical rotation of (−)-amurensinine 1b are somewhat different from the reported data.8a,12 The ee values of the synthetic

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EXPERIMENTAL SECTION

General Information. If not indicated differently, all reactions were carried out under a nitrogen atmosphere. Tetrahydrofuran was distilled over sodium metal/benzophenone. (S)-iPr-IsoQuinox was purchased from Daicel Chiral Technologies (China) CO.Ltd. All commercially obtained reagents and solvents were used without further purification. Arylboronic acids 524and 2-(2,2-dimethoxyethyl)benzaldehydes 622,30,31,32 were prepared according to the published procedures. The products were purified by flash column chromatography on silica gel (200−300 meshes) from the Yantai Jiangyou Silicon Material Company (China). Reactions were monitored by thin layer chromatography (TLC, 0.2−0.25 mm, GF254) supplied by Lebo Chemicals (China). NMR spectra were recorded on Bruker spectrometers (at 400 MHz) and are reported relative to deuterated solvent signals. High-resolution mass spectra (HRMS) were recorded on an Agilent electrospray ionization quadrupole time-of-flight (ESIQTOF) mass spectrometer. The specific optical rotation was obtained from PERKIN-ELMER 343 automatic polarimeter. Chiral HPLC analysis was performed on HP Agilent 1260 apparatus (Daicel Chiralcel AD-H and OJ-H, 4.6 × 250 mm, 5 μm). Melting points were determined in a WRS-2 melting point apparatus using open glass capillaries. 12901

DOI: 10.1021/acs.joc.7b02385 J. Org. Chem. 2017, 82, 12899−12907

Note

The Journal of Organic Chemistry General Procedure for the Preparation of β-Nitrostyrenes 4.23 Nitromethane (2.02 mL, 37.1 mmol) and a solution of KOH (292 mg, 5.22 mmol) in MeOH/H2O (v/v = 1:1, 1.5 mL) were added successively to a flask containing 6 (3.71 mmol) at 0 °C. The mixture was stirred for 7 h at 0 °C, and then quenched with sat. NH4Cl aq. (10 mL). The resulting mixture was extracted with CH2Cl2 (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated to afford a yellow oil. The above yellow oil was dissolved in CH2Cl2 (15 mL) and the solution was cooled to −50 °C. Methanesulfonyl chloride (175 mL, 2.19 mmol) and Et3N (607 mL, 4.38 mmol) were added, and the mixture was stirred for 8 h at 0 °C. Then the reaction was quenched with a sat. NH4Cl aq. (15 mL), and the resulting cold mixture was extracted with CH2Cl2 (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Mg2SO4, and concentrated to afford the crude residue, which was purified by silica gel column chromatography to afford the β-nitrostyrenes 4. (E)-1-(Benzyloxy)-4-(2,2-dimethoxyethyl)-2-methoxy-5-(2nitrovinyl)benzene (4a). Purification by column chromatography (petroleum ether/ethyl acetate = 2:1) and recrystallization (petroleum ether/ethyl acetate) to yield 4a 1.01 g (73% yield) as yellow solid, mp 134.1−134.3 °C. 1H NMR (400 MHz, CDCl3): δ 8.33 (dd, J = 13.4, 3.7 Hz, 1H), 7.48−7.35 (m, 6H), 7.04 (s, 1H), 6.85 (s, 1H), 5.16 (s, 2H), 4.45 (q, J = 4.7 Hz, 1H), 3.95 (s, 3H), 3.37 (s, 6H), 3.05−3.03 (t, J = 4.0 Hz, 2H); 13C{1H}NMR (101 MHz, CDCl3): δ 153.1, 147.3, 136.9, 136.5, 135.7, 133.6, 128.7, 128.2, 127.4, 121.3, 114.7, 112.0, 105.4, 71.4, 56.1, 54.2, 37.1; HRMS-ESI(m/z)[M+Na]+calcd for C20H23NO6Na, 396.1423; found, 396.1451. (E)-1-(2,2-Dimethoxyethyl)-4,5-dimethoxy-2-(2-nitrovinyl)benzene (4b). Purification by column chromatography (petroleum ether/ethyl acetate = 2:1) and recrystallization (petroleum ether/ethyl acetate) to yield 4b 0.79 g (72% yield) as yellow solid, mp 129.1− 133.2 °C. 1H NMR(400 MHz, CDCl3): δ 8.38 (d, J = 13.4 Hz, 1H), 7.52 (d, J = 13.4 Hz, 1H), 6.98 (s, 1H), 6.82 (s, 1H), 4.44 (t, J = 5.1 Hz, 1H), 3.94 (s,3H), 3.92 (s,3H), 3.36 (s, 6H), 3.05 (d, J = 5.1 Hz, 2H); 13C{1H}NMR (101 MHz, CDCl3): δ 152.3, 148.2, 137.0, 135.7, 133.2, 121.4, 114.3, 108.8, 105.4, 56.1, 56.0, 54.2, 37.1; HRMS-ESI(m/ z) [M+Na]+calcd for C14H19NO6Na, 320.1110; found, 320.1103. (E)-1-(2,2-Dimethoxyethyl)-4,5-methylenedioxy-2-(2-nitrovinyl)benzene (4c). Purification by column chromatography (petroleum ether/dichloromethane = 1:1) and recrystallization (petroleum ether/ ethyl acetate) to yield 4c 0.80 g (77% yield) as yellow solid, mp 150.7−151.3 °C. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 13.4 Hz, 1H), 7.44 (d, J = 13.3 Hz, 1H), 6.98 (s, 1H), 6.81 (s, 1H), 6.04 (s, 2H), 4.43 (t, J = 5.2 Hz, 1H), 3.36 (s, 6H), 3.02 (d, J = 5.2 Hz, 2H); 13 C{1H}NMR (101 MHz, CDCl3): δ 151.1, 147.3, 136.9, 135.9, 134.7, 122.7, 111.8, 105.8, 105.2, 102.0, 54.2, 37.2; HRMS-ESI (m/z) [M +Na]+calcd for C13H15NO6Na, 304.0797; found, 304.0793. General Procedure for the Preparation of Nitroacetals 3.21 Pd(TFA)2 (33 mg, 0.10 mmol, 0.050equiv) and (S)-i-Pr-IsoQuinox (36 mg, 0.15 mmol, 0.075 equiv) were added into MeOH (5 mL), and the mixture was stirred at room temperature for 0.5 h. Arylboronic acid 5 (3.0 mmol, 1.5 equiv) and nitrostyrene 4 (2.0 mmol, 1.0 equiv) were added to the solution. Then the mixture was allowed to warm to 40 °C and stirred for 24 h. After the reaction was completed (monitoring by TLC), the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel to afford the nitroacetals 3. Note that the racemic products were prepared using 2,2′-bispyridine asligand. (+)-(S)-1-(Benzyloxy)-4-(2,2-dimethoxyethyl)-5-(1-(3,4-methylenedioxyphenyl)-2-nitroethyl)-2-methoxybenzene (3aa). Purification by column chromatography (dichloromethane/petroleum ether = 4:1) to yield 3aa 0.77 g (78% yield) as colorless oil, 96% ee, [α]25 D = +19.0 (c 1.1, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.40−7.29 (m, 5H), 6.78−6.50 (m, 5H), 5.94 (s, 2H), 5.20−5.10 (m, 3H), 4.72 (d, J = 7.6 Hz, 2H), 4.39 (t, J = 4.3 Hz, 1H), 3.89 (s, 3H), 3.34 (s, 3H), 3.33 (s, 3H), 2.98−2.93 (m, 1H), 2.86−2.81 (m, 1H); 13C{1H}NMR (101 MHz, CDCl3): δ 148.7, 148.1, 146.8, 146.5, 137.1, 133.1, 129.5, 128.6, 128.5, 127.9, 127.4, 120.7, 115.2, 113.8, 105.6, 101.1, 79.2, 71.5, 56.00, 54.2, 53.9, 43.89, 36.4; HRMS-ESI (m/z) [M+NH4]+ calcd for

C27H29NO8NH4, 513.2237; found, 513.2231; HPLC [Daicel Chiralpak AD-H,hexane/i-PrOH = 80/20, 254 nm, 1.0 mL/min tR1= 12.52 min (major,S), tR2 = 15.92 min (minor,R)]. (+)-(S)-1,2-Dimethoxy-4-(2,2-dimethoxyethyl)-5-(1-(3,4-methylenedioxyphenyl)-2-nitroethyl)benzene (3ba). Purification by column chromatography (dichloromethane/ethyl acetate = 40:1) to yield 3ba 0.69 g (82% yield) as colorless oil, 95% ee, [α]25 D = +11.0 (c 0.06, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.78−6.69 (m, 5H), 5.92 (s, 2H), 5.21 (t, J = 7.9 Hz, 1H), 4.90 (d, J = 7.1 Hz, 2H), 4.39 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.34 (s, 3H), 3.33 (s, 3H), 2.99−2.96 (m, 1H), 2.87−2.83 (m, 1H); 13C{1H}NMR (101 MHz, Acetone-d6): δ 148.2, 148.0, 146.7, 134.1, 130.4, 128.0, 121.2, 115.3, 111.2, 108.4, 108.1, 105.7, 101.2, 78.9, 55.5, 55.2, 53.3, 53.0, 44.0, 36.1; HRMS-ESI (m/z) [M+NH4]+ calcd for C21H25NO8NH4, 437.1924; found, 437.1912; HPLC [Daicel Chiralpak AD-H,hexane/i-PrOH = 70/30, 254 nm, 1.0 mL/min tR1 = 8.54 min(major,S), tR2 = 20.61 min (minor,R)]. (+)-(S)-1,2-Methylenedioxy-5-(1-(3,4-methylenedioxyphenyl)-2nitroethyl)-4-(2,2-dimethoxyethyl)benzene (3ca). Purification by column chromatography (petroleum ether/ethyl acetate = 8:1 to5:1) to yield 3ca 0.69 g (85% yield) as colorless oil, 95% ee, [α]25 D = +14.3 (c 0.17, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.78−6.67 (m, 5H), 5.95 (s, 4H), 5.20 (t, J = 8.0 Hz, 1H), 4.86 (d, J = 8.0 Hz, 2H), 4.41 (t, J = 5.3 Hz, 1H), 3.36 (s, 3H), 3.35 (s, 3H), 3.00−2.95 (m, 1H), 2.88− 2.83 (m, 1H); 13C{1H}NMR (101 MHz, Acetone-d6): δ 148.1, 146.8, 146.6, 146.7, 133.8, 131.6, 129.1, 121.1, 111.2, 108.3, 108.1, 107.0, 105.5, 101.3, 101.2, 78.7, 53.3, 53.2, 43.9, 36.3; HRMS-ESI (m/z) [M +NH4]+ calcd for C20H21NO8NH4, 421.1611; found, 421.1610; HPLC [Daicel Chiralpak AD-H, hexane/i-PrOH = 90/10, 254 nm, 1.0 mL/ min tR1 = 20.96 min (major,S), tR2 = 31.63 min (minor,R)]. (+)-(S)-1-(Benzyloxy)-5-(1-(4-(benzyloxy)-3-methoxyphenyl)-2-nitroethyl)-4-(2,2-dimethoxyethyl)-2-methoxybenzene (3ab). Purification by column chromatography (petroleum ether/ethyl acetate = 4:1 to 2:1) to yield 3ab 0.99 g (84% yield) as pink oil, 97% ee; [α]25 D = +14.2 (c 0.35, CH2Cl2); 1H NMR (400 MHz, Acetone-d6): δ 7.48− 7.32 (m, 10H), 7.10−6.78 (m, 5H), 5.22−5.10 (m, 7H), 4.43 (t, J = 4.3 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.29 (s, 6H), 3.04−2.95 (m, 2H); 13C{1H}NMR (101 MHz, Acetone-d6): δ 150.1, 148.7, 147.6, 146.9, 137.7, 133.1, 130.4, 128.7, 128.3, 127.7, 127.6, 120.0, 115.6, 114.2, 113.8, 112.5, 105.7, 78.9, 70.8, 70.5, 55.4, 55.3, 53.4, 53.1, 43.8, 36.2; HRMS-ESI (m/z) [M+NH4]+ calcd for C34H37NO8NH4, 605.2863; found, 605.2857; HPLC [Daicel Chiralpak AD-H, hexane/i-PrOH = 70/30, 254 nm, 1.0 mL/min tR1 = 12.89 min (major, S), tR2 = 14.99 min (minor, R)]. (+)-(S)-1-(2,2-Dimethoxyethyl)-2-(1-(3,4-dimethoxyphenyl)-2-nitroethyl)-4,5-dimethoxybenzene (3bc). Purification by column chromatography (petroleum ether/ethyl acetate = 4:1 to 2:1) to yield 3bc 0.74 g (85% yield) as colorless oil, 96% ee, [α]25 D = +12.5 (c 0.32, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.82−6.70 (m, 5H), 5.23 (t, J = 8.0 Hz, 1H), 4.92 (d, J = 8.0 Hz, 2H), 4.35 (t, J = 4.8 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.32 (s, 3H), 3.31 (s, 3H), 2.99−2.94 (m, 1H), 2.90−2.85 (m, 1H); 13C{1H}NMR (101 MHz, CDCl3): δ 149.3, 148.3, 147.9, 147.7, 131.9, 129.6, 128.0, 119.7, 114.7, 111.3, 110.2, 105.7, 79.3, 56.1, 55.9, 54.3, 53.9, 43.9, 36.4; HRMS-ESI (m/z) [M+Na]+ calcd for C22H29NO8Na, 458.1791; found, 458.1793; HPLC [Daicel Chiralpak AD-H, hexane/iPrOH = 70/30, 254 nm, 1.0 mL/min tR1 = 7.69 min (major,S), tR2 = 12.88 min (minor,R)]. (+)-(S)-1-(2,2-Dimethoxyethyl)-2-(1-(3,4-dimethoxyphenyl)-2-nitroethyl)-4,5-methylenedioxybenzene (3cc). Purification by column chromatography (petroleum ether/ethyl acetate = 6:1 to 4:1) to yield 3cc 0.66 g (79% yield) as colorless oil, 96% ee,[α]25 D = +12.3 (c 0.13, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.80−6.67 (m, 5H), 5.93 (s, 2H), 5.21 (t, J = 8.0 Hz, 1H), 4.88 (d, J = 7.9 Hz, 2H), 4.37 (t, J = 5.1 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.34 (s, 3H), 3.32 (s, 3H), 3.00− 2.95 (m, 1H), 2.90−2.85 (m, 1H); 13C{1H}NMR (101 MHz, CDCl3): δ 149.3, 148.4, 146.7, 131.8, 131.0, 128.9, 119.6, 111.4, 106.9, 105.6, 101.2, 79.9, 55.9, 54.2, 53.9, 43.9, 36.5; HRMS-ESI (m/z) [M+Na]+ calcd for C21H25NO8Na, 442.1478; found, 442.1471; HPLC [Daicel 12902

DOI: 10.1021/acs.joc.7b02385 J. Org. Chem. 2017, 82, 12899−12907

Note

The Journal of Organic Chemistry

2H), 5.13 (s, 2H), 4.18−4.13 (m, 2H), 3.90 (s, 3H), 3.78 (s, 3H), 3.24−3.11 (m, 8H), 2.91−2.83 (m, 2H), 1.28 (s, 2H); 13C{1H}NMR (101 MHz, CDCl3): δ 149.6, 147.88, 146.6, 146.3, 137.3, 137.3, 128.9, 128.5, 128.5, 127.8, 127.3, 127.2, 119.9, 115.0, 114.1, 113.6, 112.2, 105.7, 71.2, 71.0, 56.0, 54.4, 53.8, 36.4; HRMS-ESI (m/z) [M+H]+ calcd for C34H41NO6, 558.2856; found, 558.2855. (+)-(S)-2-(2-(2,2-Dimethoxyethyl)-4,5-dimethoxyphenyl)-2-(3,4dimethoxy-phenyl)ethan-1-amine (2bc). Purification by column chromatography (dichloromethane/methanol = 15:1) to yield the desired product 2bc 1.06 g (88% yield) as colorless oil, [α]25 D = +27.3 (c 0.45, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.81−6.73 (m, 5H), 4.29−4.23 (m, 2H), 3.86−3.81 (m, 12H), 3.28−3.26 (m, 8H), 2.90 (t, J = 6.0 Hz, 2H), 1.97 (br, 2H); 13C{1H}NMR (101 MHz, CDCl3): δ 148.9, 147.6, 147.5, 147.2, 135.6, 132.9, 128.3, 119.9, 114.4, 111.7, 111.2, 110.2, 105.8, 56.0, 55.9, 55.8, 54.3, 53.7, 49.3, 47.6, 36.4; HRMS-ESI (m/z) [M+H]+calcd for C22H32NO6, 406.2230; found, 406.2229. (+)-(S)-2-(3,4-Dimethoxyphenyl)-2-(2,2-dimethoxyethyl)-4,5methylene-dioxyphenyl)ethan-1-amine (2cc). Purification by column chromatography (dichloromethane/methanol= 17:1) to yield the desired product 2cc 0.99 g (86% yield) as colorless oil, [α]25 D = +24.2 (c 0.30, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.80−6.73 (m, 5H), 5.93 (s, 2H), 4.28−4.20 (m, 2H), 3.84 (s, 6H), 3.28 (s, 6H), 3.22− 3.18 (m, 2H), 2.95−2.90 (m, 1H), 2.87−2.83 (m, 1H), 1.29 (br, 2H); 13 C{1H}NMR (101 MHz,CDCl3): δ 149.0, 147.6, 146.5, 145.7, 135.5, 134.5, 129.1, 120.0, 111.7, 111.3, 111.1, 106.9, 105. 7, 100.9, 55.9, 54.2, 53.9, 49.5, 47.6, 36.5; HRMS-ESI (m/z) [M+H]+ calcd for C21H28NO6, 390.1917; found, 390.1917. (+)-(S)-2-(5-(Benzyloxy)-2-(2,2-dimethoxyethyl)-4-methoxyphenyl)-2-(3,4-dimethoxy-phenyl)ethan-1-amine (2ac). Purification by column chromatography (dichloromethane/methanol = 17:1) to yield the desired product 2ac 1.22 g (85% yield) as colorless oil, [α]25 D = +32.2 (c 0.31, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.42−7.30 (m, 5H), 6.81−6.73 (m, 3H), 6.61−6.57 (m, 2H), 5.18 (s, 2H), 4.23− 4.15 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.75 (s, 3H), 3.27 (s, 3H), 3.25 (s, 3H), 3.10 (s, 2H), 2.93−2.82 (m, 2H), 1.44 (br, 2H); 13 C{1H}NMR (101 MHz, CDCl3): δ 148.9, 147.9, 147.5, 146.3, 137.3, 135.6, 132.7, 128.9, 128.5, 127.8, 127.3, 119.8, 114.9, 113.6, 111.6, 111.2, 105.7, 71.2, 56.0, 55.9, 55.8, 54.3, 53.7, 49.3, 47.6, 36.3; HRMSESI (m/z) [M+H]+calcd for C28H36NO6, 482.2543; found, 482.2551. General Procedure for the Preparation of (S)-Carbamate Derivatives 8.34 To a solution of 2 (5.5 mmol) in dried THF (30.0 mL) was added dropwise a solution of alkylchloroformate (6.6 mmol) and triethylamine (0.9 mL,6.6 mmol) under nitrogen atmosphere at 0 °C, and the resulting solution was stirred at room temperature. After the reaction was completed (monitoring by TLC), the distilled H2O (20.0 mL) was added. The resulting mixture was extracted with CH2Cl2 (50 mL × 3), and the combined extracts were washed with brine, dried over anhydrous Mg2SO4, and concentrated to afford the crude residue, which was purified by silica gel column chromatography to afford the desired product 8. (+)-Ethyl (S)-(2-(5-benzyloxy-2-(2,2-dimethoxyethyl)-4-methoxyphenyl)-2-(3,4-methylene-dioxyphenyl)ethyl)carbamate (8aa). Purification by column chromatography (petroleum ether/ethyl acetate = 4:1) to yield 8aa 2.81 g (95% yield) as colorless oil, [α]25 D = +25.4 (c 1.2, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.42−7.31 (m, 5H), 6.77−6.66 (m, 3H), 6.52−6.50 (m, 2H), 5.90 (s, 2H), 5.17 (s, 2H), 4.71 (s, 1H), 4.34−4.33 (m, 2H), 4.13−4.06 (m, 2H), 3.89 (s, 3H), 3.63−3.49 (m, 2H), 3.31 (s, 6H), 2.97−2.91 (m, 1H), 2.81−2.77 (m, 1H), 1.28−1.18 (m, 3H); 13C{1H}NMR (101 MHz, CDCl3): δ 156.4, 148.1, 147.8, 146.4, 146.1, 137.2, 136.0, 131.8, 128.6, 128.6, 127.9, 127.4, 120.8, 114.7, 113.6, 108.5, 108.2, 105.9, 100.9, 71.1, 60.7, 56.0, 54.5, 53.5, 45.8, 45.1, 36.1, 14.6; HRMS-ESI (m/z) [M+Na]+ calcd for C30H35NO8Na, 560.2260; found, 560.2267. (+)-Isobutyl (S)-(2-(2-(2,2-dimethoxyethyl)-4,5-dimethoxyphenyl)-2-(3,4-methylenedioxy-phenyl)ethyl)carbamate (8ba). Purification by column chromatography (petroleum ether/ethyl acetate = 4:1) to yield 8ba 2.53 g (94% yield) as colorless oil, [α]25 D = +15.0 (c 0.79, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.76−6.65 (m, 5H), 5.87 (s, 2H), 4.93 (s, 1H), 4.42 (t, J = 7.9 Hz, 1H), 4.34−4.32 (t, J = 4.0 Hz,

Chiralpak AD-H, hexane/i-PrOH = 90/10, 254 nm, 1.0 mL/min tR1= 23.33 min (minor,S), tR2 = 25.95 min (major,R)]. (+)-(S)-1-(Benzyloxy)-4-(2,2-dimethoxyethyl)-5-(1-(3,4-dimethoxyphenyl)-2-nitroethyl)-2-methoxybenzene (3ac). Purification by column chromatography (dichloromethane/petroleum ether/ethyl acetate = 10:8:1) to yield 3ac 0.79 g (77% yield) as colorless oil, 1 98% ee, [α]25 D = +8.6 (c 0.6, CH2Cl2). H NMR (400 MHz, CDCl3):δ7.39−7.30 (m, 5H), 6.79−6.57 (m, 5H), 5.17−5.07 (m, 3H), 4.77 (d, J = 8.1 Hz, 2H), 4.35 (t, J = 5.2 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.73 (s, 3H), 3.32 (s, 3H), 3.30 (s, 3H), 2.98−2.93 (m, 1H), 2.88−2.84 (m, 1H); 13C{1H}NMR (101 MHz, CDCl3):δ 149.2, 148.6, 148.2, 146.5, 137.1, 131.8, 129.6, 128.6, 128.5, 127.9, 127.3, 119.5, 115.1, 113.5, 111.2, 105.6, 79.2, 71.3, 56.0, 55.8, 54.3, 53.9, 43.8, 36.4; HRMS-ESI (m/z) [M+NH4]+ calcd for C28H33NO8NH4, 529.2550; found, 529.2555; HPLC [Daicel Chiralpak AD-H,hexane/i-PrOH = 80/20, 254 nm, 1.0 mL/min tR1= 11.65 min (major,S), tR2 = 13.78 min (minor, R)]. General Procedure for the Preparation of Aminoacetals 2.33 To a solution of 3 (2.98 mmol) in THF/MeOH (v/v = 3:1, 40 mL) was added NiCl2·6H2O (1.56 g, 6.57 mmol) under nitrogen atmosphere at room temperature, and the solution was stirred for 45 min. It was cooled to −5 °C, and NaBH4 (1.26 g, 33.33 mmol) was added in small portions. The reaction was gradually warmed to room temperature, stirred for 5 h, and then quenched with sat. NH4Cl aq. The mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and filtered. The obtained filtrate was extracted with ethyl acetate (40 mL × 3). Then the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the crude residue, which was purified by silica gel column chromatography to afford (S)-amine derivatives 2. (+)-(S)-2-(5-(Benzyloxy)-2-(2,2-dimethoxyethyl)-4-methoxyphenyl)-2-(3,4-methylenedioxy-phenyl)ethan-1-amine (2aa). Purification by column chromatography (dichloromethane/methanol = 19:1) to yield the desired product 2aa 1.12 g (81% yield) as colorless oil, [α]25 D = +26.00 (c 0.79, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.43−7.28 (m, 5H), 6.80−6.51 (m, 5H), 5.91 (s, 2H), 5.19 (s, 2H), 4.28 (t, J = 4.7 Hz, 2H), 4.13 (t, J = 6.5 Hz, 2H), 3.93 (s, 3H), 3.29 (s, 3H), 3.28 (s, 3H), 3.04 (s, 2H), 2.93−2.90 (m, 1H), 2.88−2.79 (m, 1H), 1.31(br, 2H); 13C{1H}NMR (101 MHz, CDCl3): δ 148.0, 147.7, 146.3, 145.9, 137.3, 128.9, 128.6, 127.9, 127.9, 121.00, 114.9, 113.8, 108.5, 108.1, 105.7, 100.9, 71.3, 56.0, 54.2, 53.7, 36.3; HRMS-ESI (m/ z) [M+H]+ calcd for C27H32NO6, 466.2230; found, 466.2231. (+)-(S)-2-(2-(2,2-Dimethoxyethyl)-4,5-dimethoxyphenyl)-2-(3,4methylenedioxy-phenyl)-ethan-1-amine (2ba). Purification by column chromatography (dichloromethane/methanol = 17:1) to yield the desired product 2ba 0.99 g (85% yield) as colorless oil, [α]25 D = +19.7 (c 0.33, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.78−6.67 (m, 5H), 5.88 (s, 2H), 4.29 (s, 1H), 4.22 (t, J = 6.8, 1H), 3.85 (s, 6H), 3.28 (s, 3H), 3.27 (s, 3H), 3.21 (d, J = 7.0 Hz, 2H), 2.94−2.82 (m, 2H), 1.51 (s, 2H); 13C{1H}NMR (101 MHz,CDCl3): δ 147.8, 147.7, 147.2, 146.0, 137.0, 132.9, 128.3, 121.0, 114.4, 110.1, 108.5, 108.2, 105.7, 100.9, 56.0, 55.9, 54.2, 53.7, 49.3, 47.5, 36.3; HRMS-ESI (m/z) [M+H]+ calcd for C21H28NO6, 390.1917; found, 390.1917. (+)-(S)-2-(2-(3,4-Methylenedioxyphenyl)-2-(2-(2,2-dimethoxyethyl)-4,5-methylenedioxy-phenyl)ethan-1-amine (2ca). Purification by column chromatography (dichloromethane/methanol = 19:1) to yield the desired product 2ca 0.94 g (85% yield) as colorless oil, [α]25 D = +29.6 (c 0.57, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 6.77−6.68 (m, 5H), 5.90−5.87 (m, 4H), 4.30 (t, J = 5.4 Hz, 1H), 4.19 (t, J = 7.4 Hz, 1H), 3.28 (s, 6H), 3.16 (s, 2H), 2.94−2.89 (m, 1H), 2.84−2.79 (m, 1H), 1.18 (br, 2H); 13C{1H}NMR (101 MHz, CDCl3): δ 147.8, 146.5, 146.0, 145.8, 136.8, 134.8, 129.1, 121.0, 111.0, 108.5, 108.1, 107.0, 105.6, 100.9, 54.0, 53.6, 49.4, 47.5, 36.4; HRMS-ESI (m/z) [M +H]+ calcd for C20H24NO6, 374.1604; found, 374.1606. (+)-(S)-2-(5-(Benzyloxy)-2-(2,2-dimethoxyethyl)-4-methoxyphenyl)-2-(4-(benzyloxy)-3-methoxyphenyl)ethan-1-amine (2ab). Purification by column chromatography (dichloromethane/methanol = 15:1) to yield 2ab 1.39 g (84% yield) as colorless oil, [α]25 D = +30.1 (c 0.41, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.42−7.36 (m, 10H), 6.80−6.73 (m, 3H), 6.64 (s, 1H), 6.48 (d, J = 7.8 Hz, 1H), 5.17 (s, 12903

DOI: 10.1021/acs.joc.7b02385 J. Org. Chem. 2017, 82, 12899−12907

Note

The Journal of Organic Chemistry

ESI (m/z) [M+Na]+ calcd for C31H39NO8Na, 576.2573; found, 576.2567. General Procedure for the Preparation of N-Alkyloxycarbonylisopavinane Derivatives 9.35 To a solution of compound 8 (1.18 mmol) in CH2Cl2 (40 mL) was added p-toluenesulfonic acid (448 mg, 2.36 mmol) and water (1.4 mL). The reaction mixture was heated to 45 °C and stirred for 48 h. The cooled reaction mixture was then poured into 50 mL of a sat. NaHCO3 aq. and extracted with CH2Cl2 (40 mL × 3). The combined organic layers were dried with anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure to afford the crude residue, which was purified by silica gel column chromatography to afford the desired product 9. (−)-(5R,12S)-8-Benzyloxy-9-methoxy-2,3-methylenedioxy-Nethoxycarbonylisopavinane (9aa). Purification by column chromatography (petroleum ether/ethyl acetate = 6:1) to yield 9aa 0.38 g (68% yield) as white solid, mp 62.1−63.0 °C, [α]25 D = −85.7 (c 0.38, CH2Cl2). 1H NMR (400 MHz, MeOD): δ 7.45−7.32 (m, 5H), 6.90− 6.63 (m, 4H), 5.88 (d, J = 12.0 Hz, 2H), 5.29 (s, 1H), 5.08 (s, 2H), 4.21−4.12 (m, 2H), 3.89−3.82 (m, 2H), 3.75 (s, 3H), 3.48−3.39 (m, 2H), 2.93 (d, J = 18.3 Hz, 1H), 1.34−1.24 (m, 3H); 13C{1H}NMR (101 MHz, CD3OD): δ 156.2, 155.9, 149.0, 146.8, 146.3, 146.0, 137.3, 135.0, 132.9, 129.8, 129.7, 127.2, 127.1, 115.1, 114.9, 106.7, 105.6, 100.8, 71.8, 61.3, 55.2, 54.3, 54.0, 51.5, 50.9, 45.3, 38.9, 38.4, 13.6; HRMS-ESI (m/z) [M+H]+ calcd for C28H28NO6, 474.1917; found, 474.1915. (−)-(5R,12S)-8,9-Dimethoxy-2,3-methylenedioxy-N-isobutyloxycarbonylisopavinane (9ba). Purification by column chromatography (petroleum ether/ethyl acetate = 7:1) to yield 9ba 0.34 g (68% yield) 1 as colorless oil, [α]25 D = −73.5 (c 0.07, CH2Cl2). H NMR (400 MHz, CDCl3): δ 6.79−6.69 (m, 3H), 6.54−6.52 (m, 1H), 5.92 (d, J = 19.4 Hz, 2H), 5.37 (d, J = 39.4 Hz, 1H), 4.08−3.77 (m, 10H), 3.63−3.43 (m, 2H), 3.02−2.96 (m, 1H), 2.05−1.89 (m, 1H), 1.03−0.91 (m, 6H); 13 C{1H}NMR (101 MHz, CDCl3): δ 155.9, 148.2, 146.8, 146.7, 146.3, 134.8, 132.6, 130.4, 126.5, 114.3, 111.7, 106.8, 106.1, 100.9, 71.5, 56.1, 55.9, 53.7, 50.9, 46.1, 39.0, 28.0, 19.1; HRMS-ESI (m/z) [M+H]+ calcd for C24H28NO6, 426.1917; found, 426.1916. (−)-(5R,12S)-2,3:8,9-Bis(methylenedioxy)-N-isobutyloxycarbonylisopavinane (9ca). Purification by column chromatography (petroleum ether/ethyl acetate = 10:1) to yield 9ca 0.34 g (71% yield) as 1 colorless oil, [α]25 D = −78.9 (c 0.23, CH2Cl2). H NMR (400 MHz, CDCl3): δ 6.78−6.68 (m, 3H), 6.50 (d, J = 7.4 Hz, 1H), 5.93−5.87 (m, 4H), 5.40 (s, 0.66H), 5.24 (s, 0.33H), 4.07−3.73 (m, 4H), 3.61− 3.41 (m, 2H), 2.96 (dd, J = 17.1, 7.9 Hz, 1H), 1.93−1.90 (m, 1H), 1.02−0.92 (m, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ 155.8, 146.9, 146.7, 146.4, 145.6, 134.6, 133.5, 130.4, 127.8, 110.9, 108.5, 106.7, 106.0, 100.9, 71.5, 53.6, 50.8, 46.3, 39.4, 28.1, 26.9, 19.2; HRMS-ESI (m/z) [M+H]+ calcd for C23H24NO6,410.1604; found, 410.1605. (−)-(5R,12S)-2,8-Bis(benzyloxy)-3,9-dimethoxy-N-isobutyloxycarbonylisopavinane (9ab). Purification by column chromatography (petroleum ether/ethyl acetate = 5:1) to yield 9ab 0.45 g (64% yield) 1 as colorless oil, [α]25 D = −77.4 (c 4.0, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.50−7.33 (m, 10H), 6.88 (s, 1H), 6.79 (s, 2H),6.58 (d, J = 5.5 Hz, 1H), 5.40 (s, 0.7H), 5.25 (s, 0.3H), 5.17 (d, J = 10.8 Hz, 4H), 4.09−3.74 (m, 11H), 3.62−3.46 (m, 2H), δ 2.98 (t, J = 14.4, 14.4 Hz, 1H), 1.96−1.88 (m, 1H), 1.05−0.93 (m, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ 155.9, 149.0, 147.2, 146.0, 137.3, 137.1, 134.2, 132.7, 129.2, 128.6, 128.5, 127.9, 127.9, 127.5, 127.4, 127.3, 115.0, 112.2, 109.3, 71.5, 56.2, 56.0, 53.5, 51.0, 45.8, 39.2, 28.1, 28.0, 27.0, 19.4, 19.2; HRMS-ESI (m/z) [M+H]+ calcd for C37H40NO6, 594.2856; found, 594.2858. (−)-(5R,12S)-2,3,8,9-Tetramethoxy-N-isobutyloxycarbonylisopavinane (9bc). Purification by column chromatography (petroleum ether/ethyl acetate = 5:1) to yield 9bc 0.37 g (71% yield) as colorless 1 oil, [α]25 D = −76.6 (c 0.19, CH2Cl2). H NMR (400 MHz, CDCl3): δ 6.85−6.72 (m, 3H),6.54−6.52 (m, 1H), 5.45 (s, 0.66H), 5.29 (s, 0.33H), 4.16−4.06 (m, 2H), 3.97−3.80 (m, 14H), 3.63−3.45 (m, 2H), 3.02 (d, J = 17.1 Hz, 1H), 1.94−1.87 (m, 1H), 1.04−0.91 (m, 6H); 13 C{1H}NMR (101 MHz, CDCl3): δ 155.9, 148.2, 148.1, 147.9, 146.8, 133.6, 132.8, 129.2, 126.6, 114.3, 111.8, 109.5, 108.7, 71.4, 55.8, 53.6,

1H), 3.84−3.72 (m, 10H), 3.31 (s, 3H), 3.30 (s, 3H), 2.95 (dd, J = 14.2, 6.4 Hz, 1H), 2.81 (dd, J = 14.2, 4.5 Hz, 1H), 1.84−1.79 (m, 1H), 0.85 (s, 3H), 0.83 (s, 3H); 13C{1H}NMR (101 MHz, CDCl3): δ 156.6, 147.8, 147.4, 146.1, 136.1, 132.2, 128.0, 120.8, 114.2, 110.3, 108.4, 108.2, 106.0, 100.9, 70.9, 56.0, 55.8, 54.5, 53.5, 45.8, 45.1, 36.1, 27.9, 18.9; HRMS-ESI(m/z)[M+Na]+ calcd for C26H35NO8Na, 512.2260; found, 512.2263. (+)-Isobutyl (S)-(2-(3,4-methylenedioxyphenyl)-2-(2-(2,2-dimethoxyethyl)-4,5-methylene-dioxyphenyl)ethyl)carbamate (8ca). Purification by column chromatography (petroleum ether/ethyl acetate = 4:1) to yield 8ca 2.50 g (96% yield) as colorless oil, [α]25 D = +18.1 (c 0.47, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.74−6.68 (m,5H), 5.92 (s, 2H), 5.90 (s, 2H), 4.96 (s, 1H), 4.45−4.35 (m, 2H), 3.81 (d, J = 6.6 Hz, 2H), 3.69−3.66 (m, 2H), 3.33 (s, 6H), 2.97 (dd, J = 14.3, 6.2 Hz, 1H), 2.82 (dd, J = 14.2, 4.2 Hz, 1H), 1.86−1.81 (m, 1H), 0.88 (s,3H), 0.87 (s,3H); 13C{1H}NMR (101 MHz, CDCl3): δ 156.6, 147.9, 146.9, 146.2, 146.1, 135.9, 133.6, 128.9, 120.8, 110.9, 108.5, 108.2, 107.0, 105.9, 101.0, 70.9, 54.4, 53.6, 45.8, 45.1, 36.3, 28.0, 19.0; HRMS-ESI (m/z) [M+Na]+calcd for C25H31NO8Na, 496.1947; found, 496.1943. (+)-Isobutyl (S)-(2-(5-benzyloxy-2-(2,2-dimethoxyethyl)-4-methoxyphenyl)-2-(4-(benzyloxy)-3-methoxyphenyl)ethyl)carbamate (8ab). Purification by column chromatography (petroleum ether/ethyl acetate = 3:1) to yield 8ab 3.47 g (96% yield) as colorless oil, [α]25 D = +32.3 (c 0.37, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.45−7.15 (m, 10H), 6.78−6.66 (m, 4H), 6.43 (d, J = 8.0 Hz, 1H), 5.17 (s, 2H), 5.13 (s, 2H), 4.67 (s, 1H), 4.39−4.35 (m, 1H), 4.24 (t, J = 5.3 Hz, 1H), 3.90−3.78 (m, 8H), 3.68−3.52 (m, 2H), 3.28 (s, 3H), 3.27 (s, 3H), 2.92−2.79 (m, 2H), 1.89−1.82 (m, 1H), 0.98−0.88 (m, 6H); 13 C{1H}NMR (101 MHz, CDCl3): δ 156.6, 149.6, 148.0, 146.7, 146.3, 137.2, 135.2, 131.8, 128.7, 128.5, 127.8, 127.3, 127.2, 119.7, 114.7, 114.0, 113.5, 112.0, 105.9, 71.0, 56.0, 54.7, 53.7, 45.8, 45.1, 36.3, 28.0, 19.1; HRMS-ESI (m/z) [M+Na]+ calcd for C39H47NO8Na, 680.3199; found, 680.3192. (+)-Isobutyl (S)-(2-(2-(2,2-dimethoxyethyl)-4,5-dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)ethyl)carbamate (8bc). Purification by column chromatography (petroleum ether/ethyl acetate = 3:1) to yield 8bc 2.64 g (95% yield) as colorless oil, [α]25 D = +21.4 (c 0.79, CH2Cl2). 1H NMR(400 MHz, CDCl3): δ 6.80−6.71 (m, 5H), 4.90 (s, 1H), 4.45 (t, J = 7.9 Hz, 1H), 4.31 (dd, J = 6.5, 4.5 Hz, 1H), 3.87−3.77 (m, 16H), 3.32 (s, 3H), 3.31 (s, 3H), 3.01−2.96 (m, 1H), 2.86−2.83 (m, 1H), 1.87−1.83 (m, 1H), 0.93−0.85 (m, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ 156.7, 149.0, 147.8, 147.4, 134.7, 132.1, 128.0, 119.8, 114.1, 111.4, 111.2, 110.2, 106.1, 71.0, 64.3, 60.4, 56.0, 55.8, 54.7, 53.6, 45.8, 45.0, 36.2, 28.0, 21.0, 19.0; HRMS-ESI (m/z) [M+Na]+calcd for C27H39NO8Na, 528.2573; found, 528.2561. (+)-Isobutyl (S)-(2-(3,4-dimethoxyphenyl)-2-(2-(2,2-dimethoxyethyl)-4,5-methylenedioxy-phenyl)ethyl)carbamate (8cc). Purification by column chromatography (petroleum ether/ethyl acetate = 2:1) to yield 8cc 2.58 g (96% yield) as colorless oil, [α]25 D = +17.2 (c 0.27, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.80−6.72 (m, 5H), 5.92 (s, 2H), 4.92 (s, 1H), 4.45 (t, J = 7.3 Hz, 1H), 4.33 (s, 1H), 3.84−3.66 (m, 10H), 3.33 (s, 6H), 3.00−2.95 (m, 1H), 2.86−2.82 (m, 1H), 1.87−1.82(m, 1H), 0.88−0.87(m, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ 156.6, 149.1, 147.8, 146.7, 146.0, 134.6, 133.7, 128.9, 119.8, 111.5, 111.3, 110.9, 107.0, 105.9, 101.0, 71.0, 55.9, 55.9, 54.5, 53.7, 45.8, 45.1, 36.4, 28.0, 19.0; HRMS-ESI(m/z) [M+Na]+ calcd for C26H35NO8Na, 512.2260; found, 512.2254. (+)-Ethyl (S)-(2-(5-benzyloxy-2-(2,2-dimethoxyethyl)-4-methoxyphenyl)-2-(3,4-dimethoxy-phenyl)ethyl)carbamate (8ac). Purification by column chromatography (petroleum ether/ethyl acetate = 2:1) to yield 8ac 2.89 g (95% yield) as colorless oil, [α]25 D = +23.2 (c 0.56, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.42−7.29 (m, 5H), 6.78−6.71 (m, 3H), 6.56−6.54 (m, 2H), 5.16 (s, 2H), 4.68 (s, 1H), 4.39−4.27 (m, 2H), 4.14−4.05 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.75 (s, 3H), 3.70−3.51(m, 2H), 3.30 (s, 3H), 3.29 (s, 3H), 2.96−2.91 (m, 1H), 2.84−2.79 (m, 1H), 1.29−1.19 (m,3H); 13C{1H}NMR (101 MHz, CDCl3): δ 156.4, 148.9, 148.1, 147.6, 146.4, 137.2, 134.6, 131.9, 128.7, 128.5, 127.8, 127.3, 119.7, 114.7, 113.5, 111.3, 111.1, 105.9, 71.1, 60.7, 56.0, 55.86, 55.8, 54.6, 53.6, 45.7, 45.0, 36.2, 14.6; HRMS12904

DOI: 10.1021/acs.joc.7b02385 J. Org. Chem. 2017, 82, 12899−12907

Note

The Journal of Organic Chemistry 45.8, 39.1, 28.0, 19.1; HRMS-ESI (m/z) [M+H]+ calcd for C25H32NO6, 442.2230; found, 442.2224. (−)-(5R,12S)-2,3-dimethoxy-8,9-methylenedioxy-N-isobutyloxycarbonylisopavinane (9cc). Purification by silica gel column chromatography (petroleum ether/ethyl acetate = 7:1) to yield the desired product 9cc 0.35 g (70% yield) as colorless oil, [α]25 D = −103.0 (c0.11, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.84−6.71 (m, 3H), 6.52−6.49 (m, 1H), 5.88 (d, J = 13.0 Hz, 2H), 5.43 (s, 0.66H), 5.27 (s, 0.33H), 4.09−3.77 (m, 10H), 3.61−3.43 (m, 2H), 3.00 (d, J = 17.3 Hz, 1H), 1.93−1.88 (m, 1H), 0.93−0.91 (m, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ 155.9, 148.3, 148.0, 146.8, 145.5, 133.7, 133.4, 129.2, 127.8, 111.2, 109.4, 108.7, 108.5, 100.9, 71.5, 56.1, 56.1, 53.4, 50.9, 46.1, 39.6, 28.1, 19.1; HRMS-ESI (m/z) [M+H]+calcd for C24H28NO6, 426.1917; found, 426.1907. (−)-(5R,12S)-8-Benzyloxy-2,3,9-trimethoxy-N-ethoxycarbonylisopavinane (9ac). Purification by silica gel column chromatography (petroleum ether/ethyl acetate = 6:1) to yield the desired product 9ac 1 0.39 g (67% yield) as colorless oil, [α]25 D = −85.7 (c 0.46, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.48−7.35 (m, 5H), 6.84−6.73 (m, 3H), 6.57−6.55 (m, 1H), 5.44 (s, 0.63H), 5.29 (s, 0.37H), 5.15 (s, 2H), 4.09−3.70 (m, 13H), 3.57−3.52 (m, 2H), 3.00 (d, J = 17.2 Hz, 1H), 1.37−1.23 (m,3H); 13C{1H}NMR (101 MHz, CDCl3): δ 155.9, 149.0, 148.2, 147.9, 146.0, 137.2, 133.6, 132.8, 129.2, 128.6, 127.8, 127.4, 115.0, 109.4, 108.6, 71.5, 61.3, 56.2, 56.0, 53.5, 51.0, 45.8, 39.1, 14.8; HRMS-ESI (m/z) [M+H]+ calcd for C29H32NO6, 490.2230; found, 490.2230. General Procedure for the Synthesis of Enantiopure Isopavine Alkaloids 1. To a solution of 9 (0.5 g, 1.13 mmol) in THF (40 mL) was added dropwise LiAlH4 (1 M in THF, 3.4 mL, 3.4 mmol) at 0 °C for 1 h. The resulting solution was stirred for 5 h at this temperature. After the reaction was completed (monitoring by TLC), the distilled H2O (20.0 mL) was added slowly. The resulting gelatinous mixture was diluted with CH2Cl2 (20.0 mL) and filtered through a Celite pad, washing the pad with CH2Cl2 and MeOH. The solvent was removed under reduced pressure to afford the crude residue, which was purified by silica gel column chromatography to afford the isopavine alkaloids 1.33 Note that the alkaloids 1a′, 1d′, and 1g′ could be further transformed into the corresponding alkaloids 1a, 1d, and 1g by hydrogenolytic O-debenzylation according the following operation. Pd/C (10%, 500 mg) was added to a solution of O-benzylated isopavine alkaloids (1 mmol) in MeOH (80 mL), and the mixture was stirred under hydrogen at atmospheric pressure for 7 h. After the reaction was completed (monitoring by TLC), the catalyst was removed by filtration with Celite pad, and washed with MeOH (30 mL). The organic solution was concentrated to give the crude residue, which was purified by silica gel column chromatography to afford the isopavine alkaloids 1a, 1d, and 1g. (−)-(5R,12S)-8-Benzyloxy-9-methoxy-2,3-methylenedioxy-Nmethylisopavinane (1a′). Purification by silica gel column chromatography (dichloromethane/methanol = 17:1) to yield the desired product 1a′ 0.37 g (78% yield) as colorless oil, [α]25 D = −60.9 (c 4.7, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.47−7.33 (m, 5H), 6.74− 6.58 (m, 4H), 5.90 (d, J = 25.1 Hz, 2H), 5.13 (s, 2H), 3.89 (s, 1H), 3.80 (s, 3H), 3.57−3.53 (m, 3H), 2.93 (d, J = 17.2 Hz, 1H), 2.82 (dd, J = 10.6, 4.5 Hz, 1H), 2.51 (s, 3H); 13C{1H}NMR (101 MHz, CDCl3): δ 148.7, 146.4, 146.0, 145.9, 137.3, 135.0, 134.3, 130.7, 128.5, 127.8, 127.4, 127.4, 114.9, 114.4, 107.3, 106.2, 100.7, 71.5, 62.6, 59.8,56.1, 45.8, 45.4, 38.2, 27.0; HRMS-ESI (m/z) [M+H]+ calcd for C26H26NO4, 416.1862; found, 416.1861. (−)-(5R,12S)-8-hydroxy-9-methoxy-2,3-methylenedioxy-N-methylisopavinane (1a). Purification by column chromatography (dichloromethane/methanol = 15:1) to yield 1a 0.32 g (98% yield) as 1 colorless oil, 96% ee, [α]25 D = −90.4 (c 0.9, CH2Cl2). H NMR (400 MHz, CD3OD): δ 6.79 (s, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 6.58 (s, 1H), 5.88 (d, J = 25.1 Hz, 2H), 3.97 (s, 1H), 3.76 (s, 3H), 3.63 (s, 1H), 3.48 (d, J = 11.0 Hz, 2H), 3.33 (s, 1H), 2.92−2.80 (m, 2H), 2.45 (s, 3H); 13C{1H}NMR (101 MHz, CD3OD): δ 146.8, 146.6, 146.2, 143.9, 134.9, 134.8, 129.8, 124.7, 114.4, 113.9, 107.0, 105.7, 100.7, 62.6, 59.5, 55.0, 44.8, 44.0, 36.6; HRMS calcd for C19H20NO4 [M

+H]+: 326.1392, found: 326.1387; HPLC [Daicel Chiralpak AD-H, hexane/i-PrOH = 80/20, 210 nm, 1.0 mL/min tR1= 27.63 min (minor), tR2 = 44.54 min (major)]. (−)-(5R,12S)-8,9-Dimethoxy-2,3-methylenedioxy-Nmethylisopavinane[(−)-amurensinine] (1b). Purification by column chromatography (dichloromethane/methanol= 17:1) to yield 1b 0.29 g (76% yield) as white solid, 96% ee, [α]20 D = −114.1 (c 0.9,CH2Cl2), [ 12 lit12 [α]20 D = −145.0 (c 1.0, CH2Cl2) ]; m. p.178−181 °C, [ lit 160− 163 °C]. 1H NMR (400 MHz, CDCl3): δ 6.74 (s, 2H), 6.64 (s, 1H), 6.54 (s, 1H), 5.90 (d, J = 25.3 Hz, 2H), 3.88 (s, 4H), 3.80 (s, 3H), 3.63−3.49 (m, 3H), 22.94−2.85 (m, 2H), 2.51 (s, 3H); 13C{1H}NMR (101 MHz, CDCl3): δ 147.8, 146.7, 146.3, 146.0, 135.1, 134.5, 131.1, 126.6, 114.3, 111.2, 107.3, 106.1, 100.6, 62.6, 59.9, 56.0, 55.9, 46.1, 45.3, 38.3; HRMS-ESI (m/z) [M+H]+ calcd for C20H22NO4, 340.1549; found, 340.1549; HPLC [Daicel Chiralpak AD-H, hexane/i-PrOH = 85/15, 210 nm, 1.0 mL/min tR1= 27.43 min (minor), tR2 = 30.93 min (major)]. (−)-(5R,12S)-2,3:8,9-Bis(methylenedioxy)-N-methylisopavinane[(−)-reframidine] (1c). Purification by column chromatography (dichloromethane/methanol = 19:1) to yield 1c 0.28 g (78% yield) 20 27 ascolorless oil, 95% ee, [α]25 D = −121.4 (c 4.4, MeOH), [ lit [α]D = 1 −123 ± 3 (c 0.4, MeOH) ]; H NMR (400 MHz, CDCl3): δ 6.73 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 6.51 (s, 1H), 5.93−5.85 (m, 4H), 3.83 (s, 1H), 3.61−3.46 (m, 3H), 2.92−2.82 (m, 2H), 2.49 (s, 3H); 13 C{1H}NMR (101 MHz, CDCl3): δ 146.4, 146.3, 146.0, 145.3, 135.5, 134.8, 131.1, 127.8, 111.0, 108.0, 107.2, 106.2, 100.7, 100.7, 62.4, 59.7, 53.4, 46.2, 45.3, 38.6; HRMS-ESI (m/z) [M+H]+ calcd for C19H18NO4, 324.1236; found, 324.1235; HPLC [Daicel Chiralpak OJ-H,hexane/i-PrOH = 95/5, 210 nm, 1.0 mL/min tR1= 71.95 min (major), tR2 = 85.92 min (minor)]. (−)-(5R,12S)-2,8-Bis(benzyloxy)-3,9-dimethoxy-N-methylisopavinane (1d′). Purification by column chromatography (dichloromethane/methanol = 15:1) to yield 1d′ 0.41 g (71% yield) as white 1 solid, [α]25 D = −43.5 (c 0.95, CH2Cl2), mp 135−137 °C; H NMR (400 MHz, CD3OD): δ 7.44−7.29 (m, 10H), 7.05 (s, 1H),6.95 (s, 1H),6.90 (s, 1H), 6.65 (s, 1H), 5.07 (d, J = 3.3 Hz, 4H), 4.31 (s, 1H), 3.85−3.80 (m, 4H), 3.71−3.59 (m, 5H), 3.10−2.99 (m, 2H), 2.62 (s, 3H); 13C{1H}NMR (101 MHz, CD3OD): δ 150.1, 149.1, 147.3, 146.2, 137.2, 137.2, 134.0, 133.7, 128.1, 128.0, 127.6, 127.5, 127.5, 127.4, 125.8, 125.7, 114.7, 114.4, 113.8, 109.7, 71.2, 71.0, 62.9, 59.6, 55.3, 55.2, 43.5, 43.5, 35.5; HRMS-ESI (m/z) [M+H]+ calcd for C33H34NO4, 508.2488; found, 508.2488. (−)-(5R,12S)-2,8-Dihydroxy-3,9-dimethoxy-N-methylisopavinane[(−)-thalidicine] (1d). Purification by column chromatography (dichloromethane/methanol = 13:1) to yield 1d 0.31 g (96% yield) as paste solid, 97% ee, [α]25 D = −68.9 (c 1.3, CH2Cl2); mp 202− 205 °C, [ lit27 mp 200 °C ]. 1H NMR (400 MHz, CD3OD): δ 6.97 (s, 1H), 6.92 (s, 1H), 6.72 (s, 1H), 6.66 (s, 1H), 4.63 (s, 1H), 3.95−3.68 (m, 9H), 3.36 (s, 1H), 3.13 (d, J = 18.5 Hz, 1H), 2.86 (s, 3H); 13 C{1H}NMR (101 MHz, CD3OD): δ 148.5, 147.3, 146.0, 144.7, 132.9, 131.4, 123.4, 122.1, 114.5, 114.2, 113.8, 109.0, 63.8, 60.1, 55.2, 55.1, 42.7, 34.8; HRMS calcd for C19H22NO4 [M+H]+: 328.1549, found: 328.1545; HPLC [Daicel Chiralpak AD-H, hexane/i-PrOH= 70/30, 210 nm, 1.0 mL/min tR1= 11.18 min (minor), tR2 = 37.05 min (major)]. (−)-(5R,12S)-2,3,8,9-Tetramethoxy-N-methylisopavinane[(−)-Omethylthalisopavine] (1e). Purification by column chromatography (dichloromethane/methanol= 15:1) to yield 1e 0.30 g (75% yield) as 12 [α]20 white solid, 95% ee, [α]20 D = −101.3 (c 0.8, EtOH), [ lit D = 12 −103.6 (c 0.2, EtOH) ]; mp 162−165 °C, [ lit mp 157−159 °C ]. 1H NMR (400 MHz, CD3OD): δ 6.94 (s, 1H), 6.90 (s, 1H), 6.80 (s, 1H), 6.61 (s, 1H), 3.96 (s, 1H), 3.82−3.72 (m, 13H), 3.49−3.47 (m, 2H), 2.92 (d, J = 17.6 Hz, 1H), 2.83 (dd, J = 10.9, 4.5 Hz, 1H), 2.42 (s, 3H); 13C{1H}NMR (101 MHz, CD3OD): δ 148.4, 147.9, 147.9, 146.8, 135.1, 134.2, 129.5, 126.5, 114.5, 111.7, 110.9, 109.4, 62.1, 59.7, 55.4, 55.3, 55.2, 44.8, 44.1, 36.9; HRMS-ESI (m/z) [M+H]+ calcd for C21H26NO4, 356.1862; found, 356.1860; HPLC [Daicel Chiralpak AD-H, hexane/i-PrOH = 80/20, 210 nm, 1.0 mL/min tR1= 13.58 min (minor), tR2 = 16.63 min (major)]. 12905

DOI: 10.1021/acs.joc.7b02385 J. Org. Chem. 2017, 82, 12899−12907

Note

The Journal of Organic Chemistry (−)-(5R,12S)-2,3-Dimethoxy-8,9-methylenedioxy-N-methylisopavinane [(−)-reframine] (1f). Purification by column chromatography (dichloromethane/methanol= 17:1) to yield 1f 0.29 g (76% yield) as 20 27 colorless oil, 96% ee; [α]25 D = −146.7 (c 0.6, MeOH), [ lit [α]D = 1 −146 ± 3 (c 0.5, MeOH) ]; H NMR (400 MHz, CDCl3): δ 6.78 (s, 1H), 6.75 (s, 1H), 6.66 (s, 1H), 6.52 (s, 1H), 5.86 (d, J = 16.2 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 4H), 3.63−3.50 (m, 3H), 2.89 (t, J = 17.9 Hz, 2H), 2.51 (s, 3H); 13C{1H}NMR (101 MHz, CDCl3): δ 148.1, 147.7, 146.4, 145.3, 135.7, 133.7, 127.9, 111.0, 110.2, 108.9, 108.0, 100.7, 62.2, 59.8, 56.2, 56.0, 46.0, 45.2, 38.5; HRMS-ESI (m/z) [M +H]+ calcd for C20H22NO4, 340.1549; found, 340.1550; HPLC [Daicel Chiralpak AD-H,hexane/i-PrOH = 85/15, 210 nm, 1.0 mL/min tR1= 15.13 min (minor), tR2 = 19.91 min (major)]. (−)-(5R,12S)-8-Benzyloxy-2,3,9-trimethoxy-N-methylisopavinane (1g′). Purification by column chromatography (dichloromethane/ methanol = 15:1) to yield 1g′ 0.38 g (78% yield) as colorless oil, [α]25 D = −40.66 (c 0.76, CH2Cl2). 1H NMR (400 MHz, CD3OD): δ 7.46− 7.31 (m, 5H), 6.96 (s, 1H), 6.88 (s, 1H), 6.86 (s, 1H), 6.67 (s, 1H), 5.09 (s, 2H), 4.08 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.76 (s, 3H), 3.59−3.54 (m, 3H), 2.99−2.90 (m, 2H), 2.50 (s, 3H); 13C{1H}NMR (101 MHz, CD3OD): δ 148.8, 148.6, 148.0, 145.9, 137.4, 134.7, 133.9, 128.5, 128.0, 127.5, 127.5, 126.9, 114.8, 114.5, 110.8, 109.2, 71.1, 62.3, 61.4, 59.6, 55.4, 55.3, 55.2, 44.4, 43.9, 36.6; HRMS-ESI (m/z) [M +H]+ calcd for C27H30NO4,432.2175; found, 432.2172. (−)-(5R,12S)-8-Hydroxy-2,3,9-trimethoxy-N-methylisopavinane (1g). Purification by column chromatography (dichloromethane/ methanol = 13:1) to yield 1g 0.33 g (98% yield) as white solid, 97% ee, 1 [α]25 D = −86.7(c 1.1, CH2Cl2), m.p.169−170 °C. H NMR (400 MHz, CD3OD): δ 7.08 (s, 1H), 6.99 (s, 1H), 6.72 (s, 1H), 6.65 (s, 1H),4.60 (s, 1H), 3.90−3.67 (m, 13H), 3.27 (d, J = 11.8 Hz, 1H), 3.14 (d, J = 18.2 Hz, 1H), 2.82 (s, 3H); 13C{1H}NMR (101 MHz, CD3OD): δ 149.8, 148.6, 147.3, 144.6, 133.0, 124.1, 122.5, 114.6, 113.8, 111.2, 109.3, 63.7, 59.9, 55.4, 55.3, 55.1, 43.4, 42.9, 35.0; HRMS calcd for C20H24NO4 [M+H]+: 342.1705, found: 342.1701; HPLC [Daicel Chiralpak AD-H,hexane/i-PrOH = 65/35, 210 nm, 1.0 mL/min tR1= 10.19 min (minor), tR2 = 63.9 min (major)].

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Wang, D.; Yang, C. Fitoterapia 2001, 72, 120. (c) Philipov, S.; Istatkova, R.; Yadamsurenghiin, G. O.; Samdan, J.; Dangaa, S. Nat. Prod. Res. 2007, 21, 852. (3) (a) Gee, K. R.; Barmettler, P.; Rhodes, M. R.; McBurney, R. N.; Reddy, N. L.; Hu, L.-Y. R.; Cotter, E.; Hamilton, P. N.; Weber, E.; Keana, J. F. W. J. Med. Chem. 1993, 36, 1938. (b) Webber, E.; Keana, J. W. F.; Barmettler, P. WO 90,12,575, 1990. (c) Kemp, J. A.; Foster, A. C.; Wong, E. H. F. Trends Neurosci. 1987, 10, 294. (d) Hanessian, S.; Parthasarathy, S.; Mauduit, M.; Payza, K. J. Med. Chem. 2003, 46, 34. (4) (a) Dyke, S. F.; Ellis, A. C. Tetrahedron 1971, 27, 3803. (b) Bobbitt, J. M.; Sih, J. C. J. Org. Chem. 1968, 33, 856. (c) Elliott, J. W. J. Org. Chem. 1979, 44, 1162. (5) (a) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223. (b) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Tetrahedron 2009, 65, 6454. (6) (a) Kametani, T.; Ogasawara, K. Chem. Pharm. Bull. 1973, 21, 893. (b) Kametani, T.; Hirata, S.; Ogasawara, K. J. Chem. Soc., Perkin Trans. 1 1973, 14, 1466. (7) Takayama, H.; Nomoto, T.; Suzuki, T.; Takamoto, M.; Okamoto, T. Heterocycles 1978, 9, 1545. (8) (a) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752. (b) Krishnan, S. J.; Bagdanoff, T. D.; Ebner, C.; Ramtohul, Y. K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745. (c) Ebner, D. C.; Trend, R. M.; Genet, C.; McGrath, M. J.; O’Brien, P.; Stoltz, B. M. Angew. Chem., Int. Ed. 2008, 47, 6367. (9) Dyke, S. F.; Kinsman, R. G.; Warren, P.; White, A. W. C. Tetrahedron 1978, 34, 241. (10) Gottlieb, L.; Meyers, A. I. J. Org. Chem. 1990, 55, 5659. (11) Meyers, A. I.; Dickman, D. A.; Boes, M. Tetrahedron 1987, 43, 5095. (12) Carrillo, L.; Badia, D.; Dominguez, E.; Vicario, J. L.; Tellitu, I. J. Org. Chem. 1997, 62, 6716. (13) Dragoli, D. R.; Burdett, M. T.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 10127. (14) (a) Hanessian, S.; Mauduit, M. Angew. Chem., Int. Ed. 2001, 40, 3810. (b) Hanessian, S.; Talbot, C.; Mauduit, M.; Saravanan, P.; Gone, J. R. Heterocycles 2006, 67, 205. (15) For reviews on Pictet−Spengler reaction, see: (a) Bringmann, G.; Ewers, C. L. J.; Walter, R. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 6, Chapter 4.2, p 733. (b) Stöckigt, J.; Antonchick, A. P.; Wu, F.; Waldmann, H. Angew. Chem., Int. Ed. 2011, 50, 8538. (16) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716. (17) Wang, Z. Q.; Feng, C. G.; Zhang, S. S.; Xu, M. H.; Lin, G. Q. Angew. Chem., Int. Ed. 2010, 49, 5780. (18) Xue, F.; Wang, D.; Li, X.; Wan, B. J. Org. Chem. 2012, 77, 3071. (19) Lang, F.; Chen, G.; Li, L.; Xing, J.; Han, F.; Cun, L.; Liao, J. Chem. - Eur. J. 2011, 17, 5242. (20) Huang, K. C.; Gopula, B.; Kuo, T. S.; Chiang, C. W.; Wu, P. Y.; Henschke, J. P.; Wu, H. L. Org. Lett. 2013, 15, 5730. (21) He, Q.; Xie, F.; Fu, G.; Quan, M.; Shen, C.; Yang, G.; Gridnev, I. D.; Zhang, W. Org. Lett. 2015, 17, 2250. (22) (a) Wünsch, B.; Nerdinger, S. Arch. Pharm. 1995, 328, 301. (b) Wünsch, B.; Nerdinger, S.; Höfner, G. Liebigs Ann. 1995, 1995, 1303. (c) Barreiro, E. J.; Costa, P. R. R.; Coelho, F. A. S.; Fernando, A. S.; Farias, F. M. C. J. Chem. Res., Min. 1985, 1985, 2301. (23) Krull, O.; Wünsch, B. Bioorg. Med. Chem. 2004, 12, 1439. (24) (a) Cardinal, S.; Voyer, N. Tetrahedron Lett. 2013, 54, 5178. (b) Mfuh, A. M.; Doyle, J. D.; Chhetri, B.; Arman, H. D.; Larionov, O. V. J. Am. Chem. Soc. 2016, 138, 2985. (25) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Lainé, D. Angew. Chem., Int. Ed. 2003, 42, 4241. (26) (a) Ben-Ishal, D.; Sataty, I.; Peled, N.; Goldshare, R. Tetrahedron 1987, 43, 439. (b) Venkov, A. P.; Lukanov, L. K. Synth. Commun. 1996, 26, 755. (27) Gozler, B.; Lantz, M.; Shamma, M. J. Nat. Prod. 1983, 46, 293. (28) Shinohara, T.; Takeda, A.; Toda, J.; Sano, T. Heterocycles 1998, 48, 981.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02385. 1 H and 13C NMR spectra for new compounds and final isopavine alkaloids (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Ru Jiang: 0000-0003-2583-5672 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21472240, 21272271) for financial support. REFERENCES

(1) For reviews on isopavine alkaloids, see: (a) Gözler, B. In Alkaloids; Roberts, M. F., Plenum, M. W., Eds.; New York, 1987; Vol. 31, p 317. (b) Shamma, M. In The Isoquinoline Alkaloids: Chemistry and Pharmacology; Academic Press: New York and London, 1972; p 96. (c) Shamma, M. J.; Moniot, L. In Isoquinoline Alkaloids Research; Plenum Press: New York, 1972; Vol.1978, p 61. (2) (a) Sidjimov, A. K.; Tawara, J. N.; Stermitz, F. R.; Rithner, C. D. Phytochemistry 1998, 48, 403. (b) Xie, H.; Xu, J.; Teng, R.; Li, B.; 12906

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DOI: 10.1021/acs.joc.7b02385 J. Org. Chem. 2017, 82, 12899−12907