HETEROCYCLES

Paper | Special issue | Vol. 88, No. 2, 2014, pp. 1311-1321
Received, 30th July, 2013, Accepted, 14th August, 2013, Published online, 20th August, 2013.
DOI: 10.3987/COM-13-S(S)101

■ Total Synthesis of 8-epi-Javaberine A and Javaberine A

Yasutomo Yamamoto,* Yuri Tabuchi, Ayana Baba, Kumiko Hideshima, Mai Nakano, Akari Miyawaki, and Kiyoshi Tomioka*

Faculty of Pharmaceutical Sciences, Department of Medicinal Chemistry, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe, Kyoto 610-0395, Japan

Abstract

The total synthesis of berberine alkaloid javaberine A was examined. The B/C ring of berberine was successfully constructed by sequential Bischler–Napieralski cyclization–reduction protocols, and final demethylation afforded both javaberine A and its epimer.

INTRODUCTION
Berberine alkaloid javaberine 1, isolated from the Portulacaceae plant Talinum paniculatum GAERTNER in 2001 by Yoshikawa and co-workers, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production.1 Related alkaloid theoneberine 2, isolated in 1992, has antimicrobial activity against Gram-positive bacteria.2 These alkaloids comprise an 8-benzyltetrahydroprotoberberine skeleton,3 and the cis relationship of H-14 and the 8-benzyl group is a characteristic feature (Figure 1).4 We previously reported the chiral bisoxazoline 4–lithium diisopropylamide-catalyzed asymmetric intramolecular hydroamination of aminoalkene 3 for the synthesis of isoquinoline alkaloid (S)-laudanosine (5) (Scheme 1).5-7 Herein we report the total synthesis of javaberine A (1a) starting from benzyltetrahydroisoquinoline. Our synthetic strategy is expected to provide the asymmetric total synthesis of benzylberberine alkaloids by combining our intramolecular hydroamination approach toward the asymmetric synthesis of benzyltetrahydroisoquinoline.5

RESULTS AND DISCUSSION
Our synthetic strategy is based on the amidation–Bischler–Napieralski cyclization–reduction sequence, as shown in Scheme 2. Starting tetrahydroisoquinoline 6 was expected to be prepared by N-demethylation of laudanosine (5), which was synthesized by asymmetric intramolecular hydroamination as previously reported (Scheme 1).5a

Tetrahydroisoquinoline 6 was prepared as a racemic HCl salt by amidation of 3,4-dimethoxyphenethylamine 9 with 3,4-dimethoxyphenylacetic acid 10, Bischler–Napieralski cyclization of amide 11, and NaBH4 reduction of 12, according to published procedures.8,9 Condensation of amine hydrochloride 6•HCl with 3,4-dimethoxyphanylacetic acid 10 by EDC–HOBt gave amide 7 in 89% yield. Bischler–Napieralski cyclization of 7 with phosphoryl chloride smoothly proceeded to give iminium 13,10 whose reduction with NaBH4 in MeOH at 0 °C afforded cyclization product epi-8,11 corresponding to the epimer of hexamethyl-javaberine A, in 77% yield as a single diastereomer (Scheme 3).

Determination of the relative configuration of epi-8
The relative configuration of epi-8 was determined to be (8RS,14RS) as shown in Figure 2 by NOE correlation between H14 and H8. NMR was performed to analyze the conformation of the B/C ring. According to the reported NMR of benzylprotoberberine,12 H14 proton at 3.6±0.2 ppm and the C14 carbon at 58.4±0.3 ppm indicates a B/C-trans conformation, whereas a chemical shift of the H14 proton at 4.3±0.2 ppm and the C14 carbon at 49-52 ppm indicates the B/C-cis conformation. The chemical shifts of epi-8 in CDCl3 were 3.65 ppm (H14) and 58.5 ppm (C14), suggesting a B/C-trans conformation. The presence of Bohlmann bands (2834, 2811, 2773, 2741 cm–1) in the IR spectra of epi-8 also suggested the trans form at the B/C ring junction.13 On the other hand, the conformation of javaberine A hexaacetate was reported to be B/C-cis based on NMR (4.40 ppm of H14 and 50.2 ppm of C14 in CDCl3) and IR (absence of Bohlmann bands), and the NOE correlation between H14 and the Hα methylene proton indicated an (8SR,14RS) configuration.1 Based on these findings, our synthesized epi-8 corresponded to an epimer of hexamethyl-javaberine A.

Stereochemical pathway in the reduction of iminium 13
The 8-benzyltetrahydroprotoberberine framework was successfully constructed by this route; however, only unnatural diastereomer was obtained. The reduction of iminium 13 proceeded preferentially through an axial attack of hydride via conformation 14 to give epi-8 (Scheme 4).

Total synthesis of javaberine A and 8-epi-javaberine A
Lithium aluminum hydride reduction of iminium 13 at –78 °C for 0.5 h gave desired diastereomer 8 (9%) bearing the same relative stereochemistry as javaberine A, as well as epi-8 in 90% yield (Scheme 5). Reduction of 13 with other hydride reagents (LiAlH(Ot-Bu)3, DIBAL, LiAlH4–Me3Al14) at –78 °C also gave desired 8, although the ratio of 8/epi-8 was almost 1/10. The relative configuration of 8 was determined by NOE correlation between H14 and Hα of the methylene proton (Figure 3). Moreover, the conformation at the B/C ring junction of 8 was revealed to be cis based on NMR (4.39 ppm of H14 and 50.8 ppm of C14 in CDCl3) and IR (absence of Bohlmann bands). These data are very similar to those of javaberine A hexaacetate (Figure 2).1 Diastereomers 8 and epi-8 were separated by column chromatography, and finally, demethylation of 8 and epi-8 furnished racemic javaberine A (1a) and 8-epi-javaberine A (epi-1a), respectively (Scheme 5).

The fact that tetrahydroisoquinoline 6 could be synthesized by N-demethylation of laudanosine (5), which could be asymmetrically prepared by intramolecular hydroamination,5a was encouraging for the asymmetric total synthesis of javaberine A.

CONCLUSION
In conclusion, Bischler–Napieralski cyclization–reduction protocols were successfully used to construct an 8-benzyltetrahydroprotoberberine framework. NaBH4 reduction of iminium intermediate 13 stereoselectively proceeded to give the product corresponding to the epimer of javaberine A. Although LiAlH4 reduction predominately afforded the epimer, a product with the same configuration as javaberine A was also obtained. Final demethylation afforded both javaberine A and its epimer. Asymmetric total synthesis of these alkaloids will be reported in due course.

EXPERIMENTAL
1H NMR (500 MHz) and 13C NMR (125 MHz) were measured in CDCl3 unless otherwise mentioned. Chemical shift values were expressed in ppm relative to an internal reference of tetramethylsilane (0 ppm) in 1H NMR and CDCl3 (77.0 ppm) in 13C NMR. 13C peak multiplicity assignments were made based on DEPT data. IR spectroscopy of oil and solid samples were measured as neat liquid films and KBr pellets, respectively. Coupling constants were shown in Herz. Abbreviations are as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. The wave-numbers of maximum absorption peaks of IR spectroscopy were presented in cm–1. Column chromatography was performed using silica gel as a stationary phase.

N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)acetamide (11)8
A mixture of 3,4-dimethoxyphenethylamine 9 (9.2 mL, 55.8 mmol) and homoveratric acid 10 (9.4 g, 48 mmol) was heated at 180 °C for 1 h. After cooled to room temperature, the residue was recrystallized from EtOH (40 mL) to give amide 11 (14.4 g, 83%) as white solids of mp 122.0-124.0 °C.
1H NMR: 2.68 (2H, t, J = 6.6), 3.45 (2H, dt, J = 6.6, 6.6 ), 3.48 (2H, s), 3.83 (6H, s), 3.86 (3H, s), 3.88 (3H, s), 5.40 (1H, br s), 6.52 (1H, d, J = 8.0), 6.62 (1H, s), 6.67-6.72 (3H, m), 6.80 (1H, d, J = 8.0).

1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (12)8
A mixture of amide 11 (4.96 g, 13.8 mmol) and phosphoryl chloride (2.6 mL, 27.8 mmol) in anhydrous MeCN (40 mL) was refluxed for 1 h under Ar. After concentration, the residue was crystallized by an addition of AcOEt. The solids were filtered and washed with AcOEt to give crude 3,4-dihydroisoquinoline hydrochloride 12 (6.48 g) as yellow solids of mp 114-117 °C.
1H NMR: 3.02 (2H, t, J = 8.0), 3.83 (3H, s), 3.86 (3H, s), 3,89 (3H, s), 3.96-3.99 (5H, m), 4.38 (2H, s), 6.78 (1H, d, J = 8.3), 6.79 (1H, s), 6.85 (1H, dd, J = 2.0, 8.3), 6.98 (1H, d, J = 2.0), 7.34 (1H, s).

1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (6•HCl)9
To a stirred suspension of crude 3,4-dihydroisoquinoline hydrochloride 12 (6.48 g) in MeOH (50 mL) was slowly added NaBH4 (0.8 g, 21 mmol) at 0 °C under Ar. The mixture was stirred for 10 min at room temperature and then concentrated. After an addition of brine (16 mL) and MeCN (30 mL), the resulting mixture was partitioned between AcOEt (30 mL) and H2O (30 mL). The aqueous layer was extracted twice with AcOEt–MeCN (30 mL, 1:1). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give yellow oil, which was dissolved in MeOH (10 mL). HCl in MeOH (5% solution, 20 mL) was added to the solution, and then concentrated. The residue was crystallized by an addition of Et2O, and the solids were filtered and washed with Et2O to give 6•HCl (4.67 g, 89% for 3 steps) as white solids of mp 211-215 °C.
1H NMR: 2.91 (1H, m), 3.16-3.24 (3H, m), 3.36 (1H, m), 3.56 (1H, m), 3.60 (3H, s), 3.80 (3H, s), 3.85 (6H, s), 4.73 (1H, m), 6.17 (1H, s), 6.58 (1H, s), 6.72 (1H, d, J = 8.0), 6.77-6.79 (2H, m), 9.77 (1H, br s), 10.35 (1H, br s).
1H NMR (D2O):9b 3.01-3.05 (2H, m), 3.16-3.29 (2H, m), 3.41 (1H, m), 3.53 (1H, m), 3.60 (3H, s), 3.72 (3H, s), 3.83 (6H, s), 4.73 (1H, m), 6.36 (1H, s), 6.73 (1H, s), 6.83-6.89 (2H, m), 7.00 (1H, m).

1-(1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-(3,4-dimethoxyphenyl)ethanone (7)
A mixture of 6•HCl (5.7 g, 15 mmol), homoveratric acid 10 (2.94 g, 15 mmol), HOBt (2.28 g, 16.8 mmol), EDC (3 mL, 16.8 mmol) and Et3N (6.3 mL, 45 mmol) in CH2Cl2 (300 mL) was stirred at room temperature for 17 h. The mixture was diluted with CH2Cl2 (100 mL) and was washed with 10% HCl (30 mL x 2), satd NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, filtrated and evaporated to afford yellow solids. Recrystallization from EtOH (135 mL) gave amide 7 (6.96 g, 89%) as yellow solids of mp 148–150 °C.
1H NMR (the ratio of rotamer is 66/34): 2.49-2.61 (1.32H, m), 2.70 (0.34H, m), 2.92 (0.34H, m), 2.93 (0.66H, dd, J = 8.0, 13.2), 2.98 (0.34H, dd, J = 5.2, 13.7), 3.02 (0.34H, d, J = 16.0), 3.07 (0.34H, dd, J = 9.2, 13.7), 3.10 (0.66H, dd, J = 5.8, 13.2), 3.19 (0.34H, m), 3.24 (0.34H, d, J = 16.0), 3.38 (0.66H, m), 3.61 (1.98H, s), 3.67 (1.02H, s), 3.68-3.73 (1.98H, m), 3.75 (1.98H, s), 3.80 (1.98H, s), 3.83-3.84 (6H, m), 3.86 (1.02H, s), 3.87 (3H, s), 3.88 (1.02H, s), 4.82 (0.34H, m), 4.92 (0.34H, dd, J = 5.2, 9.2), 5.67 (0.66H, dd, J = 5.8, 8.0), 6.18 (0.66H, s), 6.39 (0.34H, s), 6.43-6.45 (0.68H, m), 6.15-6.52 (1.32H, m), 6.62-6.80 (4.66H, m), 6.84 (0.34 H, d, J = 8.6). 13C NMR: 27.9 (CH2), 28.3 (CH2), 35.2 (CH2), 39.6 (CH2), 41.1 (CH2), 41.2 (CH2), 41.8 (CH2), 42.4 (CH), 54.0 (CH), 56.6 (CH3), 55.8 (CH3), 55.93 (CH3), 55.96 (CH3), 55.99 (CH3), 56.1 (CH3), 58.6 (CH), 110.1 (CH), 110.82 (CH), 110.89 (CH), 110.93 (CH), 111.2 (CH), 111.4 (CH), 111.5 (CH), 111.6 (CH), 111.8 (CH), 111.9 (CH), 112.8 (CH), 112.9 (CH), 120.8 (CH), 120.9 (CH), 121.9 (CH), 122.1 (CH), 125.6 (C), 126.7 (C), 127.5 (C), 127.7 (C), 128.0 (C), 128.3 (C), 130.5 (C), 130.7 (C), 147.0 (C), 147.4 (C), 147.69 (C), 147.72 (C), 147.9 (C), 148.2 (C), 148.3 (C), 148.9 (C), 145.1 (C), 170.1 (C), 170.4 (C). IR: 1630. HRMS-ESI m/z: [M+Na]+ calcd for C30H35NNaO7, 544.2311; found, 544.2300.

8-(3,4-Dimethoxybenzyl)-2,3,10,11-tetramethoxy-5,6,13,13a-tetrahydroisoquinolino[3,2-a]isoquinolin-7-ium chloride (13)
A mixture of amide 7 (5.21 g, 10 mmol) and phosphoryl chloride (1.9 mL, 20 mmol) in anhydrous MeCN (30 mL) was refluxed for 2 h under Ar. Concentration followed by recrystallization from EtOH (320 mL) gave 13 (5.32 g, 99%) as yellow cubes of mp 170-174 °C.
1H NMR: 2.89-2.99 (2H, m), 3.13 (1H, dd, J = 16.6, 16.6), 3.42 (1H, dd, J = 4.6, 16.6), 3.80 (1H, m), 3.83 (3H, s), 3.86 (3H, s), 3.87 (3H, s), 3.91 (3H, s), 3.92 (3H, s), 4.06 (3H, s), 4.67-4.72 (2H, m), 4.91 (1H, d, J = 16.6), 5.31 (1H, dd, J = 4.6, 16.6), 6.44 (1H, dd, J = 1.7, 8.6), 6.67 (1H, s), 6.75 (1H, d, J = 8.6), 6.82 (1H, s), 6.87 (1H, d, J = 1.7), 6.99 (1H, s), 7.43 (1H, s). 13C NMR (DMSO-d6): 28.1 (CH2), 34.5 (CH2), 35.5 (CH2), 50.4 (CH2), 55.5 (CH3), 55.6 (CH3), 55.7 (CH3), 55.9 (CH3), 56.4 (CH3), 56.5 (CH3), 59.4 (CH), 109.9 (CH), 111.0 (CH), 111.3 (CH), 112.28 (CH), 112.32 (CH), 113.7 (CH), 119.4 (C), 119.9 (CH), 125.0 (C), 125.8 (C), 126.7 (C), 135.3 (C), 148.1 (C x 2), 148.1 (C), 148.3 (C), 149.1 (C), 155.8 (C), 175.1 (C). IR: 1608, 1518, 1466, 1372, 1280, 1259. HRMS-ESI m/z: [M–Cl]+ calcd for C30H34NO6, 504.2386; found, 504.2371.

(8SR,13aSR)-8-(3,4-Dimethoxybenzyl)-2,3,10,11-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[3,2-a]isoquinoline (epi-8)
Iminium 13 (1.08 g, 2 mmol) was dissolved in MeOH (10 mL), and NaBH4 (0.6 g, 16 mmol) was slowly added at 0 °C. The mixture was stirred for 1 h at room temperature and then concentrated. To the mixture were added brine (5 mL) and CHCl3 (10 mL), and the separated aqueous layer was extracted with CHCl3 (10 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. Desired diastereomer 8 was not observed in crude NMR. The resulting crude mixture was crystallized by an addition of Et2O. After concentration, the crude was recrystallized from EtOH (20 mL) to give epi-8 (0.78 g, 77%) as yellow needles of mp 142–144 °C.
1H NMR: 2.47 (1H, dd, J = 11.0, 14.6), 2.65 (1H, m), 2.68 (1H, m), 2.96 (1H, dd, J = 2.0, 15.2), 3.04 (1H, dd, J = 5.2, 14.3), 3.07 (1H, dd, J = 5.2, 14.3), 3.11 (1H, m), 3.40 (1H, m), 3.65 (1H, d, J = 11.2), 3.67 (3H, s), 3.75 (3H, s), 3.81 (3H, s), 3.86 (3H, s), 3.87 (3H, s), 3.88 (3H, s), 3.99 (1H, dd, J = 5.2, 5.2), 6.49 (1H, s), 6.54 (1H, d, J = 1.9), 6.58 (1H, s), 6.60 (1H, dd, J = 1.9, 8.0), 6.63 (1H, s), 6.67 (1H, d, J = 8.0), 6.74 (1H, s). 13C NMR: 30.1 (CH2), 36.7 (CH2), 42.7 (CH2), 48.8 (CH2), 55.6 (CH3), 55.75 (CH3), 55.77 (CH3), 55.8 (CH3 x 2), 56.0 (CH3), 58.5 (CH), 65.4 (CH), 108.8 (CH), 110.0 (CH), 110.5 (CH), 110.8 (CH), 111.3 (CH), 113.3 (CH), 122.3 (CH), 127.2 (C), 128.5 (C), 129.5 (C), 130.6 (C), 131.4 (C), 147.0 (C x 2), 147.1 (C), 147.2 (C), 147.4 (C), 147.9 (C). IR: 2932, 2834, 2811, 2773, 2741, 1612, 1512, 1261. FABMS m/z: 506 [M+H]+. HRMS-FAB m/z: [M+H]+ calcd for C30H36NO6, 506.2543; found, 506.2558.
NOE experiment was performed in C6D6. Irradiation of H8 (3.98 ppm) yielded an appreciable NOE (5%) at H14 (3.80 ppm), Hα (3.11 ppm), and H6 (2.62 ppm), respectively. Irradiation of H14 (3.80 ppm) yielded an appreciable NOE (5%) at H8 (3.98 ppm), H6 (2.62 ppm), and H13 (2.98 ppm), respectively.
1H NMR (C6D6): 2.55 (1H, d, J = 15.7, H5), 2.62 (1H, ddd, J = 3.2, 11.8, 11.8, H6), 2.73 (1H, dd, J = 10.9, 14.9, H13), 2.98 (1H, dd, J = 2.3, 14.9, H13), 3.11 (1H, dd, J = 4.0, 14.3, Hα), 3.15 (1H, dd, J = 5.5, 14.3, Hα), 3.21 (1H, m, H5), 3.32 (1H, m, H6), 3.36 (3H, s), 3.43 (3H, s), 3.44 (3H, s), 3.48 (3H, s), 3.50 (3H, s), 3.52 (3H, s), 3.80 (1H, d, J = 10.9, H14), 3.98 (1H, dd, J = 4.0, 5.5, H8), 6.43 (1H, s), 6.539 (1H, d, J = 8.3), 6.543 (1H, s), 6.58 (1H, s), 6.66 (1H, d, J = 1.7), 6.72 (1H, dd, J = 1.7, 8.3), 6.76 (1H, s).

(8SR,13aRS)-8-(3,4-Dimethoxybenzyl)-2,3,10,11-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[3,2-a]isoquinoline (8)
To the suspension of LiAlH4 (75.9 mg, 2 mmol) in THF (2 mL) was added iminium 13 (108 mg, 0.2 mmol) in THF (1 mL) at –78 °C. The mixture was stirred for 1 h at –78 °C, and quenched with water (0.1 mL), 10% NaOH (0.1 mL) and water (0.3 mL) and then filtered through a Celite pad. The filtrate was dried over Na2SO4 and concentrated. Column chromatography (hexane/AcOEt 2/3 to 1/3) gave epi-8 (91 mg, 90%) as yellow solids and 8 (9.0 mg, 9%) as yellow amorphous solids of mp 75-77 °C.
1H NMR: 2.79-3.00 (6H, m), 3.12 (1H, m), 3.26 (1H, m), 3.57 (3H, s), 3.77 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 3.90 (3H, s), 3.94 (1H, dd, J = 6.9, 6.9), 4.39 (1H, dd, J = 4.6, 11.5), 5.99 (1H, s), 6.58 (1H, s), 6.63 (1H, s), 6.66-6.68 (3H, m), 6.78 (1H, d, J = 8.0). 13C NMR: 29.4 (CH2), 33.6 (CH2), 40.2 (CH2), 46.8 (CH2), 50.8 (CH), 55.4 (CH3), 55.7 (CH3 x 2), 55.79 (CH3), 55.88 (CH3), 55.94 (CH3), 66.6 (CH), 109.2 (CH), 110.8 (CH), 110.9 (CH), 111.0 (CH), 111.5 (CH), 113.2 (CH), 121.9 (CH), 125.2 (C), 126.1 (C), 128.9 (C), 131.2 (C), 132.7 (C), 146.2 (C), 147.2 (C), 147.3 (C), 147.4 (C), 147.5 (C), 148.5 (C). IR: 3002, 2935, 1610, 1515, 1465, 1261. HRMS-ESI m/z: [M+Na]+ calcd for C30H35NNaO6, 528.2362; found, 528.2363.
NOE experiment was performed in acetone-d6. Irradiation of H14 (4.37 ppm) yielded an appreciable NOE (5%) at Hα (3.14, 2.80 ppm) and H6 (2.94 ppm).
1H NMR (acetone-d6): 2.65-2.82 (6H, m), 2.94 (1H, dd, J = 4.6, 16.6), 3.06 (1H, m), 3.14 (1H, dd, J = 6.9, 13.7), 3.55 (3H, s), 3.65 (3H, s), 3.73 (6H, s), 3.75 (3H, s), 3.79 (3H, s), 3.95 (dd, 1H, J = 6.9, 6.9). 4.37 (dd, 1H, J = 4.6, 11.5), 6.27 (1H, s), 6.62 (1H, s), 6.65 (1H, s), 6.67 (1H, d, J = 8.2), 6.78-6.83 (3H, m). 13C NMR (acetone-d6): 29.6 (CH2), 32.9 (CH2), 40.4 (CH2), 46.7 (CH2), 50.6 (CH), 55.0 (CH3), 55.17 (CH3), 55.21 (CH3), 55.3 (CH3), 55.4 (CH3), 55.5 (CH3), 66.3 (CH), 110.5 (CH), 111.5 (CH), 111.9 (CH), 112.0 (CH), 112.4 (CH), 114.1 (CH), 121.9 (CH), 125.9 (C), 126.4 (C), 129.8 (C), 132.0 (C), 133.4 (C), 147.1 (C), 147.8 (C), 147.95 (C), 148.02 (C), 148.1 (C), 149.2 (C).

Javaberine A (1a)
To the solution of 8 (20 mg, 0.04 mmol) in CH2Cl2 (1 mL) was added BBr3 (0.6 mL, 0.6 mmol, 1 M solution in CH2Cl2) at 0 °C. The mixture was stirred for 1 h, and then MeOH (2 mL) was added. After concentration, the residue was dissolved in MeOH (1 mL), and Et3N (0.1 mL) was added to neutralize. Concentration followed by reprecipitation (MeOH/CHCl3) gave 1a (14.2 mg, 85%) as pale yellow solids of mp 190–194 °C.
1H NMR (CD3OD): 2.81 (1H, dd, J = 11.5, 17.5), 2.86-2.95 (2H, m), 3.04 (1H, m), 3.24 (1H, dd, J = 5.8, 17.5), 3.28-3.36 (3H, m), 4.30 (1H, m), 4.63 (1H, m), 5.96 (1H, s), 6.41 (1H, d, J = 8.0), 6.54 (1H, s), 6.57 (1H, s), 6.59 (1H, d, J = 1.2), 6.64 (1H, s), 6.68 (1H, d, J = 8.0). 13C NMR (CD3OD): 27.3 (CH2), 34.2 (CH2), 40.8 (CH2), 48.1 (CH2), 53.4 (CH), 67.9 (CH), 113.8 (CH), 115.7 (CH), 115.9 (CH), 116.2 (CH), 116.4 (CH), 118.0 (CH), 122.4 (CH), 123.0 (C), 123.4 (C), 127.8 (C), 130.0 (C), 144.7 (C), 145.4 (C), 145.6 (C), 146.3 (C), 146.5 (C). IR: 3373, 1618, 1525, 1376, 1261. HRMS-ESI m/z: [M+H]+ calcd for C24H24NO6, 422.1604; found, 422.1599.

8-epi-Javaberine A (epi-1a)
To the solution of epi-8 (25 mg, 0.05 mmol) in CH2Cl2 (2 mL) was added BBr3 (0.5 mL, 0.5 mmol, 1 M solution in CH2Cl2) at 0 °C. The mixture was stirred for 1 h, and then MeOH (2 mL) was added. After concentration, the residue was dissolved in MeOH (1 mL), and Et3N (0.1 mL) was added to neutralize. Concentration followed by reprecipitation (MeOH/CHCl3) gave epi-1a (19 mg, 90%) as yellow solids of mp 186–192 °C.
1H NMR (CD3OD): 2.44 (1H, dt, J = 3.4, 11.5), 2.50-2.56 (2H, m), 2.90-2.99 (4H, m), 3.32 (1H, m), 3.50 (1H, d, J = 10.3), 3.79 (1H, m), 6.49-6.51 (4H, m), 6.63 (1H, d, J = 8.0), 6.67 (1H, d, J = 1.7), 6.68 (1H, s). 13C NMR (CD3OD): 29.3 (CH2), 36.0 (CH2), 43.2 (CH2), 47.8 (CH2), 61.0 (CH), 67.3 (CH), 113.4 (CH), 114.5 (CH), 115.7 (CH), 116.0 (CH), 116.3 (CH), 117.6 (CH), 121.9 (CH), 126.0 (C), 126.9 (C), 128.7 (C), 129.3 (C), 131.9 (C), 144.8 (C), 144.95 (C), 145.00 (C), 145.2 (C), 145.4 (C), 146.2 (C). IR: 3397, 2851, 2695, 2584, 1609, 1524, 1450, 1279. HRMS-ESI m/z: [M+H]+ calcd for C24H24NO6, 422.1604; found, 422.1589.

ACKNOWLEDGEMENTS
This research was supported in part by JSPS KAKENHI Grant Numbers 23790029, 24590035.

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