Q.-X. Lin, T.-L. Ho / Tetrahedron 69 (2013) 2996e3001
2999
(s, 1H); 13C NMR (75 MHz, CDCl3)
91.2, 78.4, 71. 3, 42.4, 32.7, 30.2, 29.3; IR (KBr) 3269, 3208, 1956,
1667, 1498, 1452, 1413, 1359, 1179, 1144, 1084, 958, 715, 691 cmꢀ1
d
175.5, 137. 8, 128.4, 128.0, 127.6,
1035, 847, 700 cmꢀ1; HRMS (EI) calcd for C30H31NO5 485.2202,
found 485.2204.
;
HRMS (EI) calcd for C14H15NO2 229.1103, found 229.1104; Anal.
Calcd for C14H15NO2: C, 73.74; H, 6.59; N, 6.11. Found: C, 73.25; H,
6.67; N, 6.06.
3.1.9. 1-Benzyl-2-[(2,3,6,7-tetramethoxyphenanthren-9-yl)-methyl]
pyrrolidine (12A). To a suspension of 4 (89 mg, 0.18 mmol) in an-
hydrous THF (15 mL) at 0 ꢁC was added LiAlH4 (35 mg, 0.92 mmol)
in portions. After refluxed for 3 h, the mixture was cooled,
quenched with aq Na2SO4 and filtered through Celite. The filtrate
was concentrated, and purified by flash column chromatography on
SiO2 (CH2Cl2/MeOH, 40:1) to afford 12A (71 mg, 83%) as a white
3.1.6. 1-Benzyl-5-(2-propynyl)-2-pyrrolidinone (11B). To a solution
of 11A (1.147 g, 5.0 mmol) in anhydrous MeOH (25 mL) was added
bromophenol blue (3 drops, 1 mg/mL) and NaBH3CN (320 mg,
5.1 mmol). The solution was adjusted to pH w3 with 6 N HCl and
stirred at room temperature for 1.5 h. After neutralized with 6 N
NaOH, the mixture was evaporated. The residue was shaken in
a mixture of water and EtOAc, separated and the organic solution
was washed with brine, dried over anhydrous Na2SO4 and con-
centrated. Flash column chromatography on SiO2 (petroleum ether/
acetone, 4:1) afforded 11A (182 mg) and 11B (803 mg, 90% brsm),
the latter as a white solid: mp 95e96 ꢁC; 1H NMR (300 MHz, CDCl3)
solid: mp 105e106 ꢁC; 1H NMR (300 MHz, CDCl3)
d 7.80 (s, 1H), 7.74
(s, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.26e7.38 (m, 5H), 7.16 (s, 1H), 4.27
(d, J¼12.6 Hz, 1H), 4.10 (s, 3H), 4.08 (s, 3H), 4.01 (s, 3H), 3.99 (s, 3H),
3.57 (d, J¼12.6 Hz, 1H), 3.33 (d, J¼12.3 Hz, 1H), 2.97e3.03 (m, 2H),
2.90 (d, J¼12.9 Hz, 1H), 2.18e2.23 (m, 1H), 1.63e1.75 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 148.8, 148.7, 148.4, 139.4, 131.7, 129.0, 128.3,
127.0, 126.3, 125.6,124.9,124.8,123.6,107.9, 104.8,103.3, 102.7, 64.3,
59.2, 56.0, 56.0, 55.8, 55.8, 54. 5, 38.8, 31.0, 22.0; IR (KBr) 3001,
2934, 2832, 1619, 1508, 1475, 1429, 1253, 1201, 1151, 1039, 772,
d
7.22e7.36 (m, 5H), 5.06 (d, J¼15.3 Hz, 1H), 3.99 (d, J¼15.0 Hz, 1H),
þ
3.59 (td, J¼4.7, 12.9 Hz, 1H), 2.56e2.68 (m, 1H), 2.37e2.48 (m, 3H),
699 cmꢀ1; HRMS (ESI) calcd for C30H34NO4 472.2482, found
2.11e2.23 (m, 1H), 1.91e2.02 (m, 2H); 13C NMR (75 MHz, CDCl3)
472.2494.
d
175.2, 136.3, 128.7, 127.9, 127.5, 79.2, 71.1, 55.2, 44.1, 30.0, 23.4,
23.0; IR (KBr) 3288, 2935, 1684, 1579, 1496, 1419, 1305, 1251, 1166,
1084, 704 cmꢀ1; HRMS (EI) calcd for C14H15NO 213.1154, found
213.1151; Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found:
C, 78.80; H, 7.23; N, 6.45.
3.1.10. 2-[(2,3,6,7-Tetramethoxyphenanthren-9-yl)methyl]-pyrroli-
dine (12B). A suspension of 12A (48 mg, 0.101 mmol) and 10% Pd/C
(53.7 mg, 0.05 mmol) in anhydrous THF (5 mL) was stirred under H2
(1 atm) for 2 days. The mixture was filtered through Celite and the
residue was washed with MeOH (containing 3% NH3$H2O). The
liquid was evaporated and the product was purified by flash col-
umn chromatography on SiO2 (CH2Cl2/MeOH/Et3N, 20:1:1) to af-
ford 12B (36.8 mg, 96%) as a colorless oil: 1H NMR (300 MHz, CDCl3)
3.1.7. (Z)-1-Benzyl-5-[2,3-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)allyl-2-pyrrolidinone (5). To
a solution of 11B (215 mg,
1.01 mmol) in degassed DMF (10 mL) were added [B(pin)]2 (280 mg,
1.10 mmol) and (Ph3P)4Pt (101 mg, 0.08 mmol) sequentially. After
stirring at 80 ꢁC for 24 h the mixture was cooled to room temper-
ature, diluted with EtOAc (30 mL), washed with brine, and dried
over anhydrous MgSO4. Evaporation and purification by flash col-
umn chromatography on SiO2 (petroleum ether/acetone, 3:1) afford
5 (390 mg, 85%) as a white solid: mp 178e179 ꢁC; 1H NMR
d
7.69 (s, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.12 (s, 1H), 5.15
(br s, 1H), 4.04 (s, 3H), 4.03 (s, 6H), 3.97 (s, 3H), 3.64e3.66 (m, 1H),
3.41 (dd, J¼7.0, 13.8 Hz, 1H), 3.13e3.25 (m, 2H), 2.94e3.02 (m, 1H),
1.82e1.93 (m, 2H), 1.59e1.80 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
148.8, 148.8, 148.7, 148.6, 130.3, 126.1, 125.1, 124.8, 124.7, 123.7,
107.9, 104.5, 103.2, 102.5, 59.1, 56.2, 56.0, 55.9, 55.8, 45.8, 38.3, 31.1,
24.2; IR (KBr) cmꢀ1 3416, 2958, 2835, 1620, 1510, 1475, 1429, 1254,
1150, 1040, 843, 772, 733 cmꢀ1; HRMS (EI) calcd for C23H27NO4
381.1940, found 381.1941.
(300 MHz, CDCl3)
d 7.23e7.32 (m, 5H), 5.91 (s, 1H), 5.04 (d,
J¼15.2 Hz, 1H), 3.96 (d, J¼15.2 Hz, 1H), 3.51e3.60 (m, 1H), 2.79 (dd,
J¼1.5, 12.9 Hz, 1H), 2.28e2.52 (m, 2H), 2.06 (d, J¼12.0 Hz, 1H),
1.91e2.00 (m, 1H), 1.68e1.79 (m, 1H), 1.26 (s, 12H), 1.18 (s, 12H); 13C
NMR (75 MHz, CDCl3)
d
174.8, 150.1, 150.0, 136.5, 134.5, 134.4, 134.2,
3.1.11. Synthesis of (ꢃ)-tylophorine (1) by PicteteSpengler re-
action. To a solution of amine 12B (36.5 mg, 0.10 mmol) in EtOH
(2.5 mL) was added a formalin solution (0.55 mL, 7.34 mmol) and
134.1, 128.3, 127.8, 127.1, 83.6, 83.3, 55.7, 43.7, 42.9, 29.5, 24.6, 24.5,
23.2; IR (KBr) 2980, 2934, 1677, 1615, 1496, 1423, 1348, 1228, 1139,
973, 850, 705 cmꢀ1; HRMS (EI) calcd for C26H29NO510B2 465.3087,
found 465.3091; Anal. Calcd for C26H29NO5B2: C, 66.84; H, 8.41; N,
3.00. Found: C, 66.79; H, 8.29; N, 2.83.
concentrated HCl (55
mL, 0.66 mmol) successively. The reaction
mixture was refluxed for 2 days in the dark, evaporated to dryness,
and treated with 20% KOH (5 mL). The aqueous phase was extracted
with CH2Cl2, washed with brine and dried over anhydrous Na2SO4.
Filtration, concentration, and purification by flash column chro-
matography on SiO2 (CH2Cl2/MeOH, 20:1) afforded (ꢃ)-tylophorine
1 (31.5 mg, 84%) as a light yellow solid: mp 284e286 ꢁC.
3.1.8. Synthesis of 1-benzyl-5-[(2,3,6,7-tetramethoxyphenan-thren-
9-yl)methyl]-2-pyrrolidinone (4) by double Suzuki coupling. A solu-
tion of 6 [Ref. 3] (44 mg, 0.10 mmol) and 5 (56 mg, 0.12 mmol) in
THF (2 mL) was successively treated with (dppf)PdCl2 (7.4 mg,
0.01 mmol) and 3 N K3PO4 (0.2 mL, 0.6 mmol) under N2, and stirred
at 60 ꢁC for 3 days. Dilution with saturated NH4Cl was followed by
extraction with CH2Cl2. The combined organic extract was washed
with brine, dried over anhydrous Na2SO4, concentrated, and puri-
fied by flash column chromatography on SiO2 (petroleum ether/
acetone, 3:1) to afford 4 (24 mg, 50%) as a white solid: mp
3.1.12. 1-Benzyl-5-[3-(4,40,5,50-tetramethoxybiphenyl-2-yl)-2-
propynyl]-2-pyrrolidinone (14). To
a solution of 13 (200 mg,
0.50 mmol) and 11B (132 mg, 1.30 mmol) in anhydrous PhMe
(4 mL) under N2 were added piperidine (1.0 mL, 10.1 mmol),
(Ph3P)2PdCl2 (36 mg, 0.05 mmol), CuI (20 mg, 0.10 mmol) se-
quentially. The resulting mixture was stirred at 50 ꢁC for 18 h, di-
luted with water, and extracted with CH2Cl2. The combined organic
extract was washed with brine, dried over anhydrous Na2SO4,
concentrated, and purified by flash column chromatography on
SiO2 (petroleum ether/acetone, 5:1e3:1) to afford 14 (232 mg, 96%)
as a white foam: mp 69e71 ꢁC; 1H NMR (300 MHz, CDCl3)
258e260 ꢁC; 1H NMR (300 MHz, CDCl3)
d 7.79 (s, 1H), 7.74 (s, 1H),
7.36 (s, 1H), 7.26e7.33 (m, 3H), 7.20 (d, J¼7.3 Hz, 2H), 7.15 (s, 1H),
6.92 (s, 1H), 5.22 (d, J¼15.6 Hz, 1H), 4.10 (s, 3H), 4.09 (s, 3H), 4.03 (s,
3H), 3.89e3.99 (m, 2H), 3.67 (dd, J¼3.8, 13.2 Hz, 1H), 3.55 (s, 3H),
2.73e2.81 (m, 1H), 2.52e2.62 (m, 1H), 2.35e2.46 (m, 1H), 1.79e1.87
(m, 2H); 13C NMR (75 MHz, CDCl3)
d
175.2, 148.9, 148.7, 148.7, 148.3,
d
7.26e7.33 (m, 3H), 7.20 (d, J¼7.6 Hz, 2H), 7.04e7.07 (m, 2H), 6.95
136.3, 128.6, 128.4, 127.3, 127.2, 125.8, 125.6, 124.8, 124.7, 123.6,
107.7, 103.7, 103.1, 102.4, 55.9, 55.8, 55.8, 55.7, 55.3, 43.9, 37.4, 29.7,
24.1; IR (KBr) 2925, 2837, 1686, 1610, 1512, 1475, 1426, 1257, 1150,
(s, 1H), 6.92 (d, J¼8.5 Hz, 1H), 6.82 (s, 1H), 4.99 (d, J¼15.2 Hz, 1H),
3.92 (d, J¼15.2 Hz, 1H), 3.92 (s, 6H), 3.91 (s, 3H), 3.88 (s, 3H), 3.54
(td, J¼4.6, 12.9 Hz, 1H), 2.51 (d, J¼5.0 Hz, 2H), 2.28e2.47 (m, 2H),