8
S. Kimura, N. Saito / Tetrahedron xxx (2018) 1e11
4.04 (1H, dq, J ¼ 10.5, 7.0 Hz, OCH2CH3), 3.92 (1H, dq, J ¼ 10.5,
7.0 Hz, OCH2CH3), 3.84 (3H, s, 1-OCH3), 3.77 (3H, s, 2 or 11-OCH3),
3.76 (3H, s, 10-OCH3), 3.74 (3H, s, 2 or 11-OCH3), 3.65 (3H, s, 4-
OCH3), 3.62 (3H, s, 13-OCH3), 3.39 (1H, br d, J ¼ 8.4 Hz, 6-H), 3.21
16-CH3), 2.19 (3H, s, 3-CH3), 2.16 (3H, s, 12-CH3), 1.78 (1H, dd,
J ¼ 15.6, 12.1 Hz, 14-H 151.4 (C-4),
); 13C NMR (CDCl3, 100 MHz)
b
d
151.1 (C-13),149.7 (C-11), 149.6 (C-2),147.6 (C-1),145.6 (C-10),125.4
(C-9a), 124.5 (C-13a), 124.1 (C-3 or C-12), 124.0 (C-3 or C-12), 123.3
(C-15a), 122.7 (C-4a), 117.8 (CN), 65.7 (CH2OH), 60.8 (C-7), 60.4 (1-,
10-, and 13-OCH3), 60.1 (2 or 11-OCH3), 60.0 (2 or 11-OCH3), 59.9
(4-OCH3), 58.4 (C-9), 56.9 (C-15), 56.6 (C-14a), 55.0 (C-6), 41.8 (16-
CH3), 25.8 (C-14), 21.6 (C-5), 9.3 (3-CH3), 9.3 (12-CH3); EIMS m/z
(%): 553 (Mþ, 1), 526 (18), 523 (11), 522 (36), 288 (17), 278 (60), 250
(19), 249 (30), 248 (100), 234 (10), 218 (14); HREIMS m/z 553.2789
(Mþ, calcd for C30H39N3O7, 553.2788).
(1H, dt, J ¼ 11.7, 2.6 Hz, 14a-H), 3.14 (1H, dd, J ¼ 15.6, 2.6 Hz, 14H-
a
b
),
),
3.01 (1H, dd, J ¼ 18.3, 8.4 Hz, 5-H ), 2.39 (1H, d, J ¼ 18.3 Hz, 5-H
a
2.31 (3H, s, 16-CH3), 2.17 (6H, s, 3 and 12-CH3), 1.93 (1H, dd, J ¼ 15.6,
11.7 Hz, 14-H
b
), 1.04 (3H, t, J ¼ 7.0 Hz, OCH2CH3); 13C NMR (CDCl3,
125 MHz)
d
171.1 (CO), 151.2 (C-4), 151.0 (C-13), 149.1 (C-2 and 11),
147.6 (C-10), 145.9 (C-1), 124.6 (C-3 or 12), 124.1 (C-9a or 13a), 123.6
(C-3 or 12), 123.3 (C-4a), 123.1 (C-15a), 122.4 (C-9a or 13a), 117.7
(CN), 61.0 (C-7), 60.9 (C-9, OCH2CH3), 60.33 (1 or 13-OCH3), 60.29 (1
or 13-OCH3), 60.0 (2-, 10-, or 11-OCH3), 59.9 (2-, 10-, or 11-OCH3),
59.8 (2-, 10-. or 11-OCH3), 59.5 (4-OCH3), 56.9 (C-15), 56.3 (C-14a),
54.9 (C-6), 41.8 (16-CH3), 25.7 (C-14), 21.3 (C-5), 13.9 (OCH2CH3), 9.3
(3 or 12-CH3), 9.2 (3 or 12-CH3); EIMS m/z (%): 595 (Mþ, 15), 522
(18), 289 (13), 288 (73), 249 (34), 248 (100), 218 (13); HREIMS m/z
595.2892 (Mþ, calcd for C32H41N3O8, 595.2894).
4.12. (6S*,7R*,9R*,14aS*,15R*)-9-((1,3-Dioxoisoindolin-2-yl)
methyl)-1,2,4,10,11,13-hexamethoxy-3,12,16-trimethyl-
6,7,9,14,14a,15-hexahydro-5H-6,15-iminobenzo[4,5]azocino[1,2-b]
isoquinoline-7-carbonitrile (19)
A 40% solution of DEAD in toluene (645 mL, 4 eq, 1.2 mmol) was
added to a stirred solution of 18 (166.1 mg, 0.30 mmol), phthali-
mide (180.2 mg, 4 eq, 1.2 mmol), and PPh3 (331.3 mg, 4 eq,
1.2 mmol) in THF (7.5 mL) at 0 ꢀC, and the mixture was stirred at
25 ꢀC for 6 h. The reaction mixture was concentrated in vacuo to
give a residue, which was subjected to column chromatography on
SiO2 (14 g) with CH2Cl2-EtOAc (17:3e4:1) to a pale yellow solid.
This solid was washed with MeOH to furnish 19 (149.0 mg, 73%) as a
colorless solid. IR (KBr) 3246, 2359, 1751, 1722, 1699, 1533, 1466,
4.10.5. (6S*,7R*,9S*,14aS*,15R*)-Ethyl 7-cyano-1,2,4,10,11,13-
hexamethoxy-3,12,16-trimethyl- 6,7,9,14,14a,15-hexahydro-5H-
6,15-iminobenzo[4,5]azocino[1,2-b]isoquinoline-9-carboxylate (16)
IR (CHCl3) 3439, 3022, 2938, 2359, 1717, 1628, 1466, 1410, 1225,
1113, 1074 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d 4.60 (1H, s, 9-H), 4.24
(2H, q, J ¼ 7.2 Hz, OCH2CH3), 4.13 (1H, d, J ¼ 3.4 Hz, 15-H), 4.05 (1H,
d, J ¼ 3.0 Hz, 7-H), 4.05 (1H, overlapped, 14a-H), 3.82 (3H, s, 1-
OCH3), 3.74 (3H, s, 2-OCH3), 3.73 (3H, s, 10-OCH3), 3.69 (3H, s, 11-
OCH3), 3.61 (3H, s, 4-OCH3), 3.59 (3H, s, 13-OCH3), 3.36 (1H, br d,
1412, 1395, 1385, 1342, 1254, 1113, 1070, 1009, 961 cmꢁ1
;
1H NMR
(CDCl3, 400 MHz)
d
7.70e7.62 (4H, m, 40 and 50 and 60 and 70-H),
J ¼ 8.5 Hz, 6-H), 3.04 (1H, dd, J ¼ 17.9, 7.2 Hz, 14H-
a
), 2.99 (1H, dd,
), 2.35 (1H,
4.32 (1H, dd, J ¼ 9.8, 4.0 Hz, 9-H), 4.22 (1H, d, J ¼ 2.1 Hz, 7-H), 4.05
(1H, d, J ¼ 2.5 Hz, 15-H), 3.85 (3H, s, 1-OCH3), 3.79 (3H, s, 2-OCH3),
3.71 (3H, s, 4-OCH3), 3.63 (3H, s, 13-OCH3), 3.53 (3H, s, 10-OCH3),
3.47 (1H, dd, J ¼ 13.6, 4.0 Hz, CH2NPht), 3.41 (1H, br d, J ¼ 7.8 Hz, 6-
H), 3.32 (1H, dd, J ¼ 13.6, 9.8 Hz, CH2NPht), 3.23 (3H, s, 11-OCH3),
J ¼ 18.7, 8.5 Hz, 5-H ), 2.78 (1H, dd, J ¼ 17.9, 7.3 Hz,14-H
a
b
d, J ¼ 18.7 Hz, 5-H
b), 2.25 (3H, s, 16-CH3), 2.10 (3H, s, 3-CH3), 2.07
(3H, s,12-CH3),1.28 (3H, t, J ¼ 7.2 Hz, OCH2CH3); 13C NMR (100 MHz,
CDCl3)
d 170.7 (CO) 151.7 (C-13), 151.2 (C-4), 149.2 (C-2), 148.5 (C-
11), 147.9 (C-1), 144.8 (C-10), 124.4 (C-12), 123.7 (C-9a or 13a), 123.6
(C-3), 123.5 (C-15a), 123.1 (C-4a), 123.0 (C-9a or 13a), 117.7 (CN),
60.9 (OCH2CH3), 60.7 (C-9), 60.2 (1-OCH3), 60.1 (2 or 10-OCH3), 59.8
(2 or 10-OCH3), 59.8 (11-OCH3), 59.6 (14-OCH3), 59.5 (13-OCH3),
57.1 (C-15), 56.0 (C-6), 52.0 (C-7 and 14a), 42.3 (16-CH3), 23.5 (C-
14), 21.3 (C-5), 13.9 (OCH2CH3), 9.3 (3-CH3), 9.2 (12-CH3); EIMS m/z
(%):595 (Mþ, 14), 522 (27), 289 (12), 288 (65), 249 (37), 248 (100),
218 (13); HREIMS m/z 595.2892 (Mþ, calcd for C32H41N3O8,
595.2894).
3.20 (1H, dd, J ¼ 15.3, 2.5 Hz, 14H-
14a-H), 3.07 (1H, dd, J ¼ 18.3, 7.8 Hz, 5-H
5-H ), 2.32 (3H, s, 16-CH3), 2.22 (3H, s, 3-CH3), 2.10 (3H, s, 12-CH3),
1.79 (1H, dd, J ¼ 15.3, 11.7 Hz, 14-H
); 13C NMR (100 MHz, CDCl3)
168.0 (C-10 and 30), 151.7 (C-13), 151.1 (C-4), 149.6 (C-11), 149.1 (C-
a
), 3.12 (1H, dt, J ¼ 11.7, 2.5 Hz,
a
), 2.60 (1H, d, J ¼ 18.3 Hz,
b
b
d
2),147.4 (C-1), 145.9 (C-10), 133.5 (C-50 and 60), 132.3 (C-3'a and 7'a),
125.5 (C-9a), 124.9 (C-13a), 124.0 (C-12), 123.5 (C-3 or C-4a), 123.4
(C-3 or C-4a), 123.2 (C-15a), 122.7 (C-40 and 70), 118.2 (CN), 61.2 (C-
7), 60.7 (13-OCH3), 60.3 (1 and 10-OCH3), 59.9 (2-OCH3), 59.7 (4-
OCH3), 59.5 (11-OCH3), 57.4 (C-14a), 56.8 (C-15), 55.0 (C-6), 54.9
(C-9), 43.4 (CH2-NPht), 41.8 (16-CH3), 26.1 (C-14), 21.6 (C-5), 9.4 (3-
CH3), 9.3 (12-CH3); EIMS m/z (%): 682 (Mþ, 1), 523 (33), 522 (100),
497 (21), 496 (11), 495 (38), 288 (47), 249 (25), 248 (96), 234 (11),
218 (16); HREIMS m/z 682.2997 (Mþ, calcd for C38H42N4O8,
682.3003).
4.11. (6S*,7R*,9R*,14aS*,15R*)-9-(Hydroxymethyl)-1,2,4,10,11,13-
hexamethoxy-3,12,16-trimethyl- 6,7,9,14,14a,15-hexahydro-5H-
6,15-iminobenzo[4,5]azocino[1,2-b]isoquinoline-7-carbonitrile (18)
LiBH4 (103.2 mg, 10 eq, 4.5 mmol) and MeOH (182.1 mg, 10 eq,
4.5 mmol) were succeessively added to a stirred solution of 15
(268.1 mg, 0.45 mmol) in THF (4.5 mL), and the mixture was stirred
at 25 ꢀC for 2 h. The reaction mixture was carefully diluted with H2O
(15 mL) at 0 ꢀC and extracted with CHCl3 (30 mL x 3). The combined
extracts were washed with brine (20 mL), dried, and concentrated
in vacuo to give a residue (283.9 mg), which was subjected to col-
umn chromatography on SiO2 (14 g) with CHCl3-EtOAc (4:1e3:2) to
furnish 18 (163.5 mg, 66%) as a colorless amorphous powder. IR
(KBr) 3501, 2938, 2832, 2361, 1464, 1408, 1342, 1252, 1150, 1113,
4.13. N-(((6S*,7R*,9R*,14aS*,15R*)-7-Cyano-1,2,4,10,11,13-
hexamethoxy-3,12,16-trimethyl-6,7,9,14,14a,15- hexahydro-5H-
6,15-iminobenzo[4,5]azocino[1,2-b]isoquinolin-9-yl)methyl)-2-
oxopropanamide (20)
NH2NH2eH2O (842 mL, 100 eq, 17 mmol) was added to a stirred
solution of 19 (116.1 mg, 0.17 mmol) in EtOH (8.5 mL), and the
mixture was heated at 80 ꢀC for 1.5 h. After half volume of the
solvent was removed in vacuo, the resulting mixture was diluted
with benzene (30 mL) and then extracted with 1 M HCl (30 mL x 4).
The combined extracts were made pH 9 with concentrated NH4OH
(30 mL) and extracted with CHCl3eMeOH (19:1, 200 mL x 4), dried,
and concentrated in vacuo to give a residue (121.5 mg), and the
residue was used in the next step without further purification. N,N-
1098, 1074, 1030, 1011, 962 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d 4.12
(1H, d, J ¼ 2.7 Hz,15-H), 4.07e4.05 (2H, overlapped, 7 and 9-H), 3.85
(3H, s, 1-OCH3), 3.84 (3H, s, 10-OCH3), 3.77 (3H, s, 2 or 11-OCH3),
3.76 (3H, s, 2 or 11-OCH3), 3.72 (3H, s, 4-OCH3), 3.62 (3H, s, 13-
OCH3), 3.57 (1H, dd, J ¼ 11.0, 4.1 Hz, CH2OH), 3.41 (1H, br d,
J ¼ 7.7 Hz, 6-H), 3.26 (1H, dt, J ¼ 12.1, 2.7 Hz, 14a-H), 3.24e3.21 (1H,
overlapped, CH2OH), 3.16 (1H, dd, J ¼ 15.6, 2.7 Hz, 14H-
a
), 3.09 (1H,
Diethylaniline (61
mL, 2.2 eq, 0.374 mmol) was added to a stirred
dd, J ¼ 18.5, 7.7 Hz, 5-H ), 2.51 (1H, d, J ¼ 18.5 Hz, 5-H
a
b), 2.36 (3H, s,
solution of the crude primary amine [34] in THF (8.5 mL), and the
10.1016/j.tet.2018.07.017