Enantioselective Total Syntheses
2722 2731
to 08C and a mixture of formic acid/triethylamine (5:2, 0.105 cm3) was
added dropwise. The solution was allowed to reach 258C; after 40 min of
stirring it was diluted with ethyl acetate and the reaction was quenched
by addition of saturated aqueous potassium carbonate solution and
water. The aqueous layer was extracted with dichloromethane (4î
20 cm3); the combined organic layers were dried over sodium sulphate
and filtered, and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography on silica using di-
chloromethane/methanol (10:1) as eluent to give emetine (1) as a colour-
less foam (71 mg, 71%, >98:2 ds), [a]2D0 =ꢀ45.3 (c=0.40 in CHCl3)
([a]D25 =ꢀ46.0 (c=0.42 in CHCl3));[20] 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=0.91 (t, 3J(H,H)=7.5 Hz, 3H; 12-H), 1.08 1.32 (m, 2H; 1-Hax,
12-H), 1.38 1.52 (m, 2H; 10’-H, 3-H), 1.59 1.75 (m, 2H; 2-H, H-12),
2.06 2.10 (m, 1H; 10’-H), 2.12 (dd, 2J(H,H)=11.2 Hz, 3J(H,H)=11.2 Hz,
1H; 4-Hax), 2.52 (ddd, 2J(H,H)=11.8 Hz, 3J(H,H)=11.8, 4.1 Hz, 1H;, 6-
Hax), 2.58 2.78 (m, 4H; 2î4’-H, 1-Heq, 7-H), 2.95 3.32 (m, 6H; 2î3’-H,
4-Heq, 6-H, 7-H, 11b-H), 3.81 (s, 3H; OMe), 3.83 (s, 3H; OMe), 3.85 (s,
3H; OMe), 3.87 (s, 3H; OMe), 4.12 (m, 1H; 1’-H), 6.51 (s, 1H; 8-H or
11-H), 6.58 (s, 1H; 8-H or 11-H), 6.60 (d, 3J(H,H)=8.0 Hz, 1H; 5’-H),
7.78 ppm (s, 1H; 8’-H); 13C NMR (50 MHz, CDCl3, 258C): d=11.15 (C-
13), 23.55 (C-12), 29.01 (C-4’), 29.21 (C-7), 36.74 (C-2), 36.85 (C-1), 40.07
(C-3’), 40.68 (C-10’), 41.69 (C-3), 51.77 (C-1’), 52.24 (C-6), 55.77 (OMe),
55.80 (OMe), 55.90 (OMe), 56.20 (OMe), 61.33 (C-4), 62.38 (C-11b),
108.6, 109.1, 111.4, 111.7 (C-5’, C-8’, C-8, C-11), 126.7, 126.8, 130.1, 131.5
(C-4a’, C-8a’, C-7a, C-11a), 147.1, 147.3, 147.3, 147.4 ppm (C-6’, C-7’, C-9,
C-10); UV/Vis (acetonitrile): lmax (lge)=201.0 (4.874), 286.0 nm (3.847);
IR (film): n˜ =3331, 2935 (C-H), 2833 (OMe), 1463 (CH2), 860 cmꢀ1; MS
(70 eV, EI): m/z (%): 480.2988 (100), [M+] (C29H40N2O4 requires
480.2988), 465.2 (8) [M+ꢀCH3], 288.1 (32) [M+ꢀC11H14NO2], 272.1 (20)
[M+ꢀC12H17NO2], 192.0 (100) [C11H14NO2+].
with silica and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography on silica using
CH2Cl2/MeOH (10:1) as eluent to give dehydrotubulosine (27) as a
bright yellow foam (114 mg, 49%; 15% of starting material was recov-
ered). [a]2D0 =+15.1(c=0.45 in chloroform); 1H NMR (600 MHz, CDCl3,
3
3
258C): d=7.47 (d, J(H,H)=8.0 Hz, 2H; benzyl), 7.38 (dd, J(H,H)=7.6,
3
7.6 Hz, 2H; benzyl), 7.31 7.36 (m, 2H; benzyl, 8’-H), 7.04 (dd, J(H,H)=
8.8, 2.2 Hz, 1H; 7’-H), 7.01 (d, 3J(H,H)=2.2 Hz, 1H; 5’-H), 6.47 (s, 1H;
8-H or 11-H), 6.38 (s, 1H; 8-H or 11-H), 5.09 (s, 2H; CH2-benzyl), 3.92
(m, 1H; 3’-H), 3.85 (m, 1H; 3’-H), 3.76 (s, 3H; OMe), 3.51 (s, 3H;
OMe), 3.25 (m, 1H; 11b-H), 3.20 3.21 (m, 3H; 4-H, 7-H, 10’-H), 3.08 (m,
1H; 6-H), 2.92 (t, 3J(H,H)=8.3 Hz, 2H; 4’-H), 2.61 2.71 (m, 2H; 7-H,
10’-H), 2.58 (ddd, 2J(H,H)=10.3 Hz, 3J(H,H)=10.3, 3.5 Hz, 1H; 6-H),
2
3
2.30 (m, 1H; 1-H), 2.19 (dd, J(H,H)=10.9 Hz, J(H,H)=10.9 Hz, 1H; 4-
H), 2.10 m, 1H; 2-H), 1.67 1.78 (m, 2H, 3-H, 12-H), 1.40 (m, 1H, 1-H),
1.23 (m, 1H; 12-H), 0.90 ppm (t, 3J(H,H)=7.3 Hz, 3H; 13-H); 13C NMR
(75 MHz, CDCl3, 258C): d=164.2 (C-1’), 153.9 (C-6’), 147.4 (C-10), 147.0
(C-9), 141.8 (C-9’a), 137.0 (benzyl), 129.0 (C-11a), 128.5 (benzyl), 128.4
(C-8’a), 127.9 (benzyl), 127.5 (benzyl), 125.7 (C-7a), 125.1 (C-5’a), 120.2
(C-4’a), 118.3 (C-8’), 113.8 (C-8), 111.1 (C-11), 107.8 (C-7’), 101.6 (C-5’),
70.58 (benzyl), 62.19 (C-11b), 60.54 (C-4), 55.67, 55.52 (C-OMe), 52.17
(C-6), 46.03 (C-3’), 41.68 (C-3), 39.74 (C-10’), 37.78 (C-1), 36.56 (C-2),
28.37 (C-7), 23.51 (C-12), 19.44 (C-4’), 10.99 ppm (C-13); IR (KBr): n˜ =
3417, 2933 (C-H), 2831 (OMe), 1547 (C=N), 1463 (CH2), 854 cmꢀ1; UV/
Vis (acetonitrile): lmax (lge)=364.0 (3.841), 320.0 (4.089), 292.5 (3.912),
202.0 nm (4.793); MS (70 eV, EI): m/z (%): 565.3304 (20) [M+]
(C36H43N3O3 requires 565.3304), 290.3 (64) [C19H18N2O+], 199.2 (64)
[C12H11N2O+], 106.1 (80) [C7H6O+], 91.1 (48) [C7H7+].
O-Benzyltubulosine (28): By using the procedure for the synthesis of em-
etine (1), compound 27 (90.0 mg, 160 mmol) was converted into the pro-
tected tubulosine 28 after 80 min of stirring. Column chromatography on
silica gel using CH2Cl2/MeOH (10:1) as eluent gave 28 as a yellow
foam(70 mg, 78%, >98:2 ds) [a]2D0 =ꢀ13.4(c=0.5 in chloroform);
1H NMR (600 MHz, CDCl3, 258C): ?d=7.73 (brs, 1H, indol-NH), 7.47
(d, 3J(H,H)=8.0 Hz, 2H; benzyl), 7.38 (dd, 3J(H,H)=7.6, 7.6 Hz, 2H;
benzyl), 7.31 (dd, 3J(H,H)=7.6, 7.6 Hz, 1H; benzyl), 7.20 (d, 3J(H,H)=
8.0 Hz 1H; 8’-H), 7.03 (d, 3J(H,H)=2.2 Hz, 1H; 5’-H), 7.01 (dd,
3J(H,H)=8.8, 2.2 Hz, 1H; 7’-H,), 6.73 (s, 1H; 8-H or 11-H), 6.59 (s, 1H;
8-H or 11-H), 5.10 (s, 2H; CH2-benzyl), 4.27 (m, 1H; 1’-H), 3.85 (s, 3H;
OMe), 3.82 (s, 3H; OMe), 3.39 (ddd, 2J(H,H)=13.2 Hz, 3J(H,H)=4.5,
4.5 Hz, 1H; 3’-H), 3.05 3.22 (m, 4H; 3’-H, 4-H, 7-H, 11b-H), 3.01 (m,
1H; 6-H), 2.57 2.78(m, 4H; 1-H, 4’-H, 4’-H, 7-H), 2.52 (ddd, 2J(H,H)=
11.4 Hz, 3J(H,H)=11.3, 4.0 Hz, 1H; 6-H), 2.11 (dd, 2J(H,H)=11.3 Hz,
3J(H,H)=11.3 Hz, 1H; 4-H), 2.04 (dd, 2J(H,H)=11.3 Hz, 3J(H,H)=
11.3 Hz, 1H; 10’-H), 1.75 (m, 1H; 2-H), 1.64 (m, 1H; 12H), 1.51 (m, 1H;
10’-H), 1.45 (m, 1H; 3H), 1.23 (ddd, 2J(H,H)=11.5 Hz, 3J(H,H)=11.5,
11.5 Hz, 1H; 1-H), 1.14 (m, 1H; 12-H), 0.90 ppm (t, 3J(H,H)=7.7 Hz,
3H, 13-H); 13C NMR (150 MHz, CDCl3, 258C): d=153.1 (C-6’), 147.4
(C-10), 147.1 (C-9), 137.7 (benzyl), 137.4 (C-9’a), 130.9 (C-11a), 129.9 (C-
8’a), 128.4 (benzyl), 127.8 (C-5’a), 127.63 (benzyl), 127.5 (benzyl), 126.7
(C-7a), 111.8 (C-8), 111.4 (C-8’), 108.5 (C-11), 108.4 (C-7’), 101.9 (C-5’),
70.90 (CH2-benzyl), 62.36 (C-11b), 61.23 (C-4), 56.15, 55.70 (OMe), 52.35
(C-6), 49.30 (C-1’), 41.99 (C-3), 41.56 (C-3’), 38.54 (C-10’), 36.75 (C-1),
36.29 (C-2), 29.02 (C-7), 23.41 (C-12), 22.68 (C-4’), 11.08 ppm (C-13); IR
(KBr): n˜ =3382, 2935 (C-H), 2836 (OMe), 1453 (CH2), 860 cmꢀ1; UV/Vis
(acetonitrile): lmax (lge)=283.0 (4.054), 200.0 nm (4.844); MS (70 eV, EI):
m/z (%): 563.3148 (54) [M+] (C36H43N3O4 requires 563.3148), 290.3 (64)
[C19H18N2O+], 199.2 (68) [C12H11N2O+], 91.1 (50) [C7H7+].
2,3-(R,R)-11b-(S)-N-[2-(5-Benzyloxy-1H-indol-3-yl)-ethyl]-2-(3-ethyl-
9,10-dimethoxy-1,3,4,6,7,7a,11a,11b-octahydro-2H-pyrido[2,1-a]isoqui-
nolin-2-yl)acetamide (25): A heterogeneous mixture of benzoquinolizi-
dine 4 (200 mg, 580 mmol), O-benzylserotonine 5 (230 mg, 860 mmol) and
2-hydroxypyridine (82 mg, 860 mmol) was stirred for 3.25 h at 1708C
under an argon atmosphere in a sealed flask. The solution was cooled to
258C and the resulting solid was dissolved in CH2Cl2 and absorbed on
silica gel. Column chromatography on silica gel (CH2Cl2/MeOH, 10:1)
gave the amide 25 as a dark yellow foam (246 mg, 73%), [a]2D0 =ꢀ30.0
(c=0.4 in chloroform); 1H NMR (500 MHz, CDCl3, 258C): d=8.13 (brs,
1H, indol-NH), 7.47 (d, 3J(H,H)=8.0 Hz, 2H; benzyl), 7.38 (dd,
3J(H,H)=7.6, 7.6 Hz, 2H; benzyl), 7.31 (dd, 3J(H,H)=7.6, 7.6 Hz, 1H;
benzyl), 7.22 (d, 3J(H,H)=8.4 Hz, 1H; 8’-H), 7.12 (d, 3J(H,H)=2.2 Hz,
1H; 9’a-H), 6.96 (d, 3J(H,H)=2.0 Hz, 1H; 5’-H), 6.93 (dd, 3J(H,H)=8.4,
2.2 Hz, 1H; 7’-H), 6.66 (s, 1H; 8-H or 11-H), 6.57 (s, 1H; 8-H or 11-H),
3
5.60 (t, J(H,H)=5.8 Hz, 1H; amide-NH), 5.09 (s, 2H; CH2-benzyl), 3.83
(s, 3H; OMe), 3.76 (s, 3H; OMe), 3.66 (m, 1H; 3’-H), 3.55 (m, 1H; 3’-
H), 3.02 3.18 (m, 3H; 4-H, 7-H, 11b-H), 2.87 3.02 (m, 3H; 4’-H, 4’-H, 6-
H), 2.63 (m, 1H; 7-H), 2.45 2.57 (m, 2H, 6-H, 10’-H), 2.35 (ddd,
2J(H,H)=13.5 Hz, 3J(H,H)=3.1, 3.1 Hz, 1H; 1-H), 2.09 (dd, 2J(H,H)=
11.2 Hz, 3J(H,H)=11.2 Hz, 1H; 4-H), 1.89 (m, 1H; 2-H), 1.73 (dd,
3
2J(H,H)=13.9 Hz, J(H,H)=9.7 Hz, 1H; 10’-H), 1.59 (m, 1H, 12-H), 1.42
(m, 1H, 3-H), 1.05 1.32 (m, 2H, 1-H, 12-H), 0.89 ppm (t, 3J(H,H)=
7.7 Hz, 3H; 13-H); 13C NMR (75 MHz, CDCl3, 258C): d=172.3 (C-
amide), 153.0 (C-6’), 147.5 (C-9 or C-10), 147.1 (C-9 or C-10), 137.4 (C-
benzyl), 131.7 (C-11a), 129.4 (C-4’a), 128.4 (C-benzyl), 127.7 (C-benzyl)
127.5 (C-benzyl), 127.4 (C-7a), 123.0 (C-9’a), 112.8 (C-7’), 112.2 (C-4’a),
112.0 (C-8’), 111.4 (C-8), 108.5 (C-11), 102.0 (C-5’), 70.89 (C-benzyl),
62.29 (C-11b), 60.80 (C-4), 56.14, 55.71 (C-OMe), 52.18 (C-6), 41.3 (C-3),
40.95 (C-3’), 39.49 (C-10’), 37.88 (C-2), 37.23 (C-1), 28.83 (C-7), 25.48 (C-
4’), 23.34 (C-12), 10.98 ppm (C-13); IR (KBr): n˜ =3375 (NH), 2932 (C-
Tubulosine (2): A suspension of compound 28 (45 mg, 79 mmol) and Pd/C
(10%, 54% water, 20 mg) in MeOH (2.5 cm3) was stirred under a hydro-
gen atmosphere (1 bar) for 95 min. The catalyst was removed by filtra-
tion over silica gel using CH2Cl2/MeOH (5:1) as eluent. The solvent was
removed under reduced pressure and the crude product was purified by
column chromatography on silica gel using CH2Cl2/MeOH (5:1) as eluent
again. Compound 2 was obtained as a amorphous white powder (25 mg,
67%). [a]2D0 =ꢀ60.7(c=0.3 in pyridine), ([a]D27 =ꢀ63.9(c=2.0 in pyri-
dine))[26] 1H NMR (600 MHz, [D6]DMSO, 358C): d=10.22 (brs, 1H;
H), 2859 (OMe), 1647 (CONR2), 1513 (CONR2), 1366 (CH3), 858 cmꢀ1
;
UV/Vis (acetonitrile): lmax (lge)=281.5 (3.962), 200.0 nm (4.875); MS
(70 eV, EI): m/z (%): 581.3254 (18) [M+] (C36H41N3O3 requires 581.3254),
490.4 (100) [M+ꢀC7H7], 272.3 (42) [C17H22NO2+], 246.3 (58)
[C16H16NO2+], 191.1 (38) [C11H13NO2+], 91.1 (50) [C7H7+].
2,3-(R,R)-11b-(S)-O-Benzyl-dehydrotubulosine (27): Phosphorus oxy-
chloride (316 mg, 2.06 mmol) was added dropwise to a solution of amide
25 (240 mg, 413 mmol) in benzene (13 cm3), and the reaction mixture was
stirred under reflux for 85 min. The workup was carried out similarly as
described for dehydroemetine 26. The obtained organic layer was treated
3
5
Indol-NH), 8.39 (brs, 1H; OH), 7.02 (dd, J(H,H)=8.4, J(H,H)=2.0 Hz,
1H; 8’-H), 6.81 (s, 1H; 8-H or 11-H), 6.65 (d, 4J(H,H)=2.0 Hz, 1H; 5’-
H), 6.64 (s, 1H; 8-H or 11-H), 6.49 (ddd, 3J(H,H)=8.4, J(H,H)=2.0 Hz,
4
2.0 Hz, 1H; 7’-H), 4.11 (m, 1H; 1’-H), 3.71, 3.70 (s, 3H; OMe), 3.10
2729
Chem. Eur. J. 2004, 10, 2722 2731
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim