Total synthesis of lysergic acid
R Kanno et al
6
1.02 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 150.5 (C), 144.3 (C), 144.3 (C),
CHCl3); IR (film) 2954, 2923, 2869, 1598, 1531, 1449, 1348, 1307, 1163,
1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.6 Hz, 2H), 8.01
141.4 (C), 135.5 (CH), 135.5 (CH), 133.6 (C), 133.4 (C), 132.6 (C), 129.9 1092 cm− 1
;
(CH), 129.7 (CH), 129.2 (CH), 128.6 (CH), 127.8 (CH), 127.8 (CH), 127.3 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.30 (d, J =8.0 Hz, 1H), 7.26
(CH), 124.2 (CH), 124.2 (CH), 123.8 (CH), 114.9 (CH), 85.4 (C), 76.7 (C),
(d, J = 8.6 Hz, 2H), 7.06 (dd, J = 8.0, 8.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 5.70
54.5 (CH2), 52.6 (CH2), 46.3 (CH), 38.0 (CH), 36.4 (CH), 35.3 (CH2), 26.6 (d, J =6.3 Hz, 1H), 5.12 (d, J = 9.2 Hz, 1H), 4.29–4.21 (m, 3H), 3.61 (dd,
(CH3), 21.5 (CH3), 19.1 (C), HR-MS (ESI) 828.2201 (calcd for J = 9.2, 4.1 Hz, 1H), 3.44 (dddd, J =6.3, 4.9, 4.3, 4.1 Hz, 1H), 3.25–3.13 (m,
C43H43N3NaO7S2Si 828.2209).
2H), 2.39 (s, 3H), 2.08 (ddd, J = 12.6, 4.9, 4.6 Hz, 1H), 1.84 (s, 1H), 1.63 (m,
1H), 1.49–1.34 (m, 6H), 1.27–1.19 (m, 6H), 0.88–0.75 (m, 15H); 13C NMR
(125 MHz, CDCl3) δ 149.9 (C), 148.3 (C), 146.4 (C), 144.3 (C), 140.4 (C),
138.7 (CH), 134.2 (C), 133.6 (C), 130.3 (C), 129.8 (CH), 128.8 (CH), 128.2
(CH), 127.3 (CH), 124.3 (CH), 122.4 (CH), 112.1 (CH), 63.0 (CH2), 57.9
(CH2), 54.4 (CH), 43.1 (CH), 31.6 (CH2), 30.6 (CH), 29.0 (CH2), 27.2 (CH2),
21.5 (CH3), 13.6 (CH3), 10.0 (CH2), HR-MS (ESI) 882.2225 (calcd for
C39H53N3NaO7S2Sn 882.2244).
N-((2aR,4R,5R)-5-(3-((tert-butyldiphenylsilyl)oxy)prop-1-yn-1-yl)-
1-tosyl-1,2,2a,3,4,5-hexahydrobenzo[cd]indol-4-yl)-4-
nitrobenzenesulfonamide (19)
To a solution of aziridine 18 (4.22 g, 5.23 mmol) in dichloromethane (40 ml)
was added boron trifluoride diethyl ether complex (1.42 ml, 11.5 mmol) at
0 °C. After stirring at room temperature for 30 min, the reaction mixture was
quenched with saturated aqueous sodium bicarbonate solution and extracted
with dichloromethane three times. The combined organic phases were dried
over sodium sulfate and filtrated. The filtrate was concentrated in vacuo and the
resultant residue was purified with flash column chromatography on neutral
silica gel (10–50% ethyl acetate in hexane) to give the title compound 19
(2.93 g, 69%) as a yellow oil. [α]D23.6 –79.7 (c 1.00, CHCl3); IR (film) 3273,
2930, 2857, 1595, 1531, 1449, 1349, 1165, 1088, 739, 703 cm− 1; 1H NMR
(500 MHz, CDCl3) δ 8.28 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.70
(d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.5 Hz, 4H), 7.39–7.24 (m, 9H), 7.08 (dd,
J = 8.0, 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.35 (m, 1H), 4.23 (dd, J = 11.5,
11.5 Hz, 1H), 4.17 (s, 2H), 3.75 (m, 1H), 3.54 (m, 1H), 3.21 (m, 1H), 3.14 (dd,
J = 11.5, 9.1 Hz, 1H), 2.34 (s, 3H), 2.04 (m, 1H), 1.60 (m, 1H), 1.01 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 150.0 (C), 146.0 (C), 144.5 (C), 140.4 (C),
135.4 (CH), 133.4 (C), 132.9 (C), 132.8 (C), 130.7 (C), 129.9 (CH), 129.8
(CH), 129.8 (CH), 129.5 (C), 129.0 (CH), 128.3 (CH), 127.6 (CH), 127.6
(CH), 127.3 (CH), 124.4 (CH), 122.9 (CH), 112.4 (CH), 83.6 (C), 82.6 (C),
57.9 (CH2), 54.4 (CH), 52.6 (CH2), 35.2 (CH), 31.4 (CH), 29.3 (CH2), 26.5
(CH3), 21.5 (CH3), 19.0 (C), HR-MS (ESI) 828.2202 (calcd for
C43H43N3NaO7S2Si 828.2209).
(5aR,6aR,10aR)-7-((4-nitrophenyl)sulfonyl)-4-tosyl-9-
(tributylstannyl)-4,5,5a,6,6a,7,8,10a-octahydroindolo[4,3-fg]
quinoline (21)
To a solution of allyl alcohol 20 (1.62 g, 1.88 mmol) and triphenylphosphine
(594 mg, 2.26 mmol) in benzene (20 ml) was added diethyl azodicarboxylate
(2.2 M in toluene, 1.0 ml, 2.2 mmol) at 0 °C. After stirring at 0 °C for 30 min,
the reaction mixture was quenched with saturated aqueous sodium chloride
solution and extracted with ethyl acetate three times. The combined organic
phases were dried over sodium sulfate and filtrated. The resultant filtrate was
concentrated in vacuo and the resultant residue was purified with flash column
chromatography on neutral silica gel (5–15% ethyl acetate in hexane) to give
21.4
the title compound 21 (1.45 g, 91%) as a yellow oil. [α]D
–79.4 (c 1.28,
CHCl3); IR (film) 2954, 2924, 2851, 1597, 1530, 1453, 1349, 1162, 1094 cm−1
;
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.7 Hz, 2H), 7.95 (d, J = 8.7 Hz,
2H), 7.68 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H),
7.21 (dd, J = 8.2, 7.8 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.42 (s, 1H), 4.38–4.31
(m, 2H), 3.91 (d, J = 17.9 Hz, 1H), 3.39 (d, J = 10.5 Hz, 1H), 3.34–3.24 (m,
2H), 3.15 (ddd, J = 10.5, 10.1, 9.2 Hz, 1H), 2.61 (ddd, J = 13.9, 10.1, 7.1 Hz,
1H), 2.38 (s, 3H), 1.78 (ddd, J =13.9, 9.2, 5.5 Hz, 1H), 1.52–1.44 (m, 6H),
1.36–1.27 (m, 6H), 0.96–0.80 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 149.7
(C), 147.6 (C), 144.2 (C), 141.3 (C), 140.4 (C), 136.0 (C), 135.0 (CH), 133.8
(C), 131.2 (C), 129.7 (CH), 128.3 (CH), 128.1 (CH), 127.2 (CH), 124.2 (CH),
117.9 (CH), 112.8 (CH), 59.4 (CH), 58.7 (CH2), 52.6 (CH2), 40.0 (CH), 32.7
(CH), 30.4 (CH2), 29.0 (CH2), 27.3 (CH2), 21.5 (CH3), 13.6 (CH3), 9.42
(CH2), HR-MS (ESI) 882.2141 (calcd for C39H51N3NaO6S2Sn 864.2138).
N-((2aR,4R,5R)-5-((E)-3-hydroxy-2-(tributylstannyl)prop-1-en-1-
yl)-1-tosyl-1,2,2a,3,4,5-hexahydrobenzo[cd]indol-4-yl)-4-
nitrobenzenesulfonamide (20)
To a solution of tricyclic compound 19 (2.93 g, 3.63 mmol) in tetrahydrofuran
(20 ml) was added tetra-n-butylammonium fluoride (1.0 M in tetrahydrofuran,
18.1 ml, 18.1 mmol) at room temperature. After stirring for 1 h, the reaction
mixture was quenched with saturated aqueous ammonium chloride solution
and extracted with ethyl acetate three times. The combined organic phases were
dried over sodium sulfate and filtrated. The resultant filtrate was concentrated
in vacuo and the resultant residue was purified with flash column chromato-
graphy on neutral silica gel (10–70% ethyl acetate in hexane) to give a propargyl
alcohol (1.73 g, 84%) as a yellow oil. [α]D24.2 –74.2 (c 1.17, CHCl3); IR (film)
(5aR,6aR,10aR)-7-methyl-4-tosyl-9-(tributylstannyl)-
4,5,5a,6,6a,7,8,10a-octahydroindolo[4,3-fg]quinoline (22)
To a solution of tetracyclic compound 21 (1.45 g, 1.72 mmol) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (2.56 ml, 17.2 mmol) in acetonitrile (25 ml)
was added thioglycolic acid (794 mg, 8.62 mmol) at room temperature. After
stirring at room temperature for 45 min, the reaction mixture was quenched
with saturated aqueous sodium bicarbonate solution and extracted with ethyl
acetate three times. The combined organic phases were dried over sodium
sulfate and filtrated. The filtrate was concentrated in vacuo and the resultant
residue was used in the next reaction without further purification. To a solution
of the residue, formalin (2.0 ml) and acetic acid (2.0 ml) in methanol (17.5 ml)
was added sodium cyanoborohydride (1.08 g, 17.2 mmol) at room tempera-
ture. After stirring at room temperature for 1 h, the reaction mixture was
quenched with saturated aqueous sodium bicarbonate solution and extracted
with ethyl acetate three times. The combined organic phases were washed with
saturated aqueous sodium chloride solution, dried over sodium sulfate and
filtrated. The filtrate was concentrated in vacuo and the resultant residue was
2920, 1599, 1530, 1450, 1349, 1309, 1163, 1092 cm−1 1H NMR (500 MHz,
;
CD3OD) δ 8.33 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz,
2H), 7.28 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 7.10 (dd, J =8.0, 7.5 Hz,
1H), 6.87 (d, J = 7.5 Hz, 1H), 4.20 (dd, J = 6.9, 6.9 Hz, 1H), 3.91 (s, 2H), 3.75
(dd, J = 4.6, 3.5 Hz, 1H), 3.57 (s, 1H), 3.20–3.14 (m, 2H), 2.28 (s, 3H), 2.02
(ddd, J = 13.0, 4.6, 4.6 Hz, 1H), 1.57 (ddd, J = 13.0, 11.5, 3.5 Hz, 1H); 13C
NMR (125 MHz, CD3OD) δ 151.3 (C), 148.0 (C), 145.9 (C), 141.8 (C), 134.7
(C), 133.0 (C), 132.0 (C), 130.9 (CH), 129.7 (CH), 129.3 (CH), 128.5 (CH),
125.4 (CH), 124.2 (CH), 113.8 (CH), 84.9 (C), 83.4 (C), 59.2 (CH2), 55.8
(CH), 50.6 (CH2), 36.0 (CH), 32.7 (CH), 30.8 (CH2), 21.5 (CH3), HR-MS
(ESI) 590.1044 (calcd for C27H25N3NaO7S2 590.1031). To a solution of the
propargyl alcohol (1.73 g, 3.04 mmol) and bis(triphenylphosphine)palladium
(II) dichloride (428 mg, 0.608 mmol) in tetrahydrofuran (25 ml) was added tri- purified with flash column chromatography on silica gel (1–3% methanol in
n-butyltin hydride (0.965 ml, 3.64 mmol) at room temperature. After stirring chloroform) to give the title compound 22 (1.35 g, including thioglycolic acid)
22.8
for 1 h, the reaction mixture was quenched with saturated aqueous sodium
as a yellow oil. [α]D
–122.1 (c 1.11, CHCl3); IR (film) 2954, 2924, 2868,
chloride solution and extracted with ethyl acetate three times. The combined 2850, 1595, 1453, 1356, 1166, 1094 cm−1; H NMR (500 MHz, CDCl3) δ 7.69
1
organic phases were dried over sodium sulfate and filtrated. The resultant
(d, J = 7.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.5 Hz, 2H), 7.17 (dd,
filtrate was concentrated in vacuo and the resultant residue was purified with
J = 8.0, 7.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.32 (s, 1H), 4.38 (m, 1H), 3.40
flash column chromatography on silica gel (0–30% ethyl acetate in hexane) to (d, J = 16.6 Hz, 1H), 3.31–3.22 (m, 2H), 3.18 (m, 1H), 2.91 (m, 1H), 2.36
give the title compound 20 (1.62 g, 62%) as a yellow oil. [α]D21.8 –74.6 (c 0.982,
(s, 3H), 2.28 (s, 3H), 2.03–1.96 (m, 2H), 1.69 (m, 1H), 1.52–1.46 (m, 6H),
The Journal of Antibiotics