D
D. Przybyla, U. Nubbemeyer
Paper
Synthesis
13C NMR (100 MHz, CD2Cl2): δ = 198.4 and 197.6 (C-7), 156.5 and
155.4 (C-15), 138.6 (C-5), 135.0 and 134.8 (C-11), 129.1 and 128.6(C-
6), 120.2 and 120.0 (C-10), 106.3 (C-4), 81.1 and 80.6 (C-16), 73.4 (C-
3), 65.4 and 62.9 (C-8), 32.5 and 31.3(C-14), 31.1 (C-2), 28.6 and 28.5
(C-17), 26.9 and 26.3 (C-9), 26.1 (C-13), 18.1 (C-12), 14.7 (C-1).
HRMS (ESI): m/z [M + Na]+ calcd for C21H33NO6 + Na: 418.2206; found:
418.2205.
(E)-3-(1-Methyl-2-mercapto-5-benzyl-1H-imidazole-4-yl)-(E)-
prop-2-enoic Acid Methyl Ester (8b)
Synthesis of 2-mercaptoimidazole 8b following the procedure as de-
scribed for 8a using 7b (0.30 g, 0.72 mmol) in MeOH (5 mL), AcCl
(1.03 mL, 14.37 mmol) in MeOH (15 mL), and KSCN (0.35 g, 3.60
mmol) KSCN in AcOH (20 mL) afforded 8b as a yellow solid; yield:
0.12 g (58 %); mp 216–222 °C; Rf = 0.25 (25 % EtOAc in PE).
IR (neat): 3062, 3028, 2947, 1704, 1639, 1491, 1432, 1375, 1315,
(E)-1-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)-4-[(N-tert-
butoxycarbonyl-N-methyl)amino]-5-phenylpent-1-en-3-one (7b)
1284, 1255, 1169, 1176, 1121, 1029, 966, 912, 855, 727, 697 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 12.19 (s, 1 H, S-H), 7.41 (d, J = 15.8 Hz,
1 H, H-5), 7.31–7.19 (m, 3 H, H-12, H-13), 7.05 (d, J = 7.0 Hz, 2 H, H-
11), 6.41 (d, J = 15.8 Hz, 1 H, H-6), 4.00 (s, 2 H, H-9), 3.73 (s, 3 H, H-8),
3.36 (s, 3 H, H-4).
13C NMR (75 MHz, CDCl3): δ = 167.4 (C-7), 163.8 (C-1), 135.2 (C10),
132.7 (C-3), 129.3 (C-11), 128.1 (C-12), 127.6 (C-13), 127.4 (C-5),
122.8 (C-2), 116.6 (C-6), 52.0 (C-8), 31.9 (C-4), 29.8 (C-9).
Synthesis of ketone 7b following the procedure as described for 7a us-
ing orthoester 6 (1.75 g, 6.20 mmol) in Et2O (20 mL), t-BuLi (7.75 mL,
12.40 mmol, 1.6 M in pentane), and Weinreb amide 4b (1.00 g, 3.10
mmol) in Et2O (15 mL) gave 7b as a yellow solid; yield: 1.15 g (89 %);
mp 95–99 °C; Rf = 0.27 (6.25% EtOAc in PE).
IR (neat): 3029, 2964, 2933, 2878, 1688 (br), 1653, 1455, 1393, 1323,
1250, 1154, 1048, 996, 886, 848, 751, 699, 668 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C15H17N2O2S: 289.1011; found:
289.1004.
1H NMR (400 MHz, CD2Cl2): δ = 7.36–7.13 (m, 5 H, H-11, H-12, H-13),
6.62–6.53 (m, 2 H, H-5, H-6), 4.97 (dd, J = 9.8, 5.4 Hz, 0,5 H, H-8)), 4.55
(dd, J = 10.6, 4.5 Hz, 0,5 H, H-8), 3.95 (s, 6 H, H-3), 3.25–3.14 (m, 1 H,
H-9), 2.97–2.81 (m, 1 H, H-9), 2.59 (s, 3 H, H-14), 1.37 and 1.29 (2 s, 9
H, H-17), 0.81 (s, 3 H, H-1).
(E)-3-(1-Methyl-5-(3-methylbut-2-en-1-yl)-1H-imidazole-4-yl)-
(E)-prop-2-enoic Acid Methyl Ester (Fungerin, 1a)7a,11
To a solution of 8a (0.05 g, 0.19 mmol) in AcOH (5 mL) was added
H2O2 (0.16 mL, 1.90 mmol, 35% in H2O) at 0 °C. After 10 min, some
drops of aq 10% Na2S2O3 were added and the solution was partitioned
between distilled H2O (10 mL) and EtOAc (20 mL). The aqueous layer
was basified by the addition of solid Na2CO3 and extracted with EtOAc
(4 × 10 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The residue was purified by column chroma-
tography (100% EtOAc) to afford Fungerin (1a) as a white solid; yield:
0.038 g (85%); mp 92–94 °C; Rf = 0.44 (50% acetone in EtOAc).
13C NMR (100 MHz, CD2Cl2): δ = 197.8 and 197.2 (C-7), 156.2 and
155.0 (C-15), 138.9 (C-5), 138.8 and 138.5 (C-10), 129.7 and 129.6 (C-
11), 129.0 and 128.8 (C-12), 128.4 (C-6), 126.9 and 126.8 (C-13),
106.2 (C-4), 81.2 and 80.7 (C-16), 73.4 (C-3), 67.1 and 64.4 (C-8), 34.1
and 33.4 (C-9), 32.8 and 31.9 (C-14), 31.0 (C-2), 28.5 and 28.3 (C-17,
14.7 (C-1).
HRMS (ESI): m/z [M + Na]+ calcd for C23H31NO6 + Na: 440.2049; found:
440.2033.
IR (neat): 3103, 2949, 2913, 2858, 1703, 1632, 1515, 1433, 1379,
(E)-3-[1-Methyl-2-mercapto-5-(3-methylbut-2-en-1-yl)-1H-imid-
azole-4-yl]-(E)-prop-2-enoic Acid Methyl Ester (8a)
1270, 1166, 1045, 976, 861, 806, 734 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 15.3 Hz, 1 H, H-5), 7.36 (s, 1
H, H-1)), 6.44 (d, J = 15.3 Hz, 1 H, H-6), 5.08–5.00 (m, 1 H, H-10), 3.72
(s, 3 H, H-8), 3.50 (s, 3 H, H-4), 3.41 (d, J = 6.9 Hz, 2 H, H-9), 1.76 (s, 3
H, H-12), 1.72 (d, J = 1.0 Hz, 3 H, H-13).
13C NMR (75 MHz, CDCl3): δ = 168.5 (C-7), 139.0 (C-1), 135.8 (C-5),
134.7 (C-11), 134.6 (C-3), 134.4 (C-2), 119.8 (C-10), 114.0 (C-6), 51.5
(C-8), 31.9 (C-4), 25.7 (C-12), 22.7 (C-9), 18.0 (C-13).
AcCl (0.14 mL, 2.00 mmol) was added dropwise to MeOH (2 mL) at 0
°C and stirred for a couple of min. Then, 7a (0.05 g, 0.13 mmol) dis-
solved in MeOH (1 mL) was added and the solution was stirred for 5
min at 0 °C and for 30 min at r.t. Some drops of distilled H2O were
added and the reaction mixture was stirred for 10 min before all vola-
tiles were removed in vacuo (bath temperature 35 °C). The residue
was dissolved in AcOH (5 mL), KSCN (0.063 g, 0.65 mmol) was added
and the solution was refluxed for 30 min. All volatiles were removed
in vacuo and the residue was partitioned between EtOAc (10 mL) and
sat. aq NaHCO3 (1 mL). The aqueous layer was extracted with EtOAc (2
× 10 mL) and the combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The residue was purified by column chroma-
tography (gradient 5 → 25% EtOAc in PE) to afford 8a as a yellow oil;
yield: 0.01 g (30%); Rf = 0.27 (25% EtOAc in PE).
HRMS (ESI): m/z [M + H]+ calcd for C13H19N2O2: 235.1447; found:
235.1451.
(E)-3-(1-Methyl-5-benzyl-1H-imidazole-4-yl)-(E)-prop-2-enoic
Acid Methyl Ester (1b)
Synthesis of imidazole 1b following the procedure as described for 1a
using 7b (0.05 g, 0.17 mmol) in AcOH (5 mL), H2O2 (0.15 mL, 1.70
mmol, 35% in H2O) afforded 1b as a white solid; yield: 0.035 g (80%);
mp 114–117 °C; Rf = 0.2 (100% EtOAc).
IR (neat): 3069, 2947, 2737, 1715, 1637, 1490, 1436, 1376, 1281,
1255, 1195, 1174, 1122, 1034, 969, 919, 856, 732 cm–1
.
1H NMR (300 MHz, CD2Cl2): δ = 11.44 (s, 1 H, S-H), 7.39 (d, J = 15.8 Hz,
1 H, H-5), 6.21 (d, J = 15.8 Hz, 1 H, H-6), 5.06–4.95 (m, 1 H, H-10), 3.75
(s, 3 H, H-8), 3.52 (s, 3 H, H-4), 3.37 (d, J = 6.7 Hz, 2 H, H-9), 1.75 (s, 3
H, H-12), 1.73 (d, J = 1.5 Hz, 3 H, H-13).
13C NMR (75 MHz, CD2Cl2): δ = 167.6 (C-7), 163.9 (C-1), 136.5 (C-11),
134.8 (C-3), 128.0 (C-5), 121.5 (C-2), 118.4 (C-10), 115.5 (C-6), 52.2
(C-8), 31.9 (C-4), 25.8 (C-12), 23.8 (C-9), 18.3 (C-13).
IR (neat): 3025, 2949, 1699, 1632, 1515, 1433, 1302, 1263, 1191,
1169, 1145, 1043, 976, 863, 773, 718 cm–1
.
1H-NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 15.4 Hz, 1 H, H-5), 7.45 (s, 1
H, H-1), 7.29–7.16 (m, 3 H, H-12, H-13), 7.03 (d, J = 7.1 Hz, 2 H, H-11),
6.60 (d, J = 15.4 Hz, 1 H, H-6), 4.06 (s, 2 H, H-9), 3.73 (s, 3 H, H-8), 3.36
(s, 3 H, H-4).
13C-NMR (75 MHz, CDCl3): δ = 168.3 (C-7), 139.0 (C-1), 136.7 (C-10),
135.5 (C-3), 134.7 (C-5), 132.6 (C-2), 128.9 (C-11), 128.0 (C-12), 126.9
(C-13), 115.2 (C-6), 51.4 (C-8), 31.8 (C-4), 28.8 (C9).
HRMS (ESI): m/z [M + 1]+ calcd for C13H19N2O2S: 267.1167; found:
267.1160.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E