European Journal of Organic Chemistry
10.1002/ejoc.201601179
1H), 6.71 (dd, J = 17.6, 10.9, Hz, 1H), 5.68 (d, J = 17.6 Hz, 1H), 5.21 (d, J = 11.0 Hz,
1H), 5.03 (br, 2H), 4.56–4.36 (br, 2H), 3.90 (s, 3H), 2.24 (br. s, 1H) ppm; 13C NMR
(100 MHz, CDCl3): = 159.3 (C), 155.5 (C), 140.7 (C), 136.4 (C), 135.9 (CH), 131.2
(CH), 131.2 (C), 130.6 (C), 129.4 (C), 129.3 (CH), 128.5 (2 CH), 127.9 (CH), 127.0
(2 CH), 126.6 (CH), 113.7 (CH), 113.3 (CH), 113.2 (CH), 112.4 (CH2), 71.1 (CH2),
63.6 (CH2), 55.3 (CH3) ppm; IR (film): 3450 br, 2939, 1604, 1489, 1266, 1228, 1012,
904, 724 cm-1; MS (ESI+) m/z (%): 369 ([M+Na}+, 100%); HRMS (ESI+): m/z calcd for
C23H22NaO3 [M+Na]+ 369.1461; found: 369.1469.
(C), 128.9 (2 CH), 128.8 (CH), 128.3 (2 CH), 127.5 (CH), 126.7 (2 CH), 125.1
(CH), 121.9 (CH), 116.7 (2 CH), 114.4 (CH), 113.9 (CH), 113.1 (CH), 112.8 (CH),
70.5 (CH2), 56.1 (CH3), 55.4 (CH3), 50.8 (CH), 44.8 (CH2), 37.0 (CH2), 36.9 (CH2),
32.1 (2 CH2), 25.0 (CH2) ppm; IR (film): 2930, 1605, 1503, 1456, 1369, 1270, 1225,
1165, 905; MS (ESI+) m/z (%): 707 ([M{37Cl}+Na]+, 40%), 705 ([M{35Cl}+Na]+,
100%).
2,3,4,17,18,30-Hexahydro-22-Benzyloxy-13,27-dimethoxy-1,5-dithia-11-oxa-7,10-
etheno-12,16-metheno-19,23-methenobenzo[x]spiro[5,20]hexacosatridecaene (38): To
a solution of dithiane 37 (200 mg, 0.29 mmol) in THF (30 mL) at –78 °C was added n-
BuLi (2.44 M in hexanes, 0.13 mL, 0.32 mmol) over 3 min. The reaction mixture was
warmed to RT and after 18 h. sat. NH4Cl (10 mL) and water (5 mL) were added. The
aqueous phase was separated at extracted with Et2O (3 20 mL), then the combined
organic phases were dried over MgSO4, concentrated in vacuo and purified by column
chromatography (40-50 % Et2O/petrol) to afford the title compound 38 as a white solid
(92 mg, 48%); MP 118–120 °C (Et2O/petrol); 1H NMR (400 MHz, CDCl3): = 7.55 (br
s, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.37–7.23 (m, 7H), 7.06 (dd, J = 8.4, 2.1 Hz, 1H), 6.94
(d, J = 8.6 Hz, 1H), 6.89–6.78 (m, 4H), 6.80 (d, J = 1.9 Hz, 1H), 6.76 (d, J = 2.1 Hz,
1H), 6.63 (d, J = 1.8 Hz, 1H), 4.95 (d, J = 12.2 Hz, 1H), 4.85 (d, J = 12.0 Hz, 1H), 3.91
(s, 6H), 3.62 (d, J = 14.2 Hz, 1H), 3.52 (d, J = 14.0 Hz, 1H), 3.19–2.95 (m, 3H), 2.72–
2.55 (m, 4H), 2.47 (m, 1H), 1.98–1.87 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): =
157.6 (C), 154.6 (C), 153.1 (C), 148.8 (C), 147.2 (C), 137.2 (C), 136.3 (C), 135.6 (C),
134.8 (C), 134.6 (C), 133.4 (CH), 131.9 (C), 131.7 (CH), 130.8 (C), 128.4 (2 CH),
127.6 (CH), 127.2 (CH), 127.2 (2 CH), 127.1 (2 CH), 122.0 (CH), 117.5 (CH),
116.1 (CH), 113.8 (2 CH), 113.0 (CH), 112.1 (2 CH), 71.1 (CH2), 59.7 (C), 56.3
(CH3), 55.3 (CH3), 49.5 (CH2), 34.0 (CH2), 31.8 (CH2), 28.2 (CH2), 27.5 (CH2), 25.2
(CH2) ppm; IR (solid): 2925, 2852, 1605, 1513, 1496, 1463, 1270, 1230, 1166, 1128;
MS (ESI+) m/z (%): 669 ([M+Na]+, 100%); HRMS (ESI+): calcd for C40H38NaO4S2
[M+Na]+ 669.2104; found: 669.2103.
(E)-4-(5-(2-(6-(Benzyloxy)-2'-(hydroxymethyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)vinyl)-2-
methoxyphenoxy)benzaldehyde (34): A solution of styrene 35 (4.78 g, 13.4 mmol),
iodide 23 (5.14 g, 14.8 mmol) and potassium phosphate (4.01 g, 18.8 mmol) in DMA
(55 mL) was degassed by sonication for 20 min under argon then Pd(OAc)2 (150 mg,
0.67 mmol) was added. The reaction mixture was heated at reflux for 18 h then cooled
to RT and partitioned between water (100 mL) was and EtOAc (50 mL). The aqueous
phase was separated and extracted with EtOAc (2 50 mL) then the combined organic
phases were dried over MgSO4, concentrated in vacuo and purified by column
chromatography (65% Et2O/petrol) to afford the title compound 34 as a white solid
(5.84 g, 75 %); MP 70–71 C (Et2O/petrol); 1H NMR (400 MHz, CDCl3): = 9.91 (s,
1H), 7.84 (d, J = 8.8 Hz, 2H), 7.40 (dd, J = 8.6, 2.3 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H),
7.33–7.26 (m, 5H), 7.20–7.16 (m, 3H), 7.12 (d, J = 2.7 Hz, 1H), 7.04–6.98 (m, 4H),
6.94–6.90 (m, 3H), 5.02 (br, 2H), 4.35-4.51 (br, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 2.15 (s,
1H) ppm; 13C NMR (100 MHz, CDCl3): = 190.8 (CH), 163.4 (C), 159.4 (C), 155.4
(C), 151.0 (C), 143.1 (C), 140.7 (C), 136.4 (C), 131.9 (2 CH), 131.4 (C), 131.3 (CH),
130.9 (C), 130.9 (C), 130.7 (C), 129.4 (C), 129.4 (CH), 128.5 (2 CH), 127.9 (CH),
127.1 (2 CH), 127.0 (C), 126.9 (CH), 126.0 (CH), 124.7 (CH), 119.7 (CH), 116.2 (2
CH), 113.9 (CH), 113.4 (CH), 113.3 (CH), 113.1(CH), 71.2 (CH2), 63.7 (CH2), 56.0
(CH3), 55.3 (CH3) ppm; IR (solid): 3438 br, 2933, 2836, 1689, 1596, 1581, 1501,
1454, 1269, 1225, 1153, 725; MS (ESI+) m/z (%): 595 ([M+Na]+, 100%); HRMS
(ESI+): m/z calcd for C37H32NaO6 [M+Na]+ 595.2091; found: 595.2082.
1,2,13,14-Tetrahydro-9,23-dimethoxy-18-hydroxy-3,6-etheno-8,12-metheno-15,19-
metheno-7-oxabenzo[t]cycloeicosadecaene (39): To a solution of NiCl2.6H2O (310 mg,
1.28 mmol) in DMF (1 mL) was added sequentially a solution of dithiane 38 (0.052 g,
0.08 mmol) in THF (2 mL) and NaBH4 (96 mg, 2.56 mmol). After 18 h the mixture
filtered through Celite©, concentrated in vacuo and partitioned between water (10 mL)
and Et2O (15 mL). The aqueous phase was separated and extracted with Et2O (2 15
mL), then the combined organic phases were dried over MgSO4, concentrated in vacuo
and purified by column chromatography (30 % Et2O/petrol) to give a white solid (25
mg). That material was dissolved in EtOH (3 mL) and DCM (3 mL) and 10% Pd-C (10
mg) added. The flask was evacuated and purged with argon three times then evacuated
and purged with hydrogen twice. After 6 h the reaction mixture was filtered through
Celite©, concentrated in vacuo and purified by column chromatography (50-70%
Et2O/hexane) to afford the title compound 39 as a white solid (15.8 mg, 74%); MP 85–
87 °C (Et2O/petrol); 1H NMR (400 MHz, CDCl3): = 7.10 (d, J = 2.6 Hz, 1H), 7.05 (d,
J = 8.6 Hz, 2H), 6.88 (dd, J = 8.6, 2.7 Hz, 2H), 6.84 (d, J = 7.3 Hz, 1H), 6.80 (d J = 8.1
Hz, 1H), 6.77–6.70 (m, 3H), 6.62 (d, J = 1.8 Hz, 1H), 6.33 (br s, 1H), 6.29 (d, J = 2.0
Hz, 1H), 4.62 (s, 1H), 3.92 (s, 6H), 3.18 (br dd, J = 13.5, 3.9 Hz, 1H), 3.07–2.85 (m,
5H), 2.49–2.73 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): = 159.7 (C), 153.7 (C),
150.1 (C), 149.8 (C), 147.0 (C), 141.0 (C), 137.6 (C), 136.3 (C), 134.8 (C), 133.1 (2
CH), 130.4 (CH), 129.9 (CH), 129.3 (CH), 129.2 (C), 128.5 (CH), 126.8 (C), 121.5
(CH), 121.0 (CH), 115.4 (CH), 114.9 (CH), 114.8 (CH), 113.0 (CH), 111.6 (CH), 56.2
(CH3), 55.3 (CH3), 37.8 (CH2), 35.2 (CH2), 34.9 (CH2), 33.4 (CH2) ppm; IR (solid):
3447 br, 2956, 2924, 2854, 1505, 1463, 1269, 1230, 1128; MS (ESI+) m/z (%): 475
([M+Na]+, 100%); HRMS (ESI+): calcd for C30H28NaO4 [M+Na]+ 475.1880; found:
475.1879.
(E)-(5'-(3-(4-(1,3-Dithian-2-yl)phenoxy)-4-methoxystyryl)-2'-(benzyloxy)-4-methoxy-
[1,1'-biphenyl]-2-yl)methanol (33): A solution of arene 34 (4.53 g, 7.93 mol), propan-
1,3-dithiol (2.58 g, 23.8 mmol) and PPTS (490 mg, 1.90 mmol) in DCM (88 mL) was
heated at reflux for 18 h then cooled to RT. Water (30 mL) and saturated aqueous
NaHCO3 (100 mL) were then added and the aqueous phase was extracted with Et2O (60
mL). The combined organic phases were dried over MgSO4, concentrated in vacuo and
purified by column chromatography (70% Et2O/petrol) to afford the title compound 33
as a white foamy solid (4.79 g, 91%); MP 85–87 °C (Et2O/petrol); 1H NMR (400 MHz,
CDCl3): = 7.43–7.36 (m, 3H), 7.33 (d, J = 2.2 Hz, 1H), 7.30–7.25 (m, 3H), 7.24 (dd, J
= 8.5, 2.2 Hz, 1H), 7.19–7.15 (m, 4H), 7.12 (d, J = 2.7 Hz, 1H), 6.99 (t, J = 8.1 Hz, 2H),
6.94–6.87 (m, 5H), 5.16 (s, 1H), 5.01 (br, 2H), 4.55–4.35 (br, 2H), 3.88 (s, 3H), 3.84 (s,
3H), 3.11–3.01 (m, 2H), 2.91 (dt, J = 14.0, 3.7 Hz, 2H), 2.21–2.11 (m, 2H), 1.97–1.86
(m, 1H) ppm; 13C NMR (100 MHz, CDCl3): = 159.3 (C), 158.0 (C), 155.3 (C), 151.0
(C), 144.5 (C), 140.7 (C), 136.4 (C), 133.0 (C), 131.3 (CH), 131.1 (C), 130.9 (C), 130.8
(C), 129.5 (C), 129.3 (CH), 129.0 (2 CH), 128.5 (2 CH), 127.1 (CH), 126.9 (2
CH), 126.8 (CH), 126.6 (CH), 126.2 (CH), 123.5 (CH), 118.9 (CH), 116.9 (2 CH),
113.9 (CH), 113.4 (CH), 113.2 (CH), 112.9 (CH), 71.2 (CH2), 63.7 (CH2), 56.0 (CH3),
55.3 (CH3), 50.7 (CH), 32.1 (2 CH2), 25.0 (CH2) ppm; IR (solid): 3445 br, 2933,
2897, 1605, 1501, 1454, 1441, 1422, 1268, 1222, 1166, 1124, 1023, 907, 727; MS
(ESI+) m/z (%): 685 ([M+Na]+, 100%); HRMS (ESI+): m/z calcd for C40H38NaO5S2
[M+Na]+ 685.2053; found: 685.2058.
(5'-(3-(4-(1,3-Dithian-2-yl)phenoxy)-4-methoxyphenethyl)-2'-(benzyloxy)-4-methoxy-
[1,1'-biphenyl]-2-yl)methanol (36): A solution of stilbene 33 (1.50 g, 2.26 mmol),
tosylhydrazone (4.21 g, 22.62 mmol) and NaOAc (1.86 g, 22.62 mmol) in 1:1 v/v THF
and water (30 mL each) was heated at reflux for 18 h then cooled to RT. Saturated
K2CO3 (50 mL) and water (10 mL) were added and the reaction mixture was extracted
with Et2O (3 100 mL). The combined organic phases were dried over MgSO4,
concentrated in vacuo and purified by column chromatography (50% Et2O/petrol) to
afford the title compound 36 as a white solid (1.37 g, 91%); MP 90–92 °C (Et2O/petrol);
1H NMR (400 MHz, CDCl3): = 7.37 (d, J = 8.7 Hz, 2H), 7.31–7.27 (m, 3H), 7.20–
7.15 (m, 2H), 7.13–7.10 (m, 2H), 7.08 (dd, J = 8.3, 2.2 Hz, 1H), 6.95 (d, J = 8.4 Hz,
1H), 6.93–6.89 (m, 4H), 6.85 (d, J = 8.8 Hz, 2H), 6.81 (br s, 1H), 5.14 (s, 1H), 4.98 (br,
2H), 4.48–4.29 (br, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.14–2.98 (m, 2H), 2.90 (dt, J =
14.1, 3.7 Hz, 2H), 2.86 (br s, 4H), 2.31 (t, J = 6.2 Hz, 1H), 2.17 (m, 1H), 1.92 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3): = 159.2 (C), 158.1 (C), 154.0 (C), 149.7 (C),
143.9 (C), 140.7 (C), 136.7 (C), 134.6 (C), 134.5 (C), 132.7 (C), 131.8 (CH), 131.2
(CH), 130.4 (C), 129.7 (C), 128.9 (2 CH), 128.5 (CH), 128.4 (2 CH), 127.8 (CH),
127.1 (2 CH), 125.0 (CH), 121.8 (CH), 116.6 (2 CH), 113.9 (CH), 113.3 (CH),
113.1 (CH), 112.7 (CH), 71.3 (CH2), 63.6 (CH2) 56.0 (CH3), 55.3 (CH3), 50.7 (CH),
36.9 (CH2), 36.9 (CH2), 32.1 (2 CH2), 24.8 (CH2) ppm; IR (solid): 3447 br, 2933,
1605, 1501, 1269, 1223, 1164, 1123, 1024, 906; MS (ESI+) m/z (%): 687 ([M+Na]+,
100%); HRMS (ESI+): m/z calcd for C40H40O5S2 [M+Na]+ 687.2209; found: 687.2203.
1,2,13,14-Tetrahydro-9,18,23-trihydroxy-3,6-etheno-8,12-metheno-15,19-metheno-7-
oxabenzo[t]cycloeicosadecaene (5): To a stirred solution of the macrocyclic bisbibenzyl
39 (150 mg, 0.33 mmol) in DCM (33 mL) was added boron tribromide (1 M solution in
DCM, 3.31 mL, 3.31 mmol). After 5 h, water (10 mL) was added then the aqueous
phase was separated and extracted with Et2O (3 30 mL). The combined organic
phases were dried over MgSO4, concentrated in vacuo and purified by column
chromatography (40% Et2O/petrol) to afford the title compound 5 as a white solid (130
mg, 92%); MP 154–155 °C (Et2O/hexane); 1H NMR (400 MHz, CD3OD): = 6.93 (d, J
= 2.6 Hz, 1H), 6.89 (dd, J = 8.4, 2.1 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 1.2
Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.66–6.62 (m, 2H), 6.61–6.56 (m, 3H), 6.51 (d, J =
2.2 Hz, 1H), 6.32 (br s, 1H), 6.22 (d, J = 2.0 Hz, 1H), 3.04 (br dd, J = 12.9, 4.8 Hz, 1H),
2.96–2.65 (m, 6H), 2.43 (m, 1H) ppm; 13C NMR (100 MHz, CD3OD): = 157.9 (C),
155.6 (C), 152.8 (C), 149.6 (C), 145.5 (C), 143.4 (C), 139.8 (C), 136.6 (C), 135.0 (C),
133.4 (CH), 132.8 (CH), 132.4 (C), 130.7
(CH), 129.7 (C), 128.5 (CH), 122.7 (br, 2
CH), 121.6 (br, 2 CH), 116.9 (CH), 116.8
(CH), 116.8 (CH), 116.3 (CH), 114.4 (CH),
38.8 (CH2), 37.1 (CH2), 36.0 (CH2), 34.5
(CH2) ppm; IR (solid): 3363 br, 2954, 2923,
2853, 1505, 1445, 1222, 1163; MS (ESI–) m/z
2-(4-(5-(2-(6-(Benzyloxy)-2'-(chloromethyl)-4'-methoxy-[1,1'-biphenyl]-3-yl)ethyl)-2-
methoxyphenoxy)phenyl)-1,3-dithiane (37): To a solution of benzyl alcohol 36 (0.76 g,
1.14 mmol) in DCM (55 mL) was added DBU (0.52 g, 3.42 mmol), LiCl (0.053g, 1.25
mmol) and MsCl (0.39 g, 3.42 mmol). After 18 h the reaction mixture was concentrated
in vacuo and purified by column chromatography (30% Et2O/petrol) to afford the title
compound 37 as a colourless oil (0.69 g, 88%); 1H NMR (400 MHz, CDCl3): = 7.35
(d, J = 8.7 Hz, 2H), 7.31–7.23 (m, 3H), 7.20–7.17 (m, 2H), 7.15 (d, J = 8.4 Hz, 1H),
7.10 (d, J = 2.6 Hz, 1H), 7.05 (dd, J = 8.3, 2.3 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 6.93–
6.87 (m, 4H), 6.85–6.80 (m, 3H), 5.11 (s, 1H), 5.00 (s, 2H), 4.44 (d, J = 11.7 Hz, 1H),
4.35 (d, J = 11.3 Hz, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.09–2.98 (m, 2H), 2.89 (dt, J =
14.1, 3.8 Hz, 2H), 2.84 (s, 4H), 2.16 (m, 1H), 1.90 (m, 1H) ppm; 13C NMR
(100 MHz, CDCl3): = 159.0 (C), 158.2 (C), 154.0 (C), 149.7 (C), 143.9 (C), 137.3 (C),
137.1 (C), 134.8 (C), 134.0 (C), 132.7 (C), 131.9 (CH), 131.7 (CH), 130.6 (C), 129.2
(%): 447 ([M+Na]+, 100%); HRMS (ESI+):
calcd for C28H25O4 [M+H]+ 425.1747; found:
425.1743; X-ray: see insert.
Acknowledgements
We gratefully acknowledge the funding provided by Umm Al-Qura University, Saudi
Arabia and EPSRC via equipment grant EP/K039466/1. We also thank Dr Mark Light
for the X-ray analysis and Dr Paul Murgues for advice and guidance (to FAA).
5
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