PAPER
Bis-Anthraquinoid Core of the Angelimicins
2291
Dimethyl 5,5′,6,6′-Tetramethoxy-2,2′-bis(methoxymethoxy)-
4,4′-bis[(phenylsulfinyl)methyl]-[1,1′-biphenyl]-3,3′-dicarbox-
ylate (13) and Dimethyl 5,5′,6,6′-Tetramethoxy-2,2′-bis(meth-
oxymethoxy)-4-[(phenylsulfinyl)methyl]-4′-[(phenyl-
HRMS-ESI: m/z [M + H]+ calcd for C38H43O14S2: 787.2094; found:
787.2016.
Data for 14
Rf = 0.15 (80% EtOAc in PE).
sulfonyl)methyl]-[1,1′-biphenyl]-3,3′-dicarboxylate (14)
To a soln of 12 (345 mg, 0.641 mmol) in CCl4 (9 mL) were added
NBS (136 mg, 0.768 mmol), (PhCO2)2 (16 mg, 0.066 mmol) and
NaOAc (100 mg, 1.22 mmol). After heating at reflux for 30 min, ad-
ditional portions of NBS (136 mg, 0.768 mmol) and (PhCO2)2 (16
mg, 0.066 mmol) were added. Heating was continued for an addi-
tional 30 min, after which time the reaction was cooled to r.t. and
quenched with 10% Na2SO3 (20 mL). The mixture was extracted
with CH2Cl2 (3 × 15 mL) and the combined organic phase dried
(Na2SO4), concentrated in vacuo and purified by flash column chro-
matography to afford the corresponding 4,4′-bis-bromomethyl de-
rivative (440 mg, 98%) as a pale yellow oil.8b
1H NMR (500 MHz, CDCl3): δ = 7.83–7.81 (m, 2 H), 7.62–7.47 (m,
8 H), 4.93–4.85 (m, 2 H), 4.82–4.73 (m, 4 H), 4.54–4.51 (m, 1 H),
4.29–4.26 (m, 1 H), 3.93, 3.92 (both s, 3 H), 3.88, 3.86 (both s, 3 H),
3.77, 3.76 (both s, 3 H), 3.75 (2 s, 3 H), 3.68, 3.66 (both s, 3 H),
3.59, 3.58 (both s, 3 H), 3.12, 3.11, 3.09 (4 s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 167.5 (2 signals), 167.4 (2 sig-
nals), 153.3, 153.2 (2 signals), 153.1, 150.5, 150.3, 149.1, 148.8,
148.7, 143.9, 139.5, 133.8, 131.3, 129.2, 129.1, 128.6, 125.6, 125.4,
125.0, 124.8, 124.7, 124.6, 124.5, 124.4, 121.7, 121.6, 100.8 (2 sig-
nals), 100.7 (2 signals), 60.9 (2 signals), 60.7 (2 signals), 60.6, 60.2
(2 signals), 60.0 (2 signals), 57.0 (3 signals), 56.3 (2 signals), 53.2,
52.9, 52.8, 52.7.
Rf = 0.25 (15% EtOAc in PE).
1H NMR (500 MHz, CDCl3): δ = 4.80 (d, J = 6.0 Hz, 2 H), 4.77 (d,
J = 6.0 Hz, 2 H), 4.67 (d, J = 9.7 Hz, 2 H), 4.63 (d, J = 9.7 Hz, 2
H), 3.96 (s, 6 H), 3.95 (s, 6 H), 3.83 (s, 6 H), 3.00 (s, 6 H).
HRMS-ESI: m/z [M + H]+ calcd for C38H43O15S2: 803.2038; found:
803.2030.
13C NMR (125 MHz, CDCl3): δ = 167.1, 153.2, 149.9, 148.0, 130.9,
124.8, 124.7, 100.8, 60.8, 60.3, 56.7, 52.8, 24.0.
Dimethyl 5,5′,6,6′-Tetramethoxy-2,2′-bis(methoxymethoxy)-
4,4′-bis[(phenylsulfonyl)methyl]-[1,1′-biphenyl]-3,3′-dicarbox-
ylate (15)
To a soln of the 4,4′-bis-bromomethyl derivative from the previous
step (440 mg, 0.632 mmol) in MeOH (6 mL) were added PhSH
(0.322 mL, 3.16 mmol) and K2CO3 (872 mg, 6.32 mmol). The reac-
tion was stirred for 16 h, then diluted with H2O and extracted with
EtOAc (3 × 15 mL). The combined organic phase was dried
(Na2SO4), concentrated in vacuo and purified by flash column chro-
matography to afford the 4,4′-bis-phenylthiomethyl derivative (340
mg, 70%) as a white semi-solid.
To a soln of the mixture of 13 and 14 (100 mg, ca. 0.127 mmol) in
CH2Cl2 (2 mL) at 0 °C were added MCPBA (87 mg, 0.508 mmol)
and NaOAc (87 mg, 1.06 mmol). After TLC showed complete dis-
appearance of the starting material, the reaction was quenched with
aq 2 M Na2SO3 soln (20 mL) and extracted with CH2Cl2 (3 × 15
mL). The combined organic phase was dried (Na2SO4), concentrat-
ed in vacuo and purified by flash column chromatography to afford
15 (100 mg, 96%) as a white solid.
Rf = 0.35 (30% EtOAc in PE).
Rf = 0.33 (30% EtOAc in PE).
1H NMR (500 MHz, CDCl3): δ = 7.39 (d, J = 8.0 Hz, 4 H), 7.28–
7.25 (m, 4 H), 7.20 (t, J = 7.4 Hz, 2 H), 4.76 (d, J = 6.0 Hz, 2 H),
4.73 (d, J = 6.0 Hz, 2 H), 4.37 (d, J = 12.2 Hz, 2 H), 4.28 (d, J =
12.2 Hz, 2 H), 3.83 (s, 6 H), 3.76 (s, 6 H), 3.70 (s, 6 H), 2.99 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 167.7, 153.1, 149.8, 148.2, 136.3,
131.0, 130.9, 129.0, 126.9, 124.7, 123.5, 100.5, 61.1, 60.2, 56.8,
52.6, 30.8.
1H NMR (500 MHz, CDCl3): δ = 7.81 (d, J =7.6 Hz, 4 H), 7.61 (t,
J = 7.6 Hz, 2 H), 7.50 (t, J = 7.6 Hz, 4 H), 4.90 (d, J = 13.3 Hz, 2
H), 4.86 (d, J = 13.3 Hz, 2 H), 4.80 (d, J = 6.0 Hz, 2 H), 4.77 (d, J =
6.0 Hz, 2 H), 3.91 (s, 6 H), 3.73 (s, 6 H), 3.56 (s, 6 H), 3.11 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 167.4, 153.0, 150.5, 149.1, 139.4,
133.8, 129.1, 128.6, 125.5, 125.3, 121.7, 100.8, 60.6, 60.0, 57.0,
52.9, 23.4.
HRMS-ESI: m/z [M + Na]+ calcd for C38H42O12NaS2: 777.2015;
found: 777.2011.
HRMS-ESI: m/z [M + Na]+ calcd for C38H42O16NaS2: 841.1819;
found: 841.1812.
To a soln of the bis-phenylthiomethyl derivative from the previous
step (340 mg, 0.450 mmol) in CH2Cl2 (6 mL) at –78 °C were added
NaOAc (147 mg, 3.60 mmol) and MCPBA (309 mg, 1.80 mmol).
After TLC showed complete disappearance of the starting material,
the mixture was quenched with aq 2 M Na2SO3 soln (20 mL) and
extracted with CH2Cl2 (3 × 15 mL). The combined organic phase
was dried (Na2SO4), concentrated in vacuo and purified by flash
column chromatography to afford an approximately 1:1 ratio of bis-
sulfoxide 13 (145 mg, 41%, mixture of three diastereomers) and
mixed sulfoxide–sulfone 14 (147 mg, 41%, mixture of two diaste-
reomers).
Hauser Annulation; General Procedures
Procedure A
To a soln of i-Pr2NH (0.090 mL, 0.638 mmol) in THF (3 mL) was
added n-BuLi (0.254 mL, 0.638 mmol, 2.5 M in hexane) at –78 °C.
After 2 h, a soln of 13 (50 mg, 0.0634 mmol) in THF (1.5 mL) was
added to the mixture, dropwise, over 1 h. The mixture was warmed
to –40 °C for 1 h and then cooled to –78 °C. Cyclohex-2-enone (19
mg, 0.198 mmol) in THF (1.5 mL) was added dropwise at –78 °C,
over 1 h, to the resulting dark yellow soln. The reaction was main-
tained for an additional 2 h at this temperature, and then warmed to
r.t. Stirring was continued at r.t. for 8 h, at which point the reaction
was quenched with sat. aq NH4Cl soln. The mixture was extracted
with EtOAc (3 × 20 mL) and the combined organic phase was dried
(Na2SO4) and concentrated in vacuo. The residue was homogeneous
on TLC, and after NMR analysis was identified as the starting ma-
terial 13.
Data for 13
Rf = 0.10 (80% EtOAc in PE).
1H NMR (500 MHz, CDCl3): δ = 7.56–7.53 (m, 4 H), 7.46–7.44 (m,
6 H), 4.76–4.70 (m, 4 H), 4.52–4.48 (m, 2 H), 4.27–4.23 (m, 2 H),
3.85–3.83 (4 s, 6 H), 3.75–3.74 (4 s, 6 H), 3.67–3.64 (4 s, 6 H),
3.09–3.07 (4 s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 167.5 (2 signals), 167.4 (2 sig-
nals), 153.3, 153.2 (2 signals), 153.1, 150.1 (2 signals), 150.0 (2 sig-
nals), 148.8 (2 signals), 148.6 (2 signals), 143.8 (2 signals), 131.2
(4 signals), 129.1 (4 signals), 125.0, 124.7, 124.5, 124.4, 124.3 (sev-
eral signals overlapped), 100.6 (2 signals), 100.5 (2 signals), 60.8 (4
signals), 60.1 (4 signals), 56.9 (4 signals), 56.2 (4 signals), 52.6 (4
signals).
In another experiment, Procedure A was repeated using THF–
HMPA (10:1) as the solvent. Similar results were obtained in both
experiments.
Procedure B
To a soln of t-BuOH (47 mg, 0.635 mmol) in THF (3 mL) was add-
ed n-BuLi (0.254 mL, 0.638 mmol, 2.5 M in hexane) at –60 °C. Af-
ter 2 h, a soln of 13 (50 mg, 0.0634 mmol) in THF (1.5 mL) was
added dropwise, over 1 h and the mixture stirred at –60 °C for 4 h.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2287–2293