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C. P. Ridley et al. / Bioorg. Med. Chem. 10 (2002) 3285–3290
71.3 (CH), 56.4 (CH3), 21.7 (2CH3); HRMS m/z
319.9923 [M]+, calcd for C11H13O3I, 319.9909.
d 7.12 (dd, 1H, J=8, 2 Hz), 7.10 (d, 1H, J=2 Hz), 6.88
(s, 1H), 6.84 (d, 1H, J=8 Hz), 6.56 (s, 1H), 5.61 (s, 1H),
4.55 (septet, 2H, J=6Hz), 3.88 (s, 3H), 3.82 (s, 3H),
1.38 (d, 12H, J=6Hz); 13C NMR (100 MHz, CDCl3) d
151.8, 151.1, 149.6, 147.0, 143.9, 125.1 (CH), 118.4
(CH), 114.8, 114.2 (CH), 111.7 (CH), 101.9 (CH), 100.0,
95.2, 81.8, 71.6(CH), 71.2 (CH), 5.67 (CH 3), 56.0
(CH3), 22.1 (2CH3), 21.9 (2CH3); HRMS m/z 370.1781
[M]+, calcd for C22H26O5, 370.1780.
Coupling of acetylene 12 with iodide 13 to form aldehyde 14
To a stirred solution of iodide 13 (692 mg, 2.2 mmol) and
triethylamine (30 mL) were added acetylene 12 (411 mg,
2.2 mmol), tetrakis(triphenylphosphine)palladium (25
mg, 0.022 mmol), and copper(I) iodide (8.3 mg, 0.044
mmol). The reaction was stirred for 5 h at 45ꢀC. Diethyl
ether (30 mL) and 0.1 N hydrochloric acid (30 mL) were
added, and the organic layer was separated, neutralized
with a saturated sodium bicarbonate solution, washed
with water, and dried with sodium sulfate. The organic
layer was then evaporated to dryness and purified by
chromatography on silica (15% EtOAc/hexanes) to yield
aldehyde 14 as a yellow solid (555 mg, 66%), mp 109–
112 ꢀC. 1H NMR (300MHz, CDCl3) d 10.49 (s, 1H), 7.41
(s, 1H), 7.21 (dd, 1H, J=8.5, 2.5 Hz), 7.06(d, 1H, J=2.5
Hz), 7.03 (s, 1H), 6.84 (d, 1H, J=8.5 Hz), 4.70 (septet, 1H,
J=6Hz), 4.57 (septet, 1H, J=6Hz), 3.97 (s, 3H), 3.88 (s,
3H), 1.40 (d, 12H, J=6Hz); 13C NMR (100 MHz,
CDCl3) d 190.7 (CH), 154.5, 151.3, 147.8, 147.0, 129.8,
125.2 (CH), 121.5, 118.2 (CH), 114.5 (CH), 111.7 (CH),
110.7 (CH), 95.0, 83.4, 71.4 (CH), 71.1 (CH), 56.1
(CH3), 55.8 (CH3), 21.9 (2CH3), 21.8 (2CH3); HRMS
m/z 382.1777 [M]+, calcd for C23H26O5, 382.1780.
Iodoacetic acid (424 mg, 2.28 mmol) and DMAP (12.7
mg, 0.104 mmol) were added to a solution of phenol 16
(767.4 mg, 2.07 mmol) in CH2Cl2 (100 mL). A solution
of DCC in hexanes (0.68 M, 3.26 mL) was added and
the reaction mixture was stirred for 5 h. The pre-
cipitated urea was removed by filtration, and the filtrate
was concentrated to obtain an oily residue. The oily
residue was then purified by chromatography on silica
(CH2Cl2) to yield iodoacetate 17 (1 g, 90%) as a pale
yellow solid, mp 136 ꢀC. H NMR (400 MHz, CDCl3) d
1
7.12 (dd, 1H, J=8.5, 2 Hz), 7.06(d, 1H, J=2 Hz), 7.02
(s, 1H), 6.82 (d, 1H, J=8.5 Hz), 6.66 (s, 1H), 4.55 (sep-
tet, 2H, J=6 Hz), 3.96 (s, 2H), 3.87 (s, 6H), 1.40 (d, 6H,
J=6Hz), 1.38 (d, 6H, J=6Hz); 13C NMR (100 MHz,
CDCl3) d 167.0, 150.9, 148.0, 147.9, 146.8, 144.8, 125.2
(CH), 118.5 (CH), 115.2, 114.9 (CH), 111.6(CH), 108.5
(CH), 93.3, 82.3, 71.7 (CH), 71.5 (CH), 56.3 (CH3), 55.9
(CH3), 22.1 (2CH3), 21.9 (2CH3), 6.6 (CH2); HRMS m/z
538.0838 [M]+, calcd for C24H27O6I, 538.0852.
Conversion of aldehyde 14into iodoacetate 17
A solution of 3-chloroperoxybenzoic acid (104 mg, 0.6
mmol) in CH2Cl2 (15 mL) was added dropwise to a vig-
orously stirred solution of aldehyde 14 (77 mg, 0.2 mmol)
and KHCO3 (60 mg, 0.6 mmol) in CH2Cl2 (15 mL). After
1 h, the reaction mixture was washed successively with
cold water (40 mL), satd. NaHCO3 solution (40 mL) and
brine (40 mL), dried over anh. MgSO4 and concentrated
to yield a crude product that was further purified by
chromatography on silica (25% EtOAC/hexanes) to yield
formate 15 (71 mg, 89%) as a white crystalline solid, mp
111–112 ꢀC. IR (NaCl) 2215, 1745 cmÀ1; UV (CHCl3) 247
Coupling of iodoacetate 17 with 2,3-dihydro-5,6-
dimethoxyisoquinoline to obtain lamellarin U diisopropyl
ether (18)
3,4-Dihydro-6,7-dimethoxyisoquinoline (212 mg, 1.11
mmol) was added to a solution of iodoacetate 17 (534.4
mg, 0.99 mmol) in CH2Cl2 (50 mL) and the resulting
mixture was stirred for 21 h at room temperature. N,N-
diisopropylethylamine (142.2 mg, 1.1 mmol) was then
added and the solution was refluxed for 30 h. The sol-
vent was then removed under reduced pressure and the
resulting oil was subjected to gradient silica gel chro-
matography (CH2Cl2, then EtOAc) to yield lamellarin
U diisopropyl ether (18, 320.9 mg, 54%) as a white
1
nm (e 21,900), 294 nm (e 15,700), 346nm ( e 15,200); H
NMR (400 MHz, CDCl3) d 8.37 (s, 1H), 7.09 (dd, 1H,
J=8.5, 1.5 Hz), 7.03 (s, 1H), 7.02 (d, 1H, J=1.5 Hz), 6.83
(d, 1H, J=8.5 Hz), 6.71 (s, 1H), 4.56 (septet, 1H, J=6.5
Hz), 4.55 (septet, 1H, J=6.5 Hz), 3.89 (s, 3H), 3.88 (s,
3H), 1.41 (d, 6H, J=6.5 Hz), 1.40 (d, 6H, J=6.5 Hz); 13C
NMR (100 MHz, CDCl3) d 159.0 (CH), 150.8, 148.0,
147.9, 146.7, 144.3, 125.0 (CH), 118.5 (CH), 114.8, 114.8
(CH), 111.6(CH), 108.7 (CH), 108.4, 93.6, 82.4, 71.9
(CH), 71.7 (CH), 56.5 (CH3), 56.1 (CH3), 22.3 (2CH3),
22.2 (2CH3); HRMS m/z 398.1739 [M]+, calcd for
C23H26O6, 398.1729.
solid, mp 213–214 ꢀC. H NMR (400 MHz, CDCl3) d
1
7.08 (br s, 2H), 7.05 (s, 1H), 6.91 (s, 1H), 6.76 (s, 1H),
6.72 (s, 1H), 6.67 (s, 1H), 4.77 (m, 2H), 4.54 (m, 2H),
3.92 (s, 3H), 3.89 (s, 3H), 3.44 (s, 3H), 3.37 (s, 3H), 3.12
(t, 2H, J=6.5 Hz), 1.38 (d, 6H, J=6Hz), 1.34 (d, 6H,
J=6Hz); 13C NMR (100 MHz, CDCl3) d 155.6, 150.3,
149.1, 148.3, 147.6, 147.2, 146.7, 146.1, 135.9, 128.3,
128.2, 126.7, 123.9 (CH), 120.3, 118.4 (CH), 115.0,
113.9, 113.0, 111.2 (CH), 110.7 (CH), 108.9 (CH), 105.3
(CH), 103.9 (CH), 71.7 (2ÂCH), 56.6 (CH3), 56.2
(CH3), 55.8 (CH3), 55.4 (CH3), 42.7 (CH2), 29.0 (CH2),
22.4 (CH3), 22.3 (CH3), 22.2 (2CH3); HRMS m/z
600.2584 [M+H]+, calcd for C35H37NO8, 600.2592.
A solution of ammonia in MeOH (2 M, 0.75 mL) was
added to a stirred solution of formate 15 (423.6mg, 1.06
mmol) in 1:1 CH2Cl2/MeOH (5 mL). Anhydrous con-
ditions were not required for this reaction. After 2 h, the
reaction mixture was concentrated to dryness, and par-
titioned between CH2Cl2 and water. The organic extract
was dried over Na2SO4 and the solvent evaporated to
yield the phenol 16 (385.7 mg, 98%) as a white crystal-
Conversion of lamellarin U diisopropyl ether (18) into
lamellarin ꢀ diisopropyl ether (19)
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 391
mg, 1.72 mmol) was added to a solution of lamellarin U
line solid, mp 134–137 ꢀC. H NMR (400 MHz, CDCl3)
1