A Peyssonenyne-Inspired DNMT Modulator
MED
matography (silica gel, hexane/EtOAc, 95:5) to afford 11 as a color-
less oil (1.51 g, 80%): H NMR (400.13 MHz, CDCl3): d=4.38 (dd, J=
with CH2Cl2 (3ꢄ). The combined organic layers were dried over
Na2SO4, and the solvent was evaporated. The residue was purified
by flash chromatography (silica gel, hexane/EtOAc, 80:20) to afford
1
12.4, 6.4 Hz, 1H, H3), 1.77–1.63 (m, 3H, 2H4 +OH), 1.52–1.40 (m,
2H, 2H5), 1.37–1.20 (m, 24H, 12ꢄ-CH2-), 1.12–1.01 (m, 21H, iPr3Si),
0.88 ppm (t, J=6.8 Hz, 3H, CH3); 13C NMR (100.62 MHz, CDCl3): d=
109.2 (s), 85.3 (s), 63.1(d), 38.1 (t), 32.1 (t), 29.9 (t, 5ꢄ), 29.8 (t), 29.7
(t, 2ꢄ), 29.5 (t), 29.4 (t), 25.3 (t), 22.8 (t), 18.7 (q, 6ꢄ, iPr3-Si), 14.2
(q), 11.3 ppm (d, 3ꢄ, iPr3-Si); IR (NaCl): n˜ =3600–3300 (br, OꢀH),
2926 (s, CꢀH), 2858 (s, CꢀH), 1462 cmꢀ1 (m); MS (FAB+): m/z (%)
422 ([M+1]+, 3), 421 (M+, 7), 405 (16), 363 (32), 181 (18), 158 (16),
157 (100); HRMS (FAB+) calcd for C27H53OSi ([M+H]+): 421.3866,
found: 421.3858.
1
15 as a yellow oil (0.05 g, 99%): H NMR (400.13 MHz, CDCl3): d=
4.34–4.26 (m, 1H, H2’), 4.19 (dd, J=11.5, 4.6 Hz, 1H, H1’), 4.11 (dd,
J=11.5, 6.1 Hz, 1H, 1H1’), 4.07 (dd, J=8.5, 6.5 Hz, 1H, H3’), 3.73 (dd,
J=8.5, 6.0 Hz, 1H, H3’), 2.71–2.65 (m, 2H, 2H2 or 2H3), 2.64–2.58
(m, 2H, 2H2 or 2H3), 2.52 (t, J=7.4 Hz, 2H, 2H9), 1.68–1.57 (m, 2H,
2H10), 1.41 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.31–1.17 (m, 24H, 12ꢄ-
CH2-), 0.86 ppm (t, J=6.8 Hz, 3H, CH3); 13C NMR (100.62 MHz,
CDCl3): d=187.2 (s), 170.9 (s), 110.0 (s), 87.6 (s), 75.4 (s), 73.6 (d),
72.9 (s), 66.3 (t), 65.3 (t), 64.6 (s), 45.6 (t), 32.3 (t), 32.0 (t), 29.8 (t,
4ꢄ), 29.7 (t, 2ꢄ), 29.5 (t), 29.4 (t, 2ꢄ), 29.0 (t), 26.8 (q), 25.4 (q), 24.0
(t), 22.8 (t), 15.6 (t), 14.2 ppm (q); IR (NaCl): n˜ =2925 (s, CꢀH), 2854
(m, CꢀH), 2236 (w, CꢂC), 1743 (m, C=O), 1673 cmꢀ1 (s); HRMS (ESI+
) calcd for C29H46O5 ([M+H]+): 475.34129, found: 475.34180.
Octadec-1-yn-3-ol (12): nBu4NF (2.44 mL, 1m in THF, 2.44 mmol)
was added to a stirred solution of 1-triisopropylsilyloctadec-1-yn-3-
ol 11 (0.94 g, 2.21 mmol) in THF (58 mL), and the reaction was
stirred for 30 min at 258C. A saturated aqueous solution of
NaHCO3 was added, and the mixture was extracted with Et2O (3ꢄ).
The combined organic layers were washed with brine, dried over
Na2SO4, and the solvent was evaporated. The residue was purified
by flash chromatography (silica gel, hexane/EtOAc/Et3N, 90:8:2) to
afford 12 as a white solid (1.51 g, 82%): mp: 54–568C (hexane/
(8Z,2’R)- and (8E,2’R)-2,3-Dihydroxyprop-1-yl 8-acetoxytetracosa-
8-en-4,6-diynoate ((R)-17): Et3N (0.54 mL, 0.39 mg, 3.87 mmol),
DMAP (47 mg, 0.39 mmol), and acetic anhydride (0.44 mL, 0.47 g,
4.64 mmol) were added to a stirred solution of (2’R)-2,3-O-isopro-
pylidene-2,3-dihydroxyprop-1-yl 8-oxo-tetracosa-4,6-diynoate 15
(0.37 g, 0.77 mmol) in CH2Cl2 (20 mL) at 08C, and the reaction mix-
ture was stirred for 2 h at room temperature. A saturated NH4Cl
aqueous solution was added, and the mixture was extracted with
CH2Cl2 (3ꢄ). The combined organic layers were dried over Na2SO4,
and the solvent was evaporated. The residue was purified by flash
chromatography (silica gel, hexane/CH2Cl2/EtOAc, 80:20:10) to
afford a colorless oil (0.35 g, 88%), identified as a 70:30 mixture of
E/Z isomers, which was used in the next step.
1
Et2O); H NMR (400.13 MHz, CDCl3): d=4.36 (td, J=6.6, 1.9 Hz, 1H,
H3), 2.46 (d, J=2.1 Hz, 1H, H1), 1.92 (s, 1H, OH), 1.76–1.63 (m, 2H,
2H4), 1.50–1.38 (m, 2H, 2H5), 1.36–1.17 (m, 24H, 12ꢄ-CH2-),
0.87 ppm (t, J=6.8 Hz, 3H, CH3); 13C NMR (100.62 MHz, CDCl3): d=
85.2 (s), 72.9 (d), 62.5 (d), 37.8 (t), 32.1 (t), 29.8 (t, 6ꢄ), 29.7 (t, 2ꢄ),
29.5 (t), 29.4 (t), 25.2 (t), 22.8 (t), 14.3 ppm (q); IR (NaCl): n˜ =3600–
3300 (br, OꢀH), 2918 (s, CꢀH), 2850 cmꢀ1 (m, C-H); HRMS (ESI+)
calcd for C18H34ONa ([M+Na]+): 289.24897, found: 289.25019.
(2’R)-2,3-O-Isopropylidene-2,3-dihydroxyprop-1-yl 8-hydroxy-tet-
racosa-4,6-diynoate (14): Copper chloride (0.03 g, 0.26 mmol) was
added to a stirred solution of (2’R)-2,3-O-isopropylidene-2,3-dihy-
droxyprop-1-yl 5-iodopent-4-ynoate 13 (0.88 g, 2.61 mmol) and oc-
tadec-1-yn-3-ol 12 (1.82 g, 6.85 mmol) in degassed piperidine
(5 mL) at 08C. After stirring for 2 h, a saturated aqueous NH4Cl so-
lution was added, and the mixture was extracted with CH2Cl2 (3ꢄ).
The combined organic layers were dried over Na2SO4, and the sol-
vent was removed under vacuum. The residue was purified by
flash chromatography (silica gel, hexane/EtOAc, 80:20) to provide
14 as a white solid (0.8 g, 64%): mp: 36–388C (hexane/Et2O);
1H NMR (400.13 MHz, CDCl3): d=4.37 (dd, J=11.5, 5.9 Hz, 1H, H8),
4.31 (dd, J=11.6, 5.7 Hz, 1H, H2’), 4.2–4.0 (m, 3H, 2H1’ +1H3’), 3.75
(dd, J=8.4, 6.2 Hz, 1H, H3’), 2.65–2.52 (m, 4H, 2H2 +2H3), 1.74–1.60
(m, 2H, 2H9), 1.47–1.38 (m, 5H, CH3 +2H10), 1.36 (s, 3H, CH3), 1.33–
1.17 (m, 24H, 12ꢄ-CH2-), 0.87 ppm (t, J=6.7 Hz, 3H, CH3); 13C NMR
(100.62 MHz, CDCl3): d=171.3 (s), 110.0 (s), 79.0 (s), 77.7 (s), 73.6
(d), 69.6 (s), 66.4 (t), 65.5 (s), 65.1 (t), 62.9 (d), 37.7 (t), 32.9 (t), 32.0
(t), 29.8 (t, 6ꢄ), 29.7 (t), 29.6 (t), 29.5 (t), 29.4 (t), 26.8 (q), 25.5 (q),
25.2 (t), 22.8 (t), 15.4 (t), 14.2 ppm (q); IR (NaCl): n˜ =3600–3300 (br,
OꢀH), 2925 (s, CꢀH), 2854 (m, CꢀH), 2255 (w, CꢂC), 1742 cmꢀ1 (m,
CO); HRMS (ESI+) calcd for C29H48O5Na ([M+Na]+): 499.3379,
found: 499.3394.
Solid CAN (6 mg, 0.01 mmol) was added to a stirred solution of
(2’R)-2,3-O-methylidene-2,3-dihydroxyprop-1-yl 8-acetoxytetracosa-
8-en-4,6-diynoate 16 (0.19 g, 0.36 mmol) in CH3CN/H2O (2 mL, 1:1
v/v) at 708C. The resulting slightly yellow solution was stirred for
24 h at this temperature. After cooling to room temperature, the
reaction mixture was extracted with Et2O (3ꢄ). The combined or-
ganic layers were dried over Na2SO4, and the solvents were re-
moved in vacuo. The residue was purified by flash chromatography
(silica gel, hexane/EtOAc/Et3N, 60:38:2) to give a colorless oil
(0.13 g,74%) that was identified as a 70:30 mixture of E/Z isomers.
This mixture was separated by RP-HPLC (Nova-Pak HR C18 6 mm,
19ꢄ300 mm, CH3CN/H2O (80:20), 20 mLminꢀ1) to yield (2R’)-2,3-di-
hydroxyprop-1-yl 8-acetoxytetracosa-8-en-4,6-diynoate (R)-17 (E
isomer (tR =22.7 min): 21.5 mg, 29%;
Z isomer (tR =27.0 min):
53.2 mg, 71%).
1
Data for (8E,2’R)-17 (17A): H NMR (400.13 MHz, C6D6): d=5.67 (t,
J=8.0 Hz, 1H, H9), 4.02 (dd, 1H, J=11.5, 6.1 Hz, 1H, H1’), 3.98 (dd,
J=11.5, 5.0 Hz, 1H, H1’), 3.72–3.63 (m, 1H, H2’), 3.45 (dd, J=11.3,
4.0 Hz, 1H, H3’), 3.37 (dd, J=11.3, 6.0 Hz, 1H, H3’), 2.25–2.14 (m, 4H,
2H10 +2H2 or 2H3), 2.03 (t, J=6.9 Hz, 2H, 2H2 or 2H3), 1.63 (s, 3H,
CO2CH3), 1.41–1.15 (m, 24H, 12ꢄ-CH2-), 0.91 ppm (t, J=6.8 Hz, 3H,
CH3); 13C NMR (100.62 MHz, C6D6): d=171.2 (s), 168.4 (s), 132.4 (d),
130.4 (s), 85.5 (s), 79.4 (s), 70.4 (d), 68.6 (s), 66.0 (s), 65.8 (t), 63.6 (t),
32.5 (t), 32.4 (t), 30.2 (t, 5ꢄ), 30.0 (t), 29.9 (t, 2ꢄ), 29.4 (t), 29.2 (t),
28.4 (t), 23.1 (t), 20.1 (q), 15.5 (t), 14.4 ppm (q); IR (NaCl): n˜ =3600–
3300 (br, OꢀH), 2923 (s, CꢀH), 2853 (m, CꢀH), 2235 (w, CꢂC), 1740
(m, C=O), 1204 cmꢀ1 (m); HRMS (ESI+) calcd for C28H44O6Na ([M+
Na]+): 499.30218, found: 499.30301.
(2’R)-2,3-O-isopropylidene-2,3-dihydroxyprop-1-yl 8-oxo-tetraco-
sa-4,6-diynoate (15): DMSO (18 mL, 0.02 g, 0.25 mmol) was added
dropwise to a stirred solution of oxalyl chloride (13 mL, 0.02 g,
0.15 mmol) in CH2Cl2 (1 mL) at ꢀ608C, and the reaction was stirred
for 5 min at this temperature. Then, a solution of (2’R)-2,3-O-isopro-
pylidene-2,3-dihydroxyprop-1-yl 8-hydroxy-tetracosa-4,6-diynoate
14 (0.47 g, 0.98 mmol) in CH2Cl2 (1 mL) was added. After stirring
for 30 min, Et3N (97 mL, 0.07 g, 0.69 mmol) was added, and the re-
action was stirred for 10 min at ꢀ608C. The mixture was allowed
to warm to room temperature, poured into H2O, and extracted
1
Data for (8Z,2’R)-17 (17B): H NMR (400.13 MHz, C6D6): d=5.65 (t,
J=7.7 Hz, 1H, H9), 4.05 (dd, 1H, J=11.4, 6.1 Hz, 1H, H1’), 4.01 (dd,
J=11.5, 4.9 Hz, 1H, H1’), 3.74–3.67 (m, 1H, H2’), 3.47 (dd, J=11.3,
4.0 Hz, 1H, H3’), 3.40 (dd, J=11.3, 6.0 Hz, 1H, H3’), 2.20 (t, J=7.2 Hz,
ChemMedChem 2012, 7, 2101 – 2112
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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