Journal of Medicinal Chemistry
Article
4,6-Dibromo-2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-
en-1-yl]-5-propylbenzene-1,3-diol (9c). Compound 9c50 was
prepared as described for 9a by using a mixture of 7c (383 g, 1.23
mmol), 8 (242 mg, 1.59 mmol), and MgSO4 (372 mg, 3.09 mmol) in
dry CH2Cl2 (6 mL) and p-TsOH (118 mg, 620 μmol). Yield 9c: 70%
(380 mg, 860 μmol) as a yellow oil: [α]D20 −61.8 (c 0.5, CHCl3); 1H
NMR (360 MHz, CDCl3): δ 6.56 (br s, 1H, OH-1′/OH-3′), 5.56 (br
s, 2H, OH-1′/OH-3′), 5.46 (s, 1H, H-2), 4.53 (s, 1H, H-10trans), 4.40
(m, 1H, H-10cis), 4.07 (dm, 1H, H-1), 2.90 (m, 2H, H-1″), 2.55 (m,
1H, H-6), 2.20 (m, 1H, H-4), 2.07 (m, 1H, H-4), 1.81−1.74 (m, 2H,
H-5), 1.77 (s, 3H, H-7), 1.68 (s, 3H, H-9), 1.58 (sext, J2″,1″/3″ = 7.3
Hz, 2H, H-2″), and 1.02 (t, J3″,2″ = 7.3 Hz, 3H, H-3″); 13C NMR (90
MHz, CDCl3): δ 151.6 (C3′), 149.9 (C1′), 147.2 (C8), 139.9 (C5′),
139.3 (C3), 123.2 (C2), 115.7 (C2′), 111.6 (C10), 104.5 (C4′, C6′),
45.9 (C6), 39.5 (C1″), 38.0 (C1), 30.4 (C4), 28.2 (C5), 23.9 (C7), 21.7
(C2″), 18.9 (C9), and 14.2 (C3″); IR (ATR): 3493, 3387, 2925, 1598,
1428, 1325, 1245, 1099, and 889 cm−1.
100:1 → 10:1) to deliver 1a (38 mg, 12 μmol, 43% yield) as a light-
1
yellow oil: [α]D20 −122.0 (c 1.1, EtOH), −51.3 (c 1.7, CHCl3); H
NMR (400 MHz, CD3OD): δ 6.07 (s, 2H, H-4′, H-6′), 5.28 (s, 1H,
H-2), 4.46 (s, 1H, H-10trans), 4.42 (m, 1H, H-10cis), 3.93 (dm, J1,6
=
8.7 Hz, 1H, H-1), 2.89 (m, 1H, H-6), 2.37 (t, J1″,2″ = 7.5 Hz, 2H, H-
1″), 2.18 (m, 1H, H-4), 1.99 (m, 1H, H-4), 1.74 (m, 2H, H-5), 1.67
(s, 3H, H-7), 1.63 (s, 3H, H-9), 1.53 (quint, J2″,1″/3″ = 7.5 Hz, 2H, H-
2″), 1.29 (m, 4H, H-3″,H-4″), and 0.89 (t, J5″,4″ = 6.9 Hz, 3H, H-5″);
13C NMR (100 MHz, CD3OD): δ 157.5 (C3′), 150.3 (C8, C1′), 142.7
(C5′), 134.1 (C3), 127.3 (C2), 115.9 (C2′), 110.5 (C10), 108.3 (C4′,
C6′), 46.3 (C6), 37.5 (C1), 36.6 (C1″), 32.7 (C3″), 32.0 (C2″), 31.7
(C5), 30.7 (C4), 23.7 (C7), 23.6 (C4″), 19.5 (C9), and 14.4 (C5″); IR
(ATR): 3424, 2926, 1632, 1586, 1447, 1218, and 891 cm−1. All
spectral data are in agreement with the literature.12
5-Ethyl-2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-
yl]benzene-1,3-diol (1b). Compound 1b was prepared as described
for 1a by using a solution of 9b (709 mg, 1.65 mmol) in MeOH (7
mL), a solution of Na2SO3 (551 g, 4.37 mmol) and L-ascorbic acid
(43.6 mg, 250 μmol) in H2O (7 mL), and Et3N (830 μL, 5.94 mmol).
Yield 1b: 63% (282 mg, 1.04 mmol) as a light-brown oil: [α]D20
−86.9 (c 1.9, CHCl3); 1H NMR (400 MHz, CD3OD): δ 6.10 (s, 2H,
H-4′, H-6′), 5.28 (s, 1H, H-2), 4.48 (s, 1H, H-10trans), 4.44 (m, 1H,
H-10cis), 3.93 (dm, J1,6 = 8.7 Hz, 1H, H-1), 2.92 (m, 1H, H-6), 2.42
(q, J1″,2″ = 7.6 Hz, 2H, H-1″), 2.18 (m, 1H, H-4), 1.99 (m, 1H, H-4),
1.74 (m, 2H, H-5), 1.68 (s, 3H, H-7), 1.64 (s, 3H, H-9), and 1.15 (t,
J2″,1″ = 7.6 Hz, 3H, H-2″); 13C NMR (100 MHz, CD3OD): δ 157.5
(C3′), 150.3 (C8, C1′), 144.1 (C5′), 134.1 (C3), 127.3 (C2), 115.9
(C2′), 110.5 (C10), 107.7 (C4′, C6′), 46.3 (C6), 37.4 (C1), 31.7 (C5),
30.8 (C4), 29.5 (C1″), 23.7 (C7), 19.5 (C9), and 15.8 (C2″); IR
(ATR): 3405, 2925, 1628, 1582, 1439, 1215, and 888 cm−1. HRMS
(ESI+) calcd for [C18H24O2 + H]+ ([M + H]+), 273.1855; found,
273.1849.
4,6-Dibromo-5-butyl-2-[(1R,6R)-6-isopropenyl-3-methylcy-
clohex-2-en-1-yl]benzene-1,3-diol (9d). Compound 9d was
prepared as described for 9a by using a mixture of 7d (663 mg,
2.05 mmol), 8 (365 mg, 2.39 mmol), and MgSO4 (615 mg, 5.11
mmol) in dry CH2Cl2 (11 mL) and p-TsOH (199 mg, 1.05 mmol).
Yield 9d: 56% (522 mg, 1.14 mmol) as a yellow oil: [α]D20 −63.1 (c
1.9, CHCl3); 1H NMR (360 MHz, CDCl3): δ 6.57 (br s, 1H, OH-1′/
OH-3′), 5.56 (br s, 2H, OH-1′/OH-3′), 5.46 (s, 1H, H-2), 4.53 (s,
1H, H-10trans), 4.40 (m, 1H, H-10cis), 4.06 (dm, 1H, H-1), 2.92 (m,
2H, H-1″), 2.54 (m, 1H, H-6), 2.20 (m, 1H, H-4), 2.09 (m, 1H, H-4),
1.81−1.74 (m, 2H, H-5), 1.77 (s, 3H, H-7), 1.68 (s, 3H, H-9), 1.57−
1.42 (m, 4H, H-2″, H-3″), and 0.97 (t, J4″,3″ = 7.0 Hz, 3H, H-4″); 13
C
NMR (90 MHz, CDCl3): δ 151.8 (C3′), 150.0 (C1′), 147.3 (C8),
140.1 (C5′), 139.5 (C3), 123.2 (C2), 115.7 (C2′), 111.6 (C10), 104.4
(C4′, C6′), 45.9 (C6), 38.1 (C1), 37.4 (C1″), 30.4 (C4), 30.4 (C2″),
28.2 (C5), 23.9 (C7), 22.9 (C3″), 19.0 (C9), and 14.0 (C4″); IR
(ATR): 3494, 2924, 1600, 1429, 1328, 1247, and 892 cm−1. HRMS
(ESI−) calcd for [C20H26Br2O2 − H]− ([M − H]−), 455.0221; found,
455.0228.
2-[(1R,6R)-6-Isopropenyl-3-methylcyclohex-2-en-1-yl]-5-
propylbenzene-1,3-diol (1c). Compound 1c13 was prepared as
described for 1a by using a solution of 9c (321 mg, 723 μmol) in
MeOH (4 mL), a solution of Na2SO3 (262 g, 2.26 mmol) and L-
ascorbic acid (37 mg, 210 μmol) in H2O (4 mL), and Et3N (410 μL,
2.94 mmol). Yield 1c: 50% (103 mg, 360 μmol) as a brown oil:
4,6-Dibromo-5-hexyl-2-[(1R,6R)-6-isopropenyl-3-methylcy-
clohex-2-en-1-yl]benzene-1,3-diol (9e). Compound 9e was
prepared as described for 9a by using a mixture of 7e (629 mg,
1.79 mmol), 8 (299 mg, 1.97 mmol), and MgSO4 (537 mg, 4.47
mmol) in dry CH2Cl2 (7 mL) and p-TsOH (170 mg, 893 μmol).
Yield 9e: 64% (555 mg, 1.14 mmol) as a yellow oil: [α]D20: −56.5 (c
1.6, CHCl3); 1H NMR (360 MHz, CDCl3): δ 6.57 (br s, 1H, OH-1′/
OH-3′), 5.67 (br s, 2H, OH-1′/OH-3′), 5.47 (s, 1H, H-2), 4.53 (s,
1H, H-10trans), 4.40 (m, 1H, H-10cis), 4.06 (dm, 1H, H-1), 2.91 (m,
2H, H-1″), 2.56 (m, 1H, H-6), 2.23 (m, 1H, H-4), 2.08 (m, 1H, H-4),
1.81−1.74 (m, 2H, H-5), 1.77 (s, 3H, H-7), 1.68 (s, 3H, H-9), 1.57−
1.49 (m, 2H, H-2″), 1.43−1.34 (m, 6H, H-3″, H-4″, H-5″), and 0.91
(m, 3H, H-6″); 13C NMR (90 MHz, CDCl3): δ 151.7 (C3′), 150.0
(C1′), 147.3 (C8), 140.1 (C5′), 139.6 (C3), 123.2 (C2), 115.7 (C2′),
111.6 (C10), 104.6 (C4′, C6′), 46.0 (C6), 38.1 (C1), 37.7 (C1″), 31.7
(C4″), 30.4 (C4), 29.4 (C4″), 28.2 (C5), 28.2 (C2″), 23.9 (C7), 22.8
(C5″), 19.0 (C9), and 14.2 (C6″); IR (ATR): 3499, 3394, 2924, 1593,
1428, 1246, and 890 cm−1. HRMS (ESI−) calcd for [C22H30Br2O2 −
H]− ([M − H]−), 483.0534; found, 483.0537.
2-[(1R,6R)-6-Isopropenyl-3-methylcyclohex-2-en-1-yl]-5-
pentylbenzene-1,3-diol (1a). To a solution of 9a (130 mg, 280
μmol) in methanol (1.5 mL) was added a solution of sodium sulfite
(92 mg, 730 μmol) and L-ascorbic acid (7 mg, 40 μmol) in water (1.5
mL). To the pink suspension formed, triethylamine (140 μL, 1.2
mmol) was added in one portion. The resulting mixture was heated to
75 °C for 24 h. After cooling to rt, the reaction mixture was partially
concentrated under reduced pressure to remove most of the methanol
and volatiles. The pH of the remaining aqueous phase was adjusted to
2 with hydrochloric acid 5% w/w. Hexane (10 mL) was added, and
the mixture was stirred for 15 min. The layers were separated, and the
aqueous phase was extracted with hexane (2 × 10 mL). The
combined organic layers were washed with brine (25 mL), dried over
Na2SO4, and then evaporated under reduced pressure. The obtained
oil was purified by flash column chromatography (hexanes/EtOAc,
1
[α]D20 −138.3 (c 2.3, EtOH), −72.23. (c 0.5, CHCl3); H NMR
(400 MHz, CD3OD): δ 6.09 (s, 2H, H-4′, H-6′), 5.30 (s, 1H, H-2),
4.47 (s, 1H, H-10trans), 4.44 (m, 1H, H-10cis), 3.94 (dm, J1,6 = 8.6 Hz,
1H, H-1), 2.90 (m, 1H, H-6), 2.36 (t, J1″,2″ = 7.5 Hz, 2H, H-1″), 2.18
(m, 1H, H-4), 1.99 (m, 1H, H-4), 1.74 (m, 2H, H-5), 1.68 (s, 3H, H-
7), 1.64 (s, 3H, H-9), 1.57 (sext, J2″,1″/3″ = 7.5 Hz, 2H, H-2″), and
0.90 (t, J3″,2″ = 7.5 Hz, 3H, H-3″); 13C NMR (100 MHz, CD3OD): δ
157.4 (C3’), 150.2 (C8, C1′), 142.4 (C5′), 134.3 (C3), 127.2 (C2),
115.9 (C2′), 110.5 (C10), 108.3 (C4′, C6′), 46.3 (C6), 38.8 (C1″), 37.4
(C1), 31.6 (C5), 30.7 (C4), 25.4 (C2″), 23.7 (C7), 19.5 (C9), and 14.2
(C3″); IR (ATR): 3412, 2924, 1629, 1534, 1443, 1217, and 889 cm−1.
HRMS (ESI+) calcd for [C19H26O2 + H]+ ([M + H]+), 287.2011;
found, 287.2009.
5-Butyl-2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-
yl]benzene-1,3-diol (1d). Compound 1d14 was prepared as
described for 1a by using a solution of 9d (292 mg, 637 μmol) in
MeOH (4 mL), a solution of Na2SO3 (229 mg, 1.97 mmol) and L-
ascorbic acid (31 mg, 176 μmol) in H2O (4 mL), and Et3N (350 μL,
2.51 mmol). Yield 1d: 56% (108 mg, 360 μmol) as a brown oil:
[α]D20 −56.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CD3OD): δ 6.08
(s, 2H, H-4′, H-6′), 5.28 (s, 1H, H-2), 4.47 (s, 1H, H-10trans), 4.43
(m, 1H, H-10cis), 3.93 (dm, J1,6 = 8.6 Hz, 1H, H-1), 2.91 (m, 1H, H-
6), 2.39 (t, J1″,2″ = 7.6 Hz, 2H, H-1″), 2.18 (m, 1H, H-4), 1.99 (m,
1H, H-4), 1.74 (m, 2H, H-5), 1.68 (s, 3H, H-7), 1.64 (s, 3H, H-9),
1.53 (quint, J2″,1″/3″ = 7.6 Hz, 2H, H-2″), 1.34 (sext, J3″,2″/4″ = 7.4 Hz,
2H, H-2″), and 0.92 (t, J4″,3″ = 7.4 Hz, 3H, H-4″); 13C NMR (100
MHz, CD3OD): δ 157.5 (C3′), 150.3 (C8, C1′), 142.6 (C5’), 134.0
(C3), 127.2 (C2), 115.9 (C2′), 110.5 (C10), 108.3 (C4′, C6′), 46.3
(C6), 37.4 (C1), 36.3 (C1″), 34.6 (C2″), 31.7 (C5), 30.8 (C4), 23.7
(C7), 23.4 (C3″), 19.5 (C9), and 14.3 (C4″); IR (ATR): 3429, 2925,
1629, 1583, 1441, 1213, and 1025 cm−1. HRMS (ESI+) calcd for
[C20H28O2 + H]+ ([M + H]+), 301.2168; found, 301.2163.
9361
J. Med. Chem. 2021, 64, 9354−9364