Molecules 2020, 25, 684
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Hz, 1H, Ar-H), 6.56 (s, 2H, Ar-H), 3.82 (s, 3H,
−
OCH3), 3.68 (s, 6H,
−
OCH3), 3.54 (s, 3H,
−
COOCH3),
1.65–1.57 (m, 2H), 1.32 (s, 6H, >C(CH3)2), 1.24 (m, 6H), 1.11 (m, 2H), 0.84 (t, J = 6.7 Hz, 3H). 13C-NMR
(100 MHz, CDCl3)
51.2, 44.7, 38.2, 31.8, 30.0, 28.9, 24.7, 22.6, 14.1. Mass spectrum (ESI) m/z (relative intensity) 451 (M+ +
Na, 30), 397 (M+ + H
MeOH, 100). LC/MS analysis (Waters MicroMass ZQ system) showed retention
δ 167.9, 161.7, 156.6, 150.9, 137.5, 131.8, 124.1, 117.7, 116.7, 112.3, 102.2, 55.9, 55.3,
−
time 5.9 min for the title compound.
1-Hydroxy-9-methoxy-3-(2-methyloctan-2-yl)-6H-benzo[c]chromen-6-one (1a). To a solution of 15
(100 mg, 0.23 mmol) in anhydrous CH2Cl2 (3.0 mL) at 0 ◦C was added dropwise 9-Iodo-
9-borabicyclo[3.3.1]nonane (9-iodo-9-BBN, 0.78 mL, 1.0 M solution in hexane, 0.78 mmol). The reaction
mixture was stirred at 0 ◦C for 1 h; then, it was warmed to room temperature over a 3-h period and kept
stirring at room temperature overnight. Then, the mixture was treated with 0.5 mL of ethanolamine and
stirred for an additional 30 min. Solvent evaporation and purification by flash column chromatography
◦
on silica gel (CH2Cl2/Et2O/hexane, 2:2:6) gave 1a (67 mg, 78%) as a white solid. m.p. 149–151 C.
Literature [16], m.p. 149–151 ◦C. IR (thin film, cm−1) 3210 (OH) 1676 (CO), 1606, 1401, 1302, 1229, 1110;
1H NMR (500 MHz, CDCl3)
δ
8.49 (d, J = 2.5 Hz, 1H, Ar-H),
= 8.9, 2.5 Hz, 1H, Ar-H), 6.96 (d, J = 1.8 Hz, 1H, Ar-H), 6.67 (d, J = 1.8 Hz, 1H, Ar-H), 5.66 (brs, 1H, OH),
3.97 (s, 3H, OCH3), 1.60–1.57 (m, 2H, CH2), 1.29 (s, 6H, 2 CH3), 1.25–1.18 (m, 6H, 3 CH2), 1.08–1.03
δ 8.35 (d, J = 8.9 Hz, 1H, Ar-H), 7.07 (dd, J
×
×
(m, 2H, CH2), 0.84 (t, J = 6.7 Hz, 3H, CH3). HRMS (ESI) for C23H29O4: calculated 369.2066; found
369.2056. Mass spectrum (ESI) m/z (relative intensity) 369 (M+ + H, 100). LC/MS analysis (Waters
MicroMass ZQ system) showed retention time 5.5 min for the title compound.
1,9-Dihydroxy-3-(2-methyloctan-2-yl)-6H-benzo[c]chromen-6-one (1b). To a solution of 15 (43 mg,
0.1 mmol) in CH2Cl2 (3.0 mL) under an argon atmosphere at room temperature, 1 M solution of BBr3
in CH2Cl2 (1.2 mL, 1.2 mmol) was added, and the reaction mixture was refluxed for 2 days. After
the mixture was cooled to room temperature, water was added slowly, and the organic material was
extracted with CH2Cl2. The combined organic extracts were washed with 5% aqueous NaHCO3, water,
and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography with EtOAc/hexane (3/7) as eluent to afford 1b (26 mg,
74%) as an off-white foam. m.p. 104–108 ◦C. Literature [16], m.p. 103–108 ◦C. IR (thin film, cm−1) 3319
(OH), 2929, 1687 (CO), 1622, 1600, 1410, 1277, 1217, 1108, 1057, 748; 1H-NMR (400 MHz, MeOD-d4)
δ
8.58 (d, J = 2.4 Hz, 1H, Ar-H), 8.17 (d, J = 8.7 Hz, 1H, Ar-H), 8.94 (dd, J = 8.7, 2.4 Hz, 1H, Ar-H), 6.82
(d, J = 1.7 Hz, 1H, Ar-H), 6.77 (d, J = 1.7 Hz, 1H, Ar-H), 1.65–1.55 (m, 2H), 1.28 (s, 6H), 1.25–1.14 (m,
6H), 1.13–1.01 (m, 2H), 0.82 (t, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, MeOD-d4)
δ 165.1, 163.9, 157.7,
154.1, 154.0, 138.9, 133.2, 116.9, 113.8, 113.0, 110.7, 106.9, 105.6, 45.3, 38.8, 32.9, 31.0, 29.1, 25.8, 23.6, 14.4.
HRMS (ESI) for C22H27O4: calculated 355.1919; found 355.1912. Mass spectrum (ESI) m/z (relative
intensity) 355 (M+ + H, 100). LC/MS analysis (Waters MicroMass ZQ system) showed retention time
5.2 min for the title compound.
The experimental procedures for the synthesis and characterization data of novel compounds,
the novel experimental procedures for the synthesis and characterization data of reported compounds,
and the reproductions of NMR spectra for representative and final compounds can be found at the
supplementary materials.
4. Conclusions
Following our earlier work including a preceding article of this special issue, an efficient
synthesis of cannabilactones has been achieved via Suzuki cross-coupling reaction followed by one-step
demethylation/cyclization. The two key cannabilactone prototypes AM1710 and AM1714 were obtained
selectively in high overall yields and in a lesser number of synthetic steps when compared to our earlier
synthesis. The new synthetic approach was used to prepare cannabilactone analogs and derivatives
with modifications at four potential pharmacophoric regions including the C3 side chain, as well as the
C9/C11, C1, and C6 positions.