3.2. Procedures and Analytical Description of Compounds
Zanthosimuline
7. A suspension of 4-hydroxy-1-methyl-2-(1
H)-quinolone
5 (1.50 g, 8.56 mmol, 1 eq.), citral
6 (1.47 mL, 8.56 mmol, 1 eq.), and EDDA (0.30 g, 1.71 mmol, 0.2 eq.) in anhydrous EtOH (15 mL) was heated under MW irradiation at 150 °C for 20 min. The mixture was concentrated under reduced pressure and the desired compound purified by flash chromatography on silica gel (80 g) using heptane/EtOAc from 10:0 to 5:5 to give zanthosimuline
7 as a light-yellow oil (2.45 g, 7.91 mmol, 92%).
1H NMR (500 MHz, CDCl
3, 25 °C):
δ 7.93 (d,
J = 7.9 Hz, 1H), 7.52 (t,
J = 8.0 Hz, 1H), 7.29 (d,
J = 8.0 Hz, 1H), 7.20 (t,
J = 8.0 Hz, 1H), 6.77 (d,
J = 10.0 Hz, 1H), 5.46 (d,
J = 10.0 Hz, 1H), 5.07 (t,
J = 7.0 Hz, 1H), 3.67 (s, 3H), 2.12 (q,
J = 7.0 Hz, 2H), 1.82–1.62 (m, 2H), 1.60 (s, 3H), 1.52 (s, 3H), 1.45 (s, 3H) ppm.
13C NMR (125 MHz, CDCl
3, 25 °C):
δ 161.2, 155.6, 139.5, 132.2, 131.0, 125.4, 123.9, 123.3, 121.9, 118,6, 116.2, 114.2, 105.7, 81.5, 41.7, 29.5, 27.2, 25.8, 22.8, 17.8 ppm. HRMS (ESI+): calcd. for C
20H
24NO
2+ [M+H]
+ 310.1802, found 310.1804. Analytical data were consistent with those described by Wu and Chen [
18].
6,6,9,12-Tetramethyl-6,6a,7,8,10a,12-hexahydro-11
H-isochromeno [4,3-
c]quinolin-11-one (
8). To a solution of zanthosimuline
7 (198 mg, 0.64 mmol, 1 eq.) in anhydrous dichloromethane (6 mL) under Ar atm. was added a 1 M solution of Me
2AlCl in hexanes (1.28 mL, 1.28 mmol, 2 eq.). The reaction mixture was stirred at RT for 18 h before adding 0.5 mL of water. The mixture was dried over MgSO
4, filtrated over a Celite
® pad, and concentrated under reduced pressure to give compound
8 in a
cis/
trans mixture (2:1) as a pale-yellow oil (196 mg, 0.64 mmol, 95%).
1H NMR of
cis-8 (500 MHz, CDCl
3, 25 °C):
δ 7.93 (dd,
J = 8.0, 1.3 Hz, 1H), 7.48 (bt,
J = 8.0 Hz, 1H), 7.27 (d,
J = 8.4 Hz, 1H), 7.17 (bt,
J = 7.7 Hz, 1H), 6.47−6.41 (m, 1H), 3.66 (s, 3H), 3.55 (bs, 1H), 2.03−1.87 (m, 3H), 1.87−1.75 (m, 1H), 1.69 (bs, 3H), 1.51 (s, 3H), 1.44−1.32 (m, 1H), 1.31 (s, 3H) ppm.
1H NMR of
trans-
8 (500 MHz, CDCl
3, 25 °C):
δ 7.93 (dd,
J = 8.0, 1.3 Hz, 1H), 7.48 (bt,
J = 8.0 Hz, 1H), 7.27 (d,
J = 8.4 Hz, 1H), 7.17 (bt,
J = 7.7 Hz, 1H), 6.47−6.41 (m, 1H), 3.67 (s, 3H), 3.24–3.19 (m, 1H), 2.23−2.12 (m, 2H), 2.03−1.87 (m, 1H), 1.75−1.62 (m, 1H), 1.69 (bs, 3H), 1.53 (s, 3H), 1.54−1.43 (m, 1H), 1.14 (s, 3H) ppm. HRMS (ESI+): calcd. for C
20H
24NO
2+ [M+H]
+ 310.1802, found 310.1812. Analytical data were consistent with those described by Riveira et al. [
6].
Chloroaustralasine A
3. To a solution of
cis/
trans-
8 (44 mg, 0.14 mmol, 1 eq.) in a 1:3 mixture of
tert-butanol/citric acid buffer (0.1 M, pH 3.5, 14 mL) were added an aqueous suspension of chloroperoxidase (3000 U/mL) from
Caldariomyces fumago (40
µL, 120 U) and NaCl (8 mg, 0.14 mmol, 1 eq.). Then, a 30% H
2O
2 aqueous solution (20 µL, 0.16 mmol, 1 eq.) was added portion wise every 10 min for 1 h. The products were then extracted twice with MTBE (14 mL). The combined organic phases were dried over MgSO
4 and concentrated in vacuo. The residue was purified by semi-preparative HPLC (Kinetex C
18, H
2O-MeCN 45:55 at 4.7 mL·min
−1) to afford chloroaustralasine A
3 as a white powder (12 mg, 0.033 mmol, 24%,
tR: 13.3 min).
1H NMR (500 MHz, CDCl
3, 25 °C):
δ 7.98 (dd,
J = 8.0, 1.4 Hz, 1H), 7.55 (ddd,
J = 8.5, 7.1, 1.4 Hz, 1H), 7.34 (d,
J = 8.5 Hz, 1H), 7.23 (dd,
J = 8.0, 7.1 Hz, 1H), 5.81 (s, 1H), 3.70 (s, 3H), 3.60 (dd,
J = 11.4, 2.6 Hz, 1H), 2.17 (ddd,
J = 12.0, 11.4, 3.6 Hz 1H), 1.93 (ddd,
J = 13.7, 12.9, 5.1 Hz, 1H), 1.72–1.46 (m, 3H), 1.53 (s, 3H), 1.43 (s, 3H), 1.18 (s, 3H) ppm.
13C NMR (125 MHz, CDCl
3, 25 °C):
δ 162.9, 157.5, 139.0, 130.6, 123.4, 121.8, 116.9, 114.1, 106.3, 79.8, 72.4, 65.5, 40.1, 36.0, 32.9, 29.6, 29.4, 27.6, 22.9, 19.8 ppm. HRMS (ESI+): calcd. for C
20H
25ClNO
3+ [M+H]
+ 362.1515, found 362.1515. [
5]
7-Hydroxy-5,8,8,11a-tetramethyl-5,7,7a,8,9,10,11,11a-octahydro-6H-chromeno [3,2-c]quinolin-6-one (10). To a solution of zanthosimuline 7 (350 mg, 1.13 mmol, 1 eq.) in anhydrous dichloromethane (10 mL) under Ar atm. was added dropwise BF3.OEt2 (280 µL, 2.26 mmol, 2 eq.). After 18 h at RT, the mixture was quenched with water (0.3 mL). MgSO4 was added to the solution and the solids were eliminated by filtration over a Celite® pad. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel (24 g) with heptane/EtOAc from 10:0 to 0:10 to give compound 11 as a white solid (98 mg, 0.32 mmol, 28%) and compound 10 as a yellow gum (112 mg, 0.334 mmol, 30%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 8.02 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 4.78 (s, 1H), 3.73 (s, 3H), 2.24 (d, J = 14.5 Hz, 1H), 1.83 (qt, J = 13.8, 3.0 Hz, 1H), 1.74 (s, 1H), 1.62 (td, J = 13.8, 4.0 Hz, 1H), 1.55–1.42 (m, 2H), 1.42 (s, 3H), 1.33 (td, J = 13.8, 3.0 Hz, 1H), 1.29–1.23 (m, 1H), 1.11 (s, 3H), 0.60 (s, 3H) ppm. 13C NMR (125 MHz, CD3CN, 25 °C): δ 164.3, 156.4, 140.1, 132.0, 124.0, 122.7, 117.0, 115.5, 110.0, 79.1, 62.9, 52.6, 41.7, 39.6, 33.5, 32.0, 29.3, 26.9, 21.3, 18.6 ppm. HRMS (ESI+): calcd. for C20H25NO3+ [M+H]+ 328.1907, found 328.1897. Compound 10 was found to be unstable over a period of one week, giving compound 11.
5,8,8,11a-Tetramethyl-5,8,9,10,11,11a-hexahydro-6H-chromeno [3,2-c]quinolin-6-one (11). To a solution of zanthosimuline 7 (50 mg, 0.16 mmol, 1 eq.) in anhydrous dichloromethane (5 mL) under Ar atm. was added SnCl4 (84 mg, 0.32 mmol, 2 eq.). After 1 h at RT, the mixture was quenched with water (0.2 mL). MgSO4 was added to the solution and the solids were eliminated by filtration over a Celite® pad. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel (24 g) with heptane/EtOAc from 10:0 to 5:5 to give compound 11 as a white solid (46 mg, 0.15 mmol, 95%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.91 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.68 (d, J = 10.0 Hz, 1H), 3.69 (s, 3H), 2.19 (m, 1H), 1.97 (dt, J = 12.9, 5.0 Hz, 1H), 1.72–1.69 (m, 2H), 1.50−1.43 (m, 1H), 1.44 (s, 3H), 1.28 (s, 3H), 1.17 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 161.4, 153.9, 144.4, 139.2, 130.6, 123.1, 121.9, 116.4, 114.2, 112.4, 108.1, 80.8, 40.1, 39.6, 36.1, 31.0, 30.8, 29.5, 25.8, 19.2 ppm. HRMS (ESI+): calcd. for C20H24NO2+ [M+H]+ 310.1802, found 310.1799.
1,1,3a,9-Tetramethyl-1,1a,1a1,2,3,3a,9,10b-octahydro-10
H-4-oxa-9-azacyclobuta [7,1]indeno [5,6-
a]naphthalen-10-one (
12). To a solution of zanthosimuline
7 (50 mg, 0.16 mmol, 1 eq.) in anhydrous nitromethane (1 mL) under Ar atm. were added Ru(bpy)
3(PF
6)
2 (7 mg, 0.01 mmol, 5 mol%) and methyl viologen (6 mg, 0.02 mmol, 10 mol%). After 1 h under blue light irradiation at RT, the mixture was concentrated under reduced pressure and the product was purified by flash chromatography on silica gel (24 g) with heptane/EtOAc from 10:0 to 5:5 to give compound
12 as a yellow gum (43 mg, 0.14 mmol, 86%).
1H NMR (500 MHz, CDCl
3, 25 °C):
δ 8.00 (dd,
J = 8.0, 1.4 Hz, 1H), 7.53 (td,
J = 8.0, 1.4 Hz, 1H), 7.32 (d,
J = 8.0 Hz, 1H), 7.21 (t,
J = 8.0 Hz, 1H), 3.68 (s, 3H), 3.13 (d,
J = 9.2 Hz, 1H), 2.66 (dd,
J = 9.8, 7.6 Hz, 1H), 2.46 (t,
J = 7.6 Hz, 1H), 2.04–1.95 (m 1H), 1.79–1.69 (m, 2H), 1.67–1.58 (m, 1H), 1.51 (s, 3H), 1.46 (s, 3H), 0.84 (s, 3H) ppm.
13C NMR (125 MHz, CDCl
3, 25 °C):
δ 163.5, 155.1, 138.8, 130.0, 122.9, 121.3, 117.0, 113.7, 109.1, 85.2, 46.8, 39.5, 39.1, 38.0, 36.9, 33.8, 29.2, 27.5, 26.0, 17.6 ppm. HRMS (ESI+): calcd. for C
20H
24NO
2+ [M+H]
+ 310.1802, found 310.1807 [
21].
2-Methyl-2-(4-methylpent-3-en-1-yl)-2,6-dihydro-5
H-pyrano [3,2-
c]quinolin-5-one (
14). A suspension of 1,4-dihydroxyquinoline
13 (3.00 g, 18.6 mmol, 1 eq.), citral
6 (3.19 mL, 18.6 mmol, 1 eq.), and EDDA (0.66 g, 3.72 mmol, 0.2 eq.) in anhydrous EtOH (40 mL) was heated under MW irradiation at 150 °C for 30 min. After decanting for 10 min, the supernatant containing the expected compound was removed. The solids were rinsed twice with EtOH. The combined supernatants were then concentrated under reduced pressure to obtain a light-orange solid (4.78 g, 16.2 mmol, 87%).
1H NMR (500 MHz, CDCl
3, 25 °C):
δ 11.57 (bs, 1H), 7.87 (dd,
J = 8.1, 1.4 Hz, 1H), 7.47 (td,
J = 7.2, 1.2 Hz, 1H), 7.34 (d,
J = 7.9 Hz, 1H), 7.19 (t,
J = 7.9, 1H), 6.81 (d,
J = 10.1 Hz, 1H), 5.50 (d,
J = 10.1 Hz, 1H), 5.10 (tt,
J = 7.1, 1.3 Hz, 1H), 2.16 (q,
J = 7.9 Hz, 2H), 1.89–1.73 (m, 2H), 1.63 (s, 3H), 1.55 (s, 3H), 1.51 (s, 3H) ppm.
13C NMR (125 MHz, CDCl
3, 25 °C): δ 163.1, 157.6, 138.3, 132.0, 130.8, 125.1, 123.9, 122.5, 122.1, 117.8, 116.3, 115.2, 105.4, 81.7, 41.7, 27.2, 25.7, 22.7, 17.7 ppm. HRMS (ESI+): calcd. for C
19H
21NO
2+ [M+H]
+ 296.1645, found 296.1646. Analytical data were consistent with those described in the literature [
17,
27].
General procedure for functionalization of compound 14. To a solution of compound 14 (50 mg, 0.17 mmol, 1 eq.) in anhydrous DMF (2.5 mL), at 0 °C and under Ar atm., was added NaH (60% in mineral oil, 8 mg, 0.20 mmol, 1.2 eq.). The suspension was stirred for 30 min at 0 °C and the electrophile was added (1–2 eq.). The reaction mixture was allowed to warm to RT and stirred for 6 to 18 h. A saturated solution of NH4Cl was then added and the product was extracted with EtOAc (3 times). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. A purification by flash column chromatography on silica gel with heptane/EtOAc as eluent gave the desired pure compound.
6-Benzyl-2-methyl-2-(4-methylpent-3-en-1-yl)-2,6-dihydro-5H-pyrano [3,2-c]quinolin-5-one (15a). Following the general procedure described with benzyl bromide as the electrophile, compound 15a was isolated as a light-yellow oil (43 mg, 0.11 mmol, 66%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.96 (dd, J = 8.0, 1.3 Hz, 1H), 7.37 (dt, J = 8.0, 1.3 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.23–7.18 (m, 4H), 7.15 (t, J = 7.3 Hz, 1H), 6.84 (d, J = 10.0 Hz, 1H), 5.50 (d, J = 10.0 Hz, 1H), 5.11 (t, J = 7.0 Hz, 1H), 2.16 (q, J = 7.0 Hz, 2H), 1.91–1.84 (m, 1H), 1.80–1.73 (m, 1 H), 1.62 (s, 3H), 1.56 (s, 3H), 1.50 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 161.1, 155.7, 138.8, 136.8, 131.9, 130.8, 128.7 (2C), 127.1, 126.5 (2C), 125.2, 123.7, 123.1, 121.7, 118.4, 116.2, 114.8, 105.2, 81.5, 45.7, 41.6, 27.1, 25.6, 22.6, 17.6 ppm. HRMS (ESI+): calcd. for C26H27NO2+ [M+H]+ 386.2115, found 386.2130.
6-(3-Methoxybenzyl)-2-methyl-2-(4-methylpent-3-en-1-yl)-2,6-dihydro-5H-pyrano [3,2-c]quinolin-5-one (15b). Following the general procedure described with 3-methoxybenzyl bromide as the electrophile, compound 15b was isolated as a light-yellow oil (45 mg, 0.11 mmol, 67%). 1H NMR (500 MHz, CDCl3, 25 °C): 7.96 (dd, J = 8.0, 1.3 Hz, 1H), 7.37 (dt, J = 8.0, 1.3 Hz, 1H), 7.23–7.15 (m, 3H), 6.84 (d, J = 10.0 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.78–6.74 (m, 2H), 5.51 (d, J = 10.0 Hz, 1H), 5.12 (t, J = 7.0 Hz, 1H), 3.75 (s, 3H), 2.17 (q, J = 7.0 Hz, 2H), 1.92–1.85 (m, 1H), 1.81–1.74 (m, 1 H), 1.64 (s, 3H), 1.57 (s, 3H), 1.51 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 161.1, 160.0, 155.7, 138.9, 138.5, 132.0, 130.8, 129.8, 125.2, 123.7, 123.1, 121.8, 118.8, 118.4, 116.2, 114.9, 112.6, 112.2, 105.2, 81.5, 55.2, 45.7, 41.6, 27.1, 25.6, 22.6, 17.6 ppm. HRMS (ESI+): calcd. for C27H30NO3+ [M+H]+ 416.2220, found 416.2229.
2-Methyl-2-(4-methylpent-3-en-1-yl)-6-(pyridin-2-ylmethyl)-2,6-dihydro-5H-pyrano [3,2-c]quinolin-5-one (15c). Following the general procedure described with 2-(bromomethyl)pyridine as the electrophile, compound 15c was isolated as a yellow oil (53 mg, 0.14 mmol, 80%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 8.57 (d, J = 4.8 Hz, 1H), 7.95 (dd, J = 8.0, 1.3 Hz, 1H), 7.55 (dt, J = 8.0, 1.3 Hz, 1H), 7.43–7.35 (m, 2H), 7.20–7.12 (m, 3H), 6.84 (d, J = 10.0 Hz, 1H), 5.65 (bs, 2H), 5.52 (d, J = 10.0 Hz, 1H), 5.11 (t, J = 7.0 Hz, 1H), 2.16 (q, J = 7.0 Hz, 2H), 1.91–1.84 (m, 1H), 1.80–1.73 (m, 1 H), 1.63 (s, 3H), 1.56 (s, 3H), 1.50 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 161.1, 157.1, 155.9, 149.2, 138.9, 136.9, 132.0, 130.9, 125.2, 123.7, 123.1, 122.3, 121.9, 121.5, 118.3, 116.2, 115.1, 105.2, 81.6, 48.0, 41.6, 27.1, 25.6, 22.6, 17.6 ppm. HRMS (ESI+): calcd. for C25H27N2O2+ [M+H]+ 387.2067, found 387.2064.
6-(2-Methoxyethyl)-2-methyl-2-(4-methylpent-3-en-1-yl)-2,6-dihydro-5H-pyrano [3,2-c]quinolin-5-one (15d). Following the general procedure described with 2-bromomethyl methyl ether as the electrophile, compound 15d was isolated as a yellow oil (37 mg, 0.11 mmol, 64%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.95 (dd, J = 8.0, 1.2 Hz, 1H), 7.54–7.50 (m, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.23 (td, J = 8.0, 1.0 Hz, 1H), 6.80 (d, J = 10.0 Hz, 1H), 5.48 (d, J = 10.0 Hz, 1H), 5.09 (t, J = 6.9 Hz, 1H), 4.47 (t, J = 6.1 Hz, 2H), 3.71 (t, J = 6.1 Hz, 2H), 3.36 (s, 3H), 2.14 (q, J = 7.8 Hz, 2H), 1.89–1.81 (m, 1H), 1.78–1.68 (m, 1H), 1.62 (s, 3H), 1.55 (s, 3H), 1.48 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 160.9, 155.6, 139.2, 132.0, 130.7, 125.2, 123.8, 123.1, 121.7, 118.2, 116.1, 114.6, 105.2, 81.4, 70.1, 59.1, 42.1, 41.6, 27.1, 25.6, 22.6, 17.6 ppm. HRMS (ESI+): calcd. for C22H28NO3+ [M+H]+ 354.2064, found 354.2060.
2-Methyl-6-(3-methylbut-2-en-1-yl)-2-(4-methylpent-3-en-1-yl)-2,6-dihydro-5H-pyrano [3,2-c]quinolin-5-one (15e). Following the general procedure described with prenyl bromide as the electrophile, compound 15e was isolated as a yellow oil (45 mg, 0.13 mmol, 75%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.95 (dd, J = 8.0, 1.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 10.0 Hz, 1H), 5.45 (d, J = 10.0 Hz, 1H), 5.14 (t, J = 6.0 Hz, 1H), 5.09 (t, J = 6.9 Hz, 1H), 4.91 (d, J = 6.0 Hz, 2H), 2.14 (q, J = 7.7 Hz, 2H), 1.89 (s, 3H), 1.89–1.81 (m, 1H), 1.78–1.68 (m, 1H), 1.71 (s, 3H), 1.62 (s, 3H), 1.55 (s, 3H), 1.47 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 160.7, 155.4, 138.8, 135.6, 131.9, 130.6, 125.2, 123.8, 123.1, 121.5, 119.8, 118.4, 116.2, 114.5, 104.4, 81.2, 41.6, 40.6, 27.0, 25.6 (2C), 22.7, 18.3, 17.6 ppm. HRMS (ESI+): calcd. for C24H30NO2+ [M+H]+ 364.2271, found 364.2276.
2-Methyl-2-(4-methylpent-3-en-1-yl)-6-phenethyl-2,6-dihydro-5H-pyrano [3,2-c]quinolin-5-one (15f). Following the general procedure described with 4-phenethyl bromide as the electrophile, compound 15f was isolated as a yellow oil (42 mg, 0.11 mmol, 62%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.99 (dd, J = 7.5, 1.3 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.39–7.31 (m, 6H), 7.22 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 10.0 Hz, 1H), 5.50 (d, J = 10.0 Hz, 1H), 5.11 (t, J = 6.0 Hz, 1H), 4.49–4.44 (m, 2H), 3.04–2.99 (m, 2H), 2.16 (q, J = 7.7 Hz, 2H), 1.90–1.82 (m, 1H), 1.80–1.72 (m, 1H), 1.63 (s, 3H), 1.56 (s, 3H), 1.50 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 160.6, 155.4, 138.6, 138.5, 132.0, 130.8, 128.8 (2C), 128.7 (2C), 126.6, 125.4, 123.8, 123.4, 121.6, 118.2, 116.2, 113.8, 105.4, 81.4, 43.8, 41.6, 34.0, 27.1, 25.6, 22.6, 17.6 ppm. HRMS (ESI+): calcd. for C27H30NO2+ [M+H]+ 400.2271, found 400.2266.
2-Methyl-2-(4-methylpent-3-en-1-yl)-6-pentyl-2,6-dihydro-5H-pyrano [3,2-c]quinolin-5-one (15g). Following the general procedure described with 1-bromopentane as the electrophile, compound 15g was isolated as a yellow oil (51 mg, 0.14 mmol, 82%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.96 (dd, J = 8.0, 1.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 10.0 Hz, 1H), 5.47 (d, J = 10.0 Hz, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.25 (dd, J = 10.5, 7.6 Hz, 2H), 2.14 (q, J = 7.7 Hz, 2H), 1.89–1.81 (m, 1H), 1.78–1.68 (m, 3H), 1.62 (s, 3H), 1.55 (s, 3H), 1.47 (s, 3H), 1.46–1.36 (m, 4H), 0.93 (t, J = 7.6 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 160.7, 155.2, 138.4, 131.9, 130.7, 125.2, 123.8, 123.2, 121.4, 118.4, 116.2, 114.0, 105.4, 81.2, 42.2, 41.6, 29.2, 27.4, 27.0, 25.6, 22.6, 22.5, 17.6, 14.0 ppm. HRMS (ESI+): calcd. for C24H32NO2+ [M+H]+ 366.2428, found 366.2428.
2-Methyl-2-(4-methylpent-3-en-1-yl)-6-(phenylsulfonyl)-2,6-dihydro-5H-pyrano [3,2-c]quinolin-5-one (15h). Following the general procedure described with 1-bromopentane as the electrophile, compound 15h was isolated as a yellow oil (34 mg, 0.08 mmol, 47%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 8.18 (d, J = 7.5Hz, 2H), 8.0 (dd, J = 7.5, 1.3 Hz, 1H), 7.69–7.63 (m, 2H), 7.60–7.55 (m, 3H), 7.41 (t, J = 8.0 Hz, 1H), 6.67 (d, J = 10.0 Hz, 1H), 5.51 (d, J = 10.0 Hz, 1H), 5.07 (t, J = 6.0 Hz, 1H), 2.14 (q, J = 7.7 Hz, 2H), 1.91–1.83 (m, 1H), 1.81–1.72 (m, 1H), 1.60 (s, 3H), 1.51 (s, 3H), 1.25 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 158.7, 152.2, 145.7, 137.6, 132.2, 130.3, 129.1 (2C), 128.8 (2C), 128.2, 128.1, 125.6, 123.5, 121.8, 118.8, 116.5, 103.7, 82.0, 41.7, 29.7, 27.3, 25.6, 22.5, 17.6 ppm. HRMS (ESI): calcd. for C25H26NO4S+ [M+H]+ 436.1577, found 436.1570.
Phenyl 2-methyl-2-(4-methylpent-3-en-1-yl)-5-oxo-2H-pyrano [3,2-c]quinoline-6(5H)-carboxylate (15i). Following the general procedure described with phenyl chloroformate as the electrophile, compound 15i was isolated as a yellow oil (13 mg, 0.03 mmol, 18%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.97 (dd, J = 8.0, 1.3 Hz, 1H), 7.55 (dt, J = 8.0, 1.3 Hz, 1H), 7.50–7.45 (m, 2H), 7.44–7.40 (m, 2H), 7.36–7.25 (m, 3H), 6.74 (d, J = 10.0 Hz, 1H), 5.52 (d, J = 10.0 Hz, 1H), 5.10 (t, J = 7.0 Hz, 1H), 2.16 (q, J = 7.0 Hz, 2H), 1.93–1.86 (m, 1H), 1.81–1.74 (m, 1 H), 1.63 (s, 3H), 1.57 (s, 3H), 1.52 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 159.5, 157.2, 152.1, 151.0, 135.8, 132.2, 131.3, 129.8 (2C), 126.9, 125.5, 123.5, 123.4, 123.3, 120.9 (2C), 117.1, 115.5, 113.9, 104.9, 82.4, 41.7, 27.3, 25.6, 22.6, 17.6 ppm. HRMS (ESI+): calcd. for C26H26NO4+ [M+H]+ 416.1856, found 416.1854.
tert-Butyl 2-methyl-2-(4-methylpent-3-en-1-yl)-5-oxo-2H-pyrano [3,2-c]quinoline-6(5H)-carboxylate (15j). Following the general procedure described with phenyl chloroformate as the electrophile, compound 15j was isolated as a yellow oil (49 mg, 0.13 mmol, 74%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 8.07 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.62 (dt, J = 7.4, 1.3 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 6.49 (d, J = 10.0 Hz, 1H), 5.61 (d, J = 10.0 Hz, 1H), 5.09 (t, J = 7.0 Hz, 1H), 2.16 (q, J = 7.2 Hz, 2H), 1.92–1.85 (m, 1H), 1.82–1.75 (m, 1 H), 1.61 (s, 3H), 1.57 (s, 9H), 1.53 (s, 3H), 1.52 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 158.5, 153.0, 150.6, 146.3, 132.1, 130.2, 128.4, 128.1, 125.4, 123.5, 121.7, 119.9, 116.5, 104.3, 84.0, 81.6, 41.7, 27.7 (3C), 27.2, 25.5, 22.5, 17.5 ppm. HRMS (ESI+): calcd. for C24H30NO4+ [M+H]+ 396.2169, found 396.2177.
Methyl 5-(2-methyl-2-(4-methylpent-3-en-1-yl)-5-oxo-2H-pyrano [3,2-c]quinolin-6(5H)-yl)pentanoate (15k). Following the general procedure described with methyl 5-bromovalerate as the electrophile, compound 15k was isolated as a yellow oil (41 mg, 0.10 mmol, 59%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.96 (dd, J = 8.0, 1.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.77 (d, J = 10.0 Hz, 1H), 5.48 (d, J = 10.0 Hz, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.28 (t, J = 6.6 Hz, 2H), 3.66 (s, 3H), 2.40 (t, J = 6.6 Hz, 2H), 2.14 (q, J = 7.7 Hz, 2H), 1.88–1.70 (m, 6H), 1.62 (s, 3H), 1.55 (s, 3H), 1.47 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 173.8, 160.7, 155.3, 138.5, 131.9, 130.8, 125.3, 123.8, 123.3, 121.6, 118.3, 116.2, 113.9, 105.3, 81.3, 51.3, 41.7, 41.6, 33.7, 27.2, 27.1, 25.6, 22.6, 22.4, 17.6 ppm. HRMS (ESI+): calcd. for C25H32NO4+ [M+H]+ 410.2326, found 410.2322.
5-(2-Methyl-2-(4-methylpent-3-en-1-yl)-5-oxo-2H-pyrano [3,2-c]quinolin-6(5H)-yl)pentanoic acid (15l). To a solution of ester derivative 15k (25 mg, 0.06 mmol, 1 eq.) in a 1:1 mixture of MeOH/H2O was added LiOH.H2O (7 mg, 0.18 mmol, 3 eq.). The mixture was stirred at RT for 18 h and quenched with a 1 M aqueous solution of HCl. The product was extracted 3 times with MTBE. The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. A purification by flash chromatography on silica gel (12 g) with heptane/EtOAc from 8:2 to 0:10 gave compound 15k as a yellow oil (19 mg, 0.05 mmol, 80%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.97 (dd, J = 8.0, 1.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 6.77 (d, J = 10.0 Hz, 1H), 5.48 (d, J = 10.0 Hz, 1H), 5.09 (t, J = 7.0 Hz, 1H), 4.30 (t, J = 6.0 Hz, 2H), 2.46 (t, J = 6.0 Hz, 2H), 2.14 (q, J = 7.7 Hz, 2H), 1.89–1.70 (m, 6H), 1.62 (s, 3H), 1.55 (s, 3H), 1.47 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 178.0, 160.9, 155.6, 138.4, 132.0, 130.9, 125.4, 123.7, 123.3, 121.8, 118.2, 116.2, 114.1, 105.2, 81.5, 41.8, 41.6, 33.7, 27.1, 27.0, 25.6, 22.6, 22.1, 17.6 ppm. HRMS (ESI+): calcd. for C24H30NO4+ [M+H]+ 396.2169, found 396.2178.
5-Benzyl-8,8,11a-trimethyl-5,8,9,10,11,11a-hexahydro-6H-chromeno [3,2-c]quinolin-6-one (16a). To a solution of N-benzyl quinolone 15a (50 mg, 0.16 mmol, 1 eq.) in anhydrous dichloromethane (5 mL) under Ar atm. was slowly added SnCl4 (84 mg, 0.32 mmol, 2 eq.). After 1 h at RT, the mixture was quenched with water (0.2 mL). MgSO4 was added to the solution and the solids were eliminated by filtration over a Celite® pad. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel (24 g) with heptane/EtOAc from 10:0 to 5:5 to give compound 16a as a white solid (29 mg, 0.09 mmol, 57%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.96 (dd, J = 7.9, 1.0 Hz, 1H), 7.36 (td, J = 8.0, 1.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 2H), 7.13 (t, J = 8.0 Hz, 3H), 5.49 (bs, 2H), 4.78 (s, 1H), 2.19 (d, J = 13.6 Hz, 1H), 1.78 (dt, J = 13.6, 7.4 Hz, 1H), 1.71 (s, 1H), 1.56 (td, J = 13.9, 9.6 Hz, 1H), 1.48–1.45 (m, 1H), 1.40 (s, 3H), 1.29 (td, J = 13.9, 9.6 Hz, 1H), 1.07 (s, 3H), 0.57 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ 164.1, 156.4, 138.5, 136.6, 130.9, 128.8 (2C), 127.3, 126.5 (2C), 123.7, 122.0, 116.8, 114.9, 109.0, 78.6, 62.4, 52.0, 45.6, 41.3, 39.2, 33.0, 31.7, 26.7, 21.2, 17.9 ppm. HRMS (ESI+): calcd. for C26H28NO2+ [M+H]+ 386.2115, found 386.2125.