Concise Asymmetric Synthesis of (–)-Hongconin and (–)-1-epi-Hongconin
(4R)-4-Benzyloxypent-1-yn-3-one (14): To a solution of 13 (1.12 g, then quenched with water (5 mL). The solution was extracted with
5.9 mmol) in EtOAc (20 mL) was added IBX (1.97 g, 7.06 mmol,
1.2 equiv.), and the mixture was heated at reflux for 12 h. It was
then filtered through a pad of silica gel and concentrated. The resi-
due was purified by silica gel column chromatography (petroleum
ether/EtOAc, 9:1 to 4:1) to provide 14 (0.81 g, 73%) as a colorless
EtOAc (3ϫ20 mL), and the combined organic layers were washed
with brine, dried (Na2SO4), and concentrated. The residue was
purified by silica gel column chromatography (petroleum ether/
EtOAc, 9:1 to 4:1) to provide 16 (75 mg, 91%) as a pale-yellow oil.
[α]2D5 = –6.6 (c = 0.64, CHCl ). IR (CHCl ): ν = 3012, 2937, 2842,
˜
3
3
oil. [α]2D5 = +40.6 (c = 0.7, CHCl ). IR (CHCl ): ν = 3297, 3020,
1595, 1508, 1455, 1380, 1339, 1263, 1216, 1127, 1079, 1021, 1002,
954, 756, 699, 667 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.12 (d,
J = 6.4 Hz, 3 H, CH3), 3.91 (s, 3 H, OMe), 3.95 (s, 3 H, OMe),
3.97 (s, 3 H, OMe), 4.17–4.21 (m, 4 H, –OCH2CH2O–), 4.44 (q, J
= 6.4 Hz, 1 H, CHOBn), 4.51 (d, J = 12.2 Hz, 1 H, OCH2Ph), 4.56
˜
3
3
2929, 2864, 2098, 1686, 1517, 1455, 1372, 1216, 1074, 1021, 929,
1
758, 699, 670 cm–1. H NMR (400 MHz, CDCl3): δ = 1.47 (d, J =
7.0 Hz, 3 H, CH3), 3.41 (s, 1 H, 1-H), 4.09 (q, J = 7.0 Hz, 1 H, 4-
H), 4.49 (d, J = 11.6 Hz, 1 H, OCH2Ph), 4.75 (d, J = 11.6 Hz, 1
H, OCH2Ph), 7.32–7.41 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, (d, J = 11.9 Hz, 1 H, OCH2Ph), 6.87 (d, J = 7.3 Hz, 1 H, 6-ArH),
CDCl3): δ = 17.4, 72.1, 79.6, 80.6, 81.9, 127.9 (2 C), 128.0, 128.5
7.07 (s, 1 H, 3-ArH), 7.12–7.17 (m, 5 H, Ph), 7.40 (t, J = 8.3 Hz,
1 H, 7-ArH), 7.65 (dd, J = 8.5, 0.6 Hz, 1 H, 8-ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 15.1, 56.5, 56.9, 63.0, 65.3, 65.7,
72.8, 77.5, 105.7, 106.6, 110.8, 115.2, 126.4, 127.2, 127.7 (2 C),
127.9, 128.0 (2 C), 130.3, 132.2, 138.9, 147.3, 152.9, 157.4 ppm.
HRMS (ESI+): calcd. for [C25H28O6 + Na] 447.1783; found
447.1788.
(2 C), 137.2, 189.0 ppm. HRMS (ESI+): calcd. for [C12H12O2
Na] 211.0734; found 211.0729.
+
(2R)-2-(1-Benzyloxyethyl)-2-ethynyl-1,3-dioxolane (8): To a solution
of 14 (0.8 g, 4.25 mmol) in benzene (20 mL) was added ethylene
glycol (2.62 g, 42.25 mmol, 10 equiv.) and p-toluenesulfonic acid
(100 mg), and the reaction mixture was heated at reflux for 30 h.
After cooling to room temperature, the mixture was quenched with
a saturated solution of NaHCO3 (10 mL). The solution was ex-
tracted with EtOAc (3ϫ20 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The residue
was purified by silica gel column chromatography (petroleum ether/
EtOAc, 9:1 to 4:1) to provide 8 (0.74 g, 75%) as a colorless oil.
(R)-1-[2-(1,4,5-Trimethoxynaphthalen-2-yl)-1,3-dioxolan-2-yl]-
ethanol (6): To a solution of 16 (0.68 g, 1.6 mmol) in anhydrous
MeOH (20 mL) was added 10% Pd/C (0.161 g), and the mixture
was stirred for 6 h under an atmosphere of H2 (1 atm). It was then
filtered through a pad of Celite, and the filtrate was concentrated.
The residue was purified by silica gel column chromatography (pe-
troleum ether/EtOAc, 9:1 to 3:2) to provide 6 (0.39 g, 72%) as a
white solid. M.p. 141–142 °C. [α]2D5 = –13.9 (c = 0.50, CHCl3). IR
[α]2D5 = +17.6 (c = 1.12, CHCl ). IR (CHCl ): ν = 3280, 3046, 2984,
˜
3
3
1
2894, 2111, 1454, 1374, 1206, 1111, 946, 751, 699 cm–1. H NMR
(400 MHz, CDCl3): δ = 1.34 (d, J = 6.4 Hz, 3 H, CH3), 2.59 (s, 1
H, ϵC–H), 3.69 (q, J = 6.4 Hz, 1 H, CHOBn), 4.01–4.19 (m, 4
H, –OCH2CH2O–), 4.72 (d, J = 11.9 Hz, 1 H, OCH2Ph), 4.85 (d,
J = 12.2 Hz, 1 H, OCH2Ph), 7.28–7.42 (m, 5 H, Ph) ppm. 13C
NMR (100 MHz, CDCl3): δ = 15.8, 65.0, 65.3, 72.7, 73.3, 77.6,
80.1, 104.6, 127.4, 127.7 (2 C), 128.2 (2 C), 138.5 ppm. HRMS
(ESI+): calcd. for [C14H16O3 + Na] 255.0996; found 255.0992.
(CHCl ): ν = 3496, 2956, 2937, 2890, 2841, 1595, 1508, 1462, 1380,
˜
3
1339, 1264, 1208, 1128, 1079, 1003, 952, 855, 814, 757, 667 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.05 (d, J = 6.4 Hz, 3 H, CH3),
3.94 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 3.97 (s, 3 H, OMe), 4.03–
4.21 (m, 4 H, –OCH2CH2O–), 4.48 (q, J = 6.1 Hz, 1 H, CH–OH),
6.88 (d, J = 7.9 Hz, 1 H, 6-ArH), 6.98 (s, 1 H, 3-ArH), 7.42 (t, J
= 7.9 Hz, 1 H, 7-ArH), 7.67 (d, J = 8.2 Hz, 1 H, 8-ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 17.4, 56.4, 56.8, 63.1, 65.2, 65.4,
70.4, 105.3, 106.7, 111.0, 115.1, 118.7, 126.6, 128.4, 132.1, 147.3,
153.1, 157.3 ppm. HRMS (ESI+): calcd. for [C18H22O6 + H]
335.1494; found 335.1498.
(2R)-2-[2-(1-Benzyloxyethyl)-1,3-dioxolan-2-yl]-4,5-dimethoxynaphth-
alen-1-ol (15): To a solution of freshly prepared chromium carbene
complex 7 (0.74 g, 2.16 mmol) in dry and degassed THF (15 mL)
was added alkyne 8 (0.60 g, 2.58 mmol, 1.2 equiv.), and the reaction
mixture was stirred at 45 °C for 14 h under an atmosphere of nitro-
gen. It was then cooled to room temperature, exposed to air, and
stirred further for 30 min. The reaction mixture was concentrated,
and the residue was purified by silica gel column chromatography
(petroleum ether/EtOAc, 9:1 to 7:3) to give 15 (0.46 g, 52%) as a
colorless viscous oil. [α]2D5 = +7.9 (c = 0.84, CHCl3). IR (CHCl3):
(1R/S,2R)-2-Benzyloxy-1-(1,4,5-trimethoxynaphthalen-2-yl)-
propan-1-ol (17): To a solution of 9 (2.8 g, 9.42 mmol) in dry THF
(30 mL) at –78 °C under an atmosphere of nitrogen was added
nBuLi (3 in hexane, 3.8 mL, 11.3 mmol, 1.2 equiv.) followed by
aldehyde 10 (1.85 g, 11.27 mmol, 1.2 equiv.). The reaction mixture
was stirred at –78 °C for 2 h and then at room temperature for 12 h.
It was then quenched with a saturated solution of NH4Cl (10 mL),
and the solution was extracted with EtOAc (3ϫ25 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc, 9:1 to 7:3) to provide 17
ν = 3367, 3063, 2981, 2939, 2893, 1633, 1598, 1582, 1493, 1464,
˜
1388, 1286, 1248, 1216, 1118, 1027, 951, 930, 754, 699 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.23 (d, J = 6.1 Hz, 3 H, CH3), 3.83
(q, J = 6.1 Hz, 1 H, CHOBn), 3.90 (s, 3 H, OMe), 3.97 (s, 3 H,
OMe), 3.99–4.12 (m, 4 H, –OCH2CH2O–), 4.67 (d, J = 11.6 Hz, 1
H, OCH2Ph), 4.71 (d, J = 12.2 Hz, 1 H, OCH2Ph), 6.88 (s, 1 H, 3-
ArH), 6.92 (d, J = 8.2 Hz, 1 H, 6-ArH), 6.98 (t, J = 7.3 Hz, 1 H,
7-ArH), 7.15–7.32 (m, 5 H, Ph), 7.68 (d, J = 7.3 Hz, 1 H, 8-ArH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 15.1, 55.2, 58.9, 65.1, 65.2,
72.5, 78.4, 100.5, 108.3, 110.7, 112.5, 119.6, 120.5, 124.4, 126.8,
127.2, 127.7 (2 C), 128.0 (3 C), 139.0, 139.7, 154.9 ppm. HRMS
(ESI+): calcd. for [C24H26O6 + H] 411.1808; found 411.1812.
(3.08 g, 89%) as a yellow oil. IR (CHCl ): ν = 3479, 3065, 3009,
˜
3
2932, 2848, 1600, 1585, 1463, 1455, 1382, 1348, 1264, 1218, 1126,
1077, 1028, 1006, 810, 757, 699, 667 cm–1. 1H NMR (400 MHz,
CDCl3, major diastereomer): δ = 1.07 (d, J = 6.1 Hz, 3 H, CH3),
3.81 (s, 3 H, OMe), 3.93 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 4.59
(d, J = 11.9 Hz, 1 H, OCH2Ph), 4.65 (d, J = 11.9 Hz, 1 H,
OCH2Ph), 4.67 (q, J = 6.2 Hz, 1 H, CHOBn), 5.36 (d, J = 3.9 Hz,
1 H, CH–OH), 6.86 (d, J = 7.9 Hz, 1 H, 6-ArH), 7.03 (s, 1 H, 3-
ArH), 7.27–7.35 (m, 5 H, Ph), 7.40 (t, J = 7.9 Hz, 1 H, 7-ArH),
7.61 (d, J = 7.6 Hz, 1 H, 8-ArH) ppm. 13C NMR (100 MHz,
(2R)-2-(1-Benzyloxyethyl)-2-(1,4,5-trimethoxynaphthalen-2-yl)-1,3-
dioxolane (16): To a solution of 15 (80 mg, 0.19 mmol) in dry THF
(5 mL) at 0 °C was added NaH (13.7 mg, 0.57 mmol, 3.0 equiv.), CDCl3, major diastereomer): δ = 14.0, 56.6, 56.9, 62.0, 70.0, 71.1,
and the reaction mixture was stirred at room temperature for
30 min. It was then cooled to 0 °C and MeI (0.042 mL, 0.67 mmol,
3.5 equiv.) was added. The reaction mixture was stirred for 6 h and
77.7, 104.9, 106.6, 114.8, 126.8, 127.9 (2 C), 128.0, 128.6 (2 C),
128.7, 129.4, 131.1, 138.7, 146.3, 153.7, 157.6 ppm. HRMS (ESI+):
calcd. for [C23H26O5 + H] 383.1859; found 383.1854.
Eur. J. Org. Chem. 2010, 4306–4311
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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