Total Synthesis of (–)-13-Acetoxymodhephene and (+)-14-Acetoxymodhephene
trated. The residue was purified by flash chromatography (EtOAc/
hexane, 1:20) to give 32 mg (0.114 mmol, quant.) of the title com-
pound. 1H NMR (400 MHz, CDCl3): δ = 4.61–4.54 (m, 1 H), 3.61–
3.50 (m, 2 H), 3.43–3.30 (m, 2 H), 2.34 (dd, J = 17.6, 4.8 Hz, 1 H),
2.19 (dd, J = 17.6, 2.4 Hz, 1 H), 2.06–1.99 (m, 1 H), 1.77–1.56 (m,
39.4, 38.0, 35.1, 33.7, 32.7, 27.3, 21.0, 19.4, 15.2, 10.5 ppm. IR
(neat): ν = 3444, 2957, 1742, 1471, 1385, 1259, 1068, 1033,
˜
987 cm–1. HRMS (EI): calcd. for C17H28O3 280.2038; found
280.2025. [α]2D2
=
–39.88 (c
= 0.8, CHCl3). Data for the
(1R,2S,3S,6R)-isomer: 1H NMR (400 MHz, CDCl3): δ = 4.15 (d,
5 H), 1.44–1.13 (m, 11 H), 1.07 (s, 3 H), 0.95 (d, J = 6.7 Hz, 3 J = 11.0 Hz, 1 H), 4.04 (d, J = 11.0 Hz, 1 H), 3.38 (d, J = 11.0 Hz,
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 221.8, 99.9, 70.6, 70.1,
1 H), 2.04 (s, 3 H), 2.03–1.94 (m, 1 H), 1.64–1.49 (m, 4 H), 1.45–
1.37 (m, 2 H), 1.34–1.21 (m, 3 H), 1.13–1.08 (m, 1 H), 1.02 (d, J
62.3, 61.0, 56.6, 54.9, 50.7, 46.1, 38.8, 36.0, 34.6, 33.0, 26.5, 19.5,
18.5, 15.2, 14.1 ppm. IR (neat): ν = 2953, 1734, 1458, 1377, 1136, = 7.6 Hz, 3 H), 0.99 (s, 3 H), 0.92 (d, J = 6.5 Hz, 3 H) ppm. 13C
˜
1058 cm–1. HRMS (EI): calcd. for C18H30O3 294.2195; found
NMR (100 MHz, CDCl3): δ = 171.4, 80.2, 72.1, 63.0, 60.7, 46.7,
45.9, 39.6, 37.6, 35.7, 32.5, 32.3, 27.2, 20.9, 15.2, 13.7, 11.9 ppm.
[α]2D0 = –5.04 (c = 0.7, CHCl3).
294.2181. [α]2D3 = –8.51 (c = 1.5, CHCl3)
(1R,2S,6R)-2-Hydroxymethyl-2,4,6-trimethyltricyclo[3.3.3.0]undec-
an-3-one: To a solution of ketone (32 mg, 0.114 mmol) in THF
(1 mL) was added lithium 2,2,6,6-tetramethylpiperidide(LiTMP;
2 in THF, 0.57 mL, 1.14 mmol) [prepared from 2,2,6,6-tet-
ramethylpiperidine and nBuLi in THF at 0 °C] at 0 °C. After stir-
ring for 30 min, CH3I (0.07 mL, 1.14 mmol) and HMPA (0.1 mL,
0.57 mmol) were added to the reaction mixture. Stirring was con-
tinued for 2 h at 0 °C. The mixture was poured into H2O (2 mL),
and the aqueous layer was extracted with EtOAc (3ϫ3 mL). The
mixture was concentrated in vacuo. The crude product was dis-
solved in THF (1 mL) and 1 HCl was added to the reaction mix-
ture at room temperature. After stirring for 1 h, the mixture was
poured into H2O (2 mL), and the aqueous layer was extracted with
EtOAc (3ϫ4 mL). The combined organic layer was dried with an-
hydrous MgSO4 and concentrated. Flash chromatography of the
residue on silica gel (EtOAc/hexane, 1:5) produced 12.7 mg
(0.054 mmol, 47%) of the title compound. 1H NMR (400 MHz,
CDCl3): δ = 3.80 (d, J = 11.5 Hz, 1 H), 3.51 (d, J = 11.5 Hz, 1 H),
2.42 (q, J = 6.9 Hz, 1 H), 2.30 (br. s, 1 H, OH), 2.13–2.09 (m, 1
H), 1.82–1.78 (m, 1 H), 1.70–1.47 (m, 6 H), 1.45–1.40 (m, 1 H),
1.36–1.31 (m, 1 H), 1.25–1.22 (m, 1 H), 1.21 (s, 3 H), 1.02 (d, J =
6.9 Hz, 3 H), 0.94 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 224.2, 66.5, 60.4, 60.0, 52.9, 49.3, 39.6, 37.2, 34.3,
(+)-14-Acetoxymodhephene (3): To a stirred solution of acetate
(13.4 mg, 0.048 mmol) in CH3CN (2 mL) was added triphenylphos-
phane (50.4 mg, 0.192 mmol) and carbon tetrachloride (18.5 µL,
0.192 mmol) at room temperature. The mixture was stirred under
reflux for 2 h. The reaction mixture was cooled to room tempera-
ture. The mixture was concentrated under the reduced pressure.
Flash chromatography of the residue (EtOAc/hexane, 1:40) af-
forded 10.3 mg (0.039 mmol, 82%) of 3 as a colorless oil. 1H NMR
(400 MHz, C6D6): δ = 4.71 (q, J = 1.4 Hz, 1 H), 4.11 (d, J =
10.8 Hz, 1 H), 3.90 (d, J = 10.8 Hz, 1 H), 2.09–2.02 (m, 1 H), 1.70
(s, 3 H), 1.60–1.45 (m, 2 H), 1.52 (d, J = 1.4 Hz, 3 H), 1.42–1.19
(m, 7 H), 1.06 (s, 3 H), 1.03–0.96 (m, 1 H), 0.92 (d, J = 6.5 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.2, 144.7, 129.6,
73.4, 71.8, 65.3, 49.4, 43.4, 39.0, 35.0, 34.1, 29.9, 26.9, 21.0, 15.3,
14.0 ppm. IR (neat): ν = 2950, 1741, 1656, 1462, 1376, 1241 cm–1.
˜
HRMS (EI): calcd. for C17H26O2 262.1933; found 262.1937. [α]2D3
= + 17.60 (c = 0.5, CHCl3).
(1R,2R,6S)-2-Hydroxymethyl-2,6-dimethyltricyclo[3.3.3.0]undecan-
3-one (19): To a solution of epoxy ketone 6 (70 mg, 0.32 mmol) in
CH2Cl2 (1 mL) was added BF3·THF (0.070 mL, 0.64 mmol) at
room temperature. The reaction mixture was stirred for 10 min.
The mixture was poured into saturated aqueous NaHCO3 (2 mL),
and the aqueous layer was extracted with EtOAc (3ϫ3 mL). The
combined organic layer was dried with anhydrous MgSO4. The
mixture was concentrated in vacuo. The crude product was dis-
solved in THF (1 mL), and a solution of LiAl(OtBu)3H (1 in
THF, 0.35 mL, 0.35 mmol) was added to the reaction mixture at
–78 °C. After stirring for 1 h, the mixture was poured into H2O
(2 mL), and the aqueous layer was extracted with EtOAc
(3ϫ3 mL). The combined organic layer was dried with anhydrous
MgSO4 and concentrated. Flash chromatography of the residue on
silica gel (EtOAc/hexane, 1:3) produced 8 mg (0.036 mmol, 11%)
of 19. 1H NMR (400 MHz, CDCl3): δ = 3.80 (d, J = 11.2 Hz, 1
H), 3.49 (d, J = 11.2 Hz, 1 H), 2.55 (d, J = 18.3 Hz, 1 H), 2.09 (d,
J = 18.3 Hz, 1 H), 1.91–1.82 (m, 2 H), 1.80–1.70 (m, 3 H), 1.64–
1.58 (m, 1 H), 1.40–1.29 (m, 5 H), 1.17 (s, 3 H), 0.98 (d, J = 6.5 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 224.4, 66.2, 62.6,
57.6, 55.5, 50.3, 47.2, 38.0, 35.9, 34.0, 33.7, 26.3, 20.8, 14.4 ppm.
[α]2D5 = –13.61 (c = 1.2, CHCl3).
32.9, 32.5, 27.3, 20.2, 15.2, 8.73 ppm. IR (neat): ν = 3500, 2953,
˜
1728, 1463, 1380, 1048, 989 cm–1. HRMS (EI): calcd. for C15H24O2
236.1776; found 236.1769. [α]2D2 = + 8.26 (c = 0.9, CHCl3)
(1R,2S,3S,6R)-3-Hydroxy-2,4,6-trimethyltricyclo[3.3.3.0]undec-3-yl-
methyl Acetate: To a solution of (1R,2S,6R)-2-hydroxymethyl-
2,4,6-trimethyltricyclo[3.3.3.0]undecan-3-one (12.7 mg,
0.054 mmol) dissolved in CH2Cl2 (1 mL) was added Et3N
(0.017 mL, 0.12 mmol) and Ac2O (0.01 mL, 0.11 mmol) at 0°C, and
the mixture was allowed to stir for 4 h at room temperature. The
mixture was poured into H2O (2 mL), and the aqueous layer was
extracted with EtOAc (3ϫ3 mL). The combined extract was dried
and concentrated in vacuo. Flash chromatography of the residue
on silica gel (EtOAc/hexane, 1:15) afforded 14.3 mg (0.051 mmol,
95%) of the title compound as a colorless oil. To a stirred solution
of acetate (14.3 mg, 0.051 mmol) in methanol (1 mL) was added
NaBH4 (2.2 mg, 0.056 mmol) at 0 °C. After stirring for 20 min,
H2O (2 mL) was added to the reaction mixture and extracted with
EtOAc (3ϫ2 mL). The combined organic extract was dried with
anhydrous MgSO4, filtered, and concentrated in vacuo. The residue
was subjected to flash chromatography (EtOAc/hexane, 1:5) to give
13.4 mg (0.048 mmol, 94 %) of the products [3.2 mg of the
(1R,2R,6S)-2-[(1-Ethoxyethoxy)methyl]-2,6-dimethyltricyclo[3.3.3.0]-
undecan-3-one: To a solution of alcohol 19 (34 mg, 0.153 mmol) in
CH2Cl2 (1 mL) was added ethyl vinyl ether (EVE; 0.03 mL,
0.306 mmol) and pTosOH at room temperature. After stirring for
(1R,2S,3R,6R)-product and 10.2 mg of the (1R,2S,3S,6R)-product].
1
Data for the (1R,2S,3R,6R)-isomer: H NMR (400 MHz, CDCl3): 1 h, the mixture was poured into H2O (2 mL), and the aqueous
δ = 4.56 (d, J = 11.2 Hz, 1 H), 3.93 (d, J = 11.2 Hz, 1 H), 3.54 (d, layer was extracted with EtOAc (3ϫ3 mL). After the organic ex-
J = 3.8 Hz, 1 H), 2.56 (br. s, 1 H, OH), 2.32–2.26 (m, 1 H), 2.06
(s, 3 H), 1.99–1.94 (m, 1 H), 1.89–1.75 (m, 2 H), 1.64–.1.51 (m, 2
tract was dried and concentrated. Flash chromatography (EtOAc/
hexane, 1:20) of the residue gave 39.3 mg (0.141 mmol, 92%) of the
1
H), 1.43–1.29 (m, 4 H), 1.18–1.10 (m, 2 H), 1.07 (d, J = 7.2 Hz, 3 title compound. H NMR (400 MHz, CDCl3): δ = 4.61–4.54 (m, 1
H), 0.96 (s, 3 H), 0.87 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR H), 3.61–3.50 (m, 2 H), 3.43–3.30 (m, 2 H), 2.34 (dd, J = 17.6,
(100 MHz, CDCl3): δ = 172.3, 86.4, 68.1, 66.8, 65.7, 49.0, 44.5,
4.8 Hz, 1 H), 2.19 (dd, J = 17.6, 2.4 Hz, 1 H), 2.06–1.99 (m, 1 H),
5035
Eur. J. Org. Chem. 2009, 5028–5037
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org