Syntheses of (+)-alismoxide and (+)-4-epi-alismoxide

Article abstract of DOI:10.1021/jo061278y

(Chemical Equation Presented) The first total syntheses of (+)-alismoxide and (+)-4-epialismoxide are reported. Formal chemo-, regio-, and stereo-selective addition of water to 10α-acetoxy-1αH,5βH- guaia-3,6-diene afforded the target compounds after reduc

Full text of DOI:10.1021/jo061278y

properties. Diuretic,2c antiinflammatory,7a and vasorelaxant7b
activities and inhibition of urinary calculi formation7c have been
reported for (()-1a. (-)-1a has shown cytotoxic activity against
four cancer cell lines (murine leukemia P-388, human lung
carcinoma A-549, human colon carcinoma HT-29, and human
melanoma cells MEL-28).6a
Syntheses of (+)-Alismoxide and
(+)-4-epi-Alismoxide
Gonzalo Blay, Begon˜a Garc´ıa, Eva Molina, and
Jose´ R. Pedro*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica,
UniVersitat de Vale`ncia, Dr. Moliner 50, E-46100,
Burjassot, Vale`ncia, Spain
Structure 1a has been determined by spectroscopic analysis
and chemical correlation with alismol (2a) (Figure 1).2c,e,4b,8
From the presumed absolute stereostructure for (+)-alismol (2a)
(which was determined by CD spectral analysis),2c the absolute
stereochemistry as shown in 1a has been proposed for (+)-
alismoxide.2c,e The attempts to establish the absolute stereo-
chemistry of 1a by X-ray analysis failed.9 (()-1a and (()-2a
were first reported by Bowden and co-workers in Lemnalia
africana4a and Nephthea chabrolii,4b respectively. From their
[R]D value the authors suggested the co-occurring unstable
germacrane C (3) as their likely precursor (Scheme 1). This
proposal was confirmed by Kitagawa and co-workers, who
found that (()-1a could be obtained from an aqueous acetone
solution of 3.5 Since then, it has been assumed than 1a and 2a
and related guaienes result from oxidation-cyclization of
germacrene C (3) during the isolation procedure (Scheme 1),
although it can be also biosynthesized by the organism.2b-c,5
On the other hand, in 1979, Bohlmann and Jakupovic assigned
structures 1b and 2b (4-epi-derivatives of 1a and 2a, respective-
ly) to two natural guaienes isolated from Silphium perfoliatum.10a
Later on, 1b was identified in Sparattanthelium botocudorum10b
and Amoora yunnanensis.10c Nevertheless, the identical 1H and
13C NMR spectroscopic features reported for 1a and 1b suggest
than they could be the same compound.
jose.r.pedro@uV.es
ReceiVed June 21, 2006
The first total syntheses of (+)-alismoxide and (+)-4-epi-
alismoxide are reported. Formal chemo-, regio-, and stereo-
selective addition of water to 10R-acetoxy-1RH,5âH-guaia-
3,6-diene afforded the target compounds after reduction.
The absolute stereochemistry of (+)-alismoxide has been
established. The low [R]D +8.6 value indicates that signifi-
cant amounts of alismoxide result from biosynthetic pro-
cesses. Furthermore, the structure of the natural guaienediol
isolated from Silphium perfoliatum has been corrected to
(-)-alismoxide.
In this paper, we report the syntheses of 1a and 1b in
enantiomerically pure form. Retrosynthetic analysis (Scheme
2) suggests that 1a and 1b could be accessible from a common
intermediate, 1RΗ,5âH-guaiadiene 6 or its parent alcohol 7,
through chemo-, regio-, and stereoselective addition of water
to the C3-C4 double bond. The nonconjugated diene system in
6 and 7 could be available by reduction-olefin transposition11
from guaiadienone 8, whose synthesis from (+)-dihydrocarvone
(5) has been recently reported by us.12
Alismoxide (1a) (guaianediol, nephalbidol) is a natural guaiane
derivative which has been isolated from terrestrial and marine
sources,1 especially from the rhizome of Alisma orientale, an
important crude drug used in oriental traditional medicine.2
Compound 1a has been isolated as racemic2b,4 and dextro-2a,d-e,3b
and levorotatory samples3a,5,6 and shows interesting biological
(5) Kitagawa, I.; Kobayashi, M.; Cui, Z.; Kiyota, Y.; Ohnishi, M. Chem.
Pharm. Bull. 1986, 34, 4590-4596.
(6) (a) El Sayed, K.; Hamann, M. T. J. Nat. Prod. 1996, 59, 687-689.
(b) Su, J.-Y.; Kuang, Y.-Y.; Zeng, L.-M. Huaxue Xuebao (Acta Chim. Sin.)
2003, 61, 1097-1100.
(7) (a) Kubo, M.; Matsuda, H.; Tomohiro, N.; Yoahikawa, M. Biol.
Pharm. Bull. 1997, 20, 511-516. (b) Yoshikawa, M.; Murakami, T.;
Morikawa, T.; Matsuda, H. Chem. Pharm. Bull. 1998, 46, 1186-1188. (c)
Zhou, X.; Yin, R.; Ruan, H.; Zhang, Y.; Pi, H.; Zhao, X.; Wu, J. Bopuxue
Zazhi 2005, 22, 195-200.
(1) (a) For natural sources and mp and [R]D (CHCl3) values for natural
and synthetic alismoxide (1a) and 4-epi-alismoxide (1b), see Supporting
Information. (b) For selected 1H and 13C NMR Data for compounds 1a
and 1b, see Supporting Information.
(2) (a) Oshima Y.; Iwakawa, T. Hikino, H. Phytochemistry 1983, 22,
183-185. (b) Yoshikawa, M.; Hatakeyama, S.; Tanaka, N.; Matsuoka, T.;
Yamahara, J.; Murakami, N. Chem. Pharm. Bull. 1993, 41, 2109-2112.
(c) Yoshikawa, M.; Yamaguchi, S.; Matsuda, H.; Kohda, Y.; Ishikawa, H.;
Tanaka, N.; Yamahara, J.; Murakami, N. Chem. Pharm. Bull. 1994, 42,
1813-1816 and references therein. (d) Nakajima, Y.; Satoh, Y.; Katsumata,
M.; Tsujiyama, K.; Ida Y.; Shoji, J. Phytochemistry 1994, 36, 119-127.
(e) Peng, G.-P.; Tian, G.; Huang, X.-F.; Lou, F.-C. Phytochemistry 2003,
63, 877-881.
(3) (a) Gao, K.; Yang, L.; Jian, Z.-J. J. Chin. Chem. Soc. 1999, 46, 619-
622. (b) Min, Y. D.; Kwon, H. C.; Choi, S. Z.; Lee, K. R. Yakhak Hoeji
2004, 48, 65-69.
(4) (a) Bowden, B. F.; Coll, J. C.; Mitchell, S. J.; Skelton, B. W.; White,
A. H. Aust. J. Chem. 1980, 33, 2737-2747. (b) Bowden, B. F.; Coll, J. C.;
Mitchell, S. J. Aust. J. Chem. 1980, 33, 1833-1839.
(8) Lange, G. L.; Gottardo, C.; Merica, A. J. Org. Chem. 1999, 64, 6738-
6744.
(9) Faulkner, D. J. Nat Prod. Rep. 1984, 1, 551-598. The structure was
determined by X-ray analysis but apparently has not been published, because
the crystal has two molecules per unit cell and only one of these was clearly
observed while the second was extensively disordered.
(10) (a) Bohlmann, F.; Jakupovic, J. Phytochemistry 1979, 18. 1987-
1992. (b) De Almeida, R. N.; Barbosa-Filho, J. M. J. Braz. Chem. Soc.
1991, 2, 71-73. (c) Luo, X.; Wu, S.; Ma, Y.; Wu, D. Zhiwu Xuebao (Acta
Bot. Sin.) 2001, 43, 426-430.
(11) (a) Kabalka, G. W.; Yang, D. T. C.; Baker, J. D., Jr. J. Org. Chem.
1976, 41, 574-575. (b) Greene, A. E.; Edgar, M. T. J. Org. Chem. 1989,
54, 1468-1470 and references therein.
(12) Blay, G.; Garcia, B.; Molina, E.; Pedro, J. R. Org. Lett. 2005, 7,
3291-3293.
10.1021/jo061278y CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/06/2006
7866
J. Org. Chem. 2006, 71, 7866-7869

FIGURE 1. Alismoxide (1a), 4-epi-alismoxide (1b), alismol (2a), and
4-epi-alismol (2b).
FIGURE 2. Conformational depiction and observed NOE for 7.
SCHEME 1. Formation of 1a and 2a from Germacrane C (3)
from the approach of the borane from the less hindered R-face
of hydrazone 9 to give the 3â-hydrazine 10 followed of loss of
TsH to afford diazene 11, which decomposes sigmatropically
inserting H5 on the â-face of the molecule without migration
of the C6-C7 double bond.
Looking at the structures of compounds 6 and 7 (Figure 2),
a preferential reactivity at the C3-C4 versus the C6-C7 tri-
substituted double bond was expected due to the steric hindrance
of the isopropyl group on C7. In addition, the â-disposition of
H5 and the C10-CH3 should favor electrophilic attack from the
R-face at C3-C4. However, hydroxymercuration-demercura-
tion13 as well as several attempts of hydroxy phenylselenyla-
tion14 failed to insert a â-hydroxyl group at C4 as in alismoxide
(1a). Low chemoselectivity in hydroxymercuration-demercu-
ration was observed,13 giving mixtures (1H NMR) of starting
6, its guaia-4,6-diene isomer, and nonolefinic polar compounds.
Treatment of 6 with PhSeCl in CH3CN-H2O14a gave unexpect-
edly alcohol 7 (84%). â-Hydroxyselenide adducts could be
obtained by treatment of 6 with PhSeOH generated in situ, with
PhSeO2H-H3PO2 as precursors.15 With successive additions of
both reagents (total amount: 6 equiv of PhSeO2H, 9 equiv of
H3PO2) starting 6 was consumed and 12 and 13 could be isolated
in low yields of 21% and 10%, respectively. Compounds 12
and 13 result from the electrophilic addition of phenylselenyl
ion to the R-face of 6 followed by hydroxyl attack to C4 or C3,
respectively, from the â-face of the molecule.
SCHEME 2. Retrosynthetic Analysis
SCHEME 3. Synthesis of Guaiadiene 6a
Deselenylation of 12 with Raney nickel followed by treatment
with LiAlH4 afforded compound (+)-1a {[R]26D +8.6} in excel-
lent yield (95%) from 12. The spectroscopic data of synthetic
(+)-1a were identical with those reported for the natural
products.1b It follows from the value of [R]D +8.6 that (+)-1a
is biosynthesized by A. orientale {[R]D +3.1,2a +8.7,2d +5.22e}
and that the product isolated from corals and other sources1a
has absolute stereochemistry opposite that of (-)-1a (Scheme 4).
The synthesis of 4-epi-derivative 1b was straightforward by
selective epoxidation at C3-C4 followed by reduction (Scheme
5). Low chemoselectivity was observed in the reaction of 6 with
bulky reagents as m-chloroperbenzoic acid (m-CPBA)16 or mag-
nesium monoperphthalate (MMPP),16 but good results were
obtained with dimethyldioxirane.17 Treatment of guaiadienes
a Reagents and conditions: (a) p-TsNHNH2, EtOH, ∆; (b) catecholbo-
rane, CHCl3, -50 °C; (c) NaOAc‚3H2O, ∆, 71% from 8; (d) LiAlH4, THF,
97%.
(13) Brown, H. C.; Lynch, G. J. J Org. Chem. 1981, 46, 531-538.
(14) (a) Toshimitsu, A.; Aoai, T.; Owada, H.; Uemura, S.; Okano, M. J.
Chem. Soc., Chem. Commun. 1980, 412-413. (b) Back, T. G.; Collins, S.;
Kerr, R. G. J. Org. Chem. 1981, 46, 1564-1570. (c) Hori, T.; Sharpless,
K. B. J. Org. Chem. 1978, 43, 1689-1697.
The transformation of 8 into 6 was carried out following the
procedure applied by Greene and co-workers in the synthesis
of 1RH,5âH-guai-3-ene derivatives11b (Scheme 3). Sequential
treatment of 8 with p-TsNHNH2, catecholborane, and NaOAc
afforded nonconjugated diene 6 in 71% yield. Treatment of 6
with LiAlH4 gave the parent alcohol 7 in excellent yield (98%).
The stereochemistry at C5 was confirmed by the positive NOE
between H5 and H14 in 7 (Figure 2). This stereochemistry results
(15) Labar, D.; Krief, A.; Hevesi, L. Tetrahedron Lett. 1978, 41, 3967-
3970.
(16) (a) Blay, G.; Bargues, V.; Cardona, L.; Collado, A. M.; Garcia, B.;
Pedro, J. R. J. Org. Chem. 2000, 65, 2138-2144 and references therein.
(b) Mehta, G.; Ramesh, S. S.; Bera, M. K. Chem. Eur. J. 2003, 9, 2264-
2272.
(17) (a) Adam, W.; Curci, R.; Edward, J. O. Acc. Chem. Res. 1989, 22,
205-211. (b) Bravo, A.; Fontana, F.; Fronza, G.; Minisci, F.; Zhao, L. J.
Org. Chem. 1998, 63, 254-263 and references therein.
J. Org. Chem, Vol. 71, No. 20, 2006 7867

SCHEME 4. Synthesis of (+)-Alismoxide (1a)a
value of pure (+)-1a (Table 1, Supporting Information) indicates
that significant amounts of 1a result from biosynthetic processes.
Comparison of the spectroscopic features of (+)-1a and (+)-
1b with those reported for the natural guaienediol isolated from
S. perfoliatum,10a S. botocudorum,10b and A. yunnanensis10c has
allowed the establishment of the identity of this guaienediol
with alismoxide (1a).
Experimental Section18
(-)-10R-Acetoxy-1RH,5âH-guaia-3,6-diene (6). A solution of
compound 7 (400 mg, 1.45 mmol) and p-TsNHNH2 (349 mg, 1.90
mmol) in abs EtOH (2.4 mL) was refluxed for 90 min, and after
this time the solvent was removed under vacuum to afford crude
tosylhydrazone 8 as a yellow foamy solid. A solution under argon
of crude 8 in CHCl3 (4.3 mL, filtered through basic Al2O3) was
cooled at -50 °C, catecholborane (1 M in THF, 6 mL, 6.0 mmol)
was added via syringe, and the mixture was stirred at -50 °C for
30 min. After this time, NaAcO‚3H2O (1.44 g, 10.60 mmol) was
added, the bath was removed, and the mixture was refluxed for
1 h. Filtration through neutral Al2O3 and removal of the solvent
under vacuum followed by column chromatography (hexanes/ethyl
ether 100:0 to 98:2) afforded 271 mg (71%) of compound 6 as a
a Reagents and conditions: (a) PhSeCl, CH3CN-H2O, 84%; (b) PhSeO2H,
50% H3PO2, THF (21% 12 + 10% 13); (c) Raney Ni, EtOH, 96%; (d)
LiAlH4, THF, 97%.
SCHEME 5. Synthesis of (+)-4-epi-Alismoxide (1b)a
22
colorless oil: [R]D -15.4 (c 0.52); IR (NaCl) 3040, 1730, 1610
cm-1; MS m/e 262 (M+, 5), 202 (32), 187 (14), 159 (100), 131
(21); HRMS found 262.1939 (M+), C17H26O2 required 262.1933;
1H NMR (400 MHz) δ 5.61 (1H, d, J ) 3.1 Hz), 5.31 (1H, br s),
2.96 (1H, br d, J ) 9.6 Hz), 2.57 (1H, q, J ) 9.6 Hz), 2.30-2.06
(6H, m), 2.02-1.92 (1H, m), 1.94 (3H, s), 1.73 (3H, br s), 1.52
(3H, s), 0.98 (3H, d, J ) 6.8 Hz), 0.97 (3H, d, J ) 6.8 Hz); 13C
NMR (100 MHz) δ 170.4 (C), 148.2 (C), 140.6 (C), 124.4 (CH),
123.4 (CH), 87.4 (C), 54.1 (CH), 47.1 (CH), 36.8 (CH), 36.6 (CH2),
32.0 (CH2), 24.8 (CH2), 22.7 (CH3), 21.4 (CH3), 21.0 (CH3), 19.7
(CH3), 15.0 (CH3).
(-)-10R-Hydroxy-1RH,5âH-guaia-3,6-diene (7). To a suspen-
sion of LiAlH4 (137 mg, 3.61 mmol) in THF (2.5 mL) at 0 °C was
added dropwise a solution of compound 6 (108 mg, 0.41 mmol) in
THF (4.5 mL). After removal of the bath, the reaction mixture was
stirred at room temperature for 2 h, quenched with aqueous saturated
NH4Cl, and extracted with EtOAc. The combined organic layers
were washed with brine and dried (Na2SO4), and the solvent was
removed. Column chromatography (hexanes-EtOAc, 7:3) gave
compound 7 (88 mg, 97%) as a solid: colorless crystals; mp 65-
a Reagents and conditions: (a) dimethyldioxirane, CH2Cl2, 0 °C, (60%
15; 68% 16); (b) LiAlH4, THF (87% from 15; 53% from 16).
6 or 7 with dimethyldioxirane afforded as products only R-
monoepoxides 15 and 16 in 60% and 68% yield, respectively.
The stereochemistry of the oxirane ring was assigned by the
positive NOE between H15 and H3 and H5 in 15. These results
show clearly that the steric shielding of H5 and the C10-CH3
highly favored the R attack. Reduction of 15 or 16 with LiAlH4
afforded guaiadienol (+)-1b {[R]26D +39.7} in 52% yield from
6 or 36% yield from 7. The spectroscopic features of (+)-1b
are similar to those of (+)-1a,1b but some clear differences in
δ values, especially in the 13C NMR spectra, can be observed:
25.8 (CH3), 22.5 (CH2), 120.6 (CH), 52.5 (CH), 150.9 (C), 80.9
(C) for (+)-1b versus 22.8 (CH3), 21.7 (CH2), 121.5 (CH), 50.9
(CH), 149.9 (C), 80.4 (C) for (+)-1a. A comparison of these
spectroscopic features with those reported for the natural
guaienediol.10 show clearly than the reported data for the natural
product agree with those of (+)-1a but not with those of (+)-
1b and consequently this natural guaienediol is identical to
alismoxide (1a). It follows from the [R]D sign that levorotatory
enantiomer (-)-1a (Scheme 4) is the main component in S.
perfoliatum.10a
67 °C (hexanes-EtOAc); [R]24 -6.6 (c 0.06); IR (KBr) 3500-
D
3250, 1610 cm-1; MS m/e 220 (M+, 7), 202 (46), 177 (23), 159
(100); HRMS found 220.1834 (M+), C15H24O required 220.1827;
1H NMR (400 MHz) δ 5.63 (1H, d, J ) 3.9 Hz), 5.31 (1H, s), 2.89
(1H, br d, J ) 9.3 Hz), 2.32-2.06 (5H, m), 2.00 (1H, dd, J )
11.2, 15.7 Hz), 1.84 (1H, dd, J ) 7.2, 13.4 Hz), 1.73 (3H, s), 1.43
(1H, dd, J ) 11.0, 13.2 Hz), 1.35 (1H, br s), 1.25 (3H, s), 0.99
(3H, d, J ) 6.8 Hz), 0.98 (3H, d, J ) 6.8 Hz); 13C NMR (75 MHz)
δ 148.2 (C), 141.0 (C), 124.8 (CH), 123.3 (CH), 74.9 (C), 56.6
(CH), 48.1 (CH), 42.5 (CH2), 36.8 (CH), 31.6 (CH2), 25.2 (CH2),
22.2 (CH3), 21.3 (CH3), 21.0 (CH3), 14.9 (CH3).
10R-Acetoxy-3R-phenylselenyl-4â-hydroxy-1RH,5âH-guaia-
6-ene (12) and 10R-Acetoxy-4R-phenylselenyl-3â-hydroxy-
1RH,5âH-guaia-6-ene (13). To a suspension of compound 6 (34
mg, 0.13 mmol) and PhSeO2H (37 mg, 0.19 mmol) in THF (2 mL)
at rt under argon was added 32 µL (0.30 mmol) of 50% aq H3PO2,
and the mixture was stirred at rt. After 90 min, additional portions
of PhSeO2H (37 mg, 0.19 mmol) and 50% aq H3PO2 (32 µL, 0.30
mmol) were added, and stirring was resumed for 3 h. New additions
of PhSeO2H (37 mg, 0.19 mmol) and 50% aq H3PO2 (32 µL, 0.30
mmol) and 30 min additional reaction time consumed starting 6,
and the reaction was quenched with aq saturated NaHCO3. Extraction
In conclusion, the first total synthesis of (+)-alismoxide (1a)
and (+)-4-epi-alismoxide (1b) has been accomplished starting
from the readily available (+)-dihydrocarvone (5). The synthesis
of these compounds has allowed the establishment of the
absolute configuration of alismoxide. Furthermore, the low [R]D
(18) For a description of the general experimental methods, see the
Supporting Information.
7868 J. Org. Chem., Vol. 71, No. 20, 2006

with EtOAc as usual and removal of the solvent under vacuum
followed by column chromatography (hexanes-EtOAc, 9:1 to 7:3)
separated compound 12 (12 mg, 21%) and 13 (5.5 mg, 10%).
Compound 12: colorless crystals; mp 110-113 °C (hexanes-
EtOAc); IR (KBr) 3550-3400, 3057, 1702, 1578 cm-1; MS m/e
436 (M+, 1), 434 (0.5), 376 (25), 374 (13), 219 (15), 157 (35), 77
(100); HRMS found 436.1530 (M+), C23H32O3Se required 436.1517;
1H NMR (300 MHz) δ 7.65-7.55 (2H, m), 7.30-7.20 (3H, m),
5.49 (1H, br s), 3.33 (1H, dd, J ) 9.2, 12.3 Hz), 1.95 (3H, s), 1.54
(3H, s), 1.22 (3H, s), 0.97 (3H, d, J ) 6.9 Hz), 0.96 (3H, d, J )
6.9 Hz); 13C NMR (75 MHz) δ 170.4 (C), 149.9 (C), 133.5 (CH,
2C), 129.8 (C), 128.9 (2C, CH), 127.2 (CH), 120.8 (CH), 87.4 (C),
81.0 (C), 55.4 (CH), 47.4 (CH), 46.8 (CH), 37.1 (CH), 36.2 (CH2),
31.1 (CH2), 24.7 (CH2), 22.7 (CH3), 21.4 (CH3), 21.1 (CH3), 19.6
(CH3), 18.9 (CH3).
Compound 13: colorless oil; IR (NaCl) 3500-3400, 3060, 1710,
1560 cm-1; MS m/e 436 (M+, 0.6), 434 (0.3), 376 (20), 374 (10),
219 (30), 157 (60), 77 (100); HRMS found 436.1533 (M+),
C23H32O3Se required 436.1517; 1H NMR (300 MHz) δ 7.58-7.54
(2H, m), 7.34-7.16 (3H, m), 5.54 (1H, d, J ) 2.4 Hz), 3.91 (1H,
d, J ) 5.4 Hz), 2.71 (1H, td, J ) 5.3, 10.9 Hz), 2.61-2.46 (2H,
m), 2.27-2.11 (3H, m), 2.03 (1H, dd, J ) 9.6, 13.0 Hz), 1.95-
1.82 (1H, m), 1.90 (3H, s), 1.66 (1H, dd, J ) 5.3, 14.9 Hz), 1.50
(3H, s), 1.47 (3H, s), 0.96 (3H, d, J ) 6.8 Hz), 0.95 (3H, d, J )
6.8 Hz); 13C NMR (75 MHz) δ 170.5 (C), 150.7 (C), 138.6 (CH),
128.8 (CH), 128.7 (CH), 126.7 (C), 121.4 (CH), 87.6 (C), 78.0
(CH), 63.3 (C), 50.4 (CH), 47.4 (CH), 37.3 (CH), 36.6 (CH2), 34.1
(CH2), 24.7 (CH2), 22.9 (CH3), 21.9 (CH3), 21.5 (CH3), 21.2 (CH3),
20.0 (CH3).
(-)-10R-Acetoxy-3R,4R-epoxy-1RH,5âH-guaia-6-ene (15). To
a solution of compound 6 (50 mg, 0.19 mmol) in 1 mL of dry
CH2Cl2 at 0 °C under argon was added 0.062 M in acetone
dimethyldioxirane (3.1 mL, 0.19 mmol), and the mixture was stirred
at 0 °C for 2 h. Removal of the solvent followed by column
chromatography (hexanes-EtOAc, 7:3) afforded 32 mg (60%) of
compound 15: mp 76-79 °C (acetone); [R]26D -11.2 (c 1.07); IR
(KBr) 3032, 1726, 1261, 1240 cm-1; MS m/e 278 (M+, 0.1), 218
(79), 203 (44), 185 (31), 175 (100); HRMS found 278.1884 (M+),
1
C17H26O3 required 278.1882; H NMR (400 MHz) δ 5.63 (1H, d,
J ) 2.8 Hz), 3.27 (1H, s), 2.30-2.18 (3H, m), 2.15-2.00 (3H, m),
1.97-1.86 (2H, m), 1.92 (3H, s), 1.72-1.63 (1H, m), 1.51 (3H,
s), 1.46 (3H, s), 0.98 (3H, d, J ) 6.8 Hz), 0.97 (3H, d, J ) 6.8
Hz); 13C NMR (75 MHz) δ 170.2 (C), 150.6 (C), 120.8 (CH), 86.5
(C), 66.1 (C), 62.1 (CH), 47.9 (CH), 42.8 (CH), 36.8 (CH), 36.8
(CH2), 28.7 (CH2), 24.6 (CH2), 22.6 (CH3), 21.3 (CH3), 20.9 (CH3),
19.4 (CH3), 16.5 (CH3).
(+)-3R,4R-Epoxy-10R-hydroxy-1RH,5âH-guaia-6-ene (16). Fol-
lowing the procedure for the synthesis of compound 15, from
compound 7 (51 mg, 0.23 mmol) was obtained compound 16 (37
mg, 68%) of as a colorless oil: [R]24 +52.7 (c 0.91); IR (NaCl)
D
3500-3250, 1610, 1121 cm-1; MS m/e 236 (M+, 5), 218 (32),
203 (14), 200 (23), 175 (41), 58 (100); HRMS found 236.1786
1
(M+), C15H24O2 required 236.1776; H NMR (400 MHz) δ 5.66
(1H, d, J ) 3.8 Hz), 3.27 (1H, s), 2.26 (1H, sept, J ) 6.8 Hz),
2.18-2.04 (4H, m), 1.93 (1H, dd, J ) 11.4, 15.7 Hz), 1.79 (1H, br
dd, J ) 8.0, 13.0 Hz), 1.76-1.60 (2H, m), 1.45 (3H, s), 1.33 (1H,
t, J ) 12.2 Hz), 1.20 (3H, s), 0.99 (3H, d, J ) 6.8 Hz), 0.97 (3H,
d, J ) 6.8 Hz); 13C NMR (75 MHz) δ 150.4 (C), 121.3 (CH), 74.2
(C), 65.3 (C), 62.2 (CH), 50.0 (CH), 43.7 (CH), 42.7 (CH2), 36.8
(CH), 28.4 (CH2), 25.1 (CH2), 21.5 (CH3), 21.2 (CH3), 20.9 (CH3),
16.5 (CH3).
(-)-10R-Acetoxy-4â-hydroxy-1RH,5âH-guaia-6-ene (14). To
a solution of compound 12 (26 mg, 0.06 mmol) in 1:1 absolute
EtOH-benzene (0.3 mL) was added Raney nickel (1.73 g) in
portions at 30 min intervals. After 2 h, the mixture was filtered
through silica gel eluting with EtOAc. Removal of the solvent
(+)-4R,10R-Dihydroxy-1RH,5âH-guaia-6-ene [(+)-4-epi-Alis-
moxide)] (+)-(1b). From Compound 15. Following the procedure
for the synthesis of compound 7, from compound 15 (27 mg, 0.10
mmol) was obtained compound (+)-1b (20 mg, 87%): colorless
crystals; mp 59-62 °C (hexanes-EtOAc); [R]26D +39.7 (c 0.80);
IR (KBr) 3600-3400, 1104, 1087 cm-1; MS m/e 238 (M+, 0.1),
220 (27), 205 (20), 162 (100); HRMS found 238.1929 (M+),
afforded compound 14 (16 mg, 96%) as a colorless oil: [R]26
D
-40.6 (c 0.64); IR (NaCl) 3500-3350, 1720 cm-1; MS (CI) m/e
221 (32), 203 (100), 159 (11); HRMS found 221.1905 (M+ - AcO),
C15H25O required 221.1905; 1H NMR (400 MHz) δ 5.47 (1H, d, J
) 2.7 Hz), 2.40-2.30 (1H, m), 2.28-2.14 (4H, m), 2.08-1.99
(1H, m), 1.95 (3H, s), 1.97-1.86 (1H, m), 1.78-1.50 (5H, m),
1.54 (3H, s), 1.21 (3H, s), 0.98 (3H, d, J ) 6.8 Hz), 0.97 (3H, d,
J ) 6.8 Hz); 13C NMR (75 MHz) δ 170.5 (C), 149.6 (C), 121.0
(CH), 87.9 (C), 80.2 (C), 49.4 (CH), 48.5 (CH), 40.3 (CH2), 37.2
(CH), 36.6 (CH2), 24.8 (CH2), 22.7 (CH3, 2C), 21.7 (CH2), 21.4
(CH3), 21.2 (CH3), 18.9 (CH3).
1
C15H26O2 required 238.1933; H NMR (400 MHz) δ 5.50 (1H, d,
J ) 3.4 Hz, H6), 2.26 (1H, sept, J ) 6.8 Hz, H11), 2.20-2.08 (2H,
m, H1, H8), 1.98-1.88 (2H, m, H5, H8′), 1.88-1.68 (4H, m, H2,
2H3, H9), 1.55 (1H, dt, J ) 10.4, 13.2 Hz, H2′), 1.48-1.38 (1H,
m), 1.30 (3H, s, 3H15), 1.21 (3H, s, 3H14), 0.98 (3H, d, J ) 6.8 Hz,
3H12), 0.97 (3H, d, J ) 6.8 Hz, 3H13); 13C NMR (75 MHz) δ 150.9
(C), 120.6 (CH), 80.8 (C), 75.2 (C), 52.5(CH), 50.1 (CH), 42.5-
(CH2), 39.8 (CH2), 37.3 (CH), 25.8 (CH3), 25.1 (CH2), 22.5 (CH2),
21.4 (CH3), 21.0 (CH3), 20.8 (CH3).
(+)-4â,10R-Dihydroxy-1RH,5âH-guaia-6-ene [(+)-Alismox-
ide] (+)-(1a). Following the procedure for the synthesis of 6a,
treatment of compound 14 (11.2 mg, 0.04 mmol) in THF (0.5 mL)
with LiAlH4 (6.7 mg, 0.17 mmol) in THF (2.5 mL) for 20 min
afforded after chromatography (hexanes/EtOAc, 4:6) compound
(+)-1a (9.4 mg, 99%) with the following features: colorless
crystals; mp 138-141 °C (hexanes-EtOAc); [R]26D +8.6 (c 1.16);
IR (KBr) 3500-3350, 1100 cm-1; MS (CI) m/e 221 (M+ - OH,
22), 219 (13), 203 (100), 202 (41), 187 (10), 159 (13); HRMS found
221.1896 (M+ - OH), C15H25O required 221.1905; 1H NMR (400
MHz) δ 5.49 (1H, br d, J ) 3.0 Hz, H6), 2.21 (1H, sept, J ) 6.8
Hz, H11), 2.20-2.14 (2H, m, H5, H8), 1.92 (1H, ddd, J ) 1.2, 10.6,
16.4 Hz, H8′), 1.89-1.58 (6H, m, H1, 2H2, 2H3, H9), 1.52 (2H, br
s), 1.46 (1H, br dd, J ) 10.4, 13.2 Hz, H9′), 1.26 (3H, s, 3H14),
1.20 (3H, s, 3H15), 0.98 (3H, d, J ) 6.8 Hz, 3H12), 0.97 (3H, d, J
) 6.8 Hz, 3H13); 13C NMR (75 MHz) δ 149.7 (C), 121.3 (CH),
80.2 (C), 75.2 (C), 50.9 (CH), 50.5 (CH), 42.6 (CH2), 40.4 (CH2),
37.3 (CH), 25.1 (CH2), 22.5 (CH3), 21.5 (CH2), 21.4 (CH3), 21.3
(CH3), 21.2 (CH3).
From Compound 16. Following the procedure for the synthesis
of compound 7, from compound 16 (32 mg, 0.13 mmol) was
obtained compound (+)-1b (17 mg, 53%) with the same spectral
features as compound (+)-1b obtained from 14.
Acknowledgment. E.M. thanks the Universitat de Valencia
for a grant (V Segles Program).
Supporting Information Available: General experimental
procedures; natural sources, mp and [R]D (CHCl3) values and
1
1
selected H and 13C NMR data for 1a and 1b; H NMR and 13C
NMR spectra of compounds 6, 12-17, (+)-1a, and (+)-1b; and
NOE experiments for 7, 15, and (+)-1b. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO061278Y
J. Org. Chem, Vol. 71, No. 20, 2006 7869