Natural and Unnatural A-seco Terpenes from Pulegone
for 30 min (P = 100 W, T = 130 °C). The reaction mixture was
evaporated and the resulting crude was purified by silica gel flash
chromatography (heptane/EtOAc, 9:1) to yield 20 mg (28%) of
methyl galbanate (–)-18, which was used in the saponification reac-
tion directly. LiOH (6 mg, 0.23 mmol) was added to a solution of
methyl galbanate [(–)-18; 19 mg. 0.046 mmol] in THF/H2O
(0.5 mL/0.1 mL). After stirring for 24 h, the reaction was acidified
to pH 2 with 1 HCl, extracted five times with EtOAc, and worked
up as usual. The crude was purified by silica gel column
chromatography (heptane/EtOAc, 1:1) to yield 12 mg (69%) of
(–)-galbanic acid [(–)-1]. This compound was spectroscopically
identical to the synthesized enantiomer, only the optical rotation
was of the opposite sign. [α]D = –25 (c = 1.0, CHCl3).[13]
(d, J = 9.4 Hz, 1 H), 6.79–6.82 (m, 2 H), 7.35 (d, J = 8.5 Hz, 1 H),
7.63 (d, J = 9.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
15.6, 20.2, 20.7, 22.2, 24.1, 24.6, 30.8, 30.9, 31.9, 36.0, 38.8, 44.9,
66.3, 101.3, 112.4, 112.9, 113.0, 125.6, 128.7, 130.3, 143.4, 155.9,
161.3, 162.4, 179.7 ppm. MS (ESI, MeOH + CH2Cl2): m/z (%) =
435.2 (100) [M + Na]+. HRMS (ESI): calcd. for C25H32O5Na
435.2147; found 435.2153.
Bis-epi-secochiliotrin [(+)-6]: Dess–Martin periodinane (DMP,
136 mg, 0.32 mmol) was added to a solution of the alcohol (+)-33
(33 mg, 0.11 mmol) in DCM (0.5 mL) and pyridine (0.1 mL) and
the reaction mixture was stirred for 1 h. The solution was diluted
with heptane (white precipitate appeared) and the suspension was
subjected directly to column chromatography (heptane/EtOAc,
14:1) to yield 30 mg (91%) of the desired aldehyde. 2-Methylbut-2-
ene (0.11 mL, 0.99 mmol) and a solution of NaClO2 (12 mg,
0.13 mmol) and KH2PO4 (18 mg, 0.13 mmol) in water (0.5 mL)
were added to a solution of the aldehyde thus obtained in tBuOH
(0.2 mL). The reaction mixture was stirred for 12 h at 25 °C and
was finally quenched with brine and extracted four times with
EtOAc. The organic layer was worked up as usual. The crude ob-
tained was purified by silica gel flash chromatography (heptane/
EtOAc, 4:1) to yield 22 mg (72%) of the acid (+)-6 as a colorless
Methyl Marnerate (19): A solution of 9-BBN (2.6 mL, 0.5 in
THF) was added to the ester olefin 13 (111 mg, 0.42 mmol) and
the solution was stirred at 25 °C for 2 h. This solution was transfer-
red by cannula to a separate flask containing a mixture of the vinyl
iodide 12 (165 mg, 0.52 mmol), [Pd(dppf)Cl2] (34 mg, 0.04 mmol),
AsPh3 (19 mg, 0.06 mmol), Cs2CO3 (410 mg, 1.26 mmol), and
water (0.3 mL, 15.12 mmol) in DMF (6 mL). After 12 h the brown
reaction mixture was diluted with water and extracted three times
with diethyl ether. The organic layer was worked up as usual. The
crude was purified by silica gel flash chromatography (heptane/
EtOAc, 99:1) to yield 74 mg (41%) of (+)-20 and 65 mg (34%) of
oil. [α]D = 38 (c = 1.0, CHCl ). IR (film): ν = 3391 (b), 1706, 1452,
˜
3
1374, 1259, 1025, 873, 801 cm–1. 1H NMR (500 MHz, CHCl3): δ =
0.79 (d, J = 6.6 Hz, 3 H), 0.97 (s, 3 H), 1.20 (qd, J = 4.5, 13.2 Hz,
1 H), 1.28–1.33 (m, 1 H), 1.39–1.44 (m, 1 H), 1.48–1.55 (m, 1 H),
1.68 (br. s, 6 H), 1.75–1.81 (m, 2 H), 1.83–1.90 (m, 2 H), 2.12–2.24
(m, 2 H), 2.27–2.31 (m, 2 H), 2.47 (br. d, J = 14.5 Hz, 1 H), 2.66
(dd, J = 4.8, 11.5 Hz, 1 H), 6.21 (s, 1 H), 7.17 (s, 1 H), 7.33 (s, 1
H) ppm. 13C NMR (125 MHz, CHCl3): δ = 15.56, 19.3, 20.2, 20.8,
22.3, 24.0, 24.7, 30.9, 31.9, 32.5, 36.1, 39.2, 43.8, 111.0, 124.9,
126.1, 130.6, 138.4, 142.6, 178.9 ppm. MS (ESI, MeOH): m/z (%)
= 317.2 (100) [M – H]+. HRMS (ESI, MeOH): calcd. for C20H29O3
317.2117; found 317.2113.
(+)-19 as a colorless oil. [α]D = 85 (c = 1.0, CHCl ). IR (film): ν =
˜
3
1
2960, 2916, 2857, 1739, 1434, 1372, 1255, 1166, 726, 696 cm–1. H
NMR (500 MHz, CDCl3): δ = 0.71 (d, J = 6.7 Hz, 3 H), 0.86 (s, 3
H), 0.98–1.05 (m, 1 H), 1.17–1.31 (m, 2 H), 1.37–1.43 (m, 1 H),
1.51 (s, 3 H), 1.54 (s, 6 H), 1.60 (s, 3 H), 1.62 (s, 3 H), 1.68 (s, 3
H), 1.52 (d, J = 1.9 Hz, 3 H), 1.61 (d, J = 1.1 Hz, 3 H), 1.69–1.82
(m, 6 H), 1.86–2.02 (m, 4 H), 2.39 (m, 1 H), 2.50 (dd, J = 4.8,
11.1 Hz, 1 H), 3.58 (s, 3 H), 4.85 (m, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 15.6, 15.9, 16.0, 17.6, 20.2, 20.7, 22.3, 22.5,
24.2, 24.7, 25.7, 26.6, 26.7, 29.7, 30.9, 32.2, 36.1, 39.0, 39.7, 43.8,
51.3, 124.2, 124.4, 125.5, 130.8, 131.1, 134.2, 133.7, 134.2, 134.8,
174.7 ppm. MS (ESI, MeOH + CH2Cl2): m/z (%) = 479.4 (100)
[M + Na]+. HRMS (ESI): calcd. for C31H52O2Na 479.3865; found
479.3869.
Supporting Information (see also the footnote on the first page of
this article): Complete characterization data and 1H and 13C NMR
spectra for compounds 3, 13, 6, and 19–33.
Homogalbanic Acid (4): Oxalyl chloride (0.17 mL, 2 in DCM,
0.34 mmol) was added to a solution of dry DMSO (0.05 mL,
0.68 mmol) in dry DCM (3 mL) at –60 °C under argon. The mix-
ture was stirred for 30 min and a solution of the primary alcohol
(+)-28 (45 mg, 0.11 mmol) in dry DCM (1 mL) was added. Upon
1 h of additional stirring at –60 °C, Et3N (0.15 mL) was added and
the mixture was warmed to 0 °C, stirred for a further 20 min, and
poured into ice-cold water, diluted with DCM, washed with 1
HCl and aqueous saturated NaHCO3, and worked up as usual.
The crude obtained was used directly in the next oxidation step. 2-
Methylbut-2-ene (0.12 mL, 1.13 mmol) and a solution of NaClO2
(13 mg, 0.15 mmol) and KH2PO4 (20 mg, 0.15 mmol) in water
(0.5 mL) were added to a solution of the previously obtained alde-
hyde in tBuOH (1 mL). The reaction mixture was stirred for 12 h
at 25 °C and was finally quenched with brine and extracted four
times with EtOAc. The organic layer was worked up as usual. The
crude obtained was purified by silica gel flash chromatography
(heptane/EtOAc, 2:1) to yield 29 mg (63% over two steps) of the
Acknowledgments
Financial support from the Centre National de la Recherche Sci-
entifique (CNRS) and fellowship awards from the Institut de Chi-
mie des Substances Naturelles (ICSN) are gratefully acknowledged.
[1] a) For the structure and stereochemistry of galbanic acid from
galbanum, see: V. Y. Bagirov, V. I. Sheichenko, N. V. Veselov-
skaya, Y. E. Sklyar, A. A. Savina, I. Kir’yanova, Khim. Prir.
Soedin. 1980, 16, 620–623; for the isolation from asafetida, see:
b) G. Appendino, S. Tagliapietra, G. Nano, J. Jakupovic, Phy-
tochemistry 1994, 35, 183–186; c) G. Appendino, L. Maxia, M.
Bascope, P. J. Houghton, G. Sanchez-Duffhues, E. Muñoz, O.
Sterner, J. Nat. Prod. 2006, 69, 1101–1104; d) G. Appendino,
in: Virtual activity, real pharmacology (Ed.: L. Verotta), Trivan-
drum, 1997, pp. 1–15.
[2] a) S. K. Racnicer, J. Veeravally, Chem. Ind. (London) 1975, 12,
431; b) A. F. Artamonov, K. A. Nusipbekova, F. S. Nigmatul-
lina, B. Z. Dzhienbaev, Chemistry of Natural Compounds, vol.
33, no. 2, 1997, pp. 162–164.
acid (+)-4 as a glassy solid. [α]D = 7 (c = 1.0, CHCl ). IR (film): ν
˜
3
= 3210, 1734, 1702, 1610, 1278, 1229, 1121, 1011, 833, 753 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.83 (d, J = 6.9 Hz, 3 H), 1.03
(s, 3 H), 1.20–1.24 (m, 1 H), 1.45–1.50 (m, 1 H), 1.60 (dt, J = 7.6,
14.0 Hz, 1 H), 1.66 (d, J = 1.5 Hz, 3 H), 1.70 (s, 3 H), 1.76–1.90
(m, 5 H), 2.12–2.26 (m, 2 H), 2.51 (br. d, J = 14.0 Hz, 1 H), 2.59
(dd, J = 4.61, 11.5 Hz, 1 H), 4.03 (dd, J = 7.1, 8.1 Hz, 2 H), 6.24
[3] During in vitro experiments galbanic acid suppressed the devel-
opment of platelet aggregation induced by ADP, thrombin, his-
tamine, adrenaline, acetylcholine, and collagen at concentra-
tions of 50, 100, and 200 µg/mL. M. M. Mansurov, M. S. Mar-
tirosov, Farmakol. Toksikol. 1990, 53, 51–53.
Eur. J. Org. Chem. 2009, 6386–6392
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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