First enantioselective synthesis and absolute stereochemistry assignment of new monoterpene aldehyde-esters from Bupleurum gibraltaricum

Article abstract of DOI:10.1002/ejoc.200601080

The first enantioselective synthesis of two new monoterpene aldehyde-esters from Bupleurum gibraltaricum, starting from an enantiopure building block, is described. The key step is a strictly controlled esterification to afford the somewhat unstable targe

Full text of DOI:10.1002/ejoc.200601080

FULL PAPER
DOI: 10.1002/ejoc.200601080
First Enantioselective Synthesis and Absolute Stereochemistry Assignment of
New Monoterpene Aldehyde-Esters from Bupleurum gibraltaricum
Paul Brémond,[a] Gérard Audran,*[a] Thierry Juspin,[a] and Honoré Monti[a]
Keywords: Natural products / Terpene / Enantioselective synthesis / Absolute configuration determination
The first enantioselective synthesis of two new monoterpene
aldehyde-esters from Bupleurum gibraltaricum, starting from
an enantiopure building block, is described. The key step
is a strictly controlled esterification to afford the somewhat
unstable target compounds. The previously unknown abso-
lute stereochemistries of these natural products have been
established.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
picted in Scheme 1 and starting from a common enantio-
pure building block for the introduction and determination
of the absolute stereochemistry. The chiral information was
already encoded in this starting building block, the 3R and
5S configurations in 3 corresponding to 1R in target mole-
cule 1 and 1S in target compound 2, respectively. We envi-
sioned that the key conjugate hydroxyaldehydes 8 or 11
Introduction
Isoferulyl angelate [(–)-1] and the unnamed isomer (+)-2
(Figure 1) are monoterpene aldehyde-esters isolated from
the hexane extract of the leaves of Bupleurum gibraltaricum
Lam (B. verticale Ortega),[1–3] a species whose distribution
is restricted to southern Spain and northern Morocco.[4]
The plant is used in folk medicine and its essential oil dis-
plays marked antiinflammatory activity.[5]
Figure 1. Natural monoterpene aldehyde-esters (–)-1 and (+)-2
represented with their absolute stereochemistries as determined in
this work.
The gross structures of (–)-1 and (+)-2 had been eluci-
dated by spectroscopic analysis,[1,2,6] but during hexane ex-
traction and identification it had been shown that these
compounds were somewhat unstable and readily underwent
elimination and rearrangement to give 2,3,6-trimethylbenz-
aldehyde.[2,3] This may explain why no synthesis of (–)-1 or
(+)-2 had ever been disclosed until now, and also suggested
that the success of such a venture could not be taken for
granted at the outset.
Here we describe the first enantioselective syntheses of
(–)-1 and (+)-2, based on the retrosynthetic analysis de-
[a] Laboratoire de Réactivité Organique Sélective, U. M. R. 6180
“Chirotechnologies: Catalyse et Biocatalyse”, Université Paul
Cézanne-Aix-Marseille III,
13397 Marseille cedex 20, France
Fax: +33-4-91288862
E-mail: g.audran@univ-cezanne.fr
Scheme 1. Retrosynthetic analysis of 1 and 2.
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2007, 2802–2807
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Monoterpene Aldehyde-Esters from B. gibraltaricum
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were traceable back to 5 or 10 through double-bond isom-
erization, with these in turn being obtainable through the
partial reduction of the lactone group in 3, subsequent to a
functional group manipulation step. This methodology al-
lowed us to establish the absolute stereochemistries of natu-
ral compounds 1 and 2 by comparison of the signs of their
specific optical rotations with those of the synthetic sam-
ples.
Results and Discussion
The synthesis of the target compound (R)-1 was achieved
as presented in Scheme 2. The starting building block
(1R,3R,5S)-3-hydroxy-8,8-dimethyl-2-methylene-6-oxabi-
cylo[3.2.1]octan-7-one [(+)-3[7a]] was prepared in enantio-
merically pure form from readily available (+)-karahana
lactone (ee Ͼ 98%)[7b] through our previously reported ste-
reocontroled Sharpless allylic hydroxylation.[8] Protection
of the secondary alcohol in (+)-3 by treatment with tert-
butyldimethylsilyl chloride (TBSCl) and imidazole in DMF
at room temperature[9] furnished the protected derivative
(+)-4 in 93% yield, while reduction of (+)-4 with diisobu-
tylaluminium hydride (DIBALH) in toluene at –80 °C pro-
vided a 4:1 mixture of aldehyde 5 and lactols (ratios based
on 1H NMR analysis). The crude product mixture was sub-
jected to isomerization to the α,β-unsaturated aldehyde in
the presence of MeONa (2 equiv.) in MeOH to afford (+)-
6 in 92% yield (two steps), and subsequent dehydration of
Scheme 2. a) TBSCl, imidazole, DMF, room temp., 93%. b) DI-
BALH, toluene, –78 °C. c) MeONa, MeOH, room temp., 92% (two
steps). d) TfCl, DMAP, CH2Cl2, 0 °C, 79%. e) HF·py complex, py,
room temp., 95%. f) Angelic acid, 2,4,6-trichlorobenzoyl chloride,
Et3N, toluene, 2 h, room temp., then (–)-8, 60 °C, 36 h, 41%.
(+)-6 with trifluoromethanesulfonyl chloride (TfCl) and 4- = 1.0, hexane)[3] [α]D25 = –62.1 (c = 1.0, hexane)}, indicating
(dimethylamino)pyridine (DMAP) in dichloromethane at the synthesis of the natural enantiomer. The high optical
0 °C afforded olefin (–)-7 in 79% yield.[10] At this stage, purity of (–)-1 was established by chiral HPLC (Figure 2).
attempts to cleave the tert-butyldimethylsilyl ether in (–)-7 The R configuration was therefore unambiguously assigned
under mildly acidic (PPTS/EtOH, AcOH/THF/H2O, aq. to natural isoferulyl angelate [(–)-1].
HF/CH3CN) or basic (nBu4NF/THF) conditions failed.[11]
The synthesis of target compound (+)-2 is summarized
This problem was associated with the lability of the bisal- in Scheme 3. Early attempts to engage alcohol (+)-3 in an
lylic hydroxy group, which appeared to undergo facile de- elimination through treatment with TfCl and DMAP in
composition to form a complex mixture of unidentified dichloromethane as previously (see (–)-7 above) proved
products, together with aromatization to 2,3,6-trimethyl- sluggish at 0 °C, while raising the temperature resulted in
benzaldehyde. Finally, desilylation of (–)-7 was found to be degraded materials. Having failed to eliminate a triflate
best accomplished with HF·pyridine complex buffered in group unambiguously, we then turned to a methanesulfonyl
pyridine as solvent (without THF) by a modified literature (Ms) group. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has
procedure.[12] Under these conditions, the reaction pro- been widely used for introduction of unsaturation through
ceeded uneventfully to deliver the desired product (–)-8 in the elimination of sulfonic acids and reactions generally
95% yield.
proceed under mild conditions without side reactions.[14] In
Of the different methods developed for the preparation our case, however, treatment of mesylate 9 with DBU in a
of angelate esters from alcohols,[13] the procedure of Greene typical procedure (equimolar base, benzene, 80 °C) afforded
and co-workers[13f] is by far the more effective. By this the desired product (+)-10 only in a poor 22% yield, to-
modified Yamaguchi esterification,[13c] under carefully con- gether with intractable materials. Fortunately, though, a
trolled conditions (60 °C, 36 h) in order to balance the pro- change of the base to tBuOK and of the solvent to THF at
gress of the reaction and the moderate instability of the room temperature cleanly provided the diene (+)-10 in 60%
starting and final materials when subjected to even mild overall yield (two steps). Reduction of (+)-10 with DI-
heat,[3] the alcohol (–)-8 could be smoothly transformed BALH in toluene at –78 °C afforded a mixture of aldehyde
into (–)-isoferulyl angelate [(–)-1] in a modest 41% yield but 11 and the corresponding diastereomeric lactols (ratio 4:1,
without Z/E isomerization. The spectroscopic data for our based on 1H NMR analysis), and subsequent isomerization
synthesized compound matched those reported for natural of the crude product mixture with MeONa (2 equiv.) in
isoferulyl angelate,[1] and its optical rotation was compar- MeOH gave the α,β-unsaturated aldehyde (+)-12 in 64%
able in magnitude and the identical in sign {[α]2D7 = –67.0 (c overall yield (two steps). On application of the Yamaguchi
Eur. J. Org. Chem. 2007, 2802–2807
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. Br émond, G. Audran, T. Juspin, H. Monti
FULL PAPER
modified esterification procedure as applied with isoferulyl
angelate (–)-1, completion of the synthesis of target com-
pound (+)-2 was accomplished in a modest 38% yield. The
spectroscopic data for (+)-2 prepared in this way were con-
sistent with those reported in the literature for the natural
product,[2] and the specific rotation was the same in sign,
indicating the synthesis of the natural enantiomer. The high
optical purity of (+)-2 was confirmed by chiral HPLC (Fig-
ure 2). The S configuration was therefore assigned to natu-
ral (+)-2. In this case, however, the magnitude of the spe-
cific rotation of (+)-2 {[α]2D5 = +401.8 (c = 1.0, CHCl3)}
disagreed with that given in the literature[2] {[α]D27 = +194.2
(c = 1.0, CHCl3)}. We suggest that this disagreement could
be attributable to the presence of the levorotatory enanti-
omer in significant amounts in the biosynthesized natural
compound, or that it may be an artefact of the extractive
processes.
Conclusions
In conclusion, the first enantioselective synthesis of iso-
ferulyl angelate [(–)-1] and the unnamed isomer (+)-2 has
been accomplished in concise and stereocontrolled fashion
from a secured starting building block (+)-3, which allows
unambiguous assignment of the absolute stereochemistry.
By correlation with the signs of the specific rotations re-
ported in the literature, the absolute stereochemistries of the
natural products have thus been established as R for (–)-1
and S for (+)-2.
Figure 2. Chiral HPLC diagrams of (–)-1, (+)-2 and the corre-
sponding racemics.
Experimental Section
General Remarks: All air- and/or water-sensitive reactions were car-
ried out under argon in dry, freshly distilled solvents with use of
standard syringe&cannula/septa techniques. All corresponding
glassware was oven-dried (80 °C) and/or carefully dried in line with
a flameless heat gun. All solvents were distilled under argon: THF
from a blue solution of sodium-benzophenone ketyl radical prior
to use, and CH2Cl2, toluene and DMF from CaH2. Routine moni-
toring of reactions was performed with Merck silica gel 60 F254 alu-
minium-supported TLC plates; spots were viewed by use of UV
light and ethanolic acidic p-anisaldehyde solution or ethanolic
phosphomolybdic solution, followed by heating. Purifications by
means of column chromatography were performed on silica gel 60
(230–400 mesh) and with gradients of Et2O/petroleum ether as elu-
ent, unless otherwise stated. 1H and 13C NMR spectra were re-
corded in CDCl3 or C6D6 solutions on a Bruker AM 300 spectrom-
eter. Chemical shifts (δ) in ppm are reported with use of residual
nondeuterated solvents[15] as internal reference. The analytical chi-
ral HPLC experiments were performed on a unit composed of a
Merck D-7000 system manager, Merck–Lachrom L-7100 pump,
Merck–Lachrom L-7360 oven and on-line Jasco OR-1590 polari-
meter. Hexane and iPrOH, HPLC grade, were degassed and filtered
through a 0.45 mm membrane before use. The columns used were
Chiralcel OD-H and Chiralcel OJ (250ϫ4.6 mm) from Chiral
Technologies Europe (Illkirch, France). Rt0 was determined by in-
jection of tri-tert-butylbenzene. The sign given by the on-line pola-
rimeter is the sign of the product in the solvent used for the chro-
matographic separation. Optical rotations were measured on a Per-
Scheme 3. a) MsCl, NEt3, CH2Cl2, room temp.. b) tBuOK, THF,
room temp., 60% (two steps). c) DIBALH, toluene, –78 °C.
d) MeONa, MeOH, room temp., 64% (two steps). e) Angelic acid,
2,4,6-trichlorobenzoyl chloride, Et3N, toluene, 2 h, room temp.,
then (+)-12, 60 °C, 36 h, 38%.
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Monoterpene Aldehyde-Esters from B. gibraltaricum
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kin–Elmer 341 polarimeter. Microanalyses were performed at our
university. Melting points are uncorrected. Infrared spectra were
obtained as films or KBr pellets with a Perkin–Elmer 1600 FTIR
spectrophotometer.
2.10–1.93 (m, 2 H), 1.27 (s, 3 H), 1.15 (s, 3 H), 0.91 (s, 9 H), 0.17
(s, 3 H), 0.15 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 193.9
(CH), 150.1 (C), 139.1 (C), 74.7 (CH), 71.0 (CH), 38.8 (C), 33.8
(CH2), 25.7 (CH3), 25.7 (CH3), 22.0 (CH3), 17.9 (C), 16.0 (CH3),
–4.3 (CH ), –4.9 (CH ) ppm. IR (KBr): ν = 3417, 1718, 1649,
˜
3
3
(1R,3R,5S)-3-Hydroxy-8,8-dimethyl-2-methylene-6-oxabicyclo-
[3.2.1]octan-7-one [(+)-3]: Selenium dioxide (1.07 g, 9.6 mmol,
0.4 equiv.), tert-butyl hydroperoxide (70 wt.% in water, 9.64 mL,
96.3 mmol, 4.0 equiv.) and a catalytic amount of salicylic acid were
added under argon to a stirred solution of (+)-karahana lactone
(4.00 g, 24.1 mmol, 1.0 equiv.) in dry CH2Cl2 (250 mL). The reac-
tion mixture was heated to reflux for 5 d, allowed to cool to room
temperature, and Na2SO3 (24.3 g, 0.19 mol, 8.0 equiv.) and water
(2 mL) were added. The mixture was stirred for a further 1 h, fil-
tered through a pad of MgSO4 and concentrated to give a solid
residue. After purification by recrystallization from Et2O/hexane,
pure alcohol (+)-3 (3.79 g, 85%) was obtained as white crystals.
M.p. 155 °C. [α]2D5 = +145.0 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 5.17 (s, 1 H), 5.05 (s, 1 H), 4.40 (ABMX, d, J = 5.9 Hz,
1262 cm–1. C16H30O3Si (298.50): calcd. C 64.38, H 10.13; found: C
64.60, H 10.15.
(R)-3-(tert-Butyldimethylsilyloxy)-2,6,6-trimethylcyclohexa-1,4-
dienecarbaldehyde [(–)-7]: DMAP (737 mg, 6.03 mmol, 6.0 equiv.)
and trifluoromethanesulfonyl chloride (268 µL, 2.51 mmol,
2.5 equiv.) were added at 0 °C to a stirred solution of alcohol (+)-
6 (300 mg, 1.01 mmol, 1.0 equiv.) in CH2Cl2 (25 mL). The cloudy
mixture was stirred under argon at this temperature for 2 h and
was then diluted with diethyl ether and poured into water. The
resulting aqueous layer was extracted with diethyl ether, and the
combined organic layers were washed with water and brine, dried
with MgSO4 and concentrated. Purification by column chromatog-
raphy gave (–)-7 (223 mg, 79%) as a clear oil. [α]2D5 = –38.7 (c =
1
1 H), 4.33 (ABMX, br. d, J = 3.7 Hz, 1 H), 2.73 (br. s, 1 H), 2.20 1.0, CH2Cl2). H NMR (300 MHz, C6D6): δ = 10.07 (s, 1 H), 5.49
(ABMX, dd, J = 15.6, 3.7 Hz, 1 H), 2.06 (ABMX, ddd, J = 15.6,
(dd, J = 10.1, 3.1 Hz, 1 H), 5.39 (d, J = 10.1 Hz, 1 H), 4.27 (d, J
= 3.1 Hz, 1 H), 1.83 (s, 3 H), 1.34 (s, 3 H), 1.31 (s, 3 H), 0.92 (s, 9
5.9, 1.5 Hz, 1 H), 1.18 (s, 3 H), 0.92 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 176.8 (C), 143.8 (C), 117.0 (CH2), 84.4 H), 0.01 (s, 6 H) ppm. 13C NMR (75 MHz, C6D6): δ = 191.7 (CH),
(CH), 67.9 (CH), 56.6 (CH), 42.9 (C), 32.8 (CH2), 25.3 (CH3), 20.1
151.3 (C), 140.2 (CH), 139.4 (C), 122.5 (CH), 68.8 (CH), 35.4 (C),
(CH ) ppm. IR (KBr): ν = 3443, 3087, 1762, 907 cm–1. C H O
28.0 (CH3), 27.1 (CH3), 26.0 (3 CH3), 18.3 (C), 15.0 (CH3), –3.8
˜
3
10 14
3
(182.22): calcd. C 65.92, H 7.74; found: C 65.59, H 7.71.
(CH ), –4.2 (CH ) ppm. IR (KBr): ν = 3031, 2715, 1705, 1630 cm–1.
˜
3 3
C16H28O2Si (280.48): calcd. C 68.52, H 10.06; found: C 68.18, H
10.09.
(1S,3R,5S)-3-(tert-Butyldimethylsilyloxy)-8,8-dimethyl-2-methylene-
6-oxabicyclo[3.2.1]octan-7-one [(+)-4]: The alcohol (+)-3 (1.00 g,
5.49 mmol, 1.0 equiv.) was dissolved in DMF (10 mL), imidazole
(2.24 g, 32.9 mmol, 6.0 equiv.) and tert-butyldimethylsilyl chloride
(R)-3-Hydroxy-2,6,6-trimethylcyclohexa-1,4-dienecarbaldehyde [(–)-
8]: HF·pyridine complex (70 wt.% HF, 4.0 mL) was carefully added
(2.90 g, 19.2 mmol, 3.5 equiv.) were added, and the mixture was at 0 °C under argon to a stirred solution of pyridine (6 mL) in a
stirred for 12 h at room temp. The solution was concentrated in
vacuo and the residue was purified by column chromatography to
give compound (+)-4 (1.52 g, 93 %) as a solid. Recrystallization
from Et2O/hexane afforded pure compound (+)-4 as white crystals.
Teflon® round-bottomed flask. A solution of silyl ether (–)-7
(200 mg, 0.71 mmol) in pyridine (4 mL) was slowly added, and the
mixture was allowed to warm to room temp. After 2 h, the reaction
mixture was concentrated in vacuo, and the residue was diluted in
ether and poured into saturated aqueous NaHCO3 solution. The
aqueous layer was extracted with diethyl ether, and the combined
1
M.p. 74 °C. [α]2D5 = +60.9 (c = 1.0, CHCl3). H NMR (300 MHz,
CDCl3): δ = 4.99 (s, 1 H), 4.94 (s, 1 H), 4.33 (br. d, J = 4.7 Hz, 1
H), 4.29–4.25 (m, 1 H), 2.68 (s, 1 H), 2.07–2.03 (m, 2 H), 1.19 (s, organic layers were washed with saturated aqueous NaHCO3, water
3 H), 0.93 (s, 3 H), 0.85 (s, 9 H), 0.05 (s, 3 H), 0.01 (s, 3 H) ppm. and brine, dried with MgSO4 and concentrated. After purification
13C NMR (75 MHz, CDCl3): δ = 175.9 (C), 143.8 (C), 115.2 (CH2), by column chromatography, alcohol (–)-8 (113 mg, 95%) was ob-
84.2 (CH), 68.6 (CH), 56.9 (CH), 43.3 (C), 34.5 (CH2), 25.5 (CH3),
tained as a clear oil. [α]2D5 = –8.7 (c = 1.0, CH2Cl2). 1H NMR
(300 MHz, C6D6): δ = 10.00 (s, 1 H), 5.51 (dd, J = 10.1, 3.4 Hz, 1
H), 5.36 (d, J = 10.1 Hz, 1 H), 4.07 (br. d, J = 3.4 Hz, 1 H), 1.87
(s, 3 H), 1.30 (s, 3 H), 1.25 (s, 3 H) ppm. 13C NMR (75 MHz,
C6D6): δ = 192.2 (CH), 152.0 (C), 140.7 (CH), 139.2 (C), 122.1
(CH), 67.5 (CH), 35.4 (C), 27.7 (CH3), 27.4 (CH3), 14.9
25.4 (CH3), 20.3 (CH3), 17.8 (C), –4.7 (CH3), –5.1 (CH3) ppm. IR
(KBr): ν = 1783, 1647, 1259, 906 cm–1. C H O Si (296.48): calcd.
˜
16 28
3
C 64.82, H 9.52; found: C 64.59, H 9.54.
(3R,5S)-3-(tert-Butyldimethylsilyloxy)-5-hydroxy-2,6,6-trimethylcy-
clohex-1-enecarbaldehyde [(+)-6]: A portion (700 mg, 2.36 mmol,
1.0 equiv.) of (+)-4 was dissolved in anhydrous toluene (25 mL) and
a toluene solution of diisobutylaluminium hydride (1 , 3.10 mL,
3.10 mmol, 1.3 equiv.) was added dropwise at –80 °C under argon.
The reaction mixture was stirred for 45 min at this temperature,
quenched with Na2SO4·10H2O (3.10 g) and Celite (3.10 g), and al-
lowed to warm to room temp. Filtration through a pad of MgSO4
and concentration gave a mixture of lactols and aldehyde as a clear
oil. These compounds were used for the next reaction without fur-
ther purification. The crude mixture was dissolved in MeOH
(25 mL) and a solution of MeONa (0.5  in MeOH, 9.45 mL,
4.72 mmol, 2.0 equiv.) was added under argon. After the system
had been stirred for 2 h at room temp., weakly acidic ion-exchange
resin was added and the reaction mixture was filtered and concen-
trated. The residue was purified by chromatography to give (+)-6
(CH ) ppm. IR (KBr): ν = 3421, 3037, 2718, 1711, 1241 cm–1
.
˜
3
C10H14O2 (166.22): calcd. C 72.26, H 8.49; found: C 71.99, H 8.45.
(R)-Isoferulyl Angelate [(R)-3-Formyl-2,4,4-trimethylcyclohexa-2,5-
dienyl Angelate] [(–)-1]: 2,4,6-Trichlorobenzoyl chloride (658 µL,
4.21 mmol, 7.0 equiv.) and triethylamine (587 µL, 4.21 mmol,
7.0 equiv.) were added dropwise at 0 °C under argon to a stirred
solution of angelic acid (422 mg, 4.21 mmol, 7.0 equiv.) in toluene
(10 mL). The resulting mixture was stirred for 2 h at room temp.,
alcohol (–)-8 (100 mg, 0.60 mmol) in toluene (2 mL) was then
added, and the reaction mixture was stirred at 60 °C for 36 hours.
After dilution with ether, filtration and concentration, the residue
was purified by column chromatography to give natural angelate
ester (–)-1 (61 mg, 41%) as a clear oil. [α]2D5 = –67.0 (c = 1.0, hex-
1
ane). H NMR (300 MHz, C6D6): δ = 9.94 (s, 1 H), 5.81 (br. d, J
[650 mg, 92% yield from compound (+)-4]. [α]2D5 = +51.2 (c = 1.0,
= 3.3 Hz, 1 H), 5.70 (qq, J = 7.2, 1.5 Hz, 1 H), 5.63 (dd, J = 10.1,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 10.15 (s, 1 H), 4.17 (t, 3.3 Hz, 1 H), 5.40 (br. d, J = 10.1 Hz, 1 H), 1.93 (dq, J = 7.2,
J = 4.9 Hz, 1 H), 3.46 (dd, J = 6.8, 2.8 Hz, 1 H), 2.11 (s, 3 H),
1.5 Hz, 3 H), 1.80 (dq, J = 1.5, 1.5 Hz, 3 H), 1.64 (s, 3 H), 1.30 (s,
Eur. J. Org. Chem. 2007, 2802–2807
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P. Br émond, G. Audran, T. Juspin, H. Monti
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3 H), 1.24 (s, 3 H) ppm. 13C NMR (75 MHz, C6D6): δ = 191.4
and triethylamine (587 µL, 4.21 mmol, 1.0 equiv.) were added drop-
(CH), 167.2 (C), 147.0 (C), 142.8 (CH), 141.6 (C), 138.8 (CH), wise at 0 °C under argon to a stirred solution of angelic acid
127.8 (C), 118.4 (CH), 69.6 (CH), 35.5 (C), 27.4 (CH3), 27.2 (CH3), (422 mg, 4.21 mmol, 7.0 equiv.) in toluene (10 mL). The resulting
20.7 (CH ), 15.9 (CH ), 14.7 (CH ) ppm. IR (KBr): ν = 3037, 2719,
mixture was stirred for 2 h at room temp., alcohol (+)-12 (100 mg,
0.60 mmol, 1.0 equiv.) in toluene (2 mL) was then added, and the
solution was stirred at 60 °C for 36 h. After dilution with ether,
filtration and concentration, the residue was purified by column
chromatography to give natural angelate ester (+)-2 (57 mg, 38%)
as an oil. [α]2D5 = +401.8 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 10.17 (s, 1 H), 6.24 (dd, J = 9.5, 4.4 Hz, 1 H), 6.06
(qq, J = 7.2, 1.5 Hz, 1 H), 6.05 (d, J = 9.5 Hz, 1 H), 5.10 (d, J =
4.4 Hz, 1 H), 2.21 (s, 3 H), 1.96 (dq, J = 7.2, 1.5 Hz, 3 H), 1.86
(dq, J = 1.5, 1.5 Hz, 3 H), 1.29 (s, 3 H), 1.20 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 191.5 (CH), 167.5 (C), 145.0 (C),
138.2 (CH), 137.4 (C), 132.0 (CH), 131.8 (CH), 127.8 (C), 75.7
(CH), 37.1 (C), 23.8 (CH3), 20.5 (CH3), 19.8 (CH3), 17.6 (CH3),
˜
3
3
3
1733, 1712 cm–1. C15H20O3 (248.32): calcd. C 72.55, H 8.12; found:
C 72.84, H 8.15.
(1S,3R,5S)-8,8-Dimethyl-2-methylene-7-oxo-6-oxabicyclo[3.2.1]-
octan-3-yl Methanesulfonate (9): Methanesulfonyl chloride (637 µL,
8.23 mmol, 1.5 equiv.) and triethylamine (1.53 mL, 10.98 mmol)
were added dropwise under argon at 0 °C to a stirred solution of
alcohol (+)-3 (1.00 g, 5.49 mmol, 1.0 equiv.) in CH2Cl2 (30 mL).
The solution was allowed to warm to room temp. After 1 h, the
mixture was poured into water, the resulting aqueous layer was
extracted with CH2Cl2, and the combined organic layers were
washed with water and brine, dried (MgSO4) and filtered. Concen-
tration of the organic layer gave the corresponding mesylate 9
(1.51 g) as a clear oil. This compound was used in the next step
without any further purification.
15.7 (CH ) ppm. IR (KBr): ν = 2736, 1751, 1716, 1649 cm–1.
˜
3
C15H20O3 (248.32): calcd. C 72.55, H 8.12; found: C 71.29, H 8.16.
(1R,5S)-8,8-Dimethyl-2-methylene-6-oxabicyclo[3.2.1]oct-3-en-7-
one [(+)-10]: Dry tBuOK (1.35 g, 12.1 mmol, 2.2 equiv.) was care-
fully added in one portion to a stirred solution of the crude mesyl-
ate (1.51 g) in THF (50 mL). The mixture reaction was stirred for
2 h at room temp. under argon. After dilution with ether, the solu-
tion was poured into aqueous saturated NH4Cl, and the aqueous
layer was extracted with diethyl ether. The organic layers were com-
bined, washed with water and brine, dried with MgSO4, filtered
and concentrated in vacuo. Recrystallization from Et2O/hexane af-
forded the pure diene (+)-10 (552 mg, 61% yield from (+)-3) as
white needles. M.p. 95 °C. [α]2D5 = +385.1 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 6.27 (d, J = 9.2 Hz, 1 H), 6.12 (br.
dd, J = 9.2, 5.6 Hz, 1 H), 5.18 (s, 1 H), 5.08 (s, 1 H), 4.32 (d, J =
5.6 Hz, 1 H), 2.99 (s, 1 H), 1.26 (s, 3 H), 1.06 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 176.4 (C), 137.7 (C), 132.2 (CH),
127.7 (CH), 117.6 (CH2), 81.3 (CH), 58.6 (CH), 43.2 (C), 25.1
Acknowledgments
P. B. thanks the Ministère de l’Education Nationale, de l’Enseigne-
ment Supérieur et de la Recherche for a Ph. D. grant. The authors
are thankful to Dr. N. Vanthuyne (Stéréochimie dynamique et chi-
ralité, Professor C. Roussel) for chiral HPLC analyses, and to P.
Fournier for the English language revision of the manuscript.
[1] F. Bohlmann, C. Zdero, M. Grenz, Chem. Ber. 1975, 108, 2822–
2823.
[2] A. F. Barrero, A. Haïdour, F. Reyes, J. Nat. Prod. 1998, 61,
506–507.
(CH ), 19.5 (CH ) ppm. IR (KBr): ν = 3067, 1781, 1654, 903 cm–1.
[3] Isoferulyl angelate [ (–)-1] has also been extracted from seeds
of Eryngium paniculatum Cav. and Comby ex. Delar L., and
was found to inhibit germination of velvetleaf (Abutilon
theophrasti Medic.) G. F. Spencer, J. Nat. Prod. 1986, 49, 924–
926.
˜
3
3
C10H12O2 (164.20): calcd. C 73.15, H 7.37; found: C 72.81, H 7.33.
(S)-5-Hydroxy-2,6,6-trimethylcyclohexa-1,3-dienecarbaldehyde [(+)-
12]: A portion (500 mg, 3.05 mmol, 1.0 equiv.) of diene (+)-10 was
dissolved in anhydrous toluene (30 mL), and a toluene solution of
diisobutylaluminium hydride (1 , 4.00 mL, 4.00 mmol, 1.3 equiv.)
was added dropwise at –80 °C under argon. The reaction mixture
was stirred for 45 min at this temperature, quenched with
Na2SO4·10H2O (4.0 g) and Celite (4.0 g), and allowed to warm to
room temp. Filtration through a pad of MgSO4 and concentration
gave a mixture of lactols and aldehyde (1:4, 453 mg) as a clear oil.
These compounds were used for the next reaction without any fur-
ther purification. The crude mixture was dissolved in MeOH
(30 mL) and a solution of MeONa (0.5  in MeOH, 12.2 mL,
6.10 mmol, 2.0 equiv.) was added under argon. After the system
had been stirred for 1 h at room temp., weakly acidic ion-exchange
resin was added and the reaction mixture was filtered and concen-
trated. The residue was purified by chromatography to give (+)-12
[324 mg, 64% yield from (+)-10] as a clear oil. [α]2D5 = +248.8 (c =
1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 10.09 (s, 1 H), 6.21
(dd, J = 9.5, 4.1 Hz, 1 H), 5.93 (d, J = 9.5 Hz, 1 H), 3.85 (br. d, J
= 4.1 Hz, 1 H), 2.15 (s, 3 H), 1.21 (s, 3 H), 1.15 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 192.1 (CH), 145.1 (C), 137.3 (C),
136.0 (CH), 130.0 (CH), 74.4 (CH), 38.3 (C), 24.0 (CH3), 18.4
[4] A. M. Cauwet-Marc, J. Carbonnier, J. Agric. Bot. Appl. 1978,
25, 51–59.
[5] a) J. Cabo, M. M. Cabo, J. Jimenez, C. Navarro, M. A. Ocete,
Plantes Med. Phytother. 1986, 20, 178–182; b) J. Cabo, J. Jime-
nez, M. A. Ocete, A. Zarzuelo, Fitoterapia 1987, 58, 33–38; c)
M. A. Ocete, S. Risco, A. Zarzuelo, J. Jimenez, J. Ethnopharm-
acol. 1989, 25, 305–313.
[6] A. Velasco-Negueruela, M. J. Perez-Alonso, J. Pala-Paul, A.
Camacho, A. M. Fernandez Ocana, C. Fernandez Lopez, J. Al-
tarejos, M. C. Garcia Vallejo, J. Essent. Oil Res. 1998, 10, 9–
19.
[7] a) By use of the standard chemical software, the absolute con-
figuration of C-1 in (+)-3 is determined as S. This assignment
is incorrect; b) J.-M. Galano, G. Audran, H. Monti, Tetrahe-
dron 2000, 56, 7477–7481.
[8] J.-P. Uttaro, G. Audran, E. Palombo, H. Monti, J. Org. Chem.
2003, 68, 5407–5410.
[9] E. J. Corey, A. Venkateswarlu, J. Am. Chem. Soc. 1972, 94,
6190–6191.
[10] Y. Tanada, K. Mori, Eur. J. Org. Chem. 2003, 848–854.
[11] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Syn-
thesis, 3th ed., John Wiley & Sons, 1999, p. 127–141.
[12] a) K. C. Nicolaou, S. P. Seitz, M. R. Pavia, N. A. Petasis, J.
Org. Chem. 1979, 44, 4011–4013; b) For the preparation of
HF·pyridine buffered with excess pyridine in THF see: B. M.
Trost, C. G. Caldwell, E. Murayama, D. Heissler, J. Org. Chem.
1983, 48, 3252–3265.
(CH ), 17.7 (CH ) ppm. IR (KBr): ν = 3426, 3049, 2731, 1708 cm–1.
˜
3
3
C10H14O2 (166.22): calcd. C 72.26, H 8.49; found: C 72.55, H 8.47.
(S)-5-Formyl-4,6,6-trimethylcyclohexa-2,4-dienyl Angelate [(+)-2]:
2,4,6-Trichlorobenzoyl chloride (658 µL, 4.21 mmol, 7.0 equiv.)
2806
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2802–2807

Monoterpene Aldehyde-Esters from B. gibraltaricum
FULL PAPER
[13] a) W. M. Hoskins, D. H. G. Crout, J. Chem. Soc., Perkin Trans.
1 1977, 538–544; b) P. J. Beeby, Tetrahedron Lett. 1977, 18,
3379–3382; c) J. Inakaga, K. Hirata, H. Saeki, T. Katsuki, M.
Yamaguchi, Bull. Chem. Soc. Jpn 1979, 52, 1989–1993; d) J.
Nakayama, Y. Nakamura, T. Tajiri, M. Hoshino, Heterocycles
1986, 24, 637–640; e) S. Bal-Tembe, D. N. Bhedi, N. J.
de Souza, R. H. Rupp, Heterocycles 1987, 26, 1239–1249; f) B.
Hartmann, A. M. Kanazawa, J.-P. Deprés, A. E. Greene, Tetra-
hedron Lett. 1991, 32, 5077–5080.
[14] A. C. Savoca, in Encyclopedia of Reagents for Organic Synthesis
(Ed.: L. A. Paquette), Wiley, Chichester, 1995, vol. 2, p. 1497–
1503.
[15] H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem. 1997,
62, 7512–7515.
Received: December 13, 2006
Published Online: April 11, 2007
Eur. J. Org. Chem. 2007, 2802–2807
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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