New preparation of (3aR*,6S*,7aR*)-6,7,7-trimethylhexahydro-2-benzofuran- 1(3H)-one: Formal synthesis of (±)-γ-irone

Article abstract of DOI:10.1016/S0040-4020(00)01059-0

A four-step synthesis of (3aR*,6S*,7aR*)-6,7,7-trimethylhexahydro-2-benzofuran- 1(3H)-one 2 has been developed. Lactone 2 is an intermediate in a synthesis of γ-irone. Opening of the Diels-Alder adduct 5 with ethanol afforded hemiester 6b with 87:13 regioselectivity. Subsequent chemoselective reduction of the ester group in 6b yielded hydroxyacid 14 which was lactonized to the cis-fused bicyclic lactone 15. Finally, hydrogenation of 15 into 2 occured with complete diastereoselectivity.

Full text of DOI:10.1016/S0040-4020(00)01059-0

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 733±738
New preparation of (3aR*,6S*,7aR*)-6,7,7-trimethylhexahydro-2-
benzofuran-1(3H)-one: formal synthesis of (^)-g-irone
p
Pascal Gosselin, Angelique Perrotin and Stephane Mille
Â
Â
Á Â
Laboratoire de Synthese Organique, UMR 6011 C.N.R.S., Universite du Maine, Avenue O. Messiaen, F-72085 Le Mans Cedex 9, France
Received 1 August 2000; revised 13 October 2000; accepted 6 November 2000
AbstractÐA four-step synthesis of (3aR*,6S*,7aR*)-6,7,7-trimethylhexahydro-2-benzofuran-1(3H)-one 2 has been developed. Lactone 2 is
an intermediate in a synthesis of g-irone. Opening of the Diels±Alder adduct 5 with ethanol afforded hemiester 6b with 87:13 regio-
selectivity. Subsequent chemoselective reduction of the ester group in 6b yielded hydroxyacid 14 which was lactonized to the cis-fused
bicyclic lactone 15. Finally, hydrogenation of 15 into 2 occured with complete diastereoselectivity. q 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
fused bicyclic lactone 2 was obtained according to a seven
step process: the intramolecular Diels±Alder reaction of the
trienoic amide 3 afforded a separable mixture of cis- and
trans-adducts in 22% and 43% isolated yields, respectively.
In situ epimerization of the later raised the yield of the cis-
adduct 4 to 70%. Hydrogenation of 4 yielded a saturated
lactam which was treated with nitric acid in acetic acid.
Decomposition of the resulting N-nitrosolactam with
aqueous KOH in THF, followed by heating with p-TsOH
in benzene ®nally gave the desired cis-lactone 2 in 33%
overall yield.
While many syntheses of a- or b-irones have been
reported,1 only six preparations of cis-g-irone cis-1 have
been developed,2 among which only one is stereo-
selective.2c The dif®culty in preventing isomerization
of the double bond and the cis-relationship between
the 6-methyl and the carbonyl side chain may explain
the scarcity of these syntheses. However, not only is
cis-g-irone one of the main constituents of the iris
essential oil,3 it also exhibits the strongest and ®nest
violet-like odor.4 New efforts towards the synthesis of
1 are therefore of interest.
We report herein a new preparation of the key intermediate
2. Adduct 5 was used as the starting material. According to
our recently reported procedure,5 this anhydride is now
readily available in grams quantities by the intermolecular
A 1:9 mixture of racemic cis- and trans-g-irones 1 has been
synthesized by Mori et al.2f (Scheme 1). The requisite cis-
Scheme 1.
Keywords: bicyclic compounds; stereoselective synthesis; hemiester; lactone; (^)-g-irones.
* Corresponding author. Tel.: 133-2-43-83-33-71; fax: 133-2-43-83-33-66; e-mail: gosselin@univ-lemans.fr
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01059-0

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P. Gosselin et al. / Tetrahedron 57 (2001) 733±738
Table 1. Opening of anhydride 5 with various alcohols
ROH
T (8C)
70
Time (h)a
6:7b
% conv.b
100
% yieldc
60% 6a
(110% 7a)
73% 6b
(12% 7b)
56% 6c
(112% 7c)
a
b
c
MeOH
EtOH
i-PrOH
15
24
72
82:18
87:13
87:13
75
100
80
90
a Reactions monitored by GC.
b Determined by GC of the crude mixture.
c Isolated yield of 6 after separation by liquid chromatography on silica-gel.
Diels±Alder reaction of 3,4-dimethylpenta-1,3-diene with
maleic anhydride.
Considering the facile formation of 8, we also studied a
regioselective route to the hemiester 6a, which involved
iodolactonization10 (Scheme 2).
Mild hydrolysis of adduct 5 with aqueous Na2CO3 (2 h,
208C) afforded diacid 9 in 81% yield after recrystallization
from pentane/ether. Iodolactonization11 of 9 with KI3
resulted in crystalline iodolactone 10 (84% yield), which
was esteri®ed (3% HCl in methanol) to provide iodoester
11 (white crystals, 84% yield after recrystallization from
pentane/ether). Zn/AcOH reduction12 of 11 ®nally gave
the pure hemiester 6a in 58% yield after recrystallization,
identical in all respects with the main product resulting
from the direct opening of adduct 5 with methanol (see
Table 1). Although less regioselective, we routinely used
the direct procedure (i.e. opening of 5 with EtOH) for its
convenience.
2. Results
Direct hydride reductions of anhydride 5 (NaBH4,6
LiAlH46b) were quickly dismissed because of a lack of
regioselectivity. Likewise, catalytic reduction of 5 by
hydrogenation over Adams platinum oxide,7 afforded a
complex mixture of hydrogenated lactones. Therefore, the
regioselectivity of the opening of anhydride 5 by nucleo-
philic attack of various alcohols was studied. Results are
summarized in Table 1.
The best result was thus obtained by re¯uxing adduct 5 in
ethanol for 24 h, affording 6b in 73% isolated yield
contaminated by ca. 2% of the regioisomer 7b.8 As
expected, the alcohols attacked mainly on the less hindered
anhydride carbonyl, as was demonstrated by the transforma-
tion of 6a into the known9 lactone 8 (Table 1).
Transformation of hemiester 6b into lactone 2 involved two
steps: reduction of the hemiester into a lactone and
hydrogenation of the double bond. We considered both
possible sequences of reaction and ®rst examined the
Scheme 2. (a) i. Na2CO3, H2O, ii. 10% aq. HCl. (b) KI, I2, NaHCO3, H2O. (c) 3% HCl in MeOH. (d) Zn, AcOH.
Scheme 3. (a) PtO2 (10%), H2, AcOH, 24h. (b) i. BuLi 0.9 eq., ii. LiBH4 2.2 eq., (MeO)3B, Et2O, re¯ux, 20h, iii. 5% aq. HCl.

P. Gosselin et al. / Tetrahedron 57 (2001) 733±738
735
Scheme 4. (a) LiBH4, (MeO)3B, Et2O or Ca(BH4)2, EtOH, H2O. (b) 10% aq. HCl, 208C, 15h. (c) i. Ca(BH4)2, EtOH, H2O, 08C then 208C, 6h, ii. 5% aq. HCl
(pH 3t4), 08C. (d) DCC 1.1 eq., DMAP 0.1 eq., CH2Cl2, 208C, 2h. (e) PtO2 (10%), H2 3 bar, AcOH or EtOH, 308C, 6h.
hydrogenation step followed by the chemoselective reduc-
tion (Scheme 3).
4. Experimental
4.1. General information
After the screening of several catalyst/solvent systems,13 we
found that PtO2 (10%) in acetic acid was most effective
(97% yield of 1214 after 24 h, 3 bar H2). Chemoselective
reduction of the ester functionality in 12 with calcium boro-
hydride (2 eq.) in ethanol15 gave a ca. 50:50 mixture of 2
and unreacted 12, as was obtained with LiBH4/ether in the
presence of catalytic methanol (B(OMe)3).16 We then
blocked the carboxylic acid group (BuLi, 0.9 eq.) and
observed complete conversion. However, the 1H-NMR
spectrum showed ca. 10% of C-7a epimerised trans-lactone
13.2f
IR spectra were recorded on a Mattson Genesis FTIR spec-
trometer, in KBr dispersion for solids and thin ®lms on NaCl
plates for liquids. NMR spectra were recorded at 400 MHz
1
for H and 100 MHz for 13C on a Bruker AC400 spectro-
1
meter, in CDCl3 using TMS for H spectra and the solvent
for 13C spectra as internal references, unless otherwise
noted. Multiplicities in the 13C spectra were determined
by DEPT experiments. Low resolution mass measurements
were obtained by electron impact at 70 eV with a Finnigan
ITD800 ion trap coupled with a Varian 3400 gas chromato-
graph. High resolution mass measurements were recorded
on a Varian MAT 311spectrometer at 70 eV.
Therefore, the alternate sequence of reactions was investi-
gated (Scheme 4).
4.1.1. (^)-(1R*,6R*)-6-Methoxycarbonyl-2,2,3-trimethyl-
cyclohex-3-ene-1-carboxylic acid (6a). Anhydride
When crystalline hydroxyacid 14, resulting from the reduc-
tion of 6b with either Ca(BH4)2 or LiBH4, was treated in situ
with 10% HCl, a mixture of lactones 15 and 1617 was
obtained. It was then deemed useful to ®rst isolate hydro-
xyacid 14 under mild acidic conditions (pH 3,4). Ca(BH4)2
was found far superior (98% yield) to LiBH4 (60% yield) in
this reduction step. DMAP catalyzed18 lactonization of 14
afforded the desired lactone 15, under slightly basic condi-
tions. Finally, hydrogenation of 15 over PtO2 (10%) in
either AcOH or EtOH afforded pure lactone 2 (100% GC)
in quantitative yield after thorough elimination of the cata-
lyst by ®ltration.
5
(1.0 g, 5.15 mmol) was re¯uxed in methanol (12 mL) for
15 h with stirring, under N2. Removal of excess methanol
in vacuo gave a light-brown oil which was chromatographed
over silicagel (25£) with 9:1 cyclohexane: ethylacetate to
give 0.815 g (3.60 mmol, 70% yield) of a 90:10 mixture of
hemiesters 6a:7a, respectively. An analytically pure sample
of 6a could be prepared by recrystallization from 95:5
pentane:ether:white solid, mp 100±1018C (pentane:ether
95:5); IR (KBr) nmax: 1737 (CyO), 1690 (CyO), 1257,
1
1198 cm21. H-NMR (CDCl3) d: 1.14 and 1.17 (2s, 2£H),
1.67 (s, 3H), 2.26 (m, 1H), 2.63 (m, 1H), 2.85 (d, Jˆ4.0 Hz,
1H), 3.02 (m, 1H), 3.70 (s, 3H), 5.41 (s, 1H) ppm. 13C-NMR
(CDCl3) d: 19.10, 24.58 and 29.51 (3q), 25.16 (t), 36.62 (s),
38.52 and 51.99 (2d), 51.74 (q), 120.48 (d), 137.18 (s),
174.56 (s), 178.30 (s) ppm. MS (GCMS, EI 70 eV) m/z
(%): 180 (29), 166 (14), 151 (3), 121 (100), 107 (54), 91
(42), 79 (25), 65 (10), 53 (8). MS (GCMS, CI1 iBuH) m/z
(%): 227 (MH1, 17), 209 (100), 195 (45), 181 (23), 167
(61), 121 (12). Anal. Calcd. for C12H18O4 (226.27): C,
63.70; H, 8.02; O, 28.28. Found: C, 63.86; H, 8.06; O, 28.51.
1
IR and H-NMR data of 2 were identical to those reported
for the all-cis lactone.2f
3. Conclusion
In summary, starting with anhydride 5, we have described a
four step synthesis of the cis-lactone 2 in 64% overall yield
which represents a signi®cant improvement with regard to
the reported synthesis (seven steps, 33% overall yield).2f
The described transformation of 2 into irones yielded a
1:9 mixture of cis- and trans-g-irones 1, respectively.2f
Work is now in progress to convert lactone 2 into (^)-cis-
g-irone cis-1 in a more stereoselective way.
4.1.2. (^)-(1R*,6R*)-6-Methoxycarbonyl-4,5,5-trimethyl-
cyclohex-3-ene-1 carboxylic acid (7a). An enriched
sample was obtained from the late fractions of the liquid
chromatography of the 6a:7a mixture. IR (®lm) nmax: 3399
(OH), 1733 (CyO ester), 1708 (CyO acid), 1436, 1376,
1
1207, 1166, 1064, 1025 cm21. H-NMR d: 1.07 and 1.17

736
P. Gosselin et al. / Tetrahedron 57 (2001) 733±738
(2s, 2£3H), 1.42 (s, 3H), 2.30 (m, 1H), 2.68 (m, 1H), 2.85
(d, 1H), 3.02 (m, 1H), 3.70 (s, 3H); 5.43 (m, 1H) ppm.
13C-NMR (CDCl3) d: 19.11 and 24.58 (2q), 25.22 (t),
29.46 (q), 38.35 (s), 38.48 and 51.36 (2d), 51.15 (t),
120.37 (d), 137.19 (s), 172.95 (s), 179.65 (s) ppm. MS
(GCMS, EI 70 eV) m/z (%): 166 (25), 151 (4), 121 (31),
107 (100), 91 (54), 79 (23). MS (GCMS, CI1 iBuH) m/z
(%): 227 (MH1, 56), 209 (30), 195 (70), 167 (100), 121
(11).
1H, Jˆ4.0 Hz), 3.02 (m, 1H), 5.41 (br. s, 1H), ,12 (2H)
ppm. 13C-NMR (CDCl3) d: 19.11, 24.80, 29.68 (3q), 25.01
(t), 36.64 (s), 38.42 and 51.62 (2d), 120.55 (d), 137.03 (s),
179.38 and 180.78 (2s). Anal. Calcd. for C11H16O4 (212.25):
C, 62.25; H, 7.60; O, 30.15. Found: C, 62.01; H, 7.78; O,
29.96.
4.1.6. (^)-(1R*,2R*,4R*,5R*)-4-Iodo-5,8,8-trimethyl-7-
oxo-6-oxabicyclo[3.2.1]octane-2-carboxylic acid (10). A
solution of I2 (3.56 g, 14 mmol) and KI (7 g, 42 mmol) in
water (21 mL) was added to a magnetically stirred solution
of diacid 9 (1.01 g, 5 mmol) in 0.5 M aq. NaHCO3 (40 mL).
Stirring was continued for 18 h in the dark. Ether (25 mL)
was then added and the brownish solution was washed with
sat. aq. Na2SO3 (50 mL) then with sat. aq. NaCl (2£75 mL).
The combined aqueous layers were acidi®ed with 10% aq.
HCl (t60 mL), then extracted with ether (3£100 mL). The
combined organic layers were dried (MgSO4), ®ltered and
the solvent removed in vacuo affording 1.36 g (84% yield)
of iodolactone 10 as light-yellow crystals of suf®cient purity
for use in the next step. However, analytically pure samples
were prepared by recrystallization from pentane±ether: mp
1058C (pentane±ether, dec.). IR (KBr) nmax: 3524 (OH);
4.1.3. (^)-(1R*,6R*)-6-Ethoxycarbonyl-2,2,3-trimethyl-
cyclohex-3-ene-1 carboxylic acid (6b). Anhydride 5
(2.5 g, 12.9 mmol) was re¯uxed in abs. ethanol (30 mL)
for 24 h with stirring, under N2. Removal of excess ethanol
in vacuo gave a light-brown oil which was chromatographed
over silicagel (25£) with cyclohexane: ethylacetate (95:5 to
50:50) to give 2.33 g (9.7 mmol, 75% yield) of a 98:2
mixture of hemiesters 6b:7b, respectively, as a colorless
oil. The following data were collected upon this 98:2
mixture. IR (®lm) nmax: 1735 (CyO), 1710 (CyO), 1463,
1438, 1373, 1303, 1272, 1232, 1193, 1168, 1064,
1
1033 cm21. H-NMR d: 1.15 and 1.17 (2s, 2£3H), 1.25 (t,
Jˆ7.2 Hz, 3H), 1.70 (s, 3H), 2.26 (m, 1H), 2.62 (m, 1H),
2.84 (d, Jˆ3.9 Hz, 1H), 2.98 (m, 1H), 4.15 (q, Jˆ7.2 Hz,
2H), 5.45 (s, 1H) ppm. 13C-NMR (CDCl3) d: 14.02 and
19.05 (2q), 24.53 (q), 25.16 (t), 29.47 (q), 36.56 (s), 38.46
and 51.64 (2d), 60.76 (t), 120.52 (d), 137.07 (s), 173.99 and
178.13 (2s) ppm.
1761 (CyO); 1737 (CyO), 1204, 1180, 981, 911 cm21
.
1H-NMR (CD3COCD3) d: 1.15 (s, 3H), 1.56 (s, 3H), 1.62
(s, 3H), 2.49 (m, 1H), 2.72 (m, 1H), 2.75 (br. s, 1H), 3.29 (m,
1H), 4.62 (d, 1H, Jˆ7.6 Hz), t9.8 (br. s, 1H) ppm. 13C-
NMR (CD3COCD3) d: 20.76 (q), 22.67 (q), 24.39 (d),
25.32 (q), 34.51 (t), 36.19 (d), 45.17 (s), 53.38 (d), 88.52
(s), 172.90 and 175.12 (2s) ppm. Anal. Calcd. for C11H15IO4
(338.14): C, 39.07; H, 4.47; O, 18.93. Found C, 39.35; H,
4.58; O, 18.88.
4.1.4. Methyl (^)-(1R*,2R*,5S*)-5,8,8-trimethyl-7-oxo-
6-oxabicyclo[3.2.1]octane-2-carboxylate (8). A solution
of hemiester 6a (220 mg, 0.97 mmol) in benzene (15 mL)
and BF3.MeOH complex in methanol (15 mL) was stirred at
re¯ux for 1 h. After quenching with water (10 mL), the
mixture was diluted with ether (20 mL) and NaHCO3 (aq.)
(30 mL). After separation, the aq. layer was extracted with
ether (2£75 mL). The combined organic portions were dried
over MgSO4 and concentrated in vacuo to yield a brown
viscous oil (220 mg). Crystallization from 6:4 pentane:ether
afforded white crystals of 8 (67 mg, 30%): mp 1098C
(pentane: ether 6:4) (Lit.9 1128C). IR (KBr) nmax: 1772
(CyO lactone), 1737 (CˆO ester), 1466, 1309, 1216,
4.1.7. Methyl (^)-(1R*,2R*,4R*,5R*)-4-iodo-5,8,8-tri-
methyl-7-oxo-6-oxabicyclo[3.2.1]octane-2-carboxylate
(11). A solution of iodoacid 10 (1.19 g, 3.5 mmol) in 3%
HCl in anhydrous methanol (t21 mL, prepared by adding
acetylchloride (1 mL) to anhydrous methanol (20 mL)) was
magnetically stirred for 1 h at room temperature, under N2.
Ether (20 mL) was added and the organic layer was washed
with saturated aq. NaHCO3 (2£20 mL) and then with brine
(2£20 mL). The organic layer was dried over anhydrous
MgSO4 and the solvents were evaporated to give iodoester
11 as white crystals (1.04 g, 84%) of suf®cient purity for use
in the next step. Recrystallization from pentane±ether
afforded analytical samples. Mp 111±1138C (pentane±
ether). IR (KBr) nmax: 1784 (CyO), 1731 (CyO), 1204,
1
1098, 929 cm21. H-NMR (CDCl3) d: 1.13 (s, 3H), 1.20
(s, 3H), 1.30 (s, 3H), 1.73 to 2.17 (m, 4H), 2.63 (br. s,
1H), 3.30 (m, 1H), 3.73 (s, 3H) ppm.
4.1.5. (^)-(1R*,2R*)-3,3,4-Trimethylcyclohex-4-ene-1,2-
dicarboxylic acid (9). A stirred mixture of anhydride 5
(0.45 g, 2.3 mmol), sodium carbonate (0.4 g, 4 mmol) in
water (15 mL) was heated during a few minutes until all
of the solid had dissolved. The solution was then stirred
for 2 h at room temperature then washed with ether
(2£25 mL). The ether layer was extracted with water
(30 mL) and the combined aqueous layers were acidi®ed
to pH ,1 with 10% aq. HCl and extracted with ether
(3£20 mL). The combined organic layers were dried
(MgSO4), ®ltered and solvent removed under reduced pres-
sure to afford crude diacid 9 as a white solid which was
recrystallized in pentane±ether. Yield 0.397 g (81%): mp
150±1518C (pentane±ether), (Lit.9 150±1518C). IR (KBr)
1
1180, 1063, 911, 846 cm21. H-NMR (CDCl3) d: 1.15 (s,
3H), 1.56 (s, 3H), 1.59 (s, 3H), 2.57 (m, 1H), 2.75 (br. s,
1H), 2.80 (m, 1H), 3.21 (m, 1H), 3.75 (s, 3H), 4.44 (d, 1H,
Jˆ7.5 Hz) ppm. 13C-NMR (CDCl3) d: 20.44, 22.52, 22.87,
25.37, 33.68, 35.98, 44.57, 52.44, 52.51, 88.24, 171.73,
174.90 ppm.
4.1.8. Preparation of hemiester (6a) from iodoester (11).
Powdered zinc (4.2 g, 64 mmol) was added portionwise
under N2, to a stirred solution of iodoester 11 (0.55 g,
1.6 mmol) in acetic acid (15 mL). The mixture was then
re¯uxed for 45 min. After cooling to room temperature,
the mixture was diluted with CH2Cl2 (20 mL), ®ltered on
celite and the residue rinsed with CH2Cl2 (10 mL). The
®ltrate was washed with water (3£75 mL), then extracted
with 5% aq. Na2CO3 (3£75 mL). The combined basic
n
max: 1731 (CyO), 1626, 1427, 1268, 1233, 1216, 1063,
1
923, 735 cm21. H-NMR (CDCl3) d: 1.15 (s, 3H), 1.18 (s,
3H), 1.67 (br. s, 3H), 2.32 (m, 1H), 2.71 (m, 1H), 2.89 (d,

P. Gosselin et al. / Tetrahedron 57 (2001) 733±738
737
aqueous phases were acidi®ed until pH ,1 with 10% aq.
HCl, then extracted with CH2Cl2 (4£50 mL). The combined
organic layers were dried over MgSO4, then ®ltered and
the solvent removed in vacuo to afford a semi-crystalline
residue (0.275 g, 78% crude yield). Crystallization from
pentane:ether (95:5) yielded white crystals of pure hemi-
ester 6a (0.205 g, 58%), identical in all respects with the
main product resulting from the opening of adduct 5 with
methanol (see above).
(0.696 g, 12.4 mmol) and CaCl2 (2.31 g, 20.8 mmol) in abs.
EtOH (15 mL) was added under N2 to a stirred solution of
hemiester 6b (1.36 g, 5.7 mmol) in abs. EtOH (40 mL). The
stirred mixture was cooled to 08C and a suspension of
NaBH4 (1.38 g, 36.3 mmol) in EtOH (11.5 mL)/H2O
(1.9 mL) was added dropwise. The ice-bath was removed
at the end of the addition and the mixture stirred at room
temperature for 6.5 h. 5% aq. HCl was added at 08C (55 mL,
pH ,3±4). Most of the ethanol solvent was removed in
vacuo. The residue was taken up in water (30 mL) and the
aq. phase saturated with NaCl, extracted with CH2Cl2
(3£30 mL). The combined organic extracts were dried
over MgSO4, ®ltered and the solvent removed in vacuo.
The resulting white solid was further dried at 0.07 torr for
2 h affording hydroxyacid 14 as white crystals (1.11 g,
4.1.9. (^)-(1R*,3S*,6R*)-6-(Ethoxycarbonyl)-2,2,3-tri-
methylcyclohexanecarboxylic acid (12). A solution of
hemiester 6b (0.421 g, 1.75 mmol) in AcOH (30 mL) was
hydrogenated for 48 h under pressure (H2, 3 bar), at 308C
and with stirring in the presence of PtO2 (84 mg, 20% w/w).
Filtration and evaporation in vacuo of the solvent left
hemiester 12 as an oil (0.414 g, 97% yield) which was
used in the next step without further puri®cation. IR (®lm)
5.6 mmol, 98% yield): mp 126±1288C. IR (®lm) nmax
:
.
1704 (CˆO), 1436, 1214, 1182, 1079, 1043, 1002 cm21
1H-NMR (CD3COCD3) d: 1.24 and 1.29 (2s, 2£3H), 1.79
(s, 3H), 2.15 (m, 2H), 2.37 (m, 1H), 2.78 (d, Jˆ4.0 Hz, 1H),
3.62 (dd, Jˆ2.2 and 7.1 Hz, 2H), 5.50 (s, 1H), 10.5 (br. s,
1H) ppm. 13C-NMR (CD3COCD3) d: 19.36 and 24.93 (2q),
26.83 (t), 29.63 (1q), 36.03 (d), 36.87 (s), 53.13 (d), 66.01
(t), 122.21 (d), 137.88 (s), 174.27 (s) ppm.
n
max: 1747, 1714, 1456, 1377, 1275, 1232, 1201, 1170,
1064, 1016 cm21. H-NMR (CDCl3) d: 0.86 (d, Jˆ6.9 Hz,
3H), 0.96 and 1.11 (2s, 2£3H), 1.20 (t, Jˆ7.1 Hz, 3H), 1.27
(m, 1H), 1.53 (m, 3H), 2.24 (m, 1H), 2.50 (d, Jˆ4.8 Hz,
1H), 3.10 (m, 1H), 4.08 (q, Jˆ7.1 Hz, 2H), 11.00 (m, 1H)
ppm. 13C-NMR (CDCl3) d: 13.66 and 15.44 (2q), 17.36 (q),
25.04 and 27.53 (2t), 28.35 (q), 35.77 (s), 41.16 (d), 41.38
and 53.00 (2d), 60.55 (t), 174.27 and 180.31 (2s) ppm.
1
When more concentrated (10% to 50%) aq. HCl solution
was used to quench the reaction and the mixture then stirred
overnight in order to induce the in situ lactonization of the
intermediate hydroxyacid 14, a mixture of lactones 15 and
1617 was obtained which could be separated by liquid
chromatography on silica-gel.
4.1.10. Reduction±lactonization of hemiester (12).
n-BuLi (0.9 eq., 0.323 mL of 1.6 M sol. in hexane,
0.517 mmol) was added via syringe, under N2, to a stirred
solution of hemiester 12 (0.139 g, 0.574 mmol) in ether
(2 mL), cooled at 2788C. After 30 min stirring at 2788C,
a solution of LiBH4/(MeO)3B prepared by adding one drop
of MeOH (,7 mg, 0.2 mmol) to LiBH4 (2.2 eq., 28 mg,
1.26 mmol) in ether (2 mL), was added via syringe. After
warming up to room temperature, the solution was heated at
re¯ux for 20 h. After cooling, the mixture was quenched
with anhydrous MeOH and diluted with ether (20 mL).
10% aq. HCl (10 mL) was added and the mixture was stirred
overnight. The separated aqueous phase was saturated with
NaCl then extracted with ether (10 mL). The combined
organic layers were dried over MgSO4, ®ltered and the
solvent removed in vacuo. The oily residue was taken up
in CHCl3 and a few precipitated salts removed by ®ltration
over sand. Removal of the solvent in vacuo yielded a color-
less oil (0.085 g, 0.522 mmol, 91% combined yield).
1H-NMR analysis of the product showed it to be a mixture
of cis-lactone 2 (90%) and trans-lactone 13 (10%). For the
characterization of 2, see below.
4.1.13. (^)-2-Hydroxymethyl-5,8,8-trimethyl-6-oxabi-
cyclo[3.2.1]octan-7-one (16) (mixture of isomers). IR
(®lm) nmax: 3457 (OH), 1764 (CyO), 1187, 1145, 1099,
1
1070, 1018, 927 cm21. H-NMR (CDCl3) d: 1.04, 1.06,
1.14, 1.18, 1.22 and 1.26 (6s, 2£3Me), 2.14 (m), 2.37 (br.
s), 2.48 (d, Jˆ8 Hz), 2.70 (m), 3.56 (d, Jˆ6.6 Hz), 3.7 (s),
3.93 (dd, Jˆ7.2 and 8.8 Hz), 4.21 (dd, Jˆ7.2 and 8.8 Hz)
ppm. 13C-NMR (CDCl3) d: 18.15, 18.66, 21.20, 21.32,
23.98, 24.23, 24.98, 26.91, 30.60, 32.15, 33.90, 34.37,
38.82, 43.33, 47.99, 52.76, 64.47, 70.79, 73.20, 77.24,
89.20, 177.99, 178.48 ppm.
4.1.14. (^)-(3aR*,7aR*)-6,7,7-Trimethyl-3a,4,7,7a-tetra-
hydro-2-benzofuran-1(3H)-one (15).
A
solution of
dicyclohexylcarbodiimide (DCC, 3.351 g, 16.27 mmol,
1.1 eq.) in anhydrous CH2Cl2 (80 mL) was added at room
temperature, under N2, to a stirred solution of hydroxyacid
14 (2.92 g, 14.75 mmol) and 1,4-dimethylaminopyridin
(0.18 g, 1.47 mmol, 0.1 eq.) in anhydrous CH2Cl2
(70 mL). After 2 h stirring at room temperature, oxalic
acid (133 mg, 1.47 mmol, 0.1 eq.) was added and the
solvent was removed in vacuo. The residue was taken up
in ether (30 mL) and the precipitated DCU eliminated by
®ltration over sand and washed with ether (30 mL). The
combined organic layers were washed with NaHCO3
(2£100 mL), dried over MgSO4, ®ltered and the solvent
removed in vacuo. The residue was taken up in anhydrous
ether (5 mL) and the solution ®ltered over a fritted glass of
®ne porosity. After rinsing with ether (3 mL), the solvent
was removed in vacuo to yield lactone 15 as a colourless
oil (2.379 g, 13.2 mmol, 89.5% yield). IR (®lm) nmax: 1772
(CyO), 1469, 1450, 1371, 1139, 1105, 1035 cm21. 1H-NMR
4.1.11. (^)-(3aR*,6S*,7aS*)-6,7,7-Trimethylhexahydro-
2-benzofuran-1(3H)-one (13). The following signals were
extracted from the spectra of the 9:1 mixture of 2 and 13,
respectively. 1H-NMR2f (CDCl3) d: 0.83 (d, 3H, Jˆ6.2 Hz),
0.81 and 1.25 (2s, 2£3H), 1.56 (m, 1H), 1.74 (d, Jˆ13.8 Hz,
1H), 1.84 (m, 1H), 2.24 (m, 1H), 3.67 (dd, Jˆ11.0 et 8.3 Hz,
1H), 4.24 (dd, Jˆ8.3 et 6.8 Hz, 1H) ppm. 13C-NMR (CDCl3)
d: 14.40, 14.64 and 25.41 (3q), 28.15 and 30.56 (2t), 34.47
(s), 38.64 and 42.72 (2d), 54.16 (d), 70.72 (t), 175.88 (s)
ppm.
4.1.12. (^)-(1R*,6R*)-6-(Hydroxymethyl)-2,2,3-trimethyl-
cyclohex-3-ene-1-carboxylic acid (14). A solution of KOH

738
P. Gosselin et al. / Tetrahedron 57 (2001) 733±738
Â
Monti, H.; Laval, G.; Feraud, M. Eur. J. Org. Chem. 1999,
(8), 1825±1829. (d) Leyendecker, F.; Comte, M. T.
Tetrahedron 1987, 43 (5), 85±92. (e) Kawanobe, T.;
Iwamoto, M.; Kogami, K.; Matsui, M. Agric. Biol. Chem.
1987, 51 (5), 791±796. (f) Kitahara, T.; Tanida, K.; Mori, K.
Agric. Biol. Chem. 1983, 47 (5), 581±586.
(CDCl3) d: 1.17 and 1.31 (2s, 2£3H), 1.68 (s, 3H), 1.96 (m,
1H), 2.35 (m, 1H), 2.40 (d, Jˆ7.6 Hz, 1H), 2.85 (m, 1H),
3.93 (dd, Jˆ8.6 and 3.3 Hz, 1H), 4.25 (dd, Jˆ8.6 and
5.6 Hz, 1H), 5.29 (s, 1H) ppm. 13C-NMR (CDCl3) d:
19.24 and 23.39 (2q), 26.24 (t), 29.26 (q), 32.42 (d), 34.67
(s), 50.08 (d), 73.11 (t), 119.44 (d), 140.22 (s), 176.81 (s)
ppm. MS (GCMS, EI 70 eV) m/z (%): 180 (M1., 32), 165
(36), 121 (100), 105 (66), 93 (64), 91 (42), 85 (33), 81 (35),
73 (33), 77 (26), 41 (36). HRMS (70 eV) calcd. for
C11H16O2: 180.11502, found: 180.1153.
3. (a) Maurer, B.; Hauser, A.; Froidevaux, J.-C. Helv. Chim. Acta
È
1989, 72, 1400±1415. (b) Marner, F. J.; Runge, T.; Konig, W.
A. Helv. Chim. Acta 1990, 73 (8), 2165±2170. (c) Krick, W.;
Marner, F. J.; Jaenicke, L. Helv. Chim. Acta 1984, 67 (8),
318±324.
4.1.15. (^)-(3aR*,6S*,7aR*)-6,7,7-Trimethylhexahydro-
2-benzofuran-1(3H)-one (2). A solution of lactone 15
(2.07 g, 11.5 mmol) in AcOH (100 mL) was hydrogenated
for 6 h under pressure (H2, 3 bar), at 308C and with stirring
in the presence of PtO2 (0.206 g, 10% w/w). Filtration and
evaporation of the solvent in vacuo yielded lactone 2 as a
colourless oil (2.08 g, 11.4 mmol, 99% yield). IR2f (®lm)
Â
4. (a) Galfre, A.; Martin, P.; Petrzilka, M. J. Essent. Oil Res.
1993, 5, 265±277. (b) Garnero, J.; Joulain, D. Bull. Soc.
Chim. Fr. 1979, 15±16.
5. Gosselin, P.; Bourdy, C.; Mille, S.; Perrotin, A. J. Org. Chem.
1999, 64 (26), 9557±9565.
6. (a) Kayser, M. M.; Morand, P. Can. J. Chem. 1978, 56, 1524±
1532 and references therein. (b) Kayser, M. M.; Morand, P.
Can. J. Chem. 1980, 58, 2484±2490. (c) Soai, K.;
Yokoyama, S.; Mochida, K. Synthesis 1987, 7, 647±648.
7. McCrindle, R.; Overton, K. H.; Raphael, R. A. J. Chem. Soc.
1962, 4798±4802.
n
max: 1766 (CˆO), 1463, 1367, 1199, 1186, 1166, 1147,
1139, 1014, 970 cm21 1H-NMR2f (CDCl3) d: 0.89 (d,
.
Jˆ6.5 Hz), 0.97 and 1.14 (2s, 2£3H), 1.27 to 1.72 (m,
5H), 2.21 (d, Jˆ8.0 Hz, 1H), 2.67 (m, 1H), 3.94 (t,
Jˆ8.7 Hz, 1H), 4.18 (dd, Jˆ8.7 and 8.0 Hz, 1H) ppm.
13C-NMR (CDCl3) d: 15.64 and 19.22 (2q), 22.63 and
26.01 (2t), 25.47 (s), 29.93 (q), 34.76 and 39.40 (2d),
48.00 (d), 70.75 (t), 178.37 (s) ppm. MS (GCMS, EI
70 eV) m/z (%): 183 (70, MH1), 122 (90), 107 (41), 95
(25), 81 (66), 55 (54), 39 (100). Anal. Calcd. for C11H18O2
(182.26): C, 72.49; H, 9.95; O, 17.56. Found C, 72.32; H,
9.76; O, 17.64.
8. Opening of the anhydride 5 with either sodium methoxide or
isopropoxide was also studied. A 1:2:2 mixture of 6a:7a:60a,
where 60a is the C-6 epimer of 6a, was obtained in 90% yield
with MeONa. Treatment of 5 with i-PrONa yielded a mixture
of several compounds which were not further analyzed.
9. Ichikizaki, I.; Arai, A. Bull. Chem. Soc. Jpn 1964, 37, 432±
433.
10. For a related sequence of reactions, see: Hamanaka, N.;
Seko, T.; Miyazaki, T.; Naka, M.; Furuta, K.; Yamamoto, H.
Tetrahedron Lett. 1989, 30 (18), 1399±2402.
Acknowledgements
11. Van Tamelen, E. E.; Shamma, M. J. Am. Chem. Soc. 1954, 76,
2315±2317.
We thank the Centre National de la Recherche Scienti®que
Á
12. Zimmerman, H. E.; Mais, A. J. Am. Chem. Soc. 1959, 81,
3644±3651.
and Le Ministere de l'Education Nationale de la Recherche
et de la Technologie (Paris, France) for support of this
research. A. P. thanks Robertet S.A. (Grasse, France) for
13. Rylander, P. N. Hydrogenation MethodsÐBest Synthetic
Methods, Academic Press: London, 1990; Chapter 2.
14. The all cis con®guration of the ring substituents was
con®rmed a posteriori through the transformation of 12 into
the known cis-lactone 2.
Â
®nancial support. S. M. is grateful to the Region des Pays de
La Loire (Nantes, France) for the award of a research grant.
15. Brown, H. C.; Narasimhan, S.; Choi, Y. M. J. Org. Chem.
1982, 47, 4702±4708.
References
16. Brown, H. C.; Narasimhan, S. J. Org. Chem. 1982, 47, 1604±
1606.
1. Schulte-Elte, K. H.; Pamingle, H.; Uijttewaal, A. P.;
Snowden, R. L. Helv. Chim. Acta 1992, 75 (3), 759±765
and references cited.
17. An unseparable equimolar mixture of two diastereomeric
lactones 16 was obtained as shown by the doubling of the
2. (a) Laval, G.; Audran, G.; Galano, J.-M.; Monti, H. J. Org.
Chem. 2000, 65 (11), 3551±3554. (b) Chapuis, C.; Brauchli, R.
Helv. Chim. Acta 1993, 76 (5), 2070±2088. (c) Nussbaumer,
1
lines in both the H- and 13C-NMR spectra.
18. Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 4475±
4478.
Â
C.; Frater, G. Helv. Chim. Acta 1988, 71, 619±623. See also an
improved preparation of an intermediate prepared in (2c):