Novel stereocontrolled synthesis of the tricyclic lactone (1R,3R, 6R,9S)-6,9-dimethyl-8-oxo-7-oxatricyclo[4.3.0.03,9]nonane

Article abstract of DOI:10.1016/S0957-4166(97)00641-1

The stereocontrolled synthesis of (1R,3R,6R,9S)-6,9-dimethyl-8-oxo-7-oxatricyclo[4.3.0.0^3,9]nonane 1 from (R)-(-)-carvone has been accomplished by application of a 13-step sequence with 12% overall yield. The absolute stereochemistry of the uns

Full text of DOI:10.1016/S0957-4166(97)00641-1

Pergamon
Tetrahedron: Asymmetry 9 (1998) 293–303
Novel stereocontrolled synthesis of the tricyclic lactone (1R,3R,
6R,9S)-6,9-dimethyl-8-oxo-7-oxatricyclo[4.3.0.03,9]nonane
Rosario Rico,a Julián Zapico,a Francisco Bermejo,a,∗ S. Bamidele Sanni b and
Santiago García-Granda b
aDepartamento de Química Orgánica, Facultad de Químicas, Universidad de Salamanca, Pza de la Merced, s.n. 37008
Salamanca, Spain
bDepartamento de Química Física y Analítica, Facultad de Química, Universidad de Oviedo, Julián Clavería 8, 33006
Oviedo, Spain
Received 14 November 1997; accepted 23 December 1997
Abstract
The stereocontrolled synthesis of (1R,3R,6R,9S)-6,9-dimethyl-8-oxo-7-oxatricyclo[4.3.0.03,9]nonane 1 from
(R)-(−)-carvone has been accomplished by application of a 13-step sequence with 12% overall yield. The absolute
stereochemistry of the unsaturated acid 8a has been established by X-ray analysis of the chiral amide 8c. © 1998
Elsevier Science Ltd. All rights reserved.
1. Introduction
The tricyclic lactone (1R,3R,6R,9S)-6,9-dimethyl-8-oxo-7-oxatricyclo[4.3.0.03,9 ]nonane 1 has been
used as a key intermediate in the preparation of several representatives of the pinane1 and bergamotane2
series; furthermore, this tricyclic derivative has been described as a valuable intermediate in the total
synthesis of biologically active (+)-grandisol.3
The nitrite and hypobromite photolysis techniques for remote functionalization of unactivated carbon
atoms have proved to be suitable methods for the introduction of substituents at C-9 in the pinane series,
therefore such techniques have been successfully exercised to access the tricyclic structure present in
1 by Hortmann and Youngstrom1 in their contribution to the synthesis of 9-substituted pinanes and by
Gibson and Erman2 in the preparation of cis-bergamotenes. A quite similar approach has been used in
the total synthesis of (+)-grandisol, the male boll weevil pheromone, by Magnus and Hobbs.3
Very recently, the use of biochemical methods in the enantioselective synthesis of the α- and β- forms
of the (E)-endo-bergamoten-12-oic acids 2 and 3 have been successfully applied by Mori et al.4 These
∗
Corresponding author. E-mail: fcobmjo@gugu.usal.es
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00641-1

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Fig. 1.
two sesquiterpenes have been isolated from the leaves of wild tomato (Lycopersicon hirsutum) and have
been claimed to stimulate the oviposition behaviour of female gravid moths (Heliothis zea) whose larvae
are major agricultural pests of tomatoes, corn and cotton.5 Access to the tricyclic lactone 1 has been
envisaged through the disconection (type a) depicted in Fig. 1. The enantiomerically pure form of the
β-hydroxyketone 4 was obtained by yeast reduction of the prochiral diketone and has been used as a
starting material to access the tosyloxy lactone 5 which then led to the tricyclic lactone 1 by internal
tosylate displacement.
2. Results and discussion
We became interested in the synthetic approach to the tricyclic lactone 1 outlined in Fig. 1 (type
b of disconection) with the occasion of the total synthesis of (−)-ampullicin and (+)-isoampullicin,
two sesquiterpene amides with growth regulating activity.6 The target molecule was envisaged to be
accessible from the tosyloxy lactone 7, which can be easily prepared from (+)-trans-carveol 6. The
bicyclic lactone 12, a valuable intermediate in the synthesis of 7 (Scheme 1), would be accessed via
oxidative cyclization of the unsaturated acid 8a, which in turn would be derived by the Johnson ortho
ester Claisen rearrangement of the (+)-trans-carveol 6.7,8 The oxidative degradation of the isopropenyl
chain present in 12 followed by trivial transformations would lead to 7 which would allow us to access 1
by intramolecular cyclization.
Enough evidence must be obtained for the stereocontrol in the crucial [3.3] sigmatropic Claisen
rearrangement step9 in order to ensure the enantioselectivity of our synthetic strategy. Treatment of
(+)-trans-carveol 6 with ethyl orthoacetate and propionic acid followed by saponification of the crude
ethyl ester led to the γ,δ-unsaturated acid 8a with excellent yield. Treatment of 8a with (S)-(−)-α-
methylbenzylamine and DCC led exclusively to the chiral amide 8c in 85% yield. The same sequence
was performed on the (−)-trans-carveol 9.10 In this case the γ,δ-unsaturated acid 10a was transformed
into the amide 10c as the single product by analogous treatment. Spectroscopic evidence was obtained to
illustrate the diastereomeric relationship of both products 8c and 10c and to assess the enantiospecificity
of the Claisen rearrangement in both cases.11
The absolute configuration of the chiral amide 8c was unequivocally established by X-ray analysis
(see Fig. 2) and hence the enantioselectivity of the process to access the lactone 1 was also ensured.12
With the unsaturated acid 8a in our hands we continued our synthetic scheme to prepare the target
molecule by application of a five-step sequence in 44% yield. Oxidative cyclization of 8a by treatment
with NBS led stereospecifically to the bromolactone 11 which was further reduced with tri-n-butyl
hydride to afford the bicyclic lactone 12 with 65% yield.13
Ozonolysis of 12 followed by Baeyer–Villiger oxidation of the methyl ketone 13 yielded the acetate

R. Rico et al. / Tetrahedron: Asymmetry 9 (1998) 293–303
295
Scheme 1.
Fig. 2. ORTEP view of the X-ray crystal structure of 8c. An arbitrary numbering system is given
14 with 65% yield after flash chromatography. The alkaline methanolysis of the acetate 14 followed by
protection of the hydroxy functionality present in 15 afforded the silyl ether 16 with 78% yield.14
Introduction of the methyl substituent was achieved by treatment of 16 with LDA in THF at −78°C
followed by addition of HMPA and methyl iodide with 85% yield. As expected, the alkylation took place
stereoselectively by the exo face leading to a mixture of the two methyl derivatives 17 and 18 in a 2:98
ratio.15 Transformation of the major alkylated product 18 into the tosylate 7 was accomplished by O-silyl
deprotection followed by treatment of the crude alcohol 19 with tosyl chloride under standard conditions
to yield the tosyloxylactone 7 in 74% yield.
The intramolecular displacement of the tosylate took place successfully by treatment of 7 with LDA
and HMPA in THF at −78°C leading to the tricyclic lactone 1 with 85% yield. The synthesized material
had m.p. 36–38°C (light petroleum) [lit.3 37–38°C], the IR and 1H-NMR spectra were superimposable
with those described for (1R,3R,6R,9S)-6,9-dimethyl-8-oxo-7-oxatricyclo[4.3.0.03,9]nonane1,2; further-
more, the enantioselectivity of the process has also been ensured by the specific rotation found for 1:
24
[α]D +48.0 (c=1.3, CHCl3) [lit.3 [α]D22 +49.7 (c=3%, CHCl3)].

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3. Experimental
All the reactions were carried out using dry solvents under a nitrogen or argon atmosphere. All
the solvents and chemicals were commercially available and, unless otherwise indicated, were used
as received. Tetrahydrofuran, diethyl ether and toluene were dried over sodium benzophenone ketyl.
Methylene chloride was dried over CaH2 under argon and kept over molecular sieves. Enantiomerically
pure trans-carveols 6 and 9 were obtained following the Johnston procedure.6,8 Optical rotations were
1
determined on a digital Perkin–Elmer 241 polarimeter in a 1 dm cell. H-NMR and 13C-NMR spectra
were measured in a Bruker WP-200-SY spectrometer operating at 200 MHz and 50.3 MHz respectively;
1
chemical shifts are reported in ppm (δ), and the coupling constants are given in Hz. H-NMR spectra
were referenced to either the residual proton in the deuterated solvent or TMS. 13C-NMR spectra were
referenced to the chemical shifts of the deuterated solvent. The IR spectra were determined on a Bomen
MB-100 FT-IR spectrophotometer as indicated in each case; the frequencies in the IR spectra are given in
cm−1. Mass spectra were recorded on a Kratos MS-25 instrument operating on either EI (70 eV) or FAB
ionization (8 kV, using Xe and (HOCH2CH2S)2 as matrix). Microanalyses were realized by Dr. Benigno
Macías-Sánchez (Inorganic Chemistry Department, University of Salamanca) on a Perkin–Elmer 240-B
analyzer. The X-ray analysis of compound 8c was made by S. Bamidele Sanni and S. Garcia-Granda
of the University of Oviedo.12 Unless otherwise indicated, all the preparative chromatographies were
performed with silica gel (40–63 mm) using the technique of flash chromatography.16
3.1. (10R,50R)-2-[20-Methyl-50-(2-propenyl)-20 -cyclohexen-10-yl]-acetic acid 8a and (10R,50R)-2-[20-
methyl-50-(2-propenyl)-20-cyclohexen-10 -yl]-acetic acid methyl ester 8b
In a three-necked round-bottomed flask equipped with a distillation head were placed 15 g (0.1 mol) of
(+)-trans-carveol 6 and 130 mL (0.7 mol) of triethyl orthoacetate. The mixture was stirred at 100°C for
2 h and then a few drops of propionic acid were added and the mixture was heated at 135°C and stirred
for 15 h more, adding a drop of propionic acid when the distillation of ethanol ceased.
After cooling, the residue was diluted with ethyl acetate and the orthoester was hydrolyzed with 400
mL of 2 N HCl, then the aqueous phase was extracted with ethyl acetate, the combined organic phases
were washed with saturated NaHCO3 and brine, dried (Na2SO4) and evaporated at reduced pressure to
give a crude material which was treated with 8.5 g (0.15 mol) of KOH in 60 mL of MeOH:H2O (3:1).
After stirring at reflux for 2 h, the methanol was evaporated and the residue dissolved in water and
extracted with ethyl acetate, then the aqueous phase was acidified (6 N HCl) and extracted again with
ethyl acetate. The combined acid organic phases were washed with brine, dried (Na2SO4) and evaporated
at reduced pressure to give the carboxylic acid 8a (15.5 g, 75% yield), [α]D −53.6 (c=2.71, CHCl3). IR
(film) νmax: 2920, 1709, 1645, 1412, 1294, 889 cm−1. 1H NMR (CDCl3): δ 1.69 (s, 3H), 1.73 (s, 3H),
1.8–2.7 (m, 6H), 2.34 (dd, 1H, J=16 Hz, J=12 Hz), 2.61 (dd, 1H, J=16 Hz, J=4 Hz), 4.71 (s, 2H), 5.48
(s, 1H), 10.8 (s, 1H) ppm. 13C NMR (CDCl3): δ 20.67 (q), 21.59 (q), 30.89 (t), 32.29 (t), 37.71 (t), 35.84
(d); 35.86 (d), 108.83 (t), 123.22 (d), 134.53 (s), 149.17 (s), 179.63 (s) ppm. Analysis C12H18O2 calc.:
C, 74.19; H, 9.33; found: C, 74.12; H, 9.35.
Treatment of 8a with an ethereal diazomethane solution yielded the methyl ester 8b (15.6 g) which
was purified by flash chromatography (hexane:ether=1:1). [α]D −52.9 (c=1.08, CHCl3). IR (film) νmax
:
2922, 1738, 1645, 1437, 1258, 1169, 739 cm−1. 1H NMR (CDCl3): δ 1.67 (s, 3H), 1.70 (s, 3H), 1.8–2.2
(m, 6H), 2.25 (dd, 1H, J=16 Hz, J=11 Hz), 2.53 (dd, 1H, J=16 Hz, J=3. Hz), 3.66 (s, 3H), 4.69 (s, 2H),
5.43 (s, 1H) ppm. 13C NMR (CDCl3): δ 20.70 (q), 21.64 (q), 30.91 (t), 32.30 (t), 37.69 (t), 35.83 (d),

R. Rico et al. / Tetrahedron: Asymmetry 9 (1998) 293–303
297
36.06 (d), 51.37 (q), 108.72 (t), 122.99 (d), 134.85 (s), 149.41 (s), 173.45 (s) ppm. MS (FAB), m/z (%):
167.0 (21), 149.0 (100), 135.0 (9), 113.0 (20), 92.8 (19), 80.8 (20).
3.2. (10S,50S)-2-[20-Methyl-50-(2-propenyl)-20-cyclohexen-10 -yl]-acetic acid 10a and (10S,50S)-2-[20-
methyl-50-(2-propenyl)-20-cyclohexen-10 -yl]-acetic acid methyl ester 10b
An identical procedure to that mentioned above for the transformation of 6 into 8a and 8b applied to
(−)-trans-carveol 9 led to the carboxylic acid 10a [α]D +52.8 (c=0.3, CHCl3) and the methyl ester 10b
[α]D +51.9 (c=0.90, CHCl3) with 76% and 80% yields, respectively. Both products exhibited identical
spectroscopic properties to those exhibited by 8a and 8b. Analysis C12H18O2 calc.: C, 74.19; H, 9.33;
found: C, 74.13; H, 9.37.
3.3. (10R,50R,100S)-N-(100-Phenylethyl)-2-[20-methyl-50-(2-propenyl)-20-cyclohexen-10 -yl]-acetamide
8c
To a solution of N-hydroxysuccinimide (154 mg, 1.3 mmol) in 1 ml of dry dichloromethane were
successively added a solution of carboxylic acid 8a (217 mg, 1.1 mmol) in 2 ml of dichloromethane
and dicyclohexylcarbodiimide (DCC) (277 mg, 1.3 mmol). The reaction mixture was stirred for 1 h at
room temperature and (−)-S-α-methylbenzylamine (0.17 ml, 1.3 mmol) was added. The reaction mixture
was stirred for 4 h at room temperature. The solvent was evaporated at reduced pressure and the crude
residue was chromatographed on silica gel to yield 309 mg (93% yield) of the amide 8c, m.p. 121–122°C
1
(hexane), [α]D −89.1 (c=1.5, CHCl3). H-NMR (CDCl3): δ 1.48 (d, J=7 Hz, 3H), 1.60 (s, 3H), 1.65
(s, 3H), 2.05 (dd, J=14 Hz, J=10 Hz, 2H), 2.50 (dd, J=14 Hz, J=4 Hz, 2H), 4.66 (s, 1H), 4.71 (s, 1H),
5.16 (quintet, J=7 Hz, 1H), 5.43 (s, 1H), 5.69 (d, J=7 Hz, 1H) ppm. 13C-NMR (CDCl3): δ 20.5 (q), 21.6
(q) 21.7 (q), 30.8 (t), 31.9 (t), 35.9 (d), 36.2 (d), 40.3 (t), 48.5 (d), 108.6 (t), 122.5 (d), 125.9 (d), 126.9
(d), 128.4 (d), 135.4 (s), 143.3 (s), 159.2 (s), 171.2 (s) ppm. MS (EI), m/z (%): 297.20 (20), 254.15 (8),
163.10 (35), 150.09 (16), 133.10 (7), 119.08 (13), 105.07 (100), 91.05 (10), 79.05 (12).
3.3.1. Crystal data
C20H27NO, Mr=297.43, monoclinic, space group P21, a=8.789(7) Å, b=9.717(4) Å, c=11.406(14) Å,
β=108.84(5)°, V=921.9(14) Å3, Z=2, Dx=1.07 Mg/m3, MoKα radiation (graphite-crystal monochroma-
tor, λ=0.71073 Å), µ=0.065 mm−1, F(000)=324, T=294 K, final conventional R=0.065 and wR2=0.164,
S=0.952 for 3247 ‘observed’ reflections and 201 parameters.
3.3.2. X-Ray experimental
A colourless crystal of the titled compound, approximately 0.30×0.20×0.33 mm, was used for the
measurements at 293(2) K. The unit cell dimensions were determined from the angular settings of 25
reflections in the range 7≤θ≤12°. The space group was inferred to be P21 from systematic extinctions
and the subsequent structure determination. The intensities of 4651 reflections in the range 1.89° to
24.97° in the range −10≤h≤9, −11≤k≤11, 0≤l≤13, were measured using the w−2θ scan technique
with a scan angle of 1.5° and a variable scan rate with maximun scan time of 60 s per reflection.
MoKα radiation was used with a graphite-crystal monochromator on a Nonius CAD4 single-crystal
diffractometer. The intensity of the primary beam was checked throughout the collection by monitoring
three standard reflections every 60 min. On all reflections, profile analysis was performed.17,18 Some
double measured reflections were averaged, resulting in 4510 ‘unique’ reflections of which 3247 were
2
observed with I>2σ(I). Lorentz polarization corrections were applied, and the data reduced to Fo .

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R. Rico et al. / Tetrahedron: Asymmetry 9 (1998) 293–303
The structure was solved by direct methods using the program SHELX86,19 Isotropic least-squares
refinement on F2 using SHELXL9320 converged at R=0.120. Additional empirical absorption corrections
were applied at this stage, using the program XABS2.21 The maximun and minimun corrections were
9.515 and 0.571 respectively. It was not possible to locate the H-atoms from the difference Fourier, and
so all hydrogen atoms were geometrically placed and isotropically refined. Full matrix anisotropic least-
squares treatment with SHELXL93, on all the positional parameters, but with the temperature factors for
the H atoms fixed at 0.210 Å2 converged at R=0.065 and wR=0.164, S=0.952 for the 3247 ‘observed’
reflections and 614 variables. Since the Flack’s parameters were not reliable, in order to establish the
absolute configuration of the molecule, we calculated the average product of the calculated and observed
Bijvoet difference,22 and obtained a value of 0.541(128) on 639 Friedel pairs. The function minimized
2
2
2
2
2
was ([ΣwFo −Fc )/Σw(Fo )]1/2 where w=1/[s2(Fo )+0.1P)2] with s(Fo ) from counting statistics and
2
2
P=(Max (Fo , o)+2×Fc )/3. The maximum shift-to-error ratio in the final full matrix least-squares
cycle was 0.038 for the non-hydrogen atoms, while the highest and lowest peaks in the final difference
Fourier calculated were 0.158 e/Å−3 respectively. Atomic scattering factors were taken from International
Tables for X-ray Crystallography (1976). Plots were made with the EUCLID package.23 Geometrical
calculations were made with PARST.24 All calculations were made at the University of Oviedo at
the Scientific Computer Centre and the X-ray group VAX-AXP computers. Further details concerning
comments on the structure crystal data and structure refinements for ISOS, etc, can be obtained.12
3.4. (10S,50S,100S)-N-(100-Phenylethyl)-2-[20 -methyl-50-(2-propenyl)-20-cyclohexen-10 -yl]-acetamide
10c
An identical procedure to that described above for 8a, applied to the carboxylic acid 10a led with
85% yield to the amide 10c, m.p. 135–136°C (di-isopropyl ether); [α]D +12.6 (c=1.5, CHCl3). 1H-NMR
(CDCl3): δ 1.48 (d, J=7 Hz, 3H), 1.64 (s, 3H), 1.73 (s, 3H), 2.05 (dd, J=14 Hz, J=10 Hz, 2H), 2.49 (dd,
J=14 Hz, J=4 Hz, 2H), 4.72 (s, 2H), 5.16 (quintet, J=7 Hz, 1H), 5.43 (s, 1H), 5.69 (d, J=7 Hz, 1H) ppm.
13C-NMR (CDCl3): δ 20.6 (q), 21.6 (q), 21.7 (q), 30.9 (t), 32.2 (t), 36.1 (d), 36.3 (d), 40.4 (t), 48.7 (d),
108.7 (t) 122.6 (d), 126.1 (d), 127.1 (d), 128.5 (d), 135.6 (s), 143.4 (s), 149.3 (s), 171.2 (s) ppm. MS (EI),
m/z (%): 297 (40), 163 (45), 105 (100).
3.5. (3aR,5S,7S,7aS)-7-Bromo-5-(2-propenyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-2(3H)-
benzofuranone 11
N-bromosuccinimide (4.21 g, 24 mmol) was added to a solution of carboxylic acid 10a (3.55 g, 18
mmol) in 40 mL of acetone at 0°C. The reaction mixture was stirred at room temperature for 30 min.
The solvent was evaporated and the residue was dissolved in ether, then poured into 100 mL of an
aqueous solution of 10% NaHSO3 and extracted with ether. The combined organic phases were washed
with brine, dried (Na2SO4) and evaporated at reduced pressure. The solid residue was purified by flash
chromatography (hexane:AcOEt=7:3) to yield 4.2 g (86%) of 11, m.p. 78–80°C (hexane), [α]D −7.6
1
(c=0.97, CHCl3). IR (CHCl3) νmax: 3470, 1769, 1645, 1458, 1385, 1121, 949, 719 cm−1. H NMR
(CDCl3): δ 1.64 (s, 3H), 1.73 (s, 3H), 2.4–2.8 (m, 2H), 4.16 (dd, J=13.0 Hz, J=3.8 Hz, 1H), 4.74 (s, 1H),
4.79 (s, 1H) ppm. 13C NMR (CDCl3) δ 20.8 (q), 21.5 (q), 28.7 (t), 33.0 (t), 39.5 (t), 40.4 (d), 43.1 (d),
56.3 (d), 85.9 (s), 110.6 (t), 146.1 (s), 174.4 (s) ppm. IR (Cl3CH) νmax 3470, 1769, 1645, 1458, 1385,
1121, 949, 719 cm−1. MS (FAB), m/z (%): 272.8 (42), 193.0 (92), 153.6 (100), 104.8 (42).

R. Rico et al. / Tetrahedron: Asymmetry 9 (1998) 293–303
299
3.6. (3aR,5R,7aR)-5-(2-Propenyl)-7a-methyl-3a,4,5,6,7,7a-hexahydro-2(3H)-benzofuranone 12
Tributyltin hydride (15 ml) and a catalytic amount of AIBN were simultaneously added to a solution
of 11 (1.02 g, 3.74 mmol) in 15 mL of anhydrous THF. The mixture was stirred under argon at 60°C
until the reaction was finished (1.5 h). The reaction mixture was poured into an aqueous solution of
10% NaF, then extracted with ethyl acetate. The combined organic layers were washed with brine, dried
(Na2SO4) and evaporated at reduced pressure. The solid residue was purified by flash chromatography
(hexane:AcOEt=7:3) to yield 690 mg (95%) of 12, m.p. 53–55°C (hexane), [α]D −25.6 (c=0.99, CHCl3).
1
IR (CHCl3) νmax: 3059, 1765, 1645, 1456, 1267, 1094, 735 cm−1. H NMR (CDCl3): δ 1.44 (s, 3H),
1.68 (s, 3H), 2.4–2.7 (m, 2H), 4.68 (s, 1H), 4.70 (t, 1H, J=1.5 Hz) ppm. 13C NMR (CDCl3): δ 24.0 (q),
24.6 (q), 27.2 (t), 29.2 (t), 33.3 (t), 34.2 (t), 38.1 (d), 41.1 (d), 84.3 (s), 109.1 (t), 147.7 (s), 175.14 (s)
ppm. MS (FAB), m/z (%): 195.1 (100), 177.1 (11), 154.0 (54), 139.1 (35), 92.9 (18).
3.7. (3aR,5R,7aR)-5-Acetyl-7a-methyl-3a,4,5,6,7,7a-hexahydro-2(3H)-benzofuranone 13
A solution of 12 (1.7 g, 9 mmol) in dichloromethane (60 mL) was cooled to −78°C. Ozone was
bubbled through the solution until a blue color developed. After 15 min, the excess of ozone was removed
with an O2 purge, and dimethyl sulfide (3 ml) was added. The solution was allowed to warm to 20°C and
stirred for 15 h. The solvent was removed under vacuum, and the residue partitioned between ether and
saturated brine. The organic phase was dried, filtered and concentrated to give a crude product which
was purified by flash chromatography (ether:AcOEt=1:1) to yield 1.64 g (93%) of 13, m.p. 74–76°C
(hexane:AcOEt), [α]D −17.9 (c=0.99, CHCl3). IR (CHCl3) νmax: 3057, 2942, 1773, 1707, 1448, 1096,
1
945, 737 cm−1. H NMR (CDCl3): δ 1.36 (s, 3H), 2.10 (s, 3H), 2.35–2.65 (m, 3H) ppm. 13C NMR
(CDCl3): δ 23.8 (t), 24.5 (q), 26.5 (t), 27.9 (q), 32.8 (t), 34.1 (t), 39.4 (d), 44.4 (d), 84.1 (s), 175.3 (s),
209.8 (s) ppm. MS (FAB), m/z (%): 197.1 (100), 179.1 (37), 154.0 (73), 107.0 (42), 92.9 (11).
3.8. (3aR,5R,7aR)-5-Acetoxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-2(3H)-benzofuranone 14
3-Chloroperoxybenzoic acid (3.2 g, 18.3 mmol) and sodium bicarbonate (1.54 g 18.3 mmol) were
added to a solution of methyl ketone 13 (1.8 g, 9.2 mmol) in 50 mL of dichloromethane. The mixture
was stirred at room temperature for two days with eventual addition of one equivalent of each reactant.
When the reaction finished, dichloromethane was added and the organic phase was washed with
aqueous solutions of 10% NaHSO3, 10% NaHCO3 and brine. The organic phase was dried on Na2SO4
and evaporated at reduced pressure to lead to a solid residue (2.1 g), which was purified by flash
chromatography (hexane:AcOEt=6:4) to yield 1.7 g (87%) of 14, m.p. 64–66°C (hexane), [α]D +3.7
(c=1.00, CHCl3). IR (CHCl3) νmax: 2945, 1778, 1732, 1381, 1250, 1101, 977 cm−1. 1H NMR (CDCl3):
δ 1.40 (s, 3H), 1.5–1.9 (m, 6H), 2.01 (s, 3H), 2.23–2.41 (m, 2H), 2.65–2.85 (dd, J=15.9 Hz, J=6.2 Hz;
1H), 4.93 (m, 1H) ppm. 13C NMR (CDCl3): δ 20.7 (q), 25.3 (q), 25.5 (t), 30.0 (t), 30.3 (t), 35.5 (t), 37.8
(d), 67.6 (d), 83.4 (s), 169.8 (s), 175.2 (s) ppm. MS (FAB) m/z (%): 213.1 (27), 153.1 (100), 108.7 (8),
92.9 (21), 78.5 (4).
3.9. (3aR,5R,7aR)-5-Hydroxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-2(3H)-benzofuranone 15
A solution of 14 (294.9 mg, 1.39 mmol) in 4 ml of methanol was added at 0°C to a solution of freshly
prepared NaOMe (82.6 mg, 1.53 mmol) in 4 ml of methanol. The reaction mixture was stirred for 45 min
and then the solvent was evaporated and the residue dissolved in water and extracted with ethyl acetate.

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The combined organic layers were washed with brine, dried (Na2SO4) and evaporated under vacuum.
The crude material was purified by flash chromatography (ether:AcOEt=1:1) to yield 69.7 mg (74%) of
15, m.p. 111–113°C (hexane:AcOEt), [α]D +2.1 (c=0.99, CHCl3). IR (CHCl3) νmax: 3453, 3057, 2938,
1
1759, 1265, 1094, 739 cm−1. H NMR (CDCl3): δ 1.46 (s, 3H), 1.47–1.98 (m, 6H), 2.32 (dd, J=16.3
Hz, J=7 Hz, 1H), 2.43 (quintet, 1H, J=7 Hz), 2.72 (dd, J=16.3 Hz, J=7 Hz, 1H), 3.99 (m, 1H) ppm. 13
C
NMR (CDCl3): δ 25.6 (q), 29.4 (t), 30.4 (t), 34.5 (t), 35.9 (t), 38.3 (d), 65.1 (d), 84.3 (s), 175.9 (s) ppm.
MS (FAB), m/z (%): 171.1 (100), 153.1 (65), 108.8 (35), 90.8 (62), 80.8 (15).
3.10. (3aR,5R,7aR)-5-tert-Butyldimethylsilyloxy-7a-methyl-3a,4,5,6,7,7a-hexahydro-2(3H)-
benzofuranone 16
To a solution of 15 (146.5 mg, 0.86 mmol) in 1 ml of dimethylformamide were successively added
imidazol (146.4 mg, 2.15 mmol) and tertbutyldimethylsilyl chloride (168.8 mg, 1.12 mmol). The mixture
was stirred for 1 h under an argon atmosphere and then 5 ml of an aqueous solution of NH4Cl were
added. After extraction with AcOEt the combined organic layers were washed with brine, dried (Na2SO4)
and evaporated at reduced pressure. The solid crude material was purified by flash chromatography
(hexane:AcOEt=9:1) to yield 245 mg (100%) of 16, m.p. 30–32°C (hexane), [α]D +6.2 (c=1.01, CHCl3).
IR (CHCl3) νmax: 2930, 2857, 1780, 1256, 1096, 1061, 1007, 837 cm−1. 1H NMR (CDCl3): δ 0.04 (s,
6H), 0.87 (s, 9H), 1.39 (s, 3H), 1.15–2.05 (m, 6H), 2.21 (dd, J=17.0 Hz, J=4.2 Hz, 1H), 2.34–2.48 (m,
1H), 2.79 (dd, J=17.0 Hz, J=7.1 Hz, 1H), 3.99 (m, 1H) ppm. 13C NMR (CDCl3): δ −4.8 (q), −4.9 (q),
18.0 (s), 25.6 (q), 25.7 (q), 25.8 (q), 26.2 (q), 29.1 (t), 29.6 (t), 35.6 (t), 36.5 (t), 37.3 (d), 65.4 (d), 84.4
(s), 176.2 (s) ppm. MS (FAB), m/z (%): 285.1 (19), 227.1 (16), 153.1 (100), 92.9 (55), 74.7 (68).
3.11. (3S,3aR,5R,7aR)-5-tert-Butyldimethylsilyloxy-3,7a-dimethyl-3a,4,5,6,7,7a-hexahydro-2(3H)-
benzofuranone 17 and (3R,3aR,5R,7aR)-5-tert-butyldimethylsilyloxy-3,7a-dimethyl-3a,4,5,6,7,7a-
hexahydro-2(3H)-benzofuranone 18
A solution of buthyllithium in hexane (1.9 mmol) was added dropwise to a solution of diisopropyl-
amine (0.3 ml, 2 mmol) in 3 ml of anhydrous tetrahydrofuran at 0°C. The reaction was stirred for 1 h
and then chilled to −78°C. A solution of 16 (260 mg, 1.3 mmol) in 3 ml of tetrahydrofuran was added
dropwise and the reaction mixture was stirred for 1 h at the same temperature. Hexamethylphosphor-
amide (0.33 ml, 1.9 mmol) was then added, followed by freshly distilled methyl iodide (0.12 ml, 2
mmol) and the reaction mixture was allowed to warm up to room temperature by sudden withdrawal
of the cold bath. The reaction was stirred for an additional 4 h at room temperature and then 5 ml of
an aqueous saturated solution of ammonium chloride was added and the reaction was extracted with
ethyl acetate. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated
at reduced pressure to afford a crude reaction product which was partitioned by flash chromatography.
Elution with hexane:ethyl acetate (9:1) enabled the successive isolation of 17 (5 mg, 2%) and 18 (230
1
mg, 98%) which exhibited the following physical properties: 17, [α]D +8.2 (c=1.1, CHCl3). H-NMR
(CDCl3): δ 0.04 (s, 6H), 0.9 (s, 9H), 1.1 (d, J=7 Hz, 3H), 1.4 (s, 3H), 1.5–2.1 (m, 6H), 2.4 (m, 1H), 3.1
(quintet, J=7 Hz, 1H), 4.1 (s, 1H) ppm. 13C NMR (CDCl3): δ −4.8 (q), −4.9 (q), 9.5 (q), 18.0 (s), 25.7
(q), 25.8 (q), 25.9 (q), 26.6 (q), 27.9 (t), 28.7 (t), 31.3 (t), 39.4 (d), 39.7 (d), 64.9 (d), 82.3 (s), 179.4 (s)
ppm. Analysis C16H30O3Si calc.: C, 64.38; H, 10.13; found: C, 64.32; H, 10.16. 18, m.p. 94–96°C; [α]D
+12.9 (c=1.1, CHCl3). 1H-NMR (CDCl3): δ 0.04 (s, 6H), 0.9 (s, 9H), 1.2 (d, J=7 Hz, 3H), 1.5 (s, 3H),
1.5–2.1 (m, 7H), 2.6 (quintet, J=7 Hz, 1H), 3.7 (m, 1H) ppm. 13C NMR (CDCl3): δ −4.7 (q), 4.8 (q),

R. Rico et al. / Tetrahedron: Asymmetry 9 (1998) 293–303
301
13.7 (q), 18.0 (s), 24.6 (q), 25.6 (q), 25.7 (q), 25.8 (q), 32.2 (t), 33.0 (t), 33.6 (t), 38.9 (d), 49.9 (d), 66.7
(d), 82.3 (s), 177.8 (s) ppm. Analysis C16H30O3Si calc.: C, 64.38; H, 10.13; found: C, 64.30; H, 10.15.
3.12. (3R,3aR,5R,7aR)-5-Hydroxy-3,7a-dimethyl-3a,4,5,6,7,7a-hexahydro-2(3H)-benzofuranone 19
Addition of Bu4NF·H2O (295 mg, 0.9 mmol) to a solution of 18 (254 mg, 0.9 mmol) in 10 ml
of anhydrous tetrahydrofuran was followed by stirring of the reaction mixture for 30 min at room
temperature. The organic solvent was evaporated at reduced pressure and the crude reaction product
was chromatographed on silica gel. Elution with diethyl ether:AcOEt (1:1) followed by evaporation of
the solvent afforded 157 mg (98%) of 19, m.p. 117–119°C (CHCl3), [α]D +3.0 (c=0.8, CHCl3). 1H-NMR
(CDCl3): δ 1.21 (d, J=7 Hz, 3H); 1.5 (s, 3H), 1.5–2.1 (m, 7H), 2.6 (quintet, J=7 Hz, 1H), 3.8 (m, 1H)
ppm. 13C NMR (CDCl3): δ 13.6 (q), 22.4 (q), 31.8 (t), 32.3 (t); 33.4 (t), 38.7 (d), 49.7 (d), 65.7 (d),
82.4 (s), 178.0 (s) ppm. MS (EI), m/z (%) 185.11 (1), 169.08 (9), 166.09 (43), 141.09 (24), 126.06 (54),
122.10 (100), 112.05 (20), 107.08 (65), 93.07 (46), 83.05 (56), 69.03 (35).
3.13. (3R,3aR,5R,7aR)-5-[(4-Methylbenzene)-1-sulfonyloxy]-3,7a-dimethyl-3a,4,5,6,7,7a-hexahydro-
2(3H)-benzo furanone 7
To a solution of 19 (154 mg, 0.8 mmol) in 5 ml of anhydrous dichloromethane, were successively
added pyridine (0.3 ml), dimethylaminopyridine DMAP (25 mg) and tosyl chloride (333 mg). The
reaction mixture was stirred overnight under an argon atmosphere at room temperature. An aqueous
saturated sodium bicarbonate solution (5 ml) was added and the reaction was stirred for 1 h, extracted
with dichloromethane and successively washed with 1 N HCl, sat. NaHCO3 and brine solutions. The
organic layer was dried on Na2SO4 and evaporated to afford a crude reaction mixture which was
chromatographed on silica gel. Elution with hexane:AcOEt (7:3) followed by evaporation of the solvent
afforded 220 mg (79%) of 7, m.p. 157–159 (AcOEt), [α]D +18.3 (c=1.0, CHCl3). 1H-NMR (CDCl3): δ
1.16 (d, J=7 Hz, 3H), 1.46 (s, 3H), 1.5–2.05 (m, 8H), 2.45 (s, 3H), 4.47–4.62 (m, 1H), 7.45 (d, J=8 Hz,
2H), 7.8 (d, J=8 Hz, 2H) ppm. 13C NMR (CDCl3): δ 13.7 (q), 21.5 (q), 24.4 (q), 28.9 (t), 29.7 (t), 33.0
(t), 38.6 (d), 49.2 (d), 81.2 (s), 127.6 (d), 129.9 (d), 134.4 (s), 144.9 (s), 177.0 (s) ppm. MS (EI), m/z (%):
338.11 (5), 167.10 (85), 122.10 (90), 107.08 (45), 91.05 (100), 65.03 (22).
3.14. (1R,3S,6R,9S)-6,9-Dimethyl-8-oxo-7-oxatricyclo-[4.3.0.03,9 ]nonane 1
A solution of buthyllithium in hexane (0.9 mmol) was added dropwise to a solution of diisopropyl-
amine (0.13 ml, 0.95 mmol) in 3 ml of anhydrous tetrahydrofuran at 0°C. The reaction was stirred for 1
h and then chilled to −78°C. A solution of 7 (212 mg, 0.6 mmol) in 2 ml of tetrahydrofuran was added
dropwise and the reaction mixture was stirred for 1 h at the same temperature. Hexamethylphosphor-
amide (0.15 ml) was then added and the reaction mixture was allowed to warm up to room temperature.
The reaction was quenched by addition of 5 ml of an aqueous sat. ammonium chloride solution and
extracted with ethyl acetate. The combined organic layers were washed with brine, dried on Na2SO4 and
the solvent evaporated to afford 89 mg (85%) of 1, m.p. 36–38°C (hexane), [α]D +48.0 (c=1.3, CHCl3).
1
IR (CHCl3): νmax 2930, 1765, 1451, 1381, 1250, 1082, 926, 754 cm−1. H-NMR (CDCl3) δ 1.36 (s,
3H); 1.46 (s, 3H), 1.68 (d, J=10 Hz, 1H), 1.9 (s, 4H), 2.21–2.43 (m, 3H) ppm. 13C NMR (CDCl3) δ
16.4 (q), 23.1 (t), 23.3 (t), 29.8 (t), 24.9 (q), 42.5 (d), 49.9 (d), 52.0 (s), 87.9 (s), 178.9 (s) ppm. Analysis
C10H14O2 calc.: C, 72.26; H, 8.49; found: C, 72.21; H, 8.52.

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Acknowledgements
Financial support of this work by the Junta de Castilla y León (SA22/97) and Ministerio de Educación
y Ciencia of Spain (DGICYT PB95-0943) is gratefully acknowledged.
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1
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