Enantioselective imine Michael reaction for the preparation of the (8′R,8a′S)-8,8a′-dimethyl-1′,3′,4′, 7′,8′,8a′-hexahydrospiro[1,3-dioxolane-2,2′(6′ H)naphthalen]-6′-one building block. A formal synthesis of (+)-valencenol

Article abstract of DOI:10.1016/S0957-4166(01)00289-0

The enantioselective Michael addition of a chiral imine of 4-protected 2-methylcyclohexane-1,4-dione to phenyl crotonate led after cyclization to the corresponding bicyclic lactam. Reductive cleavage of the chiral moiety followed by saponification gave th

Full text of DOI:10.1016/S0957-4166(01)00289-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1683–1688
Enantioselective imine Michael reaction for the preparation of
the (8%R,8a%S)-8,8a%-dimethyl-1%,3%,4%,7%,8%,8a%-hexahydrospiro-
[1,3-dioxolane-2,2%(6%H)naphthalen]-6%-one building block. A
formal synthesis of (+)-valencenol
Gilbert Revial,a Ivan Jabin,b Michae¨l Redolfia and Michel Pfaua,*
aLaboratoire de Chimie Organique, CNRS (ESA 7084), ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
bURCOM, Universite´ du Havre, Faculte´ des Sciences et Techniques, 25 rue Philippe Lebon, BP 540,
76058 Le Havre Cedex, France
Received 29 March 2001; accepted 22 June 2001
Abstract—The enantioselective Michael addition of a chiral imine of 4-protected 2-methylcyclohexane-1,4-dione to phenyl
crotonate led after cyclization to the corresponding bicyclic lactam. Reductive cleavage of the chiral moiety followed by
saponification gave the corresponding keto-acid, which was cyclized to afford a lactone. Belleau–Fujimoto reaction of the lactone
then led to the title building block (diastereoselectivity 96:4, e.e. >98%) in 11% overall yield from the starting dione.
(8R,8aS)-(+)-8,8a-Dimethyl-3,4,6,7,8,8a-hexahydronaphthalen-2(1H)-one was obtained after reduction of the carbonyl group,
acetylation, and reductive cleavage–deprotection (52% overall yield), representing a formal synthesis of (+)-valencenol. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
which could lead to valancane derivatives. However, as
has already been shown,1o trans-2-pentenone does not
react at room temperature with 2-methylcyclohexanone
imines, while above 60°C, polymerization of the enone
occurs. As a consequence, phenyl crotonate 3 was
chosen as a synthetic equivalent of trans-2-pentenone.3
The secondary enamine tautomers of imines formed
from a chiral non-racemic amine and a racemic 2-sub-
stituted carbonyl compound led, through enantioselec-
tive Michael reactions, to a variety of building blocks
bearing a quaternary stereogenic center and many syn-
thetic applications have been reported.1 In particular,
the (8a%R)-8a%-methyl-1%,3%,4%,7%,8%,8a%-hexahydrospiro-
[1,3 - dioxolane - 2,2%(6%H)naphthalen] - 6% - one building
block has been obtained from the chiral imine of 4-pro-
tected 2-methylcyclohexane-1,4-dione 1 and methyl-
vinylketone.2
2. Results and discussion
Imines 2 were obtained from the monoprotected dione
1
and (R)-2-methylbenzylamine. Phenyl crotonate
3 was reacted with the crude imine at 110°C for
seven days, leading to adduct 4 which under these
conditions cyclized spontaneously to give lactam 5a
and its isomers (vide infra) in 75% overall yield
(Scheme 1).
In the Michael reaction of a- or b-substituted elec-
trophilic olefins, a tertiary stereogenic center is created
in addition to the usual quaternary one.1e If a chiral
imine of the monoprotected dione 1 was reacted with
trans-2-pentenone rather than methylvinylketone, one
could anticipate the synthesis of the title building block,
Pure lactam 5a was obtained by recrystallization and its
relative configuration was determined by 1H NMR,
which shows that the two H atoms in the a-position of
the carbonyl group have vicinal coupling constants of
11.8 and 6.6 Hz (beside their geminal coupling), imply-
* Corresponding author. Fax: +33
1 40 79 46 60; e-mail:
michel.pfau@espci.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00289-0

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G. Re6ial et al. / Tetrahedron: Asymmetry 12 (2001) 1683–1688
Scheme 1.
ing that the tertiary methyl group is in an equatorial
orientation since compound 5a is rigid, with an axial
methyl group.4 The cis-relationship of the two methyl
groups is in accordance with the theoretical model
elaborated previously.1b,c In all reported examples1d,e,o
this model has allowed prediction of the stereochemical
relationships of substituents when substituted elec-
trophilic olefins were used (see also Note 3 in Ref. 1q).
The mass spectra of the five compounds (having tR at
8.01, 8.10, 8.21, 8.28, and 8.36 min) are different
from the mass spectrum of lactam 5a (tR 8.80 min)
and thus are assigned as regioisomers 5d.5 This
applies to the two compounds 6d having tR at 4.87
and 4.92 min in comparison with lactam 6a (tR 5.67
min). The mass spectra of the two compounds having
tR at 8.56 and 8.71 min are identical to the mass
spectrum of lactam 5a and are thus diastereoisomers.5
The signal for the compound in 1% proportion (tR
8.56 min) has no equivalent in the reduced mixture
and is thus the diastereoisomer 5b, which is converted
into the enantiomer of lactam 6a after cleavage.
Lastly, the impurities in both crude mixtures at levels
of 3% can only be the diastereomers 5c and 6c (Fig.
1).6
The next step involved conversion of the lactam 5a into
the title building block 9. After unfruitful results to
homologate lactam 5a, either with organometallic
reagents (CH3MgBr and CH3Li) or by a Wittig-type
reaction using Tebbe’s reagent, a Belleau–Fujimoto
reaction was envisaged. Thus, reductive cleavage of
lactam 5a led to lactam 6a, which was hydrolyzed to
keto-acid 7. Cyclization to lactone 8 was followed by
conversion to the target compound 9 in 38% yield from
lactam 5a (11% overall yield from ketone 1) (Scheme 1).
From the results above, it can be concluded that the
reaction has a good diastereoselectivity (ca. 96:4) and
a high enantioselectivity (e.e. >98%).
In order to determine the nature and proportions of the
isomers of lactam 5a (vide supra), GLC–MS analysis of
a sample of crude lactam 5a as well as one of crude
lactam 6a resulting from its reductive cleavage were
carried out, showing the presence of the isomeric com-
pounds described in Table 1.5
As an example of the utility of building block 9, the
synthesis of enone 12 was carried out; this represents
a formal synthesis of (+)-valenc-1(10)-en-7a-ol 14,7
natural product isolated from Bazziana fauriana.8
a
Table 1. GLC–MS analyses of crude lactams 5a and 6a
Crude lactam 5aa
Crude lactam 6aa
tR (min)
%
Compound (M+=341)
Regioisomers 5d
tR (min)
%
Compound (M+=237)
Regioisomers 6d
8.01
8.10
8.21
8.28
8.36
8.56
8.71
8.80
26
4.87
4.92
27
1
3
71
Diastereomer 5b
Diastereomer 5c
Lactam 5a
–
5.51
5.67
–
3
70
–
Diastereomer 6c
Lactam 6a
a See Experimental section for conditions.

G. Re6ial et al. / Tetrahedron: Asymmetry 12 (2001) 1683–1688
1685
Figure 1.
Compound 9 was reduced with sodium borohydride to
afford the alcohol 10 in 79% yield and with a diastereo-
selectivity ]99:1. The relative all-cis configuration
shown is given in analogy with that observed in similar
reactions,10 i.e. with the hydroxy group in an equatorial
orientation (Scheme 2).
carried out with silica gel (200–450 mesh), using EtOAc/
hexanes as eluents (proportions given) containing 2% of
Et3N. GLC–MS were performed with a HP 5890 GC
apparatus (equipped with a 12 m×0.20 mm dimethyl-
polysiloxane capillary column) linked to a HP 5971
EIMS. [h]D values are given in 10−1 deg cm2 g−1. 1H and
13C NMR spectra of CDCl3 solutions were recorded,
respectively, at 300 and 75.5 MHz. Chemical shifts are
expressed in ppm using TMS as internal standard and
coupling constants (J) are given in Hz. Anhydrous
solvents were freshly distilled under argon (ether and
THF over Na/benzophenone). All reactions were per-
formed under a nitrogen atmosphere. Unless indicated
otherwise, organic phases were washed with a saturated
NaCl aqueous solution, dried over MgSO4, filtered, and
evaporated under reduced pressure.
Acetylation (97% yield) of alcohol 10 led to compound
11, which was reduced with lithium in ethylamine. Under
these conditions, the protective group was unexpectedly
removed and a mixture of ketone 129 and alcohol 139 was
obtained. Oxidation of alcohol 13 with Jones reagent
yielded the ketone 12. The identity of compound 12 with
the known compound9 (in particular the positive sign of
the specific rotation) confirms the absolute configuration
of the cyclized adduct 5a, once again in accordance with
that predicted from the heuristic rule elaborated previ-
ously,1b,c which has applied without exception to date.1
4.2. 7-Methyl-1,4-dioxaspiro[4.5]decan-8-one 1
3. Conclusion
To a solution of diisopropylamine (13.5 mL, 96.3 mmol)
in anhydrous THF (50 mL) at −30°C was added a
solution of n-BuLi in hexanes (2.5 M, 35.9 mL, 89.7
mmol) over 15 min. A solution of commercial 1,4-cyclo-
hexanedione mono-ethyleneketal (10.0 g, 64.0 mmol) in
THF (23 mL) was then added dropwise at −78°C and
after 30 min MeI (12.0 mL, 193 mmol) was rapidly added.
The temperature was raised to rt and the THF distilled
under reduced pressure. A small amount of water was
added to the residue and ether extraction followed by FC
(1:9) afforded ketone 1 (7.74 g, 45.5 mmol, 71%). A
sample was recrystallized; mp 48.5°C (pentane); IR11
The first enantioselective synthesis of ketone 12 (a direct
precursor of valencenol 14) has been accomplished from
building block 9 in 52% overall yield.
4. Experimental
4.1. General
TLC was performed with glass plates (0.25 mm) pre-
coated with silica gel and flash chromatography (FC) was
1
(Nujol) 1720 (CꢀO) cm−1; H NMR:11 l 1.03 (3H, d,
Scheme 2.

1686
G. Re6ial et al. / Tetrahedron: Asymmetry 12 (2001) 1683–1688
J=6.6 Hz, CH3CH), 1.73 (1H, dd, J=13, 13 Hz,
CH3CHCHHax), 1.90–2.13 (3H, m, CH3CHCHeqH+
COCH2CH2), 2.34 (1H, ddd, J=3.0, 5.0, 14.4 Hz,
COCHeqH), 2.58–2.82 (2H, m, COCHHax+CH3CH),
3.98–4.09 (4H, m, OCH2CH2O); 13C NMR: l 14.12
(CH3), 34.47 (CH2), 37.80 (CH2), 41.08 (CH), 42.56
(CH2), 64.42 (CH2), 64.53 (CH2), 107.2 (Cq), 211.6 (Cq);
EIMS (m/z): 170 (M+, 8%), 113 (42), 100 (30), 99 (100),
69 (10), 55 (17); HRMS: calcd for C9H14O3 (M+):
170.0945, found: 170.0943.
J=7.4 Hz, CH3CHPh), 7.18–7.35 (5H, m, Ph); 13C
NMR: l 14.49 (CH3), 15.23 (CH3) 15.63 (CH3), 34.89
(CH2), 36.78 (CH), 37.56 (CH2), 38.47 (Cq), 42.83
(CH2), 50.68 (CH), 63.95 (CH2), 64.45 (CH2), 106.5
(CH), 107.2 (Cq) 125.9 (2CH), 126.4 (CH), 128.4
(2CH), 139.9 (Cq), 142.3 (Cq), 169.2 (Cq); EIMS (m/z):
341 (M+, 11%), 255 (19), 152 (11), 151 (100), 136 (60),
105 (38), 87 (29); anal. calcd for C21H27NO3: C, 73.87;
H, 7.97. Found: C, 73.9; H, 8.0%.
4.5. (4%R,4a%S)-(−)-4%,4a%-Dimethyl-1%,3%,4%,4a%,5%,7%-hexa-
hydrospiro[1,3-dioxolane-2,6%(2%H)-quinolein]-2%-one 6a
4.3. N-{(R,S)-9-Methyl-1,4-dioxaspiro[4.5]decan-8-yli-
den}-(R)-1-phenylethylamine 2
To liquid NH3 (250 mL) at −78°C was added a solution
of lactam 5a (5.43 g, 15.9 mmol) in anhydrous THF
(100 mL). Li (0.560 g, 80.0 mmol) was then added and
the mixture was stirred for 1 h. Styrene was added until
discoloration occurred and NH3 was evaporated. After
addition of NH4Cl (3 g) and water (30 mL), ether
extraction followed by FC (3:7, then 3:2) afforded
lactam 6a (3.24 g, 13.7 mmol, 86%) as a crystalline
solid; mp 84°C (cycohexane); [h]2D0=−91 (c 2.7, EtOH);
A solution of ketone 1 (7.25 g, 42.6 mmol) and (R)-(+)-
1-phenylethylamine (e.e.=95%, 5.49 mL, 1 equiv.) in
toluene (30 mL) was heated under reflux in a Dean–
Stark apparatus for 16 h. After removal of the solvent
under reduced pressure, crude imine 2 (11.7 g) was
isolated. An analytical sample was obtained by distilla-
tion: bp 90°C (bath)/0.02 Torr; IR (neat): 1640 (CꢀN)
cm−1; 1H NMR (C6D6) (50:50 mixture of two
diastereomers): l 1.11–2.09 (5H, m, cyclohexane ring),
1.23+1.25 (3H, 2d, J=6.6 Hz, CH3CHCH2), 1.36+1.38
(3H, 2d, J=6.6 Hz, CH3CHPh), 2.54–2.74 (2H, m,
cyclohexane ring), 3.43–3.57 (4H, m, OCH2CH2O) 4.58
(1H, 2q, J=6.6 Hz, CH3CHPh), 7.04–7.48 (5H, m, Ph);
13C NMR (C6D6) (50:50 mixture of two diastereomers):
l 17.68 (CH3), 25.85 (CH2) 26.04+26.83 (CH3), 35.47+
36.20 (CH2), 39.45+40.65 (CH), 44.79+44.91 (CH2),
59.06 (CH), 65.00 (CH2), 65.04 (CH2), 108.7 (Cq),
126.5–129.3, 147.9+148.1 (Cq), 171.0+171.2 (Cq); EIMS
(m/z): 273 (M+, 7%), 187 (12), 126 (20), 115 (11), 106
(10), 105 (100).
1
IR (Nujol): 1675 (CꢀO), 1645 (CꢀC) cm−1; H NMR: l
0.91 (3H, d, J=6.6 Hz, CH3CH), 1.18 (3H, s,
CH3Cquat), 1.63 (1H, d, J=13.6 Hz, CquatCHHCquat),
1.86 (1H, ddq, J=6, 6, 12 Hz, CH3CHCH2), 1.88 (1H,
dd, J=2.2, 13.6 Hz, CquatCHHCquat), 2.23 (1H, dd,
J=12.1, 18.4 Hz, COCHHax), 2.27–2.47 (3H, m,
COCHeqH+CH2CHꢀC),
3.90–4.10
(4H,
m,
OCH2CH2O), 4.80 (1H, dd, J=3.0, 4.8 Hz, CꢀCH),
7.53 (1H, s, NH); 13C NMR: l 13.85 (CH3), 15.08
(CH3), 34.47 (CH2), 36.15 (Cq), 36.26 (CH), 36.72
(CH2), 42.21 (CH2), 63.63 (CH2), 64.37 (CH2), 101.1
(CH), 107.6 (Cq), 139.5 (Cq), 170.2 (Cq); EIMS (m/z):
237 (M+, 13%), 151 (78), 137 (10), 136 (100), 108 (10),
87 (33); HRMS: calcd for C13H19NO3 (M+): 237.1365,
found: 237.1362.
4.4. (4%R,4a%S)-(−)-4%,4a%-Dimethyl-1%-[(1R)-1-phenyl-
ethyl]-1%,3%,4%,4a%,5%,7%-hexahydrospiro[1,3-dioxo-
lane-2,6%(2%H)-quinolein]-2%-one 5a
A sample of the mixture of lactam 5a and its isomers
(vide supra) was reduced in the same conditions as
above to a mixture of lactam 6a and its isomers, and a
GLC–MS analysis was carried out at 180°C for 2 min,
then heating at 16°C/min up to 290°C (see Table 1).
The crude imine 2, phenyl crotonate 31e (8.16 g, 50.3
mmol) and a trace of hydroquinone were heated with-
out solvent at 110°C for 7 days. (GLC–MS analysis of
the crude mixture was carried out at 180°C for 2 min,
then heating at 16°C/min to 290°C, see Table 1.) Ether
(30 mL) and aqueous NaOH (2.5 M, 20 mL) were then
added to the crude mixture which was stirred at rt for
15 min. After ether extraction and FC (1:4), a mixture
of lactam 5a and its isomers (10.9 g, 31 mmol, 75%
overall yield from ketone 1) was obtained. The mixture
was then crystallized to give pure lactam 5a (5.50 g,
16.1 mmol, 38% yield from ketone 1); mp 154–155°C
(hexane); [h]2D0=−53 (c 1.4, EtOH); IR (Nujol) 1670
(CꢀO), 1645 (CꢀC) cm−1; 1H NMR: l 0.90 (3H, d,
J=6.6 Hz, CH3CHCH2), 1.10 (3H, s, CH3Cquat), 1.61
(3H, d, J=7.4 Hz, CH3CHPh), 1.65 (1H, d, J=15 Hz,
CquatCHHCquat), 1.86 (1H, dd, J=1.5, 13.6 Hz,
CquatCHHCquat), 1.99 (1H, ddq, J=7, 7, 11.8 Hz,
CH3CHCH2), 2.16–2.33 (2H, m, CH2CHꢀC), 2.28 (1H,
dd, J=11.8, 18.4 Hz, COCHHax), 2.68 (1H, dd, J=6.6,
18.4 Hz, COCHeqH), 3.88–4.04 (4H, m, OCH2CH2O),
4.74 (1H, dd, J=4.7, 4.8 Hz, CꢀCH), 6.28 (1H, q,
4.6. (bR,7S)-b,7-Dimethyl-8-oxo-1,4-dioxaspiro[4.5]-
decane-7-propanoic acid 7
Lactam 6a (2.99 g, 12.6 mmol) was dissolved in ethanol
(20 mL) and a solution of KOH (7.0 g, ca. 8 equiv.) in
ethanol (56 mL) was added to the mixture, which was
then heated at reflux for 8 h. Cooling to 0°C was
followed by the addition of water (10 mL) and a 6N
aqueous HCl solution was then slowly added to give
pH 1. After CH2Cl2 extraction, crude keto-acid 7 (3.04
g) was isolated. From 0.15 g of the crude keto-acid, an
analytical sample was obtained by FC (3:2, then
MeOH) followed by molecular distillation; bp 140°C
1
(bath)/0.02 Torr; H NMR (CD3OD): l 1.14 (3H, d,
J=6.6 Hz, CH3CH), 1.17 (3H, s, CH3Cquat), 1.87 (1H,
dd, J=1.1, 14.3 Hz, CquatCHHCquat), 2.03–2.38 (5H,
m), 2.60 (1H, ddd, J=6, 6, 15 Hz, COCH2CHH),
2.86–3.04 (2H, m), 4.10–4.25 (4H, m, OCH2CH2O); 13C
NMR (CD3OD): l 9.46 (CH3), 15.32 (CH3), 20.35
(CH), 37.16 (CH2), 38.35 (CH2), 43.54 (CH2), 47.97

G. Re6ial et al. / Tetrahedron: Asymmetry 12 (2001) 1683–1688
1687
(CH2), 52.11 (Cq), 65.55 (CH2), 66.08 (CH2), 108.9 (Cq),
4.9. (6%S,8%R,8a%S)-(+)-8,8a%-Dimethyl-3%,4%,6%,7%,8%,8a%-
177.6 (Cq), 217.0 (Cq); EIMS (m/z): 256 (M+, 3%), 199
(11), 197 (12), 169 (30), 113 (12), 100 (35), 99 (100), 87
(10), 86 (36); HRMS: calcd for C13H21O5 (M++1):
257.1389, found: 257.1381.
hexahydrospiro[1,3-dioxolane-2,2%(1%H)naphthalen]-6%-ol
10
A solution of NaBH4 (17 mg, 0.45 mmol) in ethanol (3
mL) cooled to 0°C, was slowly added to a solution of
enone 9 (421 mg, 1.78 mmol) in ethanol (7.5 mL). After
30 min, a GLC–MS analysis (140°C for 2 min, then
16°C/min up to 290°C) showed a single signal at 6.79
min. The solvent was evaporated under reduced pres-
sure and the residue extracted with ether. The solid thus
obtained was recrystallized from ethyl acetate affording
alcohol 10 (335 mg, 1.41 mmol, 79% yield); mp 149–
150°C (AcOEt); [h]2D0=+50 (c 1.3, acetone); IR (Nujol):
4.7. (4R,4aS)-(−)-4,4a-Dimethyl-3,4,4a,5-tetrahydro-
spiro{2H-1-benzopyran-6(7H),2%-[1%,3%]dioxolan}-2-one 8
Crude keto-acid 7 (2.89 g) was added to a solution of
AcONa (98 mg) in Ac2O (50 mL) and the mixture was
heated at reflux for 2 h. After distillation of Ac2O under
reduced pressure, ether extraction followed by washing
with a saturated Na2CO3 aqueous solution and FC
(1:4), lactone 8 (1.26 g, 5.29 mmol, 44% yield from
lactam 6a) was obtained and recrystallized; mp 82°C
(AcOEt/hexane, 1:4); [h]2D0=−68 (c 1.5, EtOH); IR
(Nujol): 1750 (CꢀO), 1685 (CꢀC) cm−1; 1H NMR: l
0.91 (3H, d, J=6.6 Hz, CH3CH), 1.16 (3H, s,
CH3Cquat), 1.72 (1H, d, J=13.2 Hz, CquatCHHCquat),
1.88 (1H, dd, J=2.2, 13.6 Hz, CquatCHHCquat), 1.99
(1H, ddq, J=7, 7, 13 Hz, CH3CH), 2.26–2.45 (3H, m,
CH2CHꢀC+COCHH), 2.66 (1H, dd, J=6.3, 18.8 Hz,
COCHeqH), 3.90–4.05 (4H, m, OCH2CH2O), 5.19 (1H,
dd, J=2.5, 4.8 Hz, CꢀCH); 13C NMR: l 13.85 (CH3),
14.82 (CH3), 33.88 (CH2), 35.02 (CH2), 35.90 (CH),
35.98 (Cq), 42.57 (CH2), 63.95 (CH2), 64.42 (CH2),
102.4 (CH), 107.1 (Cq) 153.8 (Cq), 167.7 (Cq); EIMS
(m/z): 238 (M+, 18%), 152 (14), 109 (11), 87 (23), 86
(100), 69 (11), 55 (14); HRMS: calcd for C13H18O4
(M+): 238.1205, found: 238.1205.
1
3440 (OH) cm−1; H NMR (CD3COCD3): l 0.85 (3H,
d, J=6.6 Hz, CH3CH), 1.04 (3H, br s, CH3Cquat), 1.23
(1H, d, J=13.6 Hz, CquatCHHCquat), 1.30–1.56 (3H,
m), 1.66 (1H, dddd, J=1, 1, 5.9, 11.8 Hz,
CH(OH)CHHeqCHCH3), 1.79 (1H, dddd, J=3, 3, 5.5
and 12.9, CꢀCCHCHeqH), 1.92 (1H, dd, J=2.9, 13.6
Hz, CquatCHeqHCquat), 2.02 (1H, ddd, J=2.6, 4.4, 14.0
Hz, CꢀCCHeqH), 2.47 (1H, ddddd, J=2, 2, 4, 14, 14
Hz, CꢀCCHaxH), 3.56 (1H, d, J=6.3 Hz, CHOH),
3.82–3.99 (4H, m, OCH2CH2O), 4.10–4.19 (1H, m,
CHOH), 5.34 (1H, d, J=1.8 Hz, CꢀCH); 13C NMR
(DMSO-d6): l 15.45 (CH3), 18.60 (CH3), 29.35 (CH2),
35.44 (CH2), 36.42 (CH2), 37.88 (Cq), 39.41 (CH), 46.23
(CH2), 62.95 (CH2), 64.13 (CH2), 65.86 (CH), 108.37
(Cq), 126.63 (CH), 141.92 (Cq); EIMS (m/z): 238 (M+,
34%), 177 (16), 176 (100), 161 (63), 152 (21), 140 (17),
137 (40), 136 (84), 123 (31), 121 (33), 119 (32), 109 (25),
99 (98), 91 (27), 87 (64), 86 (60).
4.10. (6%S,8%R,8a%S)-8,8a%-Dimethyl-3%,4%,6%,7%,8%,8a%-hexa-
hydrospiro[1,3-dioxolane-2,2%(1%H)naphthalen]-6%-yl
acetate 11
4.8. (8%R,8a%S)-(+)-8,8a%-Dimethyl-1%,3%,4%,7%,8%,8a%-hexa-
hydrospiro[1,3-dioxolane-2,2%(6%H)naphthalen]-6%-one 9
At −78°C, a solution of n-BuLi in hexanes (2.5 M, 1.97
mL, 4.93 mmol) was slowly added to a solution of
CH3P(O)(OCH3)2 (0.60 mL, 5.53 mmol) in anhydrous
THF (15 mL). After 5 min, a solution of lactone 8 (0.78
g, 3.27 mmol) in THF (10 mL) was added and the
temperature was raised to −20°C. After 3.5 h, water (3
mL) was added and the mixture was extracted with
ether. A FC (1:4) afforded enone 9 (0.59 g, 2.50 mmol,
76%), which was recrystallized; mp 136.5°C (hexane/
AcOEt, 7:3); [h]2D0 +180 (c 1.2, EtOH); IR (Nujol): 1660
(CꢀO) cm−1; 1H NMR: l 0.95 (3H, d, J=6.8 Hz,
CH3CH), 1.20 (3H, br s, CH3Cquat), 1.49 (1H, d, J=
13.6 Hz, CquatCHHCquat), 1.65 (1H, ddd, J=4.4, 12.9,
14.7 Hz, CꢀCCH2CHH), 1.88–1.96 (1H, m), 2.00 (1H,
dd, J=2.6, 13.6 Hz, CquatCHHCquat), 2.02 (1H, ddq,
J=7, 7, 13 Hz, CH3CH), 2.22–2.38 (3H, m), 2.76 (1H,
dddd, J=2.2, 5.2, 15, 15 Hz, CꢀCCHaxH), 3.92–4.06
(4H, m, OCH2CH2O), 5.80 (1H, d, J=1.5 Hz,
COCHꢀC); 13C NMR: l 14.75 (CH3), 17.32 (CH3),
30.46 (CH2), 34.32 (CH2), 39.63 (Cq), 40.96 (CH), 41.53
(CH2), 45.70 (CH2), 63.74 (CH2), 64.65 (CH2), 108.09
(Cq), 124.73 (CH), 169.10 (Cq), 199.28 (Cq); EIMS
(m/z): 236 (M+, 67%), 221 (10), 194 (28), 193 (27), 166
(15), 110 (14), 107 (23), 99 (75), 93 (17), 91 (27), 87 (27),
86 (100); anal. calcd for C14H20O3: C, 71.16; H, 8.53,
found: C, 71.2; H, 8.50%.
Ac2O (0.10 mL, 1.06 mmol) was added to a solution of
alcohol 10 (211 mg, 0.886 mmol) in pyridine (0.4 mL)
at rt. After 16 h, a FC (1:9) afforded acetate 11 (240
mg, 0.857 mmol, 97% yield) as a colorless oil; IR (neat):
1
1730 (CꢀO) cm−1; H NMR: l 0.86 (3H, d, J=6.6 Hz,
CH3CH), 1.07 (3H, br s, CH3Cquat), 1.30 (1H, d, J=
13.6 Hz, CquatCHHaxCquat), 1.39–1.60 (3H, m), 1.74–
1.83 (2H, m), 1.90 (1H, dd, J=2.9, 13.6 Hz,
CquatCHeqHCquat), 2.02 (3H, s, CH3COO), 2.07 (1H,
ddd, J=2.6, 4.8, 14.0 Hz, HCꢀCCHeqH), 2.50 (1H,
ddddd, J=2, 2, 4, 14, 14 Hz, HCꢀCCHHax), 3.8–4.0
(4H, m, OCH2CH2O), 5.27–5.34 (2H, m, CꢀCH and
COOCH); 13C NMR: l 15.18 (CH3), 18.49 (CH3),
21.23 (CH3), 29.75 (CH2), 31.94 (CH2), 35.35 (CH2),
38.30 (Cq), 39.48 (CH), 46.29 (CH2), 63.47 (CH2), 64.49
(CH2), 70.63 (CH), 108.84 (Cq), 120.30 (CH), 146.71
(Cq), 170.76 (Cq); EIMS (m/z): 280 (M+, 5%), 238 (25),
178 (37), 176 (45), 161 (24), 152 (62), 136 (36), 119 (47),
103 (50), 99 (100), 86 (54).
4.11. (8R,8aS)-(+)-8,8a-Dimethyl-3,4,6,7,8,8a-hexa-
hydronaphthalen-2(1H)-one 12 and (8R,8aS)-8,8a-
dimethyl-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-ol 13
At 0°C, Li chips were slowly added to a solution of
acetate 11 (195 mg, 0.696 mmol) in ethylamine (10 mL).

1688
G. Re6ial et al. / Tetrahedron: Asymmetry 12 (2001) 1683–1688
After appearance of the blue coloration, the mixture
was maintained at 0°C for 1 h and styrene was added
until discoloration occurred. A GLC–MS analysis
(140°C for 2 min, then 16°C/min up to 290°C) showed
two signals at 3.48 min (ketone 12) and 3.62 min
(alcohol 13). NH4Cl (35 mg) was then added to the
mixture and the ethylamine was evaporated at rt. Water
(1 mL) was added to the residue, which was extracted
with ether. A FC (1:4 then 2:3) afforded ketone 12 (37
mg, 0.208 mmol, 30%) and alcohol 13 (54 mg, 0.300
mmol, 43%).
Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459–505;
(j) D’Angelo, J.; Cave´, C.; Desmae¨le, D.; Dumas, F.
Trends Org. Chem. 1993, 4, 555–616; (k) Guingant, A.
Advances in Asymmetric Synthesis; JAI Press Inc., Vol. 2,
1997; pp. 119–188 (see pp. 159–170). Recent develop-
ments and applications: (m) Jabin, I.; Revial, G.; Mel-
loul, K.; Pfau, M. Tetrahedron: Asymmetry 1997, 8,
1101–1109 and Reference 1 included; (n) Cossy, J.;
Bouzide, A.; Pfau, M. J. Org. Chem. 1997, 62, 7106–
7113; (o) Revial, G.; Jabin, I.; Pfau, M. Tetrahedron:
Asymmetry 2000, 11, 4975–4983 and Reference
1
included; (p) Jabin, I.; Revial, G.; Pfau, M.; Decroix, B.;
Netchita¨ılo, P. Org. Lett. 1999, 1, 1901–1904; (q) Revial,
G.; Lim, S.; Viossat, B.; Lemoine, P.; Tomas, A.; Duprat,
A. F.; Pfau, M. J. Org. Chem. 2000, 65, 4593–4600; (r)
Christoffers, J.; Ro¨ssler, U.; Werner, T. Eur. J. Org.
Chem. 2000, 701–705; (s) Muri, E.; Kanazawa, A.; Bar-
reiro, E.; Greene, A. E. J. Chem. Soc., Perkin Trans. 1
2000, 731–735; (t) Toyota, M.; Wada, T.; Ihara, M. J.
Org. Chem. 2000, 65, 4565–4570; (u) Takahashi, M.;
Dodo, K.; Hashimoto, Y.; Shirai, R. Tetrahedron Lett.
2000, 41, 2111–2114; (v) Christoffers, J.; Mann, A.
Angew. Chem., Int. Ed. 2000, 39, 2752–2754; (w) Tori,
M.; Aiba, A.; Koyama, H.; Hashimoto, T.; Nakashima,
K.; Sono, M.; Asakawa, Y. Tetrahedron 2000, 56, 1655–
1659; (x) Schenato, R. A.; dos Santos, E. M.; Tenius, B.
S. M.; Costa, P. R. R.; Caracelli, I.; Zukerman-Schpec-
tor, J. Tetrahedron: Asymmetry 2001, 12, 579–584; (y)
Jabin, I.; Revial, G.; Monnier-Benoit, N.; Netchita¨ılo, P.
J. Org. Chem. 2001, 66, 256–261.
Ketone 12: colorless oil; [h]2D0=+113 (c 1.4, EtOH) [lit.,9
[h]2D0=+122.2 (c 2.70, CHCl3)]; IR (neat): 1710 (CꢀO)
1
cm−1 [lit.,9 1705]; H NMR [lit.,9 identical spectrum];
13C NMR: l 15.43 (CH3), 18.76 (CH3), 25.58 (CH2),
26.65 (CH2), 32.10 (CH2), 40.35 (CH), 41.66 (CH2),
41.68 (Cq), 53.60 (CH2), 122.68 (CH), 139.21 (Cq),
211.77 (Cq); EIMS (m/z): 178 (M+, 71%), 163 (39), 136
(48), 122 (32), 121 (38), 120 (31), 107 (41), 105 (39), 95
(21), 94 (37), 93 (67), 91 (44), 79 (100), 77 (43) [lit.,9
EIMS (m/z): 178 (M+, base), 163, 136, 121, 107, 93, 79].
Alcohol 13: colorless oil; IR (neat): 3320 (OH) cm−1
1
[lit.,9 3300]; H NMR: l [lit.,9 identical spectrum]; 13C
NMR: l 15.47 (CH3), 18.66 (CH3), 25.68 (CH2), 26.42
(CH2), 30.87 (CH2), 36.90 (CH2), 38.17 (Cq), 40.70
(CH), 48.33 (CH2), 67.73 (CH), 120.88 (CH), 141.27
(Cq); EIMS (m/z): 180 (M+, 10%), 162 (56), 147 (100),
121 (24), 120 (31), 119 (26), 107 (25), 105 (67), 93 (35),
92 (22), 91 (49), 79 (51), 77 (26), 67 (20), 55 (24) [lit.,9
EIMS (m/z): 180 (M+), 162, 147, 120, 105 (100)].
2. Pfau, M.; Jabin, I.; Revial, G. J. Chem. Soc., Perkin
Trans. 1 1993, 1935–1936.
3. Phenyl crotonate has been shown to be much more
reactive than methyl crotonate.1e,o,y
4.12. Oxidation of alcohol 13 to ketone 12
4. The same situation has already been encountered with
Jones reagent (H2CrO4/H2SO4, 0.09 mL) was added at
0°C to a solution of alcohol 13 (32 mg, 0.177 mmol) in
acetone (1 mL). After 1 h, acetone was evaporated
under reduced pressure and a FC (1:4) afforded ketone
12 (28 mg, 0.157 mmol, 89%, yield=38% from acetate
11). Thus ketone 12 was obtained in 68% combined
yield.
similar structures.1d,e,o
5. This methodology is fully illustrated for similar exam-
ples.1d,e,o
6. The other possible trans-diastereomer corresponding to
5c can be disregarded since it would result from a reac-
tion having both a low enantioselectivity and a low
diastereoselectivity.
7. No total enantioselective synthesis of valencenol is
reported in the literature. Only one hemi-synthesis start-
ing from (+)-nootkatone, in nine steps and 0.2% overall
yield, is reported, involving in the last step a Grignard
reaction of enone 12 with isopropylmagnesium bromide
leading to (+)-valencenol 14 (40% yield).9
8. Toyota, M.; Asakawa, Y. Phytochemistry 1988, 27, 2155–
2159.
9. Tori, M.; Tsuyama, N.; Nakashima, K.; Sono, M.;
Asakawa, Y. J. Chem. Res. (S) 1990, 164–165.
10. Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103,
5454–5459. Ref. 1m.
11. Compound 1 has already been reported but with 1740
cm−1 (as well as 1720 cm−1) for its IR spectrum and with
17 H rather than 14 H for its 1H NMR spectrum:
Kozikowski, A. P.; Campiani, G.; Sun, L.-Q.; Wang, S.;
Saxena, A.; Doctor, B. P. J. Am. Chem. Soc. 1996, 118,
11357–11362.
References
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(KIREX) 1985, PCT WO 85 04873. Mechanisms: (b)
Sevin, A.; Tortajada, J.; Pfau, M. J. Org. Chem. 1986, 51,
2671–2675; (c) Sevin, A.; Masure, D.; Giessner-Prettre,
C.; Pfau, M. Helv. Chim. Acta 1990, 73, 552–573; (d)
Pfau, M.; Tomas, A.; Lim, S.; Revial, G. J. Org. Chem.
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Lemoine, P.; Pfau, M. Tetrahedron: Asymmetry 1995, 6,
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