Cationic cyclization of keto-epoxides mediated by zirconium(IV) tetrachloride: Diastereoselective synthesis of cis-decalinols

Article abstract of DOI:10.1016/j.tet.2011.08.050

10-Methyl-cis-9-decalinols are important motifs in several natural products and key intermediates in total synthesis. Herein, we wish to describe a highly chemo- and diastereoselective cyclization of keto-epoxides leading to 10-methyl-cis-9-decalinols. Th

Full text of DOI:10.1016/j.tet.2011.08.050

Tetrahedron 67 (2011) 8373e8382
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Cationic cyclization of keto-epoxides mediated by zirconium(IV) tetrachloride:
diastereoselective synthesis of cis-decalinols
,
Sylvie Goncalves a, Marc Nicolas b, Philippe Maillos b, Rachid Baati a
*
a
ꢀ
ꢀ
ꢁ
Universite de Strasbourg, Faculte de Pharmacie, CNRS/UMR 7199, Laboratoire des Systemes Chimiques Fonctionnels, 74 route du Rhin BP 60024, 67401 Illkirch, France
Les Laboratoires Pierre Fabre, Centre de Developpement Chimique et Industriel, 16 rue Jean Rostand, 81600 Gaillac, France
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2011
Received in revised form 18 August 2011
Accepted 18 August 2011
Available online 25 August 2011
10-Methyl-cis-9-decalinols are important motifs in several natural products and key intermediates in
total synthesis. Herein, we wish to describe a highly chemo- and diastereoselective cyclization of keto-
epoxides leading to 10-methyl-cis-9-decalinols. This method based on the use of zirconium(IV) tetra-
chloride permits the access to a wide variety of cis-decalinols in good to excellent yields. The cationic
cyclization could also be performed with chiral keto-epoxide with complete control of the diaster-
eoselectivity affording cis-bicyclic tertiary alcohol with good enantiomeric excess. The chemo- and the
diastereoselectivity are assumed to result from the ability of Zr(IV) to generate highly stable bidentic
Keywords:
Cationic cyclization
Keto-epoxide
Diastereoselectivity
Chemoselectivity
cis-9-Decalinol
complexes with a-hydroxy-ketone intermediates.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
condensation of cyclic ketones onto methylvinylketone followed by
direct intramolecular aldolization reaction, affording bicyclic ketols
in one-pot. The direct intramolecular aldolization of dicarbonyl
systems has also been used recently by Nakada to construct highly
functionalized bicyclic tertiary alcohols towards (ꢁ)-scabrone.12
Besides these approaches, the copper-catalyzed domino re-
ductive- or conjugated addition/indirect intramolecular aldol cy-
clizations developed by Riant,13 Node14 and Renaud15 gave
successfully access to a wide range of 10-methyl-cis-9-decalinols in
an efficient manner. Quite recently Sakai et al. reported the use of
an umpolung NHC-catalyzed intramolecular crossed benzoin re-
action of cyclic 1,3-diketone aldehydes yielding, however in some
instance, only moderate yields of 10-methyl-cis-9-decalinols.16
Cascade cyclizations of naphthyl-substituted 1,3-diketones medi-
ated by excess samarium diiodideehexamethylphosphoramide
complex was also described for the preparation of steroid-like
compounds.17 Additionally, the regioselective CeH bond oxidation
of 10-methyl-cis-9-decalin could also be used for synthesizing 10-
methyl-cis-9-decalinol, however only in low to moderate yields
upon treatment with dimethyldioxirane or ruthenium porphyrin-
2,6-dichloropyridine N-oxide system as oxidative agent.18 Finally,
the last important methodology developed three decades ago by
Sutherland et al. is based on the intramolecular oxygen-directed
carbocyclization of keto-epoxides under Lewis acid conditions.19
However, cyclization results described so far are plagued with
limitations, such as moderate yields and low chemoselectivity, due
to the formation of ring contraction by-products leading to com-
plex reaction mixtures.19g Although important progress in this area
In the course of our research program devoted to the total
synthesis of (ꢀ)-triptolide 1,1,2 a natural product exhibiting an im-
pressive array of biological activities, we were interested in the
preparation of 10-methyl-cis-9-decalinol 2 (cis-configuration with
respect of the vicinal arrangement of the hydroxyl-group and the
methyl group) as key common intermediate to access 1, and for the
synthesis of cis-analogues library (Fig. 1). It is well known that
dehydration of cis-3 and trans-9-decalinol4 derivatives followed by
hydrogenolysis lead to trans-decalin skeletons highly stereo-
selectively, validating our convergent and modular approach for the
synthesis of 1. 10-Methyl-cis-9-decalinols are also prominent
structural motifs found in numerous terpenoid natural products,5,6
such as polypodine B 3,7 48 and 5.9 Additionally, substituted cis-
bicyclic ketols surrogates are often used as versatile intermediates
in a great number of total synthesis of natural compounds,3,10
highlighting the crucial importance of these molecules in organic
chemistry, and therefore the need for the development of selective
strategies for their efficient preparation.
To address these issues, methodologies giving access to 10-
methyl-cis-9-decalinols stereoselectively have been reported in
literature.12ꢁ19 The most common approach, pioneered by Fanta et
al., is a modified Robinson annelation3,10,11 based on the in situ
* Corresponding author. Tel.: þ33 368 854 301; fax: þ33 368 854 306; e-mail
address: baati@bioorga.u-strasbg.fr (R. Baati).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.050

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S. Goncalves et al. / Tetrahedron 67 (2011) 8373e8382
O
O
Me
H
O
Me
OH
cis-(+/-)-triptolide
OMe
analogues
O
OH
O
O
1
2
(-)-triptolide:
10-methyl-cis-decalinol:
O
O
OH
H
OH
H
O
OH
O
O
HO
HO
O
H
H
O
OH OH
OH
HO
HO
HO
O
4
5
3
Fig. 1. Structures of 10-methyl-cis-9-decalinol 2 and natural products 1, 3, 4 and 5.
has been realized, selective reactions are still restricted to limited
substrates, and a general procedure of cyclization for keto-epoxides
6 has not been reported to date (Fig. 2). Hence, new chemo- and
stereoselective methodologies to overcome these limitations for
widespread synthetic applications of 10-methyl-cis-9-decalinols 7
are highly desirable.
10-methyl-cis-9-decalinol (ꢀ)-2 was obtained as the single cis
diastereoisomer in 30% of yield, and no traces of the trans isomer
was detected by 1H NMR spectrometry. The stereochemistry of the
product was further confirmed unambiguously by X-ray crystal
structure analysis.24 In the light of these preliminary results, even
though the epoxide opening was regioselective, the reactionwas not
chemoselective, and the next goal was to find better conditions that
would avoid the formation of the contraction product (ꢀ)-9 as well
as the unwanted chlorohydrine (ꢀ)-10.
R1
Me
R1
Me
O
R2
The cyclization was then envisioned with BF3$Et2O, another
Lewis acid having ligands with lower nucleophilic character, in
order to avoid formation of (ꢀ)-10. However, in these conditions
(DCM, ꢁ20 ꢂC, 2 h), the reaction afforded the undesired cyclo-
pentenone (ꢀ)-9 as the major product in 68% of isolated yield,
along with cis-(ꢀ)-2 (32%, Eq. 3). These preliminary assays con-
firmed the intrinsic regio- and chemoselectivities generally en-
countered for keto-epoxides under the influence of Lewis acids.
Overall, the reactivity of such substrates appeared to be quite dif-
ficult to control and the need to find suitable conditions, that would
favour selectively the cyclization product (ꢀ)-2 over the two
identified by-products, was our next goal. It appeared that this
important reaction is largely undeveloped and that more reactive
and discriminating catalysts or reagents are needed to address this
unsolved problem in the field. In view of the reactivity of BF3$Et2O,
that avoided the formation of chlorohydrine (ꢀ)-10, we tried to
improve these conditions in order to obtain the cis-9-decalinol
(ꢀ)-2 as the major product.
Lewis acid
R2
cationic
cyclization
OH
O
O
6
(+/-)-
(+/-)-7
Fig. 2. Lewis acid promoted cyclization of keto-epoxide investigated.
In continuation of our ongoing investigations on the total syn-
thesis of (ꢀ)-triptolide and analogues,20,21 we decided to reinves-
tigate this reaction in order to widen its application scope, and to
explore possibly the asymmetric cationic cyclization version which
has no literature report. Herein, we wish to report in full details our
findings on the development of a general protocol for the efficient
cyclization of functionalized keto-epoxides under the influence of
ZrCl4 as promoter, affording in good to excellent yields 10-methyl-
cis-9-decalinols. We also disclose our results on the cyclization
of
a chiral keto-epoxide yielding enantiomerically enriched
10-methyl-cis-9-decalinol.
The influence of the solvent nature (tetrahydrofuran, nitro-
methane, acetonitrile, dichloromethane and 1,2-dichloroethane)
on the chemoselectivity as well as the temperature (from ꢁ20 ꢂC to
50 ꢂC and 90 ꢂC under microwave irradiation) were first evaluated
(See Supplementary data). In our best case, the use of DCE, a low
polarity solvent, at room temperature with BF3$Et2O (1.05 equiv)
afforded almost a 1:1 ratio for cyclized product cis-(ꢀ)-2 (48%) and
contraction product (ꢀ)-9 (52%). Next, the fine-tuning of the con-
ditions in order to promote the cyclization compared to the ring
contraction led us to the screening of Lewis acids in DCE as solvent
and at room temperature for 2 h (Table 1). It has been reported that
the strength of the Lewis acid has a crucial influence on the che-
moselectivity: the weaker the Lewis acid, the more ring contraction
product was formed.19b Experimentally, all the reactions proceeded
quite well and in most cases, high conversions were observed ex-
cept for Tl(OCOCF3)3, AuCl3, TMSOTf and Yb(OTf)3 (entries 1e4).
2. Results and discussion
Our study started first with the synthesis of our model keto-
epoxide 6a bearing an electron rich arene moiety (Scheme 1,
Eq. 1). This compound was prepared in 87% yield by epoxidation of
the functionalized 3-methylcyclohexen-2-one 820 using standard
conditions with m-CPBA22 in dichloromethane. We next studied the
cyclization of 6a under the influence of SnCl4, known to promote the
carbocyclization of keto-epoxides.19a,b However, the preliminary
assays performed at ꢁ20 ꢂC for 2 h (Eq. 2) led to the formation
of a mixture of three compounds in a 1:1:1.2 ratio, among which
the expected product (ꢀ)-2, the cyclopentenone contraction
product (ꢀ)-9 due to 1,2-carbonyl migration23 and chlorohydrine
(ꢀ)-10 (syn/anti¼100:0) issued from the nucleophilic addition of
a chlorine ion on the tertiary carbocation intermediate. The desired

S. Goncalves et al. / Tetrahedron 67 (2011) 8373e8382
m-CPBA / DCM
8375
20h / rt
O
(Eq. 1)
OMe
OMe
87%
O
O
8
6a
OMe
SnCl4 (1.05 eq.)
DCM / -20°C / 2h
O
+
OMe
O
MeO
O
OH
O
O
6a
(+/-)-2 (30%)
cis/trans : 100/0
(+/-)-9 (29%)
+
(Eq. 2)
Cl
OMe
OH
O
10 37%
(
(+/-)-
)
syn/anti : 100/0
BF3.Et2O (1.05 eq.)
DCM / -20°C / 2h
O
(Eq. 3)
2
32%
9 68%
(
(+/-)-
(
)
+
(+/-)-
)
OMe
O
6a
Scheme 1. Synthesis of keto-epoxide 6a and preliminary cyclization results.
Among these four promoters, AuCl3 was the most selective one and
afforded a good yield (61%) of cis-(ꢀ)-2, for a conversion of 70%
(entry 2). In contrast, the more oxophilic TMSOTf gave a reversed
chemoselectivity towards the unwanted ring contraction product
(ꢀ)-9 in 60% yield (entry 3). When the reaction was carried out with
FeCl3, Ga(OTf)3 and In(OTf)3, quantitative conversions were ob-
served affording almost a 1:1 to 3:2 ratios for products (ꢀ)-2 and
(ꢀ)-9 (entries 5e7).
TiCl4 permitted to obtain a 7:3 ratio for (ꢀ)-2 and (ꢀ)-9, ZrCl4
provided the highest selectivity (>9:1) (entries 9e11). With this
promoter, 88% of cis-(ꢀ)-2 was formed along with only 3% of the
undesired contraction product (ꢀ)-9 (entry 11). To our delight, the
conversion of 6a was further enhanced when the reaction was
executed in DCM at room temperature and the cyclized product
could be obtained with an excellent yield of 96% (entry 12). Finally,
under the optimum reaction conditions, cis-(ꢀ)-2 was isolated after
Table 1
Influence of the Lewis acid on the chemoselectivity for the cyclization of 6a
OMe
+
Lewis acid
(1.05 eq.)
O
OMe
D CE / rt / 2h
OH
OMe
9
O
O
O
O
(+/-)-2
6a
(+/-)-
Entry
Lewis acid
Conversion 6aa (%)
Yield (ꢀ)-2a (%)
Yield (ꢀ)-9a (%)
1
2
3
4
5
6
7
8
Tl(OCOCF3)3
AuCl3
TMSOTf
Yb(OTf)3
FeCl3
Ga(OTf)3
In(OTf)3
BF3$Et2O
AlCl3
37
70
62
16
100
96
100
100
100
100
91
22
61
d
12
8
60
3
43
36
40
42
28
25
3
10
55
57
60
58
68
73
9
10
11
12
TiCl4
ZrCl4
ZrCl4
88
100
96 (90c)
3
b
a
Conversion and yield evaluated by HPLC analysis.
DCM was used as solvent.
Isolated yield.
b
c
This selectivity is however comparable with the one first
purification on column chromatography on silica gel with an
excellent 90% yield. Control experiments carried out with stoich-
iometric and catalytic amounts of HCl in DCM were unsatisfactory,
suggesting that the unsurpassed observed chemoselectivity and
obtained with BF3$Et2O (entry 8). Reacting 6a with harder oxophilic
Lewis acids, such as AlCl3, TiCl4 and ZrCl4 favoured the formation of
10-methyl-cis-9-decalinol (ꢀ)-2. Indeed, while the use of AlCl3 and

8376
S. Goncalves et al. / Tetrahedron 67 (2011) 8373e8382
efficiency of the reaction for the cyclization pathway is ascribed to
the unique activation mode of ZrCl4 alone, and not to any residual
traces of HCl. It is worth to mention that, in strictly the same
experimental conditions, the use of AgOTf, Sc(OTf)3, CuSO4 or
Co(acac)3 was unsuccessful. Attempts to cyclize 6a with other zir-
conium salts, such as ZrF4 or Zr(OEt)4 was ineffective (unreactive),
except when ZrBr4 was employed. In this case, cis-(ꢀ)-2 was
formed in good yield (88%) without alteration of the diaster-
eoselectivity (see SD).
gave rise to the expected 10-methyl-cis-9-decalinols in good to ex-
cellent isolated yields, in the range of 74e90% (Table 2, entries 1e4).
It is important to mention that (ꢀ)-2b was obtained as a single
regioisomer and the electrophilic substitution did not involve the
ortho position of the aromatic ring (entry 1). In the case of substrates
6c and 6d, possessing a methoxy group and a protected amine, re-
spectively, two regioisomers were obtained resulting from the ad-
dition of the arene either on the ortho or on the para position, the
para substitution being the most favourable in both cases (entries 2
and 3). Whereas (ꢀ)-2c (57%) and (ꢀ)-2c0 (34%) could easily be
separated by column chromatography on silica gel, decalinols
(ꢀ)-2d and (ꢀ)-2d0 were obtained as an inseparable mixture in
a 75:25 ratio. Compared to literature report,19b the 3:2 ratio ob-
served for (ꢀ)-2c/(ꢀ)-2c0 is different and slightly higherthan the one
obtained by Sutherland (1:1 ratio), for the same substrate however
upon BF3$Et2O or SnCl4 activations (entry 2). On the opposite, keto-
epoxide 6f having an electron-deficient arene gave the chlorohy-
drine (ꢀ)-13, as the sole reaction product in 88% of yield with a syn/
anti ratio of 63:37 (entry 5). This undesired pathway is likely the
most favored kinetically in these conditions for substrates bearing
electron-deficient arenes. Interestingly, substituents on the cyclo-
hexenone moiety did not affect the efficiency, chemo- and diaster-
eoselectivity of the cyclization. Indeed, 10-methyl-cis-9-decalinol
(ꢀ)-2g was obtained highly selectively from keto-epoxide 6g
exhibiting a furanyl substituent, with a satisfactorily 77% yield
(entry 6). Results also demonstrated the possibility to modulate the
nature of the internal nucleophile. Aversatile functional group, such
as thiophene is tolerated and permitted the cyclization event to
occur regioselectively at the C2-position of the heteroaromatic ring.
Compound (ꢀ)-2h was successfully isolated in a very good 86% yield
(entry 7). Cyclizations of keto-epoxides featuring olefins and ter-
minal alkyne were also studied by reacting substrates 6i, 6j and 6k
(entries 8e10). Subjecting 6i under the optimized conditions gave
rise to the formation of the desired cis-decalinol (ꢀ)-2i in 52% of
yield along with 20% of chlorohydrine (ꢀ)-14 (syn/anti ratio 90:10)
due toa lownucleophilic unactivated terminal olefin (entry 8). In the
case of the more electron rich trisubstituted olefin 6j, the cyclization
led to the chlorinated tricyclic system (ꢀ)-2j in satisfactory yield
(66%), accompanied with other complex unidentified by-products
(entry 9). The quaternary chlorinated carbon centre is most likely
generated during the termination step between the tertiary carbo-
cation intermediate and Clꢁ. Keto-epoxide bearing a terminal alkyne
confirmed to be an excellent substrate for the reaction. Indeed,
submitting 6k to the optimal conditions permitted the selective
access to the chlorinated trisubstituted olefin 10-methyl-cis-9-
decalinol (ꢀ)-2k in excellent 89% yield (entry 10) and in agree-
ment with Sutherland’s report (using BF3$Et2O or TiCl4).19c Addi-
tionally, we also envisioned the possibility of synthesizing C5- and
C7-membered fused rings bycyclization of keto-epoxides 6l and 6m
(entries 11 and 12). Unfortunately, the desired reaction did not occur
in both cases most likely due to high energy transition states. In-
stead, the allylic alcohol 15, arising from HCl elimination on the
corresponding chlorohydrine, and product (ꢀ)-16 (syn/anti ratio
90:10) were formed in quite high yields (74% each).
The observed exclusive cis-stereochemistry preference is ratio-
nalized as shown in Fig. 3.
Under the influence of ZrCl4, the epoxide opens regioselectively
providing the
the strength of the Zr(IV)eO bonds, the metal cation binds tightly to
the generated
-hydroxyketone via a stable five-membered ring.25
a-hydroxyketone carbocation intermediate 11. Due to
a
It is assumed that the formation of this stable bidentic chelate 11
avoids the carbonyl migration, and therefore the CeC bond break-
ing responsible for the competitive contraction process. Then, nu-
cleophilic pseudo-axial attack (from the a-face) of the arene onto
the carbocation species provides the cis-decalinol junction 12,
which upon hydrolysis affords cis-(ꢀ)-2 highly diastereoselectively.
Cyclization proceeding through equally unfavourable pathway
(from the b-face) would provide the other trans-diastereoisomer,
which was not observed. It is postulated that the Zr(IV) complex 11
involved during the cyclization accounts for the unrivalled effi-
ciency and chemoselectivity of the transformation. The high bond
dissociation energy (BDE) of Zr(IV)eO bond might also be one of
the main reasons that do not permit the use of a catalytic amount of
ZrCl4. Indeed, attempts to use a catalytic amount of the promoter
were unsuccessful and this is most likely due to the turnover
blockage of Zr(IV) held tightly within intermediate 12.
Cl
Zr
Cl
Cl
Cl
O
O
Cl
Zr
Cl
Cl
Cl
O
pseudo-
axial
Me
attack
Me
MeO
O
MeO
6a
11
Cl
Zr
Cl
Me
hydrolysis
O
Me
Cl
Cl
OMe
O
OH
OMe
O
12
cis-(+/-)-2
Fig. 3. Proposed mechanism for the ZrCl4-promoted cationic cyclization of keto-
epoxide 6a.
Having rationalized the cis-stereochemistry, we were then in-
terested in studying the scope and limitation of this new ZrCl4-
promoted procedure. The optimized conditions were applied to
a large panel of keto-epoxides bearing electron rich and electron-
deficient arenes, thiophene, terminal alkene and alkyne, and a tri-
substituted olefin (Table 2). Keto-epoxides of interest (6bem) were
synthesizedeither bym-CPBAor byhydrogenperoxide epoxidations
of the corresponding C2-substituted 3-methylcyclohexenones, most
of which have been already described byourlaboratory recently.21,26
Results confirmed that the cyclization of keto-epoxides bearing
electron-donating substituents on the arene moiety proceeded well
under the influence of ZrCl4. Indeed, substrates 6b, 6c, 6d and 6e
Finally, we decided to evaluate whether our ZrCl4 cyclization
conditions could be applied to chiral keto-epoxide (1R,6R)-19
without alteration of the chiral centres. Accordingly, substrate 19
was synthesized in three steps from the parent compound 8
(Scheme 2). The a,b-unsaturated ketone 8 was first reduced enan-
tioselectively using Corey’s oxazaborolidine27 giving rise to allylic
alcohol (S)-17 in 97% of yield with an enantiomeric excess of 92%, in
agreement with Corey’s report.28 Subsequent diastereoselective
epoxidation of (S)-17 by m-CPBA in the presence of sodium
hydrogenocarbonate afforded epoxy-alcohol (1S,2S,6R)-18 quanti-
tatively in diastereoisomeric ratio >99:1, and the enantiomeric
excess was determined to be 93%.

S. Goncalves et al. / Tetrahedron 67 (2011) 8373e8382
8377
Table 2
Cationic cyclization of various keto-epoxidesa
Entry
Keto-epoxide
Product
Yieldb (%)
1
90
2
3
4
57þ34
74
89
5
6
88
77
7
8
9
86
52þ20
66
10
11
89
74
12
74
a
Conditions: ZrCl4 (1.05 equiv), DCM, 2 h, room temperature.
Isolated yield.
b

8378
S. Goncalves et al. / Tetrahedron 67 (2011) 8373e8382
Scheme 2. Assay for the cyclization of chiral keto-epoxide (1R,6R)-19.
Oxidation of the secondary alcohol using DesseMartin period-
(0.698 mmol, 1.0 equiv) in dichloromethane (6 mL) and the re-
action mixture was stirred for 20 h at room temperature. Then, after
dilution with dichloromethane (20 mL), the residue was washed
with saturated aqueous sodium hydrogenocarbonate (10 mL) and
brine (10 mL). The combined organic extracts were dried over so-
dium sulfate and evaporated. The residue was purified by chro-
matography on silica gel (eluent: cyclohexane/ethyl acetate) to give
the keto-epoxide derivatives 6aef and 6l.
inane allowed the preparation of the desired chiral (1R,6R)-19 in 80%
of yield. Cyclization conditions applied to keto-epoxide 19 afforded
successfully chiral 10-methyl-cis-9-decalinol (4aR,10aR)-2 with
a satisfactory enantiomeric excess (ee 86%). This preliminary result,
which has to be further optimized, highlights the compatibility of
our ZrCl4-promoted cationic cyclization with chiral keto-epoxide,
expanding the scope of application of this reaction.
3. Conclusion
4.2.1. 1-[2-(3-Isopropyl-2-methoxyphenyl)ethyl]-6-methyl-7-
oxabicyclo[4.1.0]heptan-2-one (6a). White solid; Rf¼0.68 (cyclo-
hexane/EtOAc 80:20); mp 46e47 ꢂC; 1H NMR (400 MHz, CDCl3):
In summary, we have developed an efficient ZrCl4-promoted
cationic cyclization of keto-epoxides for the diastereoselective prep-
aration of 10-methyl-cis-9-decalinols, an important structural motif
encountered in numerous natural products. Key for this highly dia-
stereoselective cyclization is the use of a zirconium based Lewis acid,
which permits to induce good reactivity and diastereoselectivity
compared to other promoters. This cationic cyclization appears to be
quite general and tolerates many internal nucleophiles, such as are-
nes, thiophene, alkene and alkyne. The newly developed methodol-
ogy allows also the cyclization of a chiral keto-epoxide with good
enantiomeric excess. Further developments and optimization of this
enantiomeric cyclization is underway in our laboratory and will be
reported in due course, as well as mechanistical investigations.
d
¼7.01 (m, 3H), 3.69 (s, 3H), 3.23 (hept., J¼6.8 Hz, 1H), 2.19 (m, 4H),
1.56 (m, 7H), 1.21 (dd, J¼6.8, 1.2 Hz, 6H), 0.95 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3):
66.2, 65.9, 61.4, 37.1, 30.1, 28.2, 26.4, 26.3, 24.3, 24.2, 19.4, 17.3 ppm;
d¼206.1, 155.7, 142.1, 134.6, 128.3, 125.0, 124.7,
IR (neat):
n
¼2960, 1704, 1463, 1428, 1406, 1382, 1253, 1202, 1167,
1046, 1010, 783, 765 cmꢁ1; HRMS (ESI, m/z): calcd for C19H26O3
[MþH]þ, 303.1960; found, 303.1959.
4.2.2. 6-Methyl-1-[2-(3-methylphenyl)ethyl]-7-oxabicyclo[4.1.0]hep-
tan-2-one (6b). Colourless oil; Rf¼0.45 (cyclohexane/EtOAc 80:20);
1H NMR (400 MHz, CDCl3):
2.54 (m, 3H), 2.34 (m, 1H), 2.33 (s, 3H), 2.02 (m, 2H), 1.83 (m, 3H),
1.59 (m, 1H), 1.30 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼206.7,
141.6, 138.0, 129.4, 128.4, 126.9, 125.6, 66.7, 66.4, 37.2, 31.5, 30.1,
d
¼7.15 (t, J¼7.6 Hz, 1H), 6.98 (m, 3H),
d
4. Experimental
4.1. General
28.5, 21.5, 19.9, 17.7 ppm; IR (neat):
n
¼2940, 1705, 1609, 1455, 1381,
1156, 1119, 1046, 912, 778, 702 cmꢁ1; HRMS (ESI, m/z): calcd for
C16H20O2 [MþH]þ, 245.1542; found, 245.1538.
All reagents were purchased from SigmaeAldrich, ABCR, Alfa-
Aesar and Acros and were used as received. NMR spectra were
recorded on a Brucker Advance 400 (400 MHz 1H NMR, 100 MHz
4.2.3. 1-[2-(3-Methoxyphenyl)ethyl]-6-methyl-7-oxabicyclo[4.1.0]
heptan-2-one (6c). Yellow oil; Rf¼0.52 (cyclohexane/EtOAc 80:20);
13C NMR) in CDCl3. Chemical shift values (
d
) are reported in parts
1H NMR (400 MHz, CDCl3):
d
¼7.18 (dd, J¼7.6, 8.8 Hz, 1H), 6.73 (m,
per million (residual chloroform
d
¼7.26 ppm for 1H; residual
3H), 3.80 (s, 3H), 2.54 (m, 3H), 2.32 (m, 1H), 2.03 (m, 2H), 1.84 (m,
chloroform
d
¼77.16 ppm for 13C). Infra-red spectra were recorded
3H), 1.58 (m, 1H), 1.32 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
with a Nicolet 380 FT-IR apparatus. High resolution mass spectra
were recorded with an Agilent Q-Tof 6520 apparatus equipped with
a positive ESI source.
d
¼206.7, 159.8, 143.3, 129.4, 121.0, 114.3, 111.5, 66.6, 66.5, 55.3, 37.1,
31.7, 30.1, 28.4, 19.9, 17.6 ppm; IR (neat):
n
¼2938, 1705, 1601, 1585,
1489, 1456, 1436, 1258, 1153, 1040, 781, 698 cmꢁ1; HRMS (ESI, m/z):
calcd for C16H20O3 [MþNa]þ, 283.1310; found, 283.1296.
4.2. General procedure for the synthesis of keto-epoxides by
m-CPBA epoxidation (method A)
4.2.4. tert-Butyl{3-[2-(6-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-1-yl)
ethyl]phenyl} carbamate (6d). Red oil; Rf¼0.61 (cyclohexane/EtOAc
m-CPBA (1.40 mmol, 2.0 equiv) was added to a solution of the
70:30); 1H NMR (400 MHz, CDCl3):
d
¼7.22 (s, 1H), 7.14 (m, 2H), 6.84
corresponding
C2-substituted
3-methylcyclohexenones21,26
(dt, J¼1.6, 6.8 Hz, 1H), 6.52 (s, 1H), 2.63 (m, 2H), 2.52 (m, 1H), 2.32

S. Goncalves et al. / Tetrahedron 67 (2011) 8373e8382
8379
(m, 1H), 2.02 (m, 2H), 1.840 (m, 3H), 1.50 (s, 9H), 1.27 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3):
¼206.6, 152.8, 142.7, 138.5, 129.0,
123.3, 118.6, 116.3, 80.5, 66.5, 66.4, 37.1, 31.6, 30.0, 28.4, 28.3, 19.8,
1114, 1061, 1013, 928, 781, 736, 703 cmꢁ1; HRMS (ESI, m/z): calcd for
C20H22O3 [MþH]þ, 311.1647; found, 311.1642.
d
17.6 ppm; IR (neat):
n
¼2984, 2968, 1712, 1603, 1567, 1468, 1452,
4.3.2. 6-Methyl-1-[2-(3-thienyl)ethyl]-7-oxabicyclo[4.1.0]heptan-2-
1223,1161,1094, 954, 851, 774, 695 cmꢁ1; HRMS (ESI, m/z): calcd for
one (6h). Yellow oil; Rf¼0.42 (cyclohexane/EtOAc 80:20); 1H NMR
C20H27NO4 [MþH]þ, 346.2018; found, 346.2013.
(400 MHz, CDCl3):
2.71 (m, 3H), 2.53 (dt, J¼5.2, 17.2 Hz, 1H), 2.31 (m, 1H), 2.00 (m, 2H),
d
¼7.23 (t, J¼3.6 Hz, 1H), 6.93 (d, J¼4.0 Hz, 2H),
4.2.5. 1-[2-(1,3-Benzodioxol-5-yl)ethyl]-6-methyl-7-oxabicyclo[4.1.0]
1.85 (m, 3H), 1.59 (m, 1H), 1.34 (s, 3H) ppm; 13C NMR (100 MHz,
heptan-2-one (6e). Colourless oil; Rf¼0.73 (cyclohexane/EtOAc
CDCl3):
d
¼206.5, 141.7, 128.2, 125.3, 120.3, 66.5, 66.3, 36.9, 29.9,
60:40); 1H NMR (400 MHz, CDCl3):
d
¼6.68 (m, 2H), 6.61 (dd, J¼1.6,
27.3, 25.8, 19.7, 17.5 ppm; IR (neat):
n
¼2936, 1742, 1623, 1591, 1555,
7.6 Hz,1H), 5.91 (s, 2H), 2.55 (m, 3H), 2.32 (m, 1H), 2.01 (m, 2H),1.82
1474, 1450, 1421, 1127, 1040, 821, 780, 693 cmꢁ1; HRMS (ESI, m/z):
(m, 4H), 1.57 (m, 1H), 1.34 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
calcd for C13H16O2S [MþH]þ, 237.0949; found, 237.0944.
d
¼206.7, 147.7, 145.8, 135.6, 121.2, 101.1, 108.2, 100.9, 66.6, 66.4, 37.1,
31.4, 30.1, 28.7, 19.9, 17.7 ppm; IR (neat):
n
¼2940, 1703, 1595, 1567,
4.3.3. 1-But-3-en-1-yl-6-methyl-7-oxabicyclo[4.1.0]heptan-2-one
1475, 1455, 1426, 1118, 1094, 821, 779, 693 cmꢁ1; HRMS (ESI, m/z):
(6i). Colourless oil; Rf¼0.55 (cyclohexane/EtOAc 90:10); 1H NMR
calcd for C16H18O4 [MþH]þ, 275.1283; found, 275.1579.
(400 MHz, CDCl3):
d
¼5.75 (m, 1H), 4.98 (m, 1H), 4.93 (m, 1H), 2.51
(td, J¼4.0, 17.2 Hz, 1H), 1.99 (m, 5H), 1.83 (m, 2H), 1.65 (m, 1H), 1.55
4.2.6. 1-[2-(3-Bromophenyl)ethyl]-6-methyl-7-oxabicyclo[4.1.0]hep-
(m, 1H), 1.44 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼206.6,
tan-2-one (6f). Yellow oil; Rf¼0.57 (cyclohexane/EtOAc 80:20); 1H
138.0,114.9, 66.7, 66.1, 37.1, 30.2, 29.6, 25.6, 20.1,17.7 ppm; IR (neat):
NMR (400 MHz, CDCl3):
d
¼7.31 (m, 2H), 7.11 (m, 2H), 2.66 (m, 2H),
n
¼2940, 1706, 1641, 1454, 1382, 1328, 1113, 997, 912, 825 cmꢁ1
;
2.54 (dt, J¼5.6, 18.0 Hz, 1H), 2.25 (m, 1H), 2.02 (m, 2H), 1.84 (m, 3H),
1.58 (m, 1H), 1.32 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼206.7,
144.1, 131.6, 130.1, 129.2, 127.3, 122.5, 66.6, 66.5, 37.0, 31.3, 30.0,
HRMS (ESI, m/z): calcd for C11H16O2 [MþH]þ, 181.1229; found,
d
181.1126.
28.2, 19.9, 17.6 ppm; IR (neat):
n
¼2954, 1645, 1614, 1451, 1368, 1296,
4.3.4. 1-(2-Cyclohex-1-en-1-ylethyl)-6-methyl-7-oxabicyclo[4.1.0]
1234, 1147, 1072, 774, 700 cmꢁ1; HRMS (ESI, m/z): calcd for
heptan-2-one (6j). Colourless oil; Rf¼0.52 (cyclohexane/EtOAc
C15H17BrO2 [MþNH4]þ, 326.0756; found, 326.0757.
90:10); 1H NMR (400 MHz, CDCl3):
17.2 Hz, 1H), 2.01 (m, 1H), 1.83 (m, 10H), 1.50 (m, 6H), 1.44 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3):
¼206.2, 137.3, 121.4, 66.9,
65.9, 37.1, 33.5, 30.2, 28.3, 25.3, 24.9, 23.0, 22.5, 20.0, 17.6 ppm; IR
d
¼5.38 (br, 1H), 2.49 (td, J¼4.4,
4.2.7. 6-Methyl-1-(3-methylbenzyl)-7-oxabicyclo[4.1.0]heptan-2-
d
one (6l). Colourless oil; Rf¼0.55 (cyclohexane/EtOAc 95:5); 1H NMR
(400 MHz, CDCl3):
d
¼7.05 (t, J¼7.6 Hz, 1H), 6.89 (m, 3H), 3.36 (d,
(neat):
n
¼2925, 2856, 2835, 1706, 1451, 1439, 1381, 1134, 914,
J¼14.8 Hz, 1H), 2.84 (d, J¼14.8 Hz, 2H), 2.43 (td, J¼4.0, 16.8 Hz, 1H),
833 cmꢁ1
;
HRMS (ESI, m/z): calcd for C15H22O2 [MþNH4]þ,
2.24 (s, 3H), 2.06 (m, 1H), 1.77 (m, 3H), 1.50 (m, 1H), 1.46 (s,
252.1964; found, 252.1960.
3H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼206.1, 138.0, 136.8, 130.0,
128.3, 127.1, 126.0, 66.9, 66.4, 37.3, 31.8, 30.2, 21.5, 20.5, 17.6 ppm; IR
4.3.5. 1-But-3-yn-1-yl-6-methyl-7-oxabicyclo[4.1.0]heptan-2-one
(neat):
n
¼2942, 1707, 1607, 1489, 1454, 1382, 1174, 1117, 1039, 931,
(6k). Colourless oil; Rf¼0.50 (cyclohexane/EtOAc 70:30); 1H NMR
748, 693 cmꢁ1; HRMS (ESI, m/z): calcd for C15H18O2 [MþH]þ,
(400 MHz, CDCl3):
d
¼2.50 (td, J¼4.0, 16.8 Hz, 1H), 2.31 (m, 2H), 2.19
231.1385; found, 231.1381.
(m, 1H), 2.03 (m, 2H), 1.85 (m, 4H), 1.56 (m, 1H), 1.48 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3):
d
¼206.3, 83.6, 69.0, 66.6, 65.9, 37.0,
4.3. General procedure for the synthesis of keto-epoxides by
H2O2 epoxidation (method B)
30.1, 25.2, 20.3, 17.5, 14.6 ppm; IR (neat):
n
¼2946, 1658, 1631, 1420,
1368, 1342, 1323, 1181, 1139, 1112, 1059, 631 cmꢁ1; HRMS (ESI, m/z):
calcd for C11H14O2 [MþH]þ, 179.1072; found, 179.1068.
Hydrogen peroxide 30% aq (3.0 mmol, 3.0 equiv) and an aqueous
solution of sodium hydroxide 6 N (3.0 mmol, 3.0 equiv) were
4.3.6. 6-Methyl-1-[3-(3,4,5-trimethoxyphenyl)propyl]-7-oxabicyclo
added to
a
solution of the corresponding C2-substituted
[4.1.0]heptan-2-one (6m). Colourless oil; Rf¼0.21 (cyclohexane/
3-methylcyclohexenones21,26 (1.0 mmol, 1.0 equiv) in methanol
(10 mL) at 0 ꢂC. After being stirred for 30 min at 0 ꢂC, the reaction
mixture was stirred at room temperature 3 h before a second ad-
dition of H2O2 30% (3.0 mmol, 3.0 equiv) and aqueous NaOH 6 N
(3.0 mmol, 3.0 equiv). The reaction mixture was stirred overnight,
then saturated sodium sulfite (12 mL) and water (12 mL) were
added. The aqueous phase was extracted by diethyl ether
(3ꢃ30 mL). The combined organic extracts were washed with
brine, dried over sodium sulfate and evaporated. The residue was
purified by chromatography on silica gel (eluent: cyclohexane/ethyl
acetate) to give the keto-epoxide derivatives 6gek and 6m.
EtOAc 80:20); 1H NMR (400 MHz, CDCl3):
d¼6.40 (s, 2H), 3.84 (s,
6H), 3.80 (s, 3H), 2.50 (m, 3H), 1.97 (m, 3H), 1.83 (m, 2H), 1.55 (m,
4H), 1.40 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼207.0, 153.1,
137.8, 136.2, 105.3, 67.1, 66.3, 60.9, 51.1, 37.0, 36.5, 30.0, 29.9, 19.9,
d
17.7 ppm; IR (neat):
n
¼2939, 1704, 1588, 1508, 1456, 1420, 1341,
1238, 1126, 1011, 827 cmꢁ1; HRMS (ESI, m/z): calcd for C19H26O5
[MþH]þ, 335.1859; found, 335.1859.
4.4. cis-10a-Hydroxy-7-isopropyl-8-methoxy-4a-methyl-
3,4,4a,9,10,10a-hexahydrophenanthren-1(2H)-one (( )-2)
under ZrCl4 conditions
4.3.1. 4-(2-Furyl)-6-methyl-1-[2-(3-methylphenyl)ethyl]-7-
Zirconium tetrachloride (205 mg, 0.869 mmol, 1.05 equiv) was
added to a solution of epoxide 6a (250 mg, 0.828 mmol, 1.0 equiv)
in dichloromethane (25 mL) and the reaction mixture was stirred
for 2 h at room temperature. After addition of water (50 mL), the
aqueous phase was extracted by diethyl ether (3ꢃ25 mL). The
combined organic extracts were washed with brine, dried over
sodium sulfate and evaporated. The residue was purified by chro-
matography on silica gel (eluent: cyclohexane/ethyl acetate 80:20)
to give (ꢀ)-2 as a white solid (225 mg, 90%). Rf¼0.48 (cyclohexane/
oxabicyclo[4.1.0]heptan-2-one (6g). Orange oil; Rf¼0.40 (cyclohex-
ane/EtOAc 90:10); 1H NMR (400 MHz, CDCl3):
d¼7.18 (dd, J¼0.8,
2.0 Hz, 1H), 7.17 (t, J¼7.6 Hz, 1H), 6.98 (m, 3H), 6.29 (dd, J¼2.0,
3.2 Hz, 1H), 6.00 (dt, J¼0.8, 3.2 Hz, 1H), 3.37 (m, 1H), 2.79 (ddd,
J¼1.6, 5.2, 18.0 Hz, 1H), 2.57 (m, 3H), 2.45 (m, 1H), 2.39 (m, 1H), 2.34
(s, 3H), 2.04 (dd, J¼11.6, 14.8 Hz, 1H), 1.80 (m, 1H), 1.34 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3):
d
¼204.5, 156.6, 141.6, 141.4, 138.1, 129.4,
128.4, 126.9, 125.6, 110.2, 104.5, 65.9, 65.1, 41.9, 35.5, 31.5, 28.6, 28.5,
21.5, 19.6 ppm; IR (neat):
¼2930, 1709, 1608, 1507, 1454, 1381, 1147,
n
EtOAc 80:20); mp 129e131 ꢂC; 1H NMR (400 MHz, CDCl3):
d¼7.08

8380
S. Goncalves et al. / Tetrahedron 67 (2011) 8373e8382
(d, J¼8.4 Hz, 1H), 6.99 (d, J¼8.4 Hz, 1H), 4.01 (br, 1H), 3.73 (s, 3H),
3.24 (hept., J¼6.9 Hz, 1H), 1.65e3.09 (m, 10H), 1.26 (s, 3H), 1.20 (d,
4.7. cis-10a-Hydroxy-7-methoxy-4a-methyl-3,4,4a,9,10,10a-
hex ahydrophenanthren-1(2H)-one (( )-2c) and cis-10a-
hydroxy-5-methoxy-4a-methyl-3,4,4a,9,10,10a-
J¼6.9 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3):
¼215.1, 154.6,
d
142.7, 138.8, 127.7, 124.4, 122.3, 79.8, 60.7, 45.8, 41.1, 36.9, 29.7, 26.3,
hexahydrophenanthren-1(2H)-one (( )-2c0)
24.0, 22.6, 20.8, 19.9 ppm; IR (neat):
n
¼3473, 2960, 1706, 1462, 1412,
1330, 1251, 1119, 1087, 1063, 1036, 1012, 967, 931, 814 cmꢁ1; HRMS
(ESI, m/z): calcd for C19H26O3 [MþH]þ, 303.1960; found, 303.1959.
Using the same procedure, chiral (4aR,10aR)-2 was prepared
from (1R,6R)-19 (50 mg, 0.165 mmol). Compound (4aR,10aR)-2 was
thus obtained as a white paste (36 mg, 72%) with an enantiomeric
cis-9-Decalinols (ꢀ)-2c and (ꢀ)-2c0 were obtained using the
same procedure as for the synthesis of (ꢀ)-2 with keto-epoxide 6c
(50 mg, 0.192 mmol). Purification by chromatography on silica gel
(eluent: cyclohexane/ethyl acetate 90:10) gave (ꢀ)-2c as a colour-
less solid (29 mg, 57%) and (ꢀ)-2c0 as a colourless solid (17 mg,
34%). Experimental data for (ꢀ)-2c and (ꢀ)-2c0 were identical to the
data reported in the literature.19a
excess of 86%. [
a]
24 þ12.1 (c 1 M, MeOH).
D
4.5. 2-[3-(3-Isopropyl-2-methoxyphenyl)propanoyl]-2-
methyl cyclopentanone (( )-9) and 3-chloro-2-hydroxy-2-[2-
(3-isopropyl-2-methoxyphenyl)ethyl]-3-
4.8. tert-Butyl(8a-hydroxy-4b-methyl-8-oxo-
4b,5,6,7,8,8a,9,10-octahydrophenanthren-4-yl)carbamate
(( )-2d) and tert-butyl(8a-hydroxy-4b-methyl-8-oxo-
4b,5,6,7,8,8a,9,10-octahyd rophenanthren-2-yl)carbamate
(( )-2d0)
methylcyclohexanone (( )-10) under SnCl4 conditions
Tin(IV) chloride (37 mL, 0.348 mmol, 1.05 equiv) was added to
a solution of epoxide 6a (100 mg, 0.331 mmol, 1.0 equiv) in
dichloromethane (10 mL) at ꢁ20 ꢂC and the reaction mixture was
stirred for 2 h at this temperature. After addition of water (20 mL),
the aqueous phase was extracted by diethyl ether (3ꢃ20 mL). The
combined organic extracts were washed with brine, dried over
sodium sulfate and evaporated. The residue was purified by chro-
matography on silica gel (eluent: cyclohexane/ethyl acetate 90:10)
yielding three clean products: (ꢀ)-2 as a white solid (30 mg, 30%),
(ꢀ)-9 as a white solid (29 mg, 29%) and (ꢀ)-10 as a pale white solid
(42 mg, 37%). Analysis of (ꢀ)-9: Rf¼0.61 (cyclohexane/EtOAc
cis-9-Decalinols (ꢀ)-2d and (ꢀ)-2d0 were obtained using the
same procedure as for the synthesis of (ꢀ)-2 with keto-epoxide 6d
(50 mg, 0.145 mmol). Purification by chromatography on silica gel
(eluent: cyclohexane/ethyl acetate 90:10) gave an inseparable
mixture of (ꢀ)-2d and (ꢀ)-2d0 in a 75:25 ratio (37 mg, 74%). Rf¼0.42
(cyclohexane/EtOAc 70:30); 1H NMR (400 MHz, CDCl3):
d
¼7.09 (s,
0
0
3.5H), 6.44 (s, 0.2H(ꢀ)-2d ), 6.38 (s,1H(ꢀ)-2d), 4.00 (s, 0.2H(ꢀ)-2d ), 3.88
(s, 1H(ꢀ)-2d), 3.16 (m, 1H), 2.74 (m, 1H), 2.61 (m, 1H), 2.48 (m, 1H),
2.37 (dt, J1¼6.0 Hz, J2¼13.2 Hz,1H),1.88 (m, 4H),1.76 (m,1H),1.52 (s,
0
0
3H(ꢀ)-2d ), 1.51 (s, 9H(ꢀ)-2d), 1.15 (s, 1H(ꢀ)-2d ), 1.14 (s, 3H(ꢀ)-2d) ppm;
80:20); mp 50e51 ꢂC; 1H NMR (400 MHz, CDCl3):
d¼6.95 (m, 3H),
13C NMR (100 MHz, CDCl3):
d
¼214.8, 153.0, 138.8, 136.1, 134.9, 129.2
3.73 (s, 3H), 3.22 (hept., J¼6.8 Hz, 1H), 2.86 (s, 4H), 2.52 (m, 1H),
2.24 (t, J¼7.8 Hz, 2H), 1.81 (quint, J¼6.8 Hz, 2H), 1.59 (m, 1H), 1.30 (s,
3H), 1.21 (d, J¼6.8 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3):
0
0
0
(C2d ), 126.9, 123.2 (C2d ), 118.7 (C2d), 117.3 (C2d), 85.0 (C2d ), 80.5
0
0
(C2d), 80.0 (C2d), 45.4 (C2d), 41.1 (C2d), 39.3 (C2d ), 37.9 (C2d ), 36.8
0
0
(C2d), 36.7 (C2d ), 29.9 (C2d), 29.4 (C2d ), 28.5 (C2d), 25.9 (C2d), 25.2
d
¼217.0, 207.5, 155.7, 142.2, 133.9, 127.7, 125.1, 124.5, 63.6, 61.7, 39.2,
0
0
(C2d ), 22.5 (C2d), 21.7 (C2d ), 20.6 (C2d) ppm; IR (neat):
n
¼3323,
38.1, 34.3, 26.4, 24.9, 24.1, 20.3, 19.4 ppm; IR (neat):
n
¼2962, 1737,
2971, 1719, 1708, 1593, 1539, 1366, 1241, 1160, 1088, 1078, 1053, 967,
913 cmꢁ1; HRMS (ESI, m/z): calcd for C20H27NO4 [MþH]þ, 346.2018;
found, 346.2014.
1701, 1461, 1428, 1252, 1202,1166, 1097, 1051, 1010, 797, 766 cmꢁ1
;
HRMS (ESI, m/z): calcd for C19H26O3 [MþH]þ, 303.1960; found,
303.1961. Analysis of (ꢀ)-10: Rf¼0.73 (cyclohexane/EtOAc 80:20);
mp 97e98 ꢂC; 1H NMR (400 MHz, CDCl3):
d¼7.13 (dd, J1¼2.1 Hz,
4.9. cis-4a-Hydroxy-11b-methyl-2,3,4a,5,6,11b-
hexahydrophen anthro[2,3-d][1,3]dioxol-4(1H)-one (( )-2e)
J2¼7.5 Hz, 1H), 7.02 (t, J¼7.5 Hz, 1H), 6.97 (dd, J1¼2.1 Hz, J2¼7.5 Hz,
1H), 3.95 (s, 1H), 3.69 (s, 3H), 3.24 (hept., J¼6.6 Hz, 1H), 2.55 (m,
3H), 1.92 (m, 7H), 1.68 (s, 3H), 1.24 (t, J¼6.6 Hz, 6H) ppm; 13C NMR
cis-9-Decalinol (ꢀ)-2e was obtained using the same procedure
as for the synthesis of (ꢀ)-2 with keto-epoxide 6e (22 mg,
0.082 mmol). Purification by chromatography on silica gel (eluent:
cyclohexane/ethyl acetate 80:20) gave (ꢀ)-2e as a yellow solid
(20 mg, 89%). Rf¼0.68 (cyclohexane/EtOAc 70:30); mp 165e167 ꢂC;
(100 MHz, CDCl3):
d
¼210.9, 155.6, 142.3, 134.1, 127.9, 125.4, 124.8,
83.5, 82.2, 61.9, 37.6, 36.7, 36.1, 26.4, 26.3, 25.2, 24.4, 24.1, 22.5 ppm;
IR (neat):
n
¼3490, 2961, 1719, 1460, 1428, 1314, 1255, 1202, 1173,
1122, 1114, 1078, 1050, 1008, 840, 799, 766, 607, 533 cmꢁ1; HRMS
(ESI, m/z): calcd for C19H27ClO3 [MþH]þ, 338.1649; found, 338,1652.
1H NMR (400 MHz, CDCl3):
d
¼6.71 (s, 1H), 6.57 (s, 1H), 5.87 (dd,
J1¼1.2 Hz, J2¼9.6 Hz, 1H), 4.00 (s, 1H), 3.10 (m, 1H), 2.65 (dt,
J1¼6.4 Hz, J2¼12.8 Hz, 1H), 2.61 (m, 2H), 2.42 (m, 1H), 1.79 (m, 5H),
4.6. cis-10a-Hydroxy-7-isopropyl-8-methoxy-4a-methyl-
3,4,4a,9,10,10a-hexahydrophenanthren-1(2H)-one (( )-2b)
1.21 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d¼214.8, 146.4, 145.8,
136.9, 127.3,108.5,106.2,100.8, 79.9, 45.8, 41.1, 36.8, 30.0, 25.9, 22.4,
cis-9-Decalinol (ꢀ)-2b was obtained using the same procedure
as for the synthesis of (ꢀ)-2 with keto-epoxide 6b (45 mg,
0.183 mmol). Purification by chromatography on silica gel (eluent:
cyclohexane/ethyl acetate 80:20) gave (ꢀ)-2b as a white solid
(41 mg, 90%). Rf¼0.25 (cyclohexane/EtOAc 80:20); mp 79e82 ꢂC; 1H
20.9 ppm; IR (neat):
n
¼3481, 2949, 1706, 1504, 1489, 1376, 1240,
1218, 1041, 966, 932, 846 cmꢁ1; HRMS (ESI, m/z): calcd for C16H18O4
[MþK]þ, 313.0837; found, 313.0837.
4.10. cis-3-(2-Furyl)-10a-hydroxy-4a,7-dimethyl-
3,4,4a,9,10,10a-hexahydrophenanthren-1(2H)-one (( )-2g)
NMR (400 MHz, CDCl3):
d
¼7.13 (d, J¼8.0 Hz, 1H), 6.99 (d, J¼8.0 Hz,
1H), 6.95 (s, 1H), 3.99 (s, 1H), 3.18 (m, 1H), 2.69 (dd, J1¼6.0 Hz,
J2¼18.0 Hz, 1H), 2.53 (m, 1H), 2.41 (qd, J1¼2.4 Hz, J2¼14.0 Hz, 1H),
2.30 (m, 1H), 2.21 (s, 3H), 1.96 (dd, J1¼4.0 Hz, J2¼13.6 Hz, 1H), 1.82
(m, 2H), 1.72 (m, 1H), 1.52 (m, 1H), 1.26 (s, 3H) ppm; 13C NMR
cis-9-Decalinol (ꢀ)-2g was obtained using the same procedure
as for the synthesis of (ꢀ)-2 with keto-epoxide 6g (112 mg,
0.361 mmol). Purification by chromatography on silica gel (eluent:
cyclohexane/ethyl acetate 90:10) gave (ꢀ)-2g as an orange oil
(86 mg, 77%). Rf¼0.62 (cyclohexane/EtOAc 90:10); 1H NMR
(100 MHz, CDCl3):
80.1, 45.5, 41.1, 36.9, 29.9, 25.6, 22.5, 20.9, 20.6 ppm; IR (neat):
d
¼214.9, 140.9, 135.4, 133.8, 129.6, 127.3, 126.2,
n
¼3471, 2921, 1702, 1499, 1448, 1428, 1380, 1311, 1247, 1226, 1151,
(400 MHz, CDCl3):
d
¼7.31 (m, 1H), 7.16 (d, J¼8.0 Hz, 1H), 6.99 (d,
1119, 1087, 1057, 964, 937, 812 cmꢁ1; HRMS (ESI, m/z): calcd for
J¼8.0 Hz, 1H), 6.96 (s, 1H), 6.28 (q, J¼1.6 Hz, 1H), 6.02 (d, J¼3.6 Hz,
C16H20O2 [MþH]þ, 245.1542; found, 245.1546.
1H), 3.98 (s, 1H), 3.34 (m, 1H), 3.20 (m, 1H), 2.76 (m, 3H), 2.59 (m,

S. Goncalves et al. / Tetrahedron 67 (2011) 8373e8382
8381
1H), 2.45 (m, 1H), 2.30 (s, 3H), 2.13 (m, 1H), 1.67 (dd, J¼1.6, 19.2 Hz,
1H), 1.35 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼213.2, 156.4,
141.6, 140.2, 135.7, 133.7, 129.6, 127.4, 126.2, 110.2, 104.3, 79.7, 46.0,
44.2, 41.4, 33.9, 30.0, 27.0, 25.5, 21.0, 20.9 ppm; IR (neat):
2935,1707,1504,1454, 1383,1352, 1224,1191,1153,1067,1047,1012,
967, 911, 845, 731 cmꢁ1; HRMS (ESI, m/z): calcd for C20H22O3
[MþH]þ, 311.1646; found, 311.1642.
0.224 mmol). Purification by chromatography on silica gel (eluent:
cyclohexane/ethyl acetate 90:10) gave (ꢀ)-2k as a white solid
(41 mg, 89%). Experimental data for (ꢀ)-2k were identical to the
data reported in the literature.19c
d
n
¼3477,
4.15. 2-[2-(3-Bromophenyl)ethyl]-3-chloro-2-hydroxy-3-
methylcyclohexanone (( )-13)
4.11. cis-5a-Hydroxy-9a-methyl-5,5a,7,8,9,9a-hexahydronaph
to[1,2-b]thiophen-6-(4H)-one (( )-2h)
Compound (ꢀ)-13 was obtained using the same procedure as for
the synthesis of (ꢀ)-2 with keto-epoxide 6f (131 mg, 0.422 mmol).
Purification by chromatography on silica gel (eluent: cyclohexane/
ethyl acetate 80:20) gave (ꢀ)-13 as a white solid in a syn/anti ratio of
63:37 (106 mg, 88%). Rf¼0.75 (cyclohexane/EtOAc 80:20); mp
cis-9-Decalinol (ꢀ)-2h was obtained using the same procedure as
for the synthesis of (ꢀ)-2 with keto-epoxide 6h (45 mg, 0.188 mmol).
Purification by chromatography on silica gel (eluent: cyclohexane/
ethyl acetate 80:20) gave (ꢀ)-2h as a yellowsolid (38 mg, 86%). Rf¼0.30
(cyclohexane/EtOAc 80:20); mp 96e99 ꢂC; 1H NMR (400 MHz, CDCl3):
62e64 ꢂC; 1H NMR (400 MHz, CDCl3):
d¼7.30 (m, 2H), 7.13 (t, J¼7.6 Hz,
1H), 7.07 (m, 1H), 2.39 (m, 5H), 2.16 (m, 2H), 1.96 (m, 3H), 1.48 (s, 2H,
Mesyn),1.42 (s,1.2H, Meanti) ppm; 13C NMR (100 MHz, CDCl3):
d¼214.3
d
¼7.10 (d, J¼5.2 Hz,1H), 6.75 (d, J¼5.2 Hz,1H), 4.04 (s,1H), 2.89 (m,1H),
(anti), 211.1 (syn),143.6 (syn),140.8 (anti),131.7 (anti),131.5 (syn),130.2
(syn), 129.6 (anti), 129.5 (anti), 129.4 (syn), 128.1 (anti), 127.2 (syn),
122.6 (syn), 119.7 (anti), 91.7 (anti), 84.9 (syn), 79.7 (anti), 76.6 (syn),
40.9 (anti), 39.3 (syn), 37.7 (syn), 36.7 (anti), 36.6 (syn), 36.1 (anti), 30.6
(syn), 29.0 (syn), 25.2 (syn), 22.4 (anti), 21.6 (syn), 20.5 (anti) ppm; IR
2.73 (m, 1H), 2.62 (dd, J¼7.2, 14.0 Hz, 1H), 2.51 (m, 1H), 2.38 (dd, J¼6.4,
12.0 Hz, 1H), 2.12 (dd, J¼4.0, 13.6 Hz, 1H), 1.89 (m, 3H), 1.66 (dd, J¼6.0,
12.0 Hz, 1H), 1.28 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d¼214.1,
144.6,132.8,127.2,122.3, 80.2, 46.1, 41.6, 36.9, 30.5, 22.5, 22.3, 21.7ppm;
IR (neat):
n
¼3468, 2967, 2923, 1704, 1447, 1428, 1377, 1310, 1249, 1174,
(neat):
n
¼3471, 2967, 1709, 1593, 1567, 1474, 1426, 1380, 1311, 1154,
1150,1117,1080,1056, 965, 952, 917, 719, 699, 683 cmꢁ1; HRMS (ESI, m/
z): calcd for C13H16O2S [MþH]þ, 237.0951; found, 237.0948.
1120, 1072, 978, 847, 783, 732, 688, 669, 601 cmꢁ1; HRMS (ESI, m/z):
calcd for C15H18BrClO2 [MþNH4]þ, 361.0444; found, 361.0446.
4.12. cis-8a-Hydroxy-4a-methyl-3,4,4a,5,8,8a-
hexahydronaphtalen-1(2H)-one (( )-2i) and 2-but-3-en-1-yl-
3-chloro-2-hydroxy-3-methylcyclohexanone (( )-14)
4.16. 3-Chloro-2-hydroxy-3-methyl-2-[3-(3,4,5-
trimethoxyphenyl)propyl]cyclohexanone (( )-16)
Compound (ꢀ)-16 was obtained using the same procedure as for
the synthesis of (ꢀ)-2 with keto-epoxide 6m (58 mg, 0.174 mmol).
Purification by chromatography on silica gel (eluent: cyclohexane/
ethyl acetate 80:20) gave (ꢀ)-16 as a colourless oil in a syn/anti ratio
of 90:10 (48 mg, 74%). Rf¼0.38 (cyclohexane/EtOAc 60:40); 1H NMR
cis-9-Decalinol (ꢀ)-2i and (ꢀ)-14 were obtained using the same
procedure as for the synthesis of (ꢀ)-2 with keto-epoxide 6i (77 mg,
0.426 mmol). Purification by chromatography on silica gel (eluent:
cyclohexane/ethyl acetate 95:5) gave (ꢀ)-2i as a colourless oil (39 mg,
52%) and (ꢀ)-14 as a colourless oil (19 mg, 20%) in a syn/anti ratio of
90:10. Analysis of (ꢀ)-2i were identical to the ones reported in the
literature.19a Analysis of (ꢀ)-14: Rf¼0.65 (cyclohexane/EtOAc 90:10);
(400 MHz, CDCl3):
d
¼6.34 (s, 2H), 4.01 (s, 1H), 3.83 (s, 6H), 3.80 (s,
3H), 2.13 (m, 8H), 1.91 (m, 2H), 1.62 (m, 2H), 1.45 (s, 2.6H, Mesyn),
1.30 (s, 0.3H, Meanti) ppm; 13C NMR (100 MHz, CDCl3):
d
¼212.5
1H NMR (400 MHz, CDCl3):
d¼5.73 (m, 1H), 4.99 (qd, J1¼1.6 Hz,
(anti), 211.1 (syn), 153.2, 137.5 (syn), 136.3 (anti), 105.3, 85.1 (syn),
78.8 (anti), 76.8 (syn), 60.9 (syn), 56.2 (syn), 39.3 (syn), 38.6 (anti),
37.5 (anti), 36.5 (syn), 36.3 (syn), 36.2 (anti), 35.2 (syn), 33.9 (anti),
26.3 (anti), 25.1 (syn), 24.7 (syn), 21.5 (syn), 19.4 (anti), 17.4
J2¼17.2 Hz, 1H), 4.95 (qd, J1¼1.6 Hz, J2¼10.0 Hz, 1H), 4.01 (s, 1H), 2.48
(m, 3H), 2.28 (m, 1H), 1.97 (m, 4H), 1.52 (m, 2H), 1.47 (s, 2.7H, Mesyn),
1.45 (s, 0.3H, Meanti) ppm; 13C NMR (100 MHz, CDCl3):
115.4, 84.9 (syn), 76.7 (anti), 70.86, 40.2 (anti), 39.3 (syn), 36.7 (syn),
35.1 (syn), 34.0 (anti), 28.7 (anti), 27.2 (syn), 26.3 (anti), 25.1 (syn), 23.7
d
¼211.1, 137.5,
(anti) ppm; IR (neat):
n
¼3479, 2938, 2838, 1713, 1589, 1508, 1456,
1420, 1341, 1239, 1182, 1126, 1009 cmꢁ1; HRMS (ESI, m/z): calcd for
(anti), 21.6 (syn), 20.0 (anti) ppm; IR (neat):
n
¼3474, 2968,1715,1441,
C19H27ClO5 [MþH]þ, 371.1625; found, 371.1629.
1381, 1311, 1143, 1112, 1078, 914, 855, 606 cmꢁ1; HRMS (ESI, m/z):
calcd for C11H17ClO2 [MþH]þ, 217.0995; found, 217.0994.
4.17. 2-Hydroxy-3-methyl-2-(3-methylbenzyl)cyclohex-3-en-
1-one (15)
4.13. cis-8a-Chloro-10a-hydroxy-4a-
methyldodecahydrophena nthren-1(2H)-one (( )-2j)
Compound 15 was obtained using the same procedure as for the
synthesis of (ꢀ)-2 with keto-epoxide 6l (93 mg, 0.403 mmol). Pu-
rification by chromatography on silica gel (eluent: cyclohexane/
ethyl acetate 95:5) gave 15 as a yellow solid (69 mg, 74%). Rf¼0.27
(cyclohexane/EtOAc 95:5); mp 49e52 ꢂC; 1H NMR (400 MHz,
cis-9-Decalinol (ꢀ)-2j was obtained using the same procedure as
for the synthesis of (ꢀ)-2 with keto-epoxide 6j (51 mg, 0.128 mmol).
Purification by chromatography on silica gel (eluent: cyclohexane/
ethyl acetate 90:10) gave (ꢀ)-2j as a colourless oil (23 mg, 66%).
Rf¼0.50 (cyclohexane/EtOAc 80:20); 1H NMR (400 MHz, CDCl3):
CDCl3):
d
¼7.14 (t, J¼7.6 Hz, 1H), 7.03 (d, J¼7.6 Hz, 1H), 6.97 (s, 1H),
6.92 (d, J¼7.6 Hz, 1H), 6.72 (m, 1H), 3.71 (s, 1H), 2.79 (m, 2H), 2.54
d
¼2.63 (m, 1H), 2.15 (dd, J¼6.4, 17.6 Hz, 1H), 2.04 (m, 1H), 1.90 (m,
(m, 1H), 2.45 (m, 1H), 2.32 (s, 3H), 2.11 (m, 1H), 1.97 (m, 1H), 1.85 (s,
2H), 1.62 (m, 8H), 1.14 (m, 6H), 0.8 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3):
¼212.1, 99.7, 80.6, 57.0, 53.7, 42.8, 39.9, 33.9, 31.3, 25.9, 24.6,
3H) ppm; 13C NMR (100 MHz, CDCl3):
d¼202.4, 145.1, 137.8, 135.6,
d
133.6, 131.2, 128.0, 127.6, 127.3, 75.8, 42.7, 33.9, 24.3, 21.5, 15.9 ppm;
23.4, 23.2, 22.3, 20.2 ppm; IR (neat):
n¼3475, 2934, 2861, 1721, 1448,
IR (neat):
n
¼3486, 2922, 1668, 1449, 1431, 1362, 1345, 1218, 1107,
1093,1064, 1050, 970, 944, 915, 745 cmꢁ1; HRMS (ESI, m/z): calcd for
1057, 1022, 882, 792, 770, 721, 712 cmꢁ1; HRMS (ESI, m/z): calcd for
C15H23ClO2 [MþNa]þ, 293.1284; found, 293.1286.
C15H18O2 [MþH]þ, 231.1385; found, 231.1381.
4.14. 6-Chloro-8a-hydroxy-4a-methyl-3,4,4a,7,8,8a-hexahydro
naphtalen-1(2H)-one (( )-2k)
4.18. (1S)-2-[2-(3-Isopropyl-2-methoxyphenyl)ethyl]-3-
methyl cyclohex-2-en-1-ol ((S)-17)
cis-9-Decalinol (ꢀ)-2k was obtained using the same procedure
as for the synthesis of (ꢀ)-2 with keto-epoxide 6k (40 mg,
BH3$Me2S (110
mL, 1.117 mmol, 1.6 equiv) was added dropwise at
0
ꢂC to a stirred suspension of (R)-oxazaborolidine (232 mg,

8382
S. Goncalves et al. / Tetrahedron 67 (2011) 8373e8382
0.838 mmol, 1.2 equiv) in dry tetrahydrofuran (9 mL). After 30 min
at solution of -unsaturated ketone (200 mg,
ꢂC,
in the online version, at doi:10.1016/j.tet.2011.08.050. These data
include MOL files and InChIKeys of the most important compounds
described in this article.
0
a
a,
b
8
0.698 mmol, 1.0 equiv) in dry tetrahydrofuran (11 mL) was added
dropwise and the mixture was stirred for 1 h at 0 ꢂC. Methanol was
then slowly added and the mixture concentrated. The residue was
purified by chromatography on silica gel (eluent: cyclohexane/ethyl
acetate 70:30) to give (S)-17 as a colourless oil (196 mg, 97%) with
an enantiomeric excess of 92%. Rf¼0.54 (cyclohexane/EtOAc 70:30);
References and notes
1. Deng, F.; Zhou, B.; Song, G.; Hu, C. Yaoxue Xuebao 1982, 17, 146e150.
2. Kupchan, S. M.; Court, W. A.; Dailey, R. G.; Gilmorej, C. J.; Bryan, R. F. J. Am.
Chem. Soc. 1972, 94, 7194e7195.
[
a
]
D þ32.2 (c 1 M, MeOH) ; 1H NMR (400 MHz, CDCl3):
¼7.02 (m,
d
ꢁ
3. (a) Castellanos, L.; Duque, C.; Rodriguez, J.; Jimenez, C. Tetrahedron 2007, 63,
3H), 4.10 (br, 1H), 3.74 (s, 3H), 3.28 (quint, J¼6.6 Hz, 1H), 2.43 (m,
1544e1552; (b) Caron, P.-Y.; Deslongchamps, P. Org. Lett. 2010, 12, 508e511; (c)
Shimona, F.; Kondo, H.; Yuuya, S.; Suzuki, T.; Haghiwara, H.; Ando, M. J. Nat.
Prod. 1998, 61, 22e28.
4. (a) Herzig, P. T.; Ehrenstein, M. J. Org. Chem. 1951, 16, 1050e1063; (b) Balant, C.
P.; Ehrenstein, M. J. Org. Chem. 1952, 17, 1587e1596; (c) Macias, F. A.; Aguilar, J.
M.; Molinillo, J. M. G.; Rodriguez-Luis, F.; Collado, I. G.; Massanet, G. M.;
Fronczek, F. R. Tetrahedron 2000, 56, 3409e3414.
5. (a) Liu, Y.; Wang, L.; Jung, J. H.; Zhang, S. Nat. Prod. Rep. 2007, 24, 1401e1429; (b)
Ghershenzon, J.; Dudareva, N. Nat. Chem. Biol. 2007, 3, 408e414; (c) Salminen,
A.; Lehtonen, M.; Suuronen, T.; Kaarniranta, K.; Huuskonen, J. Cell. Mol. Life Sci.
2008, 65, 2979e2999; (d) Garcia, P. A.; Braga de Oliveira, A.; Batista, R. Mole-
cules 2007, 12, 455e483; (e) Wang, L.-Q.; Chen, Y.-G.; Xu, J.-J.; Liu, Y.; Li, X.-M.;
Zhao, Y. Chem. Biodiversity 2008, 5, 1879e1899; (f) Sladic, D.; Gasic, M. J. Mol-
ecules 2006, 11, 1e33; (g) Paduch, R.; Kandefer-Szerszen, M.; Trytek, M.; Fie-
durek, J. Arch. Immunol. Ther. Exp. 2007, 55, 315e327; (h) Zubia, E.; Ortega, M. J.;
Carballo, J. L. J. Nat. Prod. 2008, 71, 2004e2010; (i) Laube, T.; Bernet, A.; Dahse,
H.-M.; Jacobsen, I. D.; Seifert, K. Bioorg. Med. Chem. 2009, 17, 1422e1427; (j)
Takikawa, H. Biosci. Biotechnol. Biochem. 2006, 70, 1082e1088; (k) Sunazuka, T.;
Omura, S. Chem. Rev. 2005, 105, 4559e4580.
6. (a) Ahmed, A. F.; Dai, C.-F.; Kuo, Y.-H.; Sheu, J.-H. Steroids 2003, 68, 377e381; (b)
Yasmeen, S.; Riaz, N.; Bibi, A.; Afza, N.; Malik, A.; Tareen, R. B. Helv. Chim. Acta
2009, 92, 404e408.
7. Kokoska, L.; Janovska, D. Phytochemistry 2009, 70, 842e855.
8. Ahmed, A. F.; Hsieh, Y.-T.; Wen, Z.-H.; Wu, Y.-C.; Sheu, J.-H. J. Nat. Prod. 2006, 69,
1275e1279.
9. Deng, M.; Dong, W.; Jiao, W.; Lu, R. Helv. Chim. Acta 2009, 92, 495e501.
10. Tanaka, A.; Kamata, H.; Yamashita, K. Agric. Biol. Chem. 1988, 52, 2043e2048.
11. (a) Marshall, J. A.; Fanta, W. I. J. Org. Chem. 1964, 29, 2501e2505; (b) Marshall, J.
A.; Fanta, W. I.; Roebke, H. J. Org. Chem. 1966, 31, 1016e1020; (c) Marshall, J. A.;
Hochstetler, A. R. J. Org. Chem. 1968, 33, 2593e2595; (d) Ando, M.; Sayama, S.;
Takase, K. J. Org. Chem. 1985, 50, 251e264.
2H), 1.57e1.93 (m, 9H), 1.47 (s, 3H), 1.23 (d, J¼6.6 Hz, 3H), 1.19 (d,
J¼6.6 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼155.7, 141.8,
d
135.2, 132.8, 131.3, 128.0, 124.6, 124.5, 61.8, 38.9, 32.4, 32.3, 32.1,
29.9, 26.5, 24.2, 23.9, 19.0, 17.9 ppm; IR (neat):
n
¼3422, 2958, 2934,
1465, 1460, 1257, 1203, 1167, 1052, 1015, 765, 680, 669 cmꢁ1; HRMS
(ESI, m/z): calcd for C19H28O2 [MþH]þ, 289.2168; found, 289.2164.
4.19. (1S,2S,6R)-1-[2-(3-Isopropyl-2-methoxyphenyl)ethyl]-6-
methyl-7-oxabicylo[4.1.0]heptan-2-ol ((1S,2S,6R)-18)
NaHCO3 (103 mg, 1.22 mmol, 2.0 equiv) and m-CPBA (180 mg,
0.730 mmol, 1.2 equiv) were added at 0 ꢂC to a solution of (S)-17
(175 mg, 0.608 mmol, 1.0 equiv) in dichloromethane (6.5 mL). After
1 h at 0 ꢂC, an aqueous solution of sodium thiosulfate 1 M (6.5 mL)
was added and the mixture was partionned between diethyl ether
(16.5 mL) and NaHCO3 saturated. The organic phase was washed
with NaHCO3 saturated (6 mL) and brine (2ꢃ6 mL), dried over so-
dium sulfate and evaporated to give (1S,2S,6R)-18 as a colourless
solid (185 mg, quantitative) with an enantiomeric excess of 93%.
Rf¼0.40 (cyclohexane/EtOAc 80:20); [
a
]
D þ29.4 (c 1 M, MeOH) ; 1H
NMR (400 MHz, CDCl3):
d
¼7.11 (dd, J1¼7.2 Hz, J2¼3.0 Hz, 1H), 7.02
(m, 2H), 4.05 (br s, 1H), 3.75 (s, 3H), 3.28 (sept., J¼6.8 Hz, 1H), 2.74
(t, J¼8.6 Hz, 2H), 2.25 (m, 2H), 1.41e1.84 (m, 8H), 1.21 (d, J¼7.0 Hz,
6H), 1.15 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d¼155.7, 142.1,
12. Watanabe, H.; Nakada, M. Tetrahedron Lett. 2008, 49, 1518e1522.
13. Deschamps, J.; Riant, O. Org. Lett. 2009, 11, 1217e1220.
14. Katoh, T.; Mizumoto, S.; Fudesaka, M.; Takeo, M.; Kajimoto, T.; Node, M.
Tetrahedron: Asymmetry 2006, 17, 1655e1662.
15. Beauseigneur, A.; Ericsson, C.; Renaud, P.; Schenk, K. Org. Lett. 2009, 11,
3778e3781.
134.4, 127.7, 125.0, 124.5, 67.3, 66.9, 66.3, 61.8, 33.1, 31.3, 31.1, 27.0,
26.4, 26.2, 24.2, 20.1, 15.7 ppm; IR (neat):
n
¼3326, 2935, 1968, 1461,
1428, 1251, 1203, 1167, 1080, 1049, 1012, 862, 796, 765 cmꢁ1; HRMS
(ESI, m/z): calcd for C19H28O3 [MþH]þ, 305.2117; found, 305.2115.
16. Ema, T.; Oue, Y.; Akihara, K.; Miyazaki, Y.; Sakai, T. Org. Lett. 2009, 11,
4866e4869.
4.20. (1S)-2-[2-(3-Isopropyl-2-methoxyphenyl)ethyl]-3-
methylcyclohex-2-en1-ol ((1R,6R)-19)
17. Wefelscheid, U. K.; Reissig, H.-U. Adv. Synth. Catal. 2008, 350, 65e69.
18. (a) Iida, T.; Shiraishi, K.; Ogawa, S.; Goto, T.; Mano, N.; Goto, J.; Nambara, T.
Lipids 2003, 38, 281e287; (b) Iida, T.; Ogawa, S.; Shiraishi, K.; Kakiyama, G.;
Goto, T.; Mano, N.; Goto, J. ARKIVOC 2003, vii, 171e179; (c) Shingaki, T.; Miura,
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Tetrahedron 2000, 56, 8779e8794.
A solution of (1S,2S,6R)-18 (187 mg, 0.648 mmol, 1.0 equiv) in
dry dichloromethane (1.2 mL) was added at room temperature to
a solution of DesseMartin periodinane (314 mg, 0.617 mmol,
1.0 equiv) in dry dichloromethane (400 mL) and the mixture was
stirred for 2 h. After concentration, the residue was purified by
chromatography on silica gel (eluent: cyclohexane/ethyl acetate
80:20) to give (1R,6R)-19 as a white solid (151 mg, 86%). The
recorded experimental data (1H, 13C, IR and MS) were identical to
24 þ30.2 (c 1 M, MeOH) .
20. Goncalves, S.; Hellier, P.; Nicolas, M.; Wagner, A.; Baati, R. Chem. Commun. 2010,
those found for 6a. [a]
D
5778e5780.
21. Goncalves, S.; Santoro, S.; Nicolas, M.; Wagner, A.; Maillos, P.; Himo, F.; Baati, R.
J. Org. Chem. 2011, 76, 3274e3285.
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23. Klix, R. C.; Bach, R. D. J. Org. Chem. 1987, 52, 580e586.
24. Supplementary crystallographic data could be obtained from the Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/datarequest/cif with the
deposited number CCDC 795124.
Acknowledgements
We acknowledge the Laboratoire Pierre Fabre (Plantes et In-
dustries) and the CNRS for financial support of S.G.
25. (a) Fleming, F. F.; Wei, G.; Steward, O. W. J. Org. Chem. 2008, 73, 3674e3679; (b)
Tisserand, S.; Baati, R.; Nicolas, N.; Mioskowski, C. J. Org. Chem. 2004, 69,
8982e8983.
Supplementary data
26. Goncalves, S.; Maillos, P.; Nicolas, M.; Wagner, A.; Baati, R. Tetrahedron 2010, 66,
7856e7860.
27. Kita, Y.; Furukawa, A.; Futamara, J.; Higuchi, K.; Ueda, K.; Fujioka, H. Tetrahedron
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Procedures for the preparation of unknown starting C2-
substituted 3-methylcyclohexenones, 1H and 13C NMR spectra as
well as HPLC chromatograms for enantioselectivity exploration are
given. Supplementary data associated with this article can be found
28. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986e2012.