Cationic cyclization of 2-alkenyl-1,3-dithiolanes: Diastereoselective synthesis of trans-decalins

Article abstract of DOI:10.1021/jo2001116

An unprecedented and highly diastereoselective 6-endo-trig cyclization of 2-alkenyl-1,3-dithiolanes has been developed yielding trans-decalins, an important scaffold present in numerous di- and triterpenes. The novelty of this 6-endo-trig cyclization stan

Full text of DOI:10.1021/jo2001116

ARTICLE
pubs.acs.org/joc
Cationic Cyclization of 2-Alkenyl-1,3-dithiolanes: Diastereoselective
Synthesis of trans-Decalins
Sylvie Goncalves,† Stefano Santoro,‡ Marc Nicolas,§ Alain Wagner,† Philippe Maillos,§ Fahmi Himo,‡ and
Rachid Baati*,†
†Universitꢀe de Strasbourg, Facultꢀe de Pharmacie UMR/CNRS 7199, Laboratoire des Systꢁemes Chimiques Fonctionnels,
74 route du Rhin, BP 60024, 67401 Illkirch, France
‡Department of Organic Chemistry, Arrhenius Laboratory, SE-10691 Stockholm, Sweden
§Les Laboratoires Pierre Fabre, Centre de Dꢀeveloppement Chimique et Industriel, 16 rue Jean Rostand, 81600 Gaillac, France
S Supporting Information
b
ABSTRACT: An unprecedented and highly diastereoselective
6-endo-trig cyclization of 2-alkenyl-1,3-dithiolanes has been
developed yielding trans-decalins, an important scaffold present
in numerous di- and triterpenes. The novelty of this 6-endo-trig
cyclization stands in the stepwise mechanism involving 2-alke-
nyl-1,3-dithiolane, acting as a novel latent initiator. It is sug-
gested that the thioketal opens temporarily under the influence
of TMSOTf, triggering the cationic 6-endo-trig cyclization, and
closes after CꢀC bond formation and diastereoselective pro-
tonation to terminate the process. DFT calculations confirm
this mechanistic proposal and provide a rationale for the observed diastereoselectivity. The reaction tolerates a wide range of
functionalities and nucleophilic partners within the substrate. We have also shown that the one-pot 6-endo-trig cyclization followed
by in situ 1,3-dithiolane deprotection afford directly the corresponding ketone. This improvement allowed the achievement of the
shortest total synthesis of triptophenolide and the shortest formal synthesis of triptolide.
’ INTRODUCTION
is to have a good initiator embedded within the substrate such as
acetal, epoxide, allylic alcohol, N-acetal, 1,3-dicarbonyl,8 aziridine,9
or hydroxylactam.10 Despite the fact that a considerable amount of
effort has been directed toward improving the efficacy of these
cyclizations, primarily by achieving high diastereoselectivities and
enantioselectivities, the discovery of novel reagents and new broadly
applicable strategies remains a goal of paramount importance for the
stereoselective preparation of decalin carbocycles.
The design of new strategies for the stereoselective synthesis
of decalin carbocycles continues to be of great interest in organic
synthesis due to the crucial importance of this skeleton as part of
biologically relevant natural products.1 For instance, trans-decalin is
the central structure of many di- and triterpenes such as sesterstatin
6 (1),1a polygodial1b (2), and (ꢀ)-triptolide1c (3) that exhibit a
wide diversity of biological activities (Figure 1).
To date, numerous reports of methodologies targeting the
trans-decalin scaffold of di- and triterpenes have been developed,2
and the bioinspired acid-induced polycationic cyclization of poly-
prenoides,3 originally pioneered by van Tamelen, Johnson, and
Goldsmith, remains the most widely used methods for the fashion-
ing of polycylic terpenoids.4 Recently, the radical-mediated polyene
cyclization reported by MacMillan has also emerged as a powerful
approach for the stereoselective construction of complex steroidal
and terpenoidal frameworks exhibiting trans-decalinic units.5 Halo-
nium-induced cyclization of polyolefine has also been demonstrated
recently to be a powerful alternative for the construction of
functionalized decalins with impressive trans-stereoselection.6 Be-
sides these approaches, a number of elegant stereoselective meth-
ods, including substrate controlled hydrogenation of unsaturated
bicylic systems, have been developed to access this important class of
compounds.7 As mentioned recently by Loh,8 the key to a successful
highly diastereoselective cationic cyclization delivering trans-decalin
As part of our ongoing program devoted to the total synthesis
of triptolide, we have recently communicated our preliminary
endeavors on the construction of trans-decalin dithiolane 5a (R1 =
OMe, R2 = iPr, R3 = H) by using a novel 6-endo-trig cyclization of
the corresponding 2-alkenyl-1,3-dithiolane 4a as a highly promis-
ing latent initiator upon Lewis acid treatment (Scheme 1).11
The critical choice of this novel initiator has been driven by the
failure of the parent enone 6 (Scheme 2) to cyclize efficiently and
with high diastereoselectivity.11Herein we wish to report in full details
our findings on the successful development of the first TMSOTf
induced 6-endo-trig cationic cyclization of 2-alkenyl-1,3-dithiolane that
displays a broad and significant substrate scope and holds broad
promises for applications in natural product syntheses, as well as the
exploration of the suggested mechanism by DFT calculations.
Received: January 24, 2011
Published: March 29, 2011
r
2011 American Chemical Society
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Scheme 2. Synthesis of the C2-Alkylated 3-Methylcylohexe-
none 6
Figure 1. Structure of sesterstatin 6 (1), polygodial (2), and (ꢀ)-
triptolide (3).
Scheme 1. 6-endo-trig Cationic Cyclization of 2-Alkenyl-1,
3-dithiolanes
Scheme 3. Synthesis of 2-Alkenyl 1,3-Dithiolane 4a
’ RESULTS AND DISCUSSION
Synthesis of 2-Alkenyl-1,3-dithiolane 4a. Initial efforts
focused on establishing optimal conditions for the diastereose-
lective cyclization of 2-alkenyl-1,3-dithiolane 4a to trans-decalin
5a (Scheme 1). Prior to embarking on this investigation, we first
studied the synthesis of the precursor enone 6 by investigating
different routes based either on the electrophilic alkylation of
(a) 3-methylcyclohexenone 7,12 (b) Hagemann ester 9,13 and
(c) Enders’s diene 1014 with the known iodide 815 or on (d) the
de novo construction of 2-substituted 3-methylcyclohexenone
system (Scheme 2).16 While the approaches aꢀc afforded the
desired enone 6 in one to three steps, however, in low yields,
we have finally found a novel practical protocol based on a one-
pot four-step domino cascade reaction of triketone 1117 (route d)
for the preparation of 6 starting from commercially available
methyl acetoacetate and iodide 8. In addition, during our
optimization work, a novel three-step synthetic strategy to
access iodide 8 in large scale has been developed, allowing its
preparation in 84% overall yield (see the Supporting In-
formation) compared to previous syntheses (4 steps in 27%
overall yield).15 This route (d) permitted access to the desired
R,β-unsaturated ketone 6 in satisfactory 66% yield over 3 steps
(Scheme 2).
Investigation of the 6-endo-trig Cyclization. Initial cycliza-
tion experiments of 4a were performed with Br€onsted acid such
as TfOH in dichloromethane (DCM) as solvent and at room
temperature for 16 h (Table 1). Even though a large excess of
TfOH was used (15 equiv), the conversion of 4a was marginal
(only 5%), and the cyclized product 5a was not obtained
(Table 1, entry 1). The challenge of developing a diastereoselec-
tive cyclization of 2-alkenyl-1,3-dithiolanes appears to be asso-
ciated with the low reactivity and eventually the low nucleophi-
licity of the nonconjugated olefin of the substrate 4a. As a
consequence, we decided to evaluate the reactivity of hard Lewis
acids such as Sc(OTf)3, BF3 Et2O, TiCl4, SnCl4, ZrCl4, and
3
AlCl3 (Table 1, entries 2ꢀ7). Notably, the use of these reagents,
except for Sc(OTf)3 and ZrCl4 (entries 2 and 6), established the
feasibility of the cyclization for 4a, since the trans-decalin 5a was
obtained diastereoselectively (dr trans:cis = 100:0)11,19 in the range
of 27ꢀ44% yield (entries 3ꢀ5 and 7). It is worth mentioning that in
these conditions the conversion of 4a was always high and between
88% and 100%; however, all of the reactions suffered from competi-
tive background pathways such as the irreversible rupture of the
1,3-dithiolane moiety before cyclization, leading back to enone 6
(30ꢀ40%). These results suggested that the CꢀC bond-forming
reaction might eventually be triggered by the initial rupture of one
CꢀS bond of the 1,3-dithiolane 4a, under the influence of the Lewis
Finally 1,3-dithiolane 4a was synthesized by protecting the
ketone using 1,2-ethanedithiol in the presence of a catalytic
amount of indium(III) trifluoromethanesulfonate in excellent
isolated 98% yield (Scheme 3).18
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Table 1. Lewis Acid Screening for the 6-endo-trig Cationic
Cyclization of 4a
Table 2. Influence of Solvent Nature on the 6-endo-trig
Cyclization of 4a
entry
Lewis acida
conversion (%)b
yield (%)c
entry
solventa
conversion (%)a yield (%)b dr 5a: trans/cis(%)c
1
TfOH
5
36
1
2
3
4
5
DCM
100
6
64
100
2
Sc(OTf)3
Et2O
3
BF3 Et2O
88
44
27
31
2
1,4-dioxane
MeNO2
DCE
3
4
TiCl4
91
94
75
88
100
5
SnCl4
100
100
98
100
97/3
6
ZrCl4
a Conversion quantified by HPLC analysis. b Yield evaluated by HPLC.
c dr was determined by HPLC analysis.
7
AlCl3
29
8
Yb(OTf)3
FeCl3
42
to the complexation of TMSOTf with the thioketal moiety and/
or to the formation of TfOH. We also noticed that the efficiency
of the cyclization for 4a was temperature-dependent, and lower
temperatures, such as ꢀ78 and ꢀ20 °C, either inhibited the reaction
or delivered 5a in diminished yield for the same reaction time and
concentration of substrate, respectively (see the Supporting In-
formation). Additionally, it was found through a screening of solvents
that Et2O and 1,4-dioxane were not valuable solvents for the reaction
(Table 2, entries 2 and 3), whereas nitromethane and 1,2-dichloro-
ethane (DCE) afforded 5a with improved yields compared to DCM
(entries 1, 4, and 5), with DCE being the most effective solvent in
terms of chemical isolated yield of 5a. It is noteworthy to mention that
in all solvents the reactions were highly diastereoselective, providing
trans-5a exclusively, except when DCE was used, when a 97/3 trans/
cis ratio was obtained (Table 2, entry 5).
A mechanism that can account for the observed trans-stereo-
chemistry preference is proposed in Scheme 4. It is assumed that
the TMSOTf-induced thioketal 4a opening leads first to the reactive
vinyl thionium ion 13.20 The resulting highly electrophilic inter-
mediate is subsequently attacked by the aromatic ring, affording
intermediate 16, after deprotonationꢀrearomatization. Protonation
of the latter furnishes the trans-decalin junction of 17. Finally,
1,3-dithiolane reinstallation affords the final product 5a.
Investigation of the Mechanism by DFT Calculations. In
order to investigate the energetic feasibility of this mechanistic
proposal and to rationalize the origin of the observed diastereo-
selectivity, we have performed density functional calculations on
the cyclization of 2-alkenyl-1,3-dithiolane 4a to decalin 5a (see
Experimental Section for computational details). The first step,
the formation of the SiꢀS bond with a subsequent ring opening
of the dithiolane moiety to afford intermediate 13/14, has been
found to be endothermic by ca. 9 kcal/mol. However, this value is
rather uncertain since it involves the transformation of two neutral
species into two charged ones. In this case the solvation effects are
rather large and lead thus to large uncertainties. The calculations here
are used merely to show that this step is feasible. The following CꢀC
bond-formation step has also been found to be endothermic by 24.8
kcal/mol. However, the subsequent deprotonation-rearomatization
step, mediated by the triflate ion (15 f 16), is exothermic by 26.3
kcal/mol. So the sum of the two steps is about thermoneutral. It is
likely that they occur concertedly, which avoids the large endother-
micity of the former step. Here, it should be noted that after the ring
opening of the dithiolane the 2-((trimethylsilyl)thio)ethyl chain can
freely rotate and thus cannot be considered as shielding one of the
two faces, neither for the nucleophilic attack by the aromatic ring nor
for the protonation step. The latter is the only step determining the
diasteroselectivity of the process. We have hence located the transi-
tion states for the protonation on the two faces of 16. It turns out that
the barriers are quite similar (6.5 and 7.2 kcal/mol for the formation
9
100
99
10
11
12
13
14
In(OTf)3
TMSNTf2
TMSOTf
TMSOTf d
TMSOTf e
10
52
64
64
26
100
100
100
42
a 15 equiv of acid was used, in DCM at rt and for 16 h. b Conversion
quantified by HPLC analysis. c Yield determined by HPLC. d 1.1 equiv of
TMSOTf was used. e 0.5 equiv of TMSOTf was used.
acid, generating a vinyl sulfonium cation that would induce the
cyclization event. After the trans-decalin formation, it is then
postulated that the 1,3-dithiolane is regenerated in situ affording
the desired product 5a.11,20 It was then thought that the use of softer
Lewis acid would avoid the competitive complete deprotection of
the carbonyl group of 4a while generating the reactive vinyl
sulfonium ion needed for the efficient cationic 6-endo-trig cyclization.
Unfortunately, the use of Yb(OTf)3, FeCl3, and In(OTf)3 in the
same conditions was unsuccessful in fulfilling our expectations,
because of either low conversion of 4a (entry 8) and/or mainly
degradation of the starting material (entries 8 and 10). We decided
next to evaluate the reactivity of silicon-based electrophilic reagents
such as TMSNTf221 and TMSOTf that could activate sulfur atoms.20
Gratifyingly, exposure of a dichloromethane solution of 4a with 15
equiv of TMSNTf2 or TMSOTf resulted in the formation of 5a with
substantially improved chemical yields, 52% and 64%, respectively
(entries 11 and 12), compared to BF3 Et2O (44%), and without
3
alteration of the diastereoselectivity (100% trans). While TMSOTf
catalyzed or uncatalyzed CꢀC bond-forming reactions are usually
used to activate oxygen atoms (acetal, epoxide, or carbonyl group)22
or nitrogen (trichloroacetimidate),23 the observed 6-endo-trig cycli-
zation differs significantly since the reaction involves CꢀS bond
activation leading to a transformation with no literature precedent.
Encouraged by this promising result, and with the best
identified Lewis acid, that is, TMSOTf, we next turned our
attention on the optimization of the reaction conditions by (i)
diminishing the Lewis acid quantity, (ii) identifying the optimal
temperature for the transformation, and (iii) finding the suitable
solvent for the reaction. It appeared that the 6-endo-trig cycliza-
tion of 4a can also be promoted efficiently, without altering the
diastereoselectivity, when 1.1 equiv of TMSOTf is used (0.03 M,
DCM, rt, 16 h) (64% of 5a, entry 13). Conversely, we noticed
that in the presence of a catalytic amount of TMSOTf (0.5
equiv), under otherwise identical conditions, 5a is obtained in
lower isolated yield (26%) as a result of limited conversion of 4a,
even after prolonged reaction time. This result suggests the
irreversible transformation of TMSOTf during the reaction
precluding any possible recycling of the reagent, eventually due
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Scheme 4. Suggested Mechanism for the 6-endo-trig Cyclization for 4a
Figure 2. Optimized transition states and products of the protonation step. Energies are relative to 16.
of the cis and the trans isomer, respectively, see Figure 2 for optimized
structures). However, the energies of the resulting intermediates
differ quite substantially, trans-17 being 3.8 kcal/mol lower than
cis-17. The energy difference stems mainly from the unfavorable ring
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Scheme 5. Three-Step Synthesis of 2-Alkenyl-1,3-dithiolanes 4bꢀ4g and 4j
Table 3. Scope and Limitations for the 6-endo-trig Cationic
Cyclization
junction of cis-17 and is very similar to the experimental value for
trans/cis isomerism measured for decalin.24 Since this step is
endothermic and hence reversible, these energies show that the
selectivity is thermodynamically controlled. The calculated trans/cis
energy difference is in good agreement with the observed diastere-
omeric ratio of 97:3. Finally, we have calculated that the whole
process, i.e., the conversion of substrate 4a to product trans-5a, is
exothermic by 5.9 kcal/mol. Here, it should be mentioned that an
alternative mechanism involving activation of the olefin by the
trimethylsilyl group has also been considered. However, one key
intermediate for this pathway was found to be very high in energy
when compared to intermediate 13 (more than 40 kcal/mol), which
is enough to rule out this mechanism (see Supporting Information
for details).
Application of the 6-endo-trig Cyclization to Various
Dithiolanes. Having rationalized the stereochemical outcome
of the 6-endo-trig cyclization for 4a, we evaluated next the
substrate scope of our newly developed 6-endo-trig cationic
cyclization reaction in the optimized conditions. To reach that
goal, a panel of 2-alkenyl-1,3-dithiolanes 4bꢀ4g and 4j bearing
electron-rich and electron-deficient arenes, a thiophenyl moiety, and
a terminal olefin were synthesized in a three-step protocol starting
from the corresponding 2-acyl 1,3-cyclohexanediones 18bꢀ18g
and 18j (Scheme 5) (see the Supporting Information).25 Com-
pounds 4h and 4i have been prepared by a different protocol based
on a recently published one-pot four-step domino reaction for
the construction of the C2-substituted-3-methylcyclohex-2-enone
moiety (compounds 21h and 21i)17 followed by construction of the
1,3-dithiolane moiety. Further dithiolane protection of the enone
upon treatment with 1,2-ethanedithiol, as described in Scheme 5,
afforded the desired 2-alkenyl-1,3-dithiolanes. Additionally, in order
to determine whether the ring size of the thioketal initiator would
influence the efficiency of the reaction and/or the diastereoselec-
tivity, we prepared substrate 22 and envisioned to study its reactivity
in the same conditions as substrates 4aꢀ4j (Figure 3). Attempts to
prepare also 2-alkenyl-1,3-dioxolanes analogues from the corre-
sponding enones (21), in order to study eventually the influence of
the ketals functionality in the reactivity, failed, and their generation
still remains an unsolved problem.
a 15% of 4d recovered. b Isolated as an inseparable mixture with 58% of
c
4f. 67% of 4i was recovered. d 47% of 4j recovered. e Isolated as an
Finally, with 4bꢀ4j and 19 in hand we were able to perform
inseparable mixture with 23% of 22 along with 42% of 6.
our cyclization study. The results confirmed that the
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Figure 3. 2-Alkenyl-1,3-dithiolanes 4bꢀ4j and 1,3-dithiane 22 investigated in this study.
Scheme 6. One-Pot 6-endo-trig Cyclization/1,3-Dithiolane Deprotection of 4a
intramolecular 6-endo-trig reaction proceeded well when 1,3-
dithiolanes 4b, 4c, and 4d bearing electron-donating substituents
on the aromatic part were used (Table 3, entries 1ꢀ3). Good
yields of the expected trans-decalins 5b, 5c, and 5d, respectively,
were obtained in 68ꢀ83% (entries 1ꢀ3). In these cases, the cis-
decalin isomers were not detected by 1H NMR spectroscopy or
HPLC analysis of the crude reaction mixture. Subjecting electron-
deficient arene 4e to the same reaction conditions yielded trans-
decalin 5e (41%) in 41% yield along with 41% of the starting reactant
(entry 4). The low reactivity observed for 4e might be ascribed to
the lower nucleophilicity of the bromoarene moiety, limiting the
consumption of the substrate. We further examined whether
substituents on the thioketal cyclohexenyl part would affect both
the reactivity and the stereoselectivity. gem-Dimethyl dithiolane 4f
was submitted to cyclization conditions; however, the reaction
afforded 5f with a moderate yield of 36%, as an inseparable mixture
with 58% of the starting material 4j (entry 5). Conversely, the 1,3-
dithiolane 4g, featuring a thiophenyl group, provided regioselec-
tively and exclusively as a single diastereoisomer the trans-decalin 5g
in good isolated yield (59%) (entry 6).
affecting the C3 position. Pleasingly, the cyclization also underwent
in a stereoselective manner when the olefinic substrate 4h was
treated in the same conditions providing ready access to the trans-
decalins regioisomers 5h and 5h0 in a 3:1 ratio and in an acceptable
yield (44%, entry 7). Attempts to promote 5-endo-trig and 7-endo-
trig cyclization for 2-alkenyl-1,3-dithiolanes 4i and 4j, respectively,
were unsuccessful, presumably due to high energy transition state
(entries 8 and 9). It is not surprising that the 5-endo-trig cyclization
was not observed since this pathway is generally disfavored by
Baldwin rules and difficult to achieve due to severe spatial distortion
and bond angles requirements.26 However, even though the 7-endo-
trig cyclization pathway was favored, the reaction was not promoted
under our room temperature conditions and may necessitate higher
energy activation to increase the rate of the reaction. In both cases,
starting materials were recovered along with 15ꢀ20% of the
corresponding enones 21i and 21j, respectively. Finally, we also
found that 1,3-dithiane 22 was significantly less reactive in the
6-endo-trig cyclization compared to 1,3-dithiolane analogue 4b. It
clearly appeared that an increase of the thioketal ring size was
accompanied by a decreased reactivity of 22 and yield (23%) of the
corresponding cyclized decalin product 23 (trans:cis = 100:0),
leading mainly to 1,3-dithiane side reaction deprotection (42%)
The cyclization event involved highly regioselectively the
substitution at the C2 position of the thiophenyl surrogate without
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(entry 10). This result demonstrates the crucial importance of the
1,3-dithiolane functionality combined with the unique activation
mode of TMSOTf in the 6-endo-trig cationic cyclization. Overall,
this study illustrates that the TMSOTf-induced 6-endo-trig cycliza-
tion of 2-alkenyl-1,3-dithiolane is sensitive to steric hindrance and in
some extent to the nucleophilicity of the arene or the alkenyl group.
It is important to mention that this method appears to be quite
general and permits the access to a variety of trans-decalin moiety
with a high to exclusive trans diastereoselectivity. Additionally the
failure of 1,3-dithiane 22 to promote efficiently 6-endo-trig cycliza-
tions demonstrates the unique reactivity of 2-alkenyl-1,3-dithiolanes
over 2-alkenyl-1,3-dithianes.
Finally, to further illustrate the synthetic utility of our devel-
oped methodology, we achieved successfully the shortest total
synthesis of (()-triptophenolide 25 and the shortest formal total
synthesis of (()-triptolide 3 starting from the common inter-
mediate 4a (Scheme 6). Indeed, in this context, we have further
discovered that the one-pot 6-endo-trig cyclization followed by
in situ 1,3-dithiolane deprotection afforded directly ketone (()-
24 in satisfactory isolated yield of 35% over two steps. This
synthetic improvement, compared to our previous synthesis,11
made it possible to reach, after further functional group trans-
formation of (()-24,27 (()-triptophenolide 2528 in only 8 steps
starting from the known iodide 8, for which we have considerably
improved the preparation (see Supporting Information). To the
best of our knowledge, this synthesis represents the shortest
synthesis reported to date of (()-25, but also the shortest formal
total synthesis of (()-triptolide 3.29 It is anticipated that this
powerful cationic 6-endo-trig cyclization of 2-alkenyl-1,3-dithio-
lanes and its one-pot cyclization/deprotection version could be
strategically used for the fashioning of many other natural
products featuring trans-decalin scaffold.
gel plates with F254 indicator. Visualization was accomplished by UV
light (254 nm), cerium sulfate, or vanillin stains. Yields refer to chromato-
graphically and spectroscopically pure compounds, unless otherwise in-
dicated. Purifications by column chromatography were carried out using
silica gel Si 60 (0.040ꢀ0.063). Yields determined by liquid chromatography
were done with a 300SB-C18 column, using a mixture of acetonitrile and
1
water as eluent. H NMR and 13C NMR were recorded on at 400 and
100 MHz, respectively. Chemical shift values (δ) are reported in ppm
(residual chloroform δ = 7.26 ppm for 1H; residual chloroform δ = 77.16
ppm for 13C). The proton spectra are reported as follows δ (multiplicity,
coupling constant J, number of protons). Multiplicities are indicated by s
(singlet), d (doublet), t (triplet), q (quartet), quint. (quintuplet), hept
(heptuplet), m (multiplet). High resolution mass spectra were recorded
with a mass apparatus equipped with a positive ESI source. Melting points
were recorded using the capillary method.
3-Isopropyl-2-methoxybenzaldehyde. Potassium carbonate
(17.12 g, 123.9 mmol, 1.5 equiv) and methyl iodide (7.8 mL, 123.9
mmol, 1.5 equiv) were added to a solution of 2-hydroxy-3-isopropylbenzal-
dehyde (13.56 g, 82.6 mmol, 1.0 equiv) in dry DMF (80 mL). Then, the
mixture was stirred for 14 h. After addition of saturated NH4Cl (100 mL) and
water (500 mL), the aqueous phase was extracted with Et2O (3 ꢁ 100 mL).
The combined organic extracts were dried with Na2SO4 and filtered, and the
solvent was removed under reduce pressure. The residue was purified by flash
column chromatography on SiO2 (cyclohexane/EtOAc 95:5) to give 5 as a
pale yellow oil (14.72 g, 100%); Rf = 0.68 (cyclohexane/EtOAc 80:20); 1H
NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 7.68 (dd, J1 = 3.0 Hz, J2 = 6.0 Hz,
1H), 7.52 (dd, J1 = 3.0 Hz, J2 = 6.0 Hz, 1H), 7.19 (t, J = 6.0 Hz, 1H), 3.90 (s,
3H), 3.33 (m, J = 6.0 Hz, 1H), 1.22 ppm (dd, J1 = 6.0 Hz, J2 = 9.0 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ190.4, 160.7, 143.1, 133.4, 129.3, 126.7,
124.9, 64.8, 26.0, 23.7 ppm; IR (neat) ν 2965, 2870, 1690, 1587, 1473, 1458,
1429, 1388, 1256, 1241, 1211, 1093, 1050, 1004, 854, 798, 768, 743 cmꢀ1
;
HRMS (ESI, m/z) calcd for C11H14O2 [M þ H]þ 179.1072, found
179.1069.
1-Isopropyl-2-methoxy-3-vinylbenzene. To a solution of
PPh3MeI (18.3 g, 44.1 mmol, 1.4 equiv) in dry THF (130 mL) under
argon was added NaHMDS (25.2 mL, 50.4 mmol). After 3 h of stirring at
room temperature, a solution of 5 (5.61 g, 31.5 mmol, 1.0 equiv) in dry
THF (130 mL) was added at ꢀ78 °C. Then, the mixture was stirred
overnight at room temperature. After addition of water (200 mL), the
aqueous phase was extracted with Et2O (4 ꢁ 100 mL). The combined
organic extracts were dried with Na2SO4 and filtered, and the solvent
was removed under reduce pressure. The residue was purified by flash
column chromatography on SiO2 (cyclohexane/EtOAc 95:5) to give 6
as a colorless liquid (5.22 g, 94%); Rf = 0.78 (cyclohexane/EtOAc
90:10); 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 6.0 Hz, 1H), 7.18 (d,
J = 6.0 Hz, 1H), 7.06 (t, J = 6.0 Hz, 1H), 6.98 (dd, J1 = 12.0 Hz, J2 = 18.0
Hz, 1H), 5.78 (d, 1H), 5.28 (d, 1H), 3.74 (s, 3H), 3.29 (m, J = 6.0 Hz,
1H), 1.23 ppm (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
155.1, 142.1, 132.2, 131.1, 126.3, 124.5, 124.0, 114.8, 62.0, 26.4, 23.9
ppm; IR (neat) ν 2964, 2870, 1628, 1459, 1429, 1410, 1336, 1253, 1206,
1170, 1099, 1053, 1011, 911, 815, 800, 764 cmꢀ1; HRMS (ESI, m/z)
calcd for C12H16O [M þ H]þ 177.1279, found 177.1276.
’ CONCLUSION
In summary, we have developed a novel and efficient cationic
6-endo-trig cyclization of 2-alkenyl-1,3-dithiolanes for the stereo-
selective preparation of trans-decalins, the most prevalent struc-
tural unit contained within natural products. Key for the success of
this highly diastereoselective 6-endo-trig cyclization is the use of
TMSOTf, which was found to be unique in inducing good reactivity
and diastereoselectivity. The unprecedented cyclization of these
latent initiators, 2-alkenyl-1,3-dithiolanes, appeared to be quite
general and tolerated arenes, thiophene, and alkene as internal
nucleophiles. DFT calculations have been performed in order to
explore the energetics of the postulated mechanism and to investi-
gate the origin of the diastereoselectivity. It turns out that the
selectivity is introduced at the reversible protonation step and that it
is thermodynamically controlled, i.e., the transition states leading to
the two diastereomers are quite similar, but the resulting intermedi-
ates differ significantly, due to the newly formed ring junction. This
approach opens new opportunities for the invention of related intra-
and intermolecular asymmetric processes. This work is under
progress in our laboratory.
1-(2-Iodoethyl)-3-isopropyl-2-methoxybenzene (8). To a
solution of ZrCp2Cl2 (1.86 g, 6.24 mmol, 1.1 equiv) in dry THF (15 mL)
under argon at 0 °C was added drop by drop DIBAL-H (6.24 mL, 6.24
mmol, 1.1 equiv), and the mixture stirred for 30 min. Then, a solution of 6
(1.0 g, 5.67 mmol, 1.0 equiv) in dry THF (6 mL) was added at 0 °C, and the
mixture was stirred for 1 h at room temperature. After cooling at ꢀ78 °C, a
solution of iodine (1.87 g, 7.36 mmol, 1.3 equiv) in dry THF (10 mL) was
added, and the mixture was allowed to stir at room temperature overnight.
Then, HCl 2 N (30 mL) was slowly added, and the aqueous phase was
extracted with Et2O (3 ꢁ 50 mL). The combined organic extracts were
washed with saturated Na2S2O3 (20 mL), saturated NaHCO3 (20mL), and
brine (20 mL), dried with Na2SO4, and filtered, and the solvent was
’ EXPERIMENTAL SECTION
General Experimental Methods. All reactions were carried out
in flame-dried glassware under an argon atmosphere with dry solvents,
under anhydrous conditions unless otherwise indicated. Solvents for
reactions were dried using a dry solvent station. All reactions were
controlled by analytical thin-layer chromatography using precoated silica
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ARTICLE
removed under reduce pressure. The residue was purified by flash column
chromatography on SiO2 (cyclohexane/EtOAc 95:5) to give 8 as an orange
oil (1.53 g, 89%). Analyses were identical to the ones described in
literature.15b
780 cmꢀ1; HRMS (m/z) calcd for C15H17BrO2 [M þ K]þ 347.0049,
found 347.0044.
3-Methoxy-5,5-dimethyl-2-[2-(3-methylphenyl)ethyl]cyclohex-2-en-
1-one (20f). Obtained as a colorless oil (2.28 g, 42% over two steps) from
starting triketone 18f (5.45 g, 20.00 mmol). Rf = 0.48 (cyclohexane/
EtOAc 70:30); 1H NMR (400 MHz, CDCl3) δ 7.12 (t, J = 7.2 Hz, 1H),
7.00 (m, 2H), 6.95 (d, J = 7.2 Hz, 1H), 3.65 (s, 3H), 2.53 (m, 4H), 2.35 (s,
3H), 2.32 (s, 3H), 2.22 (s, 2H), 1.06 ppm (s, 6H); 13C NMR (100 MHz,
CDCl3 ) δ 198.0, 170.2, 142.9, 137.5, 129.6, 127.9, 126.3, 125.8, 117.9,
55.1, 50.5, 38.9, 34.7, 32.0, 28.7, 24.0, 21.5 ppm; IR (neat) ν 2954, 1646,
1615, 1458, 1368, 1297, 1235, 1147, 1072, 774, 700 cmꢀ1; HRMS (m/z)
calcd for C18H24O2 [M þ H]þ: 273.1855, found 273.1851.
General Procedure for the Synthesis of Cyclic Enol Ether.
Sodium cyanoborohydride (1.5 equiv) was added to a solution of the
triketone 18bꢀg or 18j (1.5 equiv) in tetrahydrofuran (25 mL) and HCl
2 N (20 mL) at 0 °C. The reaction mixture was stirred 30 min at 0ꢀ5 °C.
Then, after addition of ethyl acetate (40 mL) and water (10 mL), the
aqueous phase was extracted by ethyl acetate (3 ꢁ 20 mL). The combined
organic extracts were washed with brine, dried over sodium sulfate, and
evaporated. The residue was purified by flash chromatography on a silica gel
column (eluent: cyclohexane/ethyl acetate) to give the diketone product
19bꢀg and 19j, which appeared to be very unstable. So, it was immediately
put in reaction without further analysis. Trimethylsilyl chloride (1.6 equiv)
was added to a solution of the diketone 19bꢀg or 19j (1.0 equiv) in
methanol (3 mL), and the reaction mixture was stirred overnight. Then, after
addition of triethylamine (150 μL) and evaporation of methanol, the residue
was taken up into water (20 mL) and extracted by ethyl acetate (3 ꢁ
20 mL). The combined organic extracts were washed with brine, dried over
sodium sulfate, and evaporated. The residue was purified by flash chroma-
tography on a silica gel column (eluent: cyclohexane/ethyl acetate) to give
the enol ether 20bꢀg and 20j.
3-Methoxy-2-[2-(3-thienyl)ethyl]cyclohex-2-en-1-one (20g). Ob-
tained as a white solid (1.21 g, 41% over two steps) from starting triketone
18g (2.98 g, 12.61 mmol). Rf = 0.41 (cyclohexane/EtOAc 40:60); mp
111ꢀ114 °C; 1H NMR (400 MHz, CDCl3) δ 7.18 (dd, J1 = 3.2 Hz, J2 = 4.8
Hz, 1H), 6.95 (dd, J1 =1.2Hz, J2 = 4.8 Hz, 1H), 6.91 (dd, J1 =1.2 Hz, J2 =3.2
Hz, 1H), 3.69 (s, 3H), 2.56 (m, 4H), 2.50 (t, J = 6.0 Hz, 2H), 2.31 (t, J = 5.6
Hz, 2H), 1.93 ppm (quint., J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3 )
δ 198.1, 172.3, 143.2, 128.7, 124.5, 119.9, 118.9, 55.1, 36.5, 29.1, 24.8, 23.1,
20.9 ppm; IR (neat) ν2945, 1641, 1608, 1368, 1239, 1160, 1138, 1081, 1044,
778 cmꢀ1;HRMS(m/z) calcd for C13H16O2S[Mþ Na]þ 259.0767, found
259.0763.
2-{3-[4-(1-Hydroxyethyl)-3,5-dimethoxyphenyl]propyl}-3-methox-
ycyclohex-2-en-1-one (20j). Obtained as a yellow oil (763 mg, 38% over
two steps) from starting triketone 18j (2.00 g, 5.97 mmol). Rf = 0.26
(cyclohexane/EtOAc 40:60); 1H NMR (400 MHz, CDCl3) δ 6.41 (s,
2H), 3.83 (s, 6H), 3.80 (s, 3H), 3.78 (s, 3H), 2.52 (m, 4H), 2.30 (m,
4H), 1.92 (quint., J = 6.4 Hz, 2H), 1.58 ppm (m, 2H); 13C NMR (100
MHz, CDCl3) δ 198.4, 172.0, 153.0, 138.9, 135.9, 119.6, 105.3, 60.9,
56.1, 55.2, 36.5, 36.5, 30.2, 24.9, 22.1, 21.0 ppm; IR (neat) ν 2941, 1642,
1609, 1588, 1507, 1456, 1420, 1369, 1237, 1124, 1011 cmꢀ1; HRMS
(m/z) calcd for C19H26O5 [M þ H]þ 335.1858, found 335.1861.
General Procedure for the Synthesis of 3-Methylcyclohex-
2-enones. Methyllithium 1.6 M in diethyl ether (1.25 equiv) was added
slowly to a solution of the enol ether 20bꢀg or 20j (1.0 equiv) in diethyl
ether (2 mL) at 0 °C. The reaction mixture was stirred 2 h at room tempera-
ture. Then, after addition of water (10 mL), the aqueous phase was extracted
by ethyl acetate (3 ꢁ 10 mL). The combined organic extracts were washed
with brine, dried over sodium sulfate, and evaporated. The residue was
purified by flash chromatography on a silica gel column (eluent: cyclohexane/
ethyl acetate) to give the 3-methylcyclohexenone 21bꢀg and 21j.
3-Methyl-2-[2-(3-methylphenyl)ethyl]cyclohex-2-en-1-one (21b).
Obtained as a yellow oil (464 mg, 71%) from enol ether 20b (700
mg, 2.87 mmol). Rf = 0.47 (cyclohexane/EtOAc 60:40). 1H NMR and
IR analysis are identical to the ones reported in literature.30 13C NMR
(100 MHz, CDCl3) δ 198.7, 156.0, 142.3, 137.8, 134.9, 129.5, 128.2,
126.5, 125.7, 38.0, 35.1, 32.9, 27.7, 22.4, 21.4, 21.17 ppm; HRMS (m/z)
calcd for C16H20O [M þ H]þ 229.1592, found 229.1596.
3-Methoxy-2-[2-(3-methylphenyl)ethyl]cyclohex-2-en-1-one (20b).
Obtained as a yellow oil (1.58 g, 41% over two steps) from starting triketone
18b (3.88 g, 15.89 mmol). Rf = 0.57 (cyclohexane/EtOAc 40:60); 1H NMR
(400 MHz, CDCl3) δ 7.13 (t, J = 7.6 Hz, 1H), 6.97 (m, 3H), 6.67 (s, 3H),
2.55 (m, 4H), 2.49 (t, J = 6.0 Hz, 2H), 2.34 (t, J = 6.0 Hz, 2H), 2.33 (s, 3H),
1.94 ppm (quint., J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 198.1,
172.1, 142.9, 137.4, 129.5, 127.9, 126.2, 125.7, 119.1, 55.1, 36.5, 34.7, 24.8,
24.2, 21.4, 20.9 ppm; IR (neat) ν 2944, 1643, 1610, 1458, 1367, 1237, 1159,
1078, 1044, 785, 702 cm ꢀ1; HRMS (m/z) calcd for C16H20O2 [M þ H]þ
245.1542, found 245.1545.
3-Methoxy-2-[2-(3-methoxyphenyl)ethyl]cyclohex-2-en-1-one (20c).
Obtained as a yellow oil (869 mg, 24% over two steps) from starting
triketone 18c (3.63 g, 13.96 mmol). Rf = 0.52 (cyclohexane/EtOAc 40:60);
1H NMR (400 MHz, CDCl3) δ 7.14 (t, J = 7.6 Hz, 1H), 6.79 (td, J1 = 1.6
Hz, J2 = 7.6 Hz, 1H), 6.76 (t, J = 0.8 Hz, 1H), 6.68 (qd, J1 = 0.8 Hz, J2 = 8.0
Hz, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 2.54 (m, 4H), 2.49 (t, J = 6.0 Hz, 2H),
2.32 (t, J = 6.0 Hz, 2H), 1.93 ppm (quint., J = 6.4 Hz, 2H); 13C NMR (100
MHz, CDCl3 ) δ 198.1, 172.2, 159.5, 144.6, 128.9, 121.2, 119.0, 114.2,
111.1, 55.2, 55.1, 36.5, 34.9, 24.8, 24.0, 21.0 ppm; IR (neat) ν 2944, 1643,
1608, 1488, 1369, 1254, 1239, 1161, 1079, 1041, 783, 698 cmꢀ1; HRMS
(m/z) calcd for C16H20O3 [M þ Na]þ 283.1310, found 283.1314.
2-[2-(1,3-Benzodioxol-5-yl)ethyl]-3-methoxycyclohex-2-en-1-one
(20d). Obtained as a white solid (727 mg, 48% over two steps) from
starting triketone 18d (1.52 g, 5.54 mmol). Rf = 0.58 (cyclohexane/
EtOAc 30:70); mp 107ꢀ110 °C; 1H NMR (400 MHz, CDCl3) δ 6.63
(m, 3H), 5.89 (s, 2H), 3.71 (s, 3H), 2.50 (m, 6H), 2.31 (t, J = 6.0 Hz,
2H), 1.93 ppm (quint., J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
198.2, 172.2, 147.3, 145.4, 136.9, 121.3, 119.0, 109.2, 107.9, 100.6, 55.1,
36.5, 34.6, 24.0, 24.4, 21.0 ppm; IR (neat) ν 2944, 1642, 1609, 1489,
1369, 1242, 1161, 1081, 1038, 927, 810 cm ꢀ1; HRMS (m/z) calcd for
C16H18O4 [M þ Na]þ 297.1103, found, 297.1099.
2-[2-(3-Methoxyphenyl)ethyl]3-methylcyclohex-2-en-1-one (21c).
Obtained as a colorless oil (645 mg, 82%) from enol ether 20c (839
mg, 3.22 mmol). Rf = 0.72 (cyclohexane/EtOAc 60:40); 1H NMR (400
MHz, CDCl3) δ 7.15 (t, J = 7.2 Hz, 1H), 6.99 (m, 3H), 2.57 (s, 3H), 2.58
(s, 4H), 2.37 (t, J = 6.4 Hz, 2H), 2.28 (t, J = 6.0 Hz, 2H), 1.90 (quint., J =
6.0 Hz, 2H), 1.77 ppm (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.7,
156.6, 156.1, 144.0, 134.8, 129.2, 121.1, 114.3, 111.3, 55.2, 38.0, 35.3,
32.9, 27.6, 22.4, 21.1 ppm; IR (neat) ν 2936, 1659, 1601, 1584, 1489,
1454, 1379, 1256, 1152, 1038, 781, 698 cmꢀ1; HRMS (m/z) calcd for
C16H20O2 [M þ H]þ 245.1542, found 245.1539.
2-[2-(3-Bromophenyl)ethyl]-3-methoxycyclohex-2-en-1-one (20e).
Obtained as a white solid (1.44 g, 41% over two steps) from starting
triketone 18e (3.52 g, 11.39 mmol). Rf = 0.39 (cyclohexane/EtOAc
40:60); mp 87ꢀ88 °C; 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 1.6
Hz, 1H), 7.25 (m, 1H), 7.10 (m, 32), 3.64 (s, 3H), 2.52 (m, 4H), 2.48 (t,
J = 6.0 Hz, 2H), 2.31 (t, J = 6.0 Hz, 2H), 1.93 ppm (quint., J = 6.4 Hz,
2H); 13C NMR (100 MHz, CDCl3 ) δ 198.1, 172.4, 145.3, 131.8, 129.5,
128.6, 127.5, 121.9, 118.4, 55.1, 36.5, 34.4, 24.8, 23.8, 20.9 ppm; IR
(neat) ν 2945, 1644, 1612, 1369, 1239, 1160, 1094, 1075, 1043,
2-[2-(1,3-Benzodioxol-5-yl)ethyl]-3-methylcyclohex-2-en-1-one
(21d). Obtained as a colorless solid (398 mg, 60%) from enol ether 20d
(700 mg, 2.55 mmol). Rf = 0.79 (cyclohexane/EtOAc 40:60); mp
85ꢀ86 °C; 1H NMR (400 MHz, CDCl3) δ 6.68 (m, 2H), 6.60 (dd, J1 =
1.6 Hz, J2 = 7.6 Hz, 1H), 5.90 (s, 2H), 2.52 (s, 4H), 2.36 (t, J = 6.4 Hz, 2H),
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ARTICLE
2.29 (t, J = 6.0 Hz, 2H), 1.89 (quint., J = 6.0 Hz, 2H), 1.78 ppm (s, 3H); 13
NMR (100 MHz, CDCl3) δ 198.7, 156.1, 147.5, 145.6, 136.2, 134.7, 121.4,
109.2, 108.1, 100.8, 38.0, 34.9, 32.9, 27.9, 22.4, 21.2 ppm; IR (neat) ν
C
1329, 1261, 1230, 1165, 1037, 917, 821, 736, 662 cmꢀ1; HRMS (ESI, m/z)
calcd for C18H24S2 [M þ H]þ 305.1398, found 305.1396.
6-[2-(3-Methoxyphenyl)ethyl]-7-methyl-1,4-dithiaspiro[4.5]dec-6-
ene (4c). Obtained as a colorless oil (307 mg, 68%). Rf = 0.71 (cyclo-
hexane/EtOAc 70:30); The product appeared to be very unstable neat
ꢀ1
2928, 1657, 1502, 1489, 1442, 1379, 1243, 1185, 1037, 928, 808 cm
;
HRMS (m/z) calcd for C16H18O3 [M þ H]þ 259.1334, found 259.1329.
1
2-[2-(3-Bromophenyl)ethyl]-3-methylcyclohex-2-en-1-one (21e).
Obtained as a colorless solid (905 mg, 71%) from enol ether 20e
(1.35 g, 4.37 mmol). Rf = 0.59 (cyclohexane/EtOAc 80:20); mp
and in solution. Only H NMR could be done and HRMS analysis if
injected rapidly in the apparatus. 1H NMR (400 MHz, CDCl3) δ 7.16
(t, J = 8.8 Hz, 1H), 6.72 (dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 2H), 6.57 (d, J = 3.2
Hz, 1H), 3.78 (s, 3H), 3.22 (m, 2H), 3.12 (m, 2H), 2.82 (m, 4H), 2.23
(m, 2H), 2.04 (m, 2H), 1.91 (m, 2H), 1.39 ppm (s, 3H); HRMS (ESI,
m/z) calcd for C18H24OS2 [M þ H]þ 321.1347, found 321.1351.
5-[2-(7-Methyl-1,4-dithiaspiro[4.5]dec-6-en-6-yl)ethyl]-1,3-benzo-
dioxole (4d). Obtained as a colorless oil (175 mg, 80%). Rf = 0.77
(cyclohexane/EtOAc 90:10); 1H NMR (400 MHz, CDCl3) δ 6.69 (m,
3H), 5.91 (s, 2H), 3.29 (m, 4H), 2.78 (m, 2H), 2.47 (m, 2H), 2.21 (m,
2H), 1.98 (t, J = 6.0 Hz, 2H), 1.76 (m, 2H), 1.74 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 147.5, 145.5, 137.3, 134.5, 130.7, 120.9, 108.8,
108.2, 100.8, 72.2, 44.4, 40.3, 36.7, 33.9, 31.8, 22.5, 20.9 ppm; IR (neat) ν
2954, 2922, 2861, 1483, 1451, 1437, 1314, 1258, 1045, 919, 815, 734,
660 cmꢀ1; HRMS (ESI, m/z) calcd for C18H22O2S2 [M þ H]þ
335.1139, found 335.1134.
1
51ꢀ53 °C; H NMR (400 MHz, CDCl3) δ 7.28 (m, 2H), 7.11 (m,
2H), 2.52 (m, 4H), 2.37 (t, J = 6.4 Hz, 2H), 2.29 (t, J = 6.0 Hz, 2H), 1.90
(quint., J = 6.0 Hz, 2H), 1.75 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 198.6, 156.4, 144.6, 134.4, 131.8, 129.8, 128.9, 127.4, 122.2,
38.0, 34.8, 32.9, 27.4, 22.3, 21.2 ppm; IR (neat) ν 2930, 1659, 1627,
1567, 1473, 1426, 1378, 1179, 1071, 779, 694 cm ꢀ1; HRMS (m/z) calcd
for C15H17BrO [M þ H]þ 293.0541, found 293.0543.
3,5,5-Trimethyl-2-[2-(3-methylphenyl)ethyl]cyclohex-2-en-1-one
(21f). Obtained as a yellow oil (474 mg, 56%) from enol ether 20f (898
mg, 3.30 mmol). Rf = 0.55 (cyclohexane/EtOAc 90:10); 1H NMR (400
MHz, CDCl3) δ 7.13 (t, J = 7.2 Hz, 1H), 7.02 (m, 3H), 2.58 (s, 4H), 2.32
(s, 3H), 2.25 (s, 2H), 2.18 (s, 2H), 1.75 (s, 3H), 1.01 ppm (s, 6H); 13
C
NMR (100 MHz, CDCl3 ) δ 198.9, 153.4, 142.3, 137.8, 133.7, 129.6,
128.2, 126.6, 125.7, 51.5, 47.2, 35.2, 37.8, 28.4, 27.6, 21.5, 21.3 ppm; IR
(neat) ν 2955, 1662, 1632, 1610, 1451, 1378, 1367, 1317, 1192, 1148,
1105, 778, 700 cmꢀ1; HRMS (m/z) calcd for C18H24O [M þ Na]þ
279.1725, found 279.1720.
6-[2-(3-Bromophenyl)ethyl]-7-methyl-1,4-dithiaspiro[4.5]dec-6-
ene (4e). Obtained as a colorless oil (308 mg, 89%). Rf = 0.82
(cyclohexane/EtOAc 70:30); 1H NMR (400 MHz, CDCl3) δ 7.40 (t,
J = 1.6 Hz, 1H), 7.30 (dt, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H), 7.13 (m, 2H),
3.31 (m, 4H), 2.84 (m, 2H), 2.50 (m, 2H), 2.22 (m, 2H), 1.99 (t, J =
6.2 Hz, 2H), 1.78 (m, 2H), 1.74 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 145.7, 134.8, 131.3, 130.4, 129.9, 128.8, 127.0, 122.4, 72.1,
44.4, 40.3, 36.6, 33.3, 31.8, 22.5, 20.9 ppm; IR (neat) ν 2957, 2925,
2863, 1496, 1434, 1335, 1248, 1231, 1159, 1032, 920, 821, 736,
658 cmꢀ1; HRMS (ESI, m/z) calcd for C17H21BrS2 [M þ H]þ
369.0346, found 369.0341.
3-Methyl-2-[2-(3-thienyl)ethyl]cyclohex-2-en-1-one (21g). Obtained
as an orange oil (775 mg, 71%) from enol ether 20g (1.18 g, 4.98 mmol).
Rf = 0.72 (cyclohexane/EtOAc 60:40); 1H NMR (400 MHz, CDCl3) δ
7.20 (dd, J1 = 2.8 Hz, J2 = 4.8 Hz, 1H), 6.93 (dd, J1 = 1.6 Hz, J2 = 4.8 Hz,
1H), 6.90 (dd, J1 = 1.2 Hz, J2 = 2.8 Hz, 1H), 2.55 (m, 4H), 2.37 (t, J = 6.0
Hz, 2H), 2.29 (t, J = 6.0 Hz, 2H), 1.89 (quint., J = 6.0 Hz, 2H), 1.77 ppm (s,
3H); 13C NMR (100 MHz, CDCl3 ) δ 198.7, 156.2, 142.6, 134.7, 128.6,
125.0, 120.3, 38.0, 32.9, 29.4, 26.7, 22.4, 21.1 ppm; IR (neat) ν 2927, 1659,
2626, 1453, 1428, 1379, 1326, 1179, 1136, 1078, 776 cmꢀ1; HRMS (m/z)
calcd for C13H16OS [M þ H]þ 221.1000, found 221.0995.
7,9,9-Trimethyl-6-[2-(3-methylphenyl)ethyl]-1,4-dithiaspiro[4.5]dec-
6-ene (4f). Obtained as a colorless oil (48 mg, 15%). Rf = 0.71-
1
(cyclohexane/EtOAc 90:10); H NMR (400 MHz, CDCl3) δ 7.17 (t,
J = 8.0 Hz, 1H), 7.06 (m, 2H), 7.00 (d, J = 7.6 Hz, 1H), 3.32 (m, 4H), 2.87
(m, 2H), 2.54 (m, 2H), 2.35 (s, 3H), 2.29 (s, 2H), 1.88 (s, 2H), 1.78 (s,
3H), 1.01 ppm (s, 6H); 13C NMR (100 MHz, CDCl3) δ 143.4, 137.9,
132.5, 130.7, 129.0, 128.34, 126.5, 125.2, 71.1, 57.0, 46.5, 40.7, 36.9, 33.4,
31.0, 28.9, 21.5, 21.4 ppm; IR (neat) ν 2957, 2925, 2863, 1496, 1434,
1335, 1248, 1231, 1159, 1032, 920, 821, 736, 658 cmꢀ1; HRMS (ESI,
m/z) calcd for C20H28S2 [M þ H]þ 333.1711, found 333.1714.
7-Methyl-6-[2-(3-thienyl)ethyl]-1,4-dithiaspiro[4.5]dec-6-ene (4g).
Obtained as a colorless oil (158 mg, 59%). Rf = 0.92 (cyclohexane/
EtOAc 60:40). Due to its important unstability, 17f was engaged directly
into the 6-endo-trig cyclization, without further analysis.
3-Methyl-2-[3-(3,4,5-trimethoxyphenyl)propyl]cyclohex-2-en-1-one
(21j). Obtained as a pale yellow oil (427 mg, 61%) from enol ether 20j
1
(730 mg, 2.19 mmol). Rf = 0.66 (cyclohexane/EtOAc 60:40); H NMR
(400MHz, CDCl3) δ6.40 (s, 2H), 3.84 (s, 6H), 3.80 (s, 3H), 2.55 (t, J=7.6
Hz, 2H), 2.31 (m, 6H), 1.87 (m, 5H), 1.58 ppm (m, 2H); 13C NMR (100
MHz, CDCl3) δ 198.9, 155.4, 153.1, 138.3, 136.0, 135.6, 105.3, 60.9, 56.1,
38.0, 36.5, 32.9, 30.6, 25.2, 22.4, 21.3 ppm; IR (neat) ν 2936, 1660, 1588,
1508, 1455, 1420, 1379, 1329, 1238, 1181, 1126, 1011 cm ꢀ1; HRMS (m/z)
calcd for C19H26O4 [M þ H]þ 319.1909; found, 319.1912.
General Procedure for the Synthesis of 2-Alkenyl-1,3-
dithiolanes. 1,2-Ethanedithiol (5.76 mmol, 1.1 equiv) and In(OTf)3
(0.524 mmol, 0.1 equiv) were added successively to a solution of the
corresponding R,β-unsaturated ketone 21bꢀ21j (5.24 mmol, 1.0 equiv) in
DCM (25 mL), and the reaction mixture was stirred for 24 h. Then,
additional 1,2-ethanedithiol (5.76 mmol, 1.1 equiv) and In(OTf)3 (0.524
mmol, 0.1 equiv) were added. After 6 h of stirring, dilution with DCM
(20 mL) and quenching with water (40 mL), the aqueous phase was
extracted by DCM (2 ꢁ 20 mL). The combined organic extracts were
washed with brine, dried over sodium sulfate, and evaporated. The residue
was purified by flash chromatography on a silica gel column (eluent:
cyclohexane/EtOAc 95:5) to give the 1,3-dithiolane derivative 4b-4j.
7-Methyl-6-[2-(3-methylphenyl)ethyl]-1,4-dithiaspiro[4.5]dec-6-ene
(4b). Obtained as a colorless solid (272 mg, 91%). Rf = 0.87 (cyclohexane/
6-But-3-en-1-yl-7-methyl-1,4-dithiaspiro[4.5]dec-6-ene (4h). Obtained
as a colorless oil (316 mg, 63%). Rf = 0.93 (cyclohexane/EtOAc 80:20); 1H
NMR (400 MHz, CDCl3) δ5.84 (m, 1H), 5.02 (dd, J1 = 2.0 Hz, J2 = 17.2
Hz, 1H), 4.92 (dd, J1 =2.0Hz,J2 = 10.0 Hz, 1H), 3.26 (m, 4H), 2.31 (s, 4H),
2.18 (m, 2H), 1.95 (t, J = 6.4 Hz, 2H), 1.73 (m, 2H), 1.67 ppm (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ139.3, 134.2, 130.7, 113.8, 72.0, 44.4, 40.2, 35.0,
31.8, 30.4, 22.5, 20.8 ppm; IR (neat) ν 2968, 2925, 1513, 1433, 1346, 1251,
1178, 1158, 1032, 920, 845, 732, 667 cmꢀ1; HRMS (ESI, m/z) calcd for
C13H20S2 [M þ H]þ 241.1085, found 241.1081.
7-Methyl-6-(3-methylbenzyl)-1,4-dithiaspiro[4.5]dec-6-ene (4i). Ob-
tained as a colorless oil (205 mg, 76%). Rf = 0.85 (cyclohexane/EtOAc
1
90:10); H NMR (400 MHz, CDCl3) δ7.15 (t, J = 7.2 Hz, 1H), 6.95
1
EtOAc 70:30); mp 56ꢀ57 °C; H NMR (400 MHz, CDCl3) δ 7.17
(m, 3H), 3.72 (s, 2H), 3.28 (s, 4H), 2.34 (s, 3H), 2.30 (m, 2H), 2.07
(t, J = 6.4 Hz, 2H), 1.84 (m, 2H), 1.50 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3) δ141.7, 137.6, 137.0, 128.8, 128.7, 128.0, 126.2, 124.8, 72.3, 44.2,
40.1, 36.4, 31.9, 22.4, 21.7, 21.6 ppm; IR (neat) ν 2953, 2920, 2861, 1483,
1455, 1389, 1316, 1257, 1045, 919, 815, 731 cmꢀ1; HRMS (ESI, m/z) calcd
for C17H22S2 [M þ H]þ 291.1241, found 291.1237.
(t, J=8.0Hz, 1H), 7.07(m, 2H), 7.00(d, J= 7.2 Hz, 1H), 3.30 (m, 4H), 2.85
(m, 2H), 2.53 (m, 2H), 2.35 (s, 3H), 2.23 (m, 2H), 2.00 (t, J = 6.4 Hz, 2H),
1.79 (m, 2H), 1.77 ppm (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.3,
137.9, 134.44, 130.9, 129.1, 128.3, 126.5, 125.3, 72.2, 44.4, 40.3, 36.9, 33.5,
31.8, 22.5, 21.5, 20.9 ppm; IR (neat) ν 2957, 2925, 2862, 1483, 1451, 1436,
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7-Methyl-6-[3-(3,4,5-trimethoxyphenyl)propyl]-1,4-dithiaspiro[4.5]dec-
6-ene (4j). Obtained as a colorless oil (57 mg, 48%). Rf = 0.33 (cyclohexane/
EtOAc 90:10); 1H NMR (400 MHz, CDCl3) δ 6.44 (s, 2H), 3.84 (s, 6H),
3.81 (s, 3H), 3.14 (m, 4H), 2.57 (t, J = 7.6 Hz, 2H), 2.15 (m, 4H), 1.85 (m,
4H), 1.71 (m, 2H), 1.62 ppm (s, 3H); 13C NMR (100 MHz, CDCl3) δ
138.4, 136.0, 133.8, 131.3, 105.6, 72.1, 60.6, 56.1, 44.3, 40.1, 36.8, 32.0, 31.7,
30.7, 22.5, 20.8 ppm; IR (neat) ν 2954, 2916, 2855, 1483, 1446, 1410, 1303,
1227, 1041, 912, 826, 740, 652 cmꢀ1; HRMS (ESI, m/z) calcd for
C21H30O3S2 [M þ H]þ 395.1715, found 395.1713.
(()-11b0-Methyl-20,30,4a0,50,60,11b0-hexahydro-10H-spiro[1,3-dithio-
lane-2,40-phenanthro[2,3-d][1,3]dioxole] ((()-5d). Obtained as a col-
1
orless oil (99 mg, 68%). Rf = 0.86 (cyclohexane/EtOAc 90:10); H
NMR (400 MHz, CDCl3) δ 6.74 (s, 1H), 6.50 (s, 1H), 5.87 (s, 2H), 3.10
(m, 5H), 2.83 (m, 2H), 2.27 (m, 2H), 2.14 (d, J = 11.2 Hz, 1H), 2.02 (dd,
J1 = 2.0 Hz, J2 = 11.6 Hz, 1H), 1.87 (m, 3H), 1.62 (m, 1H), 1.23 ppm (s,
3H); 13C NMR (100 MHz, CDCl3) δ 145.9, 145.4, 141.4, 128.4, 108.6,
104.7, 100.7, 72.9, 51.6, 46.7, 40.7, 39.7, 38.4, 38.3, 30.5, 24.8, 22.0, 21.5
ppm; IR (neat) ν 2925, 1501, 1481, 1435, 1374, 1237, 1201, 1098, 1038,
936, 909, 876, 854, 844 cmꢀ1; HRMS (ESI, m/z) calcd for C18H22O2S2
[M þ H]þ 335.1139, found 335.1134.
2-Isopropyl-6-[2-(8-methyl-1,5-dithiaspiro[5.5]undec-7-en-7-yl)-
ethyl]phenyl Methyl Ether (22). 1,3-Propanedithiol (30 μL, 0.384 mmol,
1.1 equiv), and In(OTf)3 (20.0 mg, 0.0349 mmol, 0.1 equiv) were added
successively to a solution of the corresponding R,β-unsaturated ketone 6
(100 mg, 0.349 mmol, 1.0 equiv) in DCM (2 mL), and the reaction mixture
was stirred for 24 h. Then, additional 1,3-propanedithiol (30 μL, 0.384
mmol, 1.1 equiv) and In(OTf)3 (20.0 mg, 0.0349 mmol, 0.1 equiv) were
added. After 6 h of stirring and dilution with DCM (10 mL) and water
(20 mL), the aqueous phase was extracted by DCM (2 ꢁ 10 mL). The
combined organic extracts were washed with brine, dried over sodium
sulfate, and evaporated. The residue was purified by flash chromatography
on a silica gel column (eluent: cyclohexane/EtOAc 95:5) to give 22 as a
colorless oil (79 mg, 60%). Rf = 0.70 (cyclohexane/EtOAc 95:5); 1H NMR
(400 MHz, CDCl3) δ7.21 (dd, J1 = 2.0 Hz, J2 = 7.2 Hz, 1H), 7.11 (dd, J1 =
2.0 Hz, J2 = 7.2 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 3.80 (s, 3H), 3.31 (hept.,
J = 6.8 Hz, 1H), 3.04 (td, J1 = 2.8 Hz, J2 = 12.4 Hz, 2H), 2.85 (m, 2H), 2.61
(m, 5H), 2.42 (m, 2H), 2.05 (t, J = 6.4 Hz, 3H), 1.81 (s, 3H), 1.75 (m, 2H),
1.23 ppm (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ155.6, 141.8,
136.6, 135.8, 131.4, 127.6, 124.4, 62.1, 56.6, 36.6, 32.5, 31.4, 31.3, 26.9, 26.4,
25.1, 24.2, 20.7, 19.9 ppm; IR (neat) ν 2958, 2934, 2863, 1498, 1462, 1403,
1327, 1277, 1032, 916, 804, 732, 651 cmꢀ1; HRMS (ESI, m/z) calcd for
C22H32OS2 [M þ NH4]þ 394.2245, found 394.2242.
(()-70-Bromo-4a0-methyl-30,40,4a0,90,100,10a0-hexahydro-20H-spiro-
[1,3-dithiolane-2,10-phenanthrene] ((()-5e). Obtained in 41% yield
(106 mg) after a slow atmospheric pressure column chromatography on
1
silica. H NMR (400 MHz, CDCl3) δ 7.09 (m, 3H), 3.21 (m, 4H),
3.10 (m, 1H), 2.84 (m, 2H), 2.50 (m, 1H), 2.22 (m, 3H), 1.87 (m, 4H),
1.23 ppm (s, 3H); 13C NMR (75 MHz, CDCl3) δ 147.4, 137.9, 131.9,
128.9, 126.6, 119.4, 72.8, 51.2, 46.7, 40.8, 39.6, 38.5, 37.9, 30.1, 24.9,
21.9, 21.2 ppm; HRMS (ESI, m/z) calcd for C17H21BrS2 [M þ H]þ
369.0346, found 369.0344.
(()-3,30,4a0,70-Tetramethyl-30,40,4a0,90,100,10a0-hexahydro-20H-spiro-
[1,3-dithiolane-2,10-phenanthrene] ((()-5f). Obtained in 43.3 mg
(94%) as an inseparable mixture with 2-alkenyl-1,3-dithiolane 4f in a
1:1.6 ratio. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.0 Hz, 2H), 7.06
(m, 3H), 7.00 (m, 2H), 3.22 (m, 7H), 3.09 (m, 2H), 2.87 (m, 4H), 2.53
(m, 3H), 2.34 (m, 5H), 2.29 (s, 2H), 2.28 (s, 1H), 1.85 (s, 2H), 1.78 (s,
3H), 1.44 (d, J = 2.0 Hz, 1H), 1.38 (s, 3H), 1.33 (s, 3H), 1.01 (s, 6H),
0.99 ppm (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.0, 134.9, 134.3,
129.9, 126.6, 124.8, 72.0, 57.3, 51.5, 51.1, 41.8, 39.4, 37.9, 36.5, 32.8,
30.3, 29.1, 26.6, 21.3, 20.9 ppm.
9a0-Methyl-50,5a0,70,80,90,9a0-hexahydro-40H-spiro[1,3-dithiolane-
2,60-naphtho[1,2-b]thiophene] ((()-5g). Obtained as a pale yellow
solid (93 mg, 59%). Rf = 0.92 (cyclohexane/EtOAc 60:40); mp
97ꢀ98 °C; 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 5.2 Hz, 1H),
6.68 (d, J = 5.2 Hz, 1H), 3.29 (m, 2H), 3.10 (m, 2H), 2.81 (m, 1H), 2.61
(m, 1H), 2.22 (m, 3H), 2.04 (m, 1H), 1.79 (m, 3H), 1.61 (m, 2H), 1.59
ppm (s, 3H); 13C NMR (100 MHz, CDCl3) δ 134.8, 127.4, 127.3, 122.2,
74.0, 52.5, 39.7, 39.2, 38.4, 37.0, 32.5, 25.5, 22.2 ppm; IR (neat) ν 2925,
2859, 1458, 1378, 1327, 1276, 1231, 1042, 913, 867, 848 cmꢀ1; HRMS
(ESI, m/z) calcd for C15H20S3 [M þ H]þ 297.0805, found 297.0800.
4a0-Methyl-30,40,4a0,70,80,8a0-hexahydro-20H-spiro[1,3-dithiolane-
2,10-naphthalene] ((()-5h) and 4a0-Methyl-30,40,4a0,50,80,8a0-hexahy-
dro-20H-spiro[1,3-dithiolane-2,10-naphthalene] ((()-5h0). Obtained
in 125 mg (44%) in a 3:1 ratio (()-5h:(()-5 h0. 1H NMR (400
MHz, CDCl3) δ 5.66 (m, 0.75H), 5.48 (m, 0.75H), 5.42 (m, 0.25H),
5.33 (td, J1 = 2.0 Hz, J2 = 9.6 Hz, 0.25H), 3.06 (m, 4H), 2.12 (m, 2H),
1.86 (m, 3H), 1.70 (m, 2H), 1.46 (m, 3H), 1.16 (m, 2H), 1.03 (s, 0.8H),
0.95 ppm (s, 2.4H); 13C NMR (100 MHz, CDCl3) δ 139.5, 126.6, 124.2,
123.9, 72.4, 52.0, 49.3, 47.5, 47.3, 44.5, 41.0, 40.9, 40.6, 40.2, 38.8, 38.4,
38.0, 37.5, 34.7, 30.4, 27.0, 25.9, 21.6, 20.9, 18.9 ppm; HRMS (ESI, m/z)
calcd for C13H20S2 [M þ H]þ 241.1085, found 241.1080.
General Procedure for the Synthesis of trans-Decalins.
Fresh TMSOTf (0.243 mmol, 1.1 equiv) was added to a solution of
1,3-dithiolane 4bꢀj or 1,3-dithiane 22 (0.221 mmol, 1.0 equiv) in
1,2-dichloroethane (7 mL), and the reaction mixture was stirred 16 h at
room temperature. Then, after addition of water (20 mL), the aqueous
phase was extracted by DCM (3 ꢁ 10 mL). The combined organic
extracts were washed with brine, dried over sodium sulfate, and
evaporated. The residue was purified by flash chromatography on a
silica gel column (eluent: cyclohexane/EtOAc 95:5) to give the trans-
decalins (()-5b-j and 23.
(()-4a0,70-Dimethyl-30,40,4a0,90,100,10a0-hexahydro-20H-spiro[1,3-
dithiolane-2,10-phenanthrene] ((()-5b). Obtained as a colorless oil
(201 mg, 83%). Rf = 0.83 (cyclohexane/EtOAc 80:20); 1H NMR (400
MHz, CDCl3) δ 7.15 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.91
(s, 1H), 3.07 (m, 6H), 2.91 (m, 2H), 2.26 (m, 7H), 2.07 (dd, J1 = 2.0 Hz,
J2 = 12.0 Hz, 1H), 1.89 (q, J = 12.4 Hz, 2H), 1.27 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 145.4, 135.2, 135.0, 129.8, 126.7, 124.5, 73.0, 51.5,
46.8, 40.7, 39.4, 38.4, 38.0, 30.2, 25.0, 22.0, 21.5, 20.9 ppm; IR (neat) ν
2918, 2859, 1497, 1450, 1433, 1375, 1276, 1066, 813, 778, 733,
565 cmꢀ1; HRMS (ESI, m/z) calcd for C18H24S2 [M þ H]þ 305.1398,
found 305.1394.
70-Isopropyl-4a0-methyl-30,40,4a0,90,100,10a0-hexahydro-20H-spiro-
[1,3-dithiane-2,10-phenanthren]-80-yl Methyl Ether ((()-23. Obtained
in 37 mg (47%) as an inseparable mixture with 2-alkenyl-1,3-dithiane 22 in a
(()-70-Methoxy-4a0-methyl-30,40,4a0,90,100,10a0-hexahydro-20H-
spiro[1,3-dithiolane-2,10-phenanthrene] ((()-5c). Obtained as a color-
less oil (182 mg, 82%). Rf = 0.88 (cyclohexane/EtOAc 90:10); 1H NMR
(400 MHz, CDCl3) δ 7.15 (d, J = 8.8 Hz, 1H), 6.70 (dd, J1 = 2.8 Hz, J2 =
8.8 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 3.77 (s, 3H), 3.11 (m, 5H), 2.91
(m, 2H), 2.24 (m, 4H), 2.05 (dd, J1 = 1.6 Hz, J2 = 12.0 Hz, 1H), 1.88 (m,
3H), 1.24 ppm (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.3, 140.8,
136.7, 125.7, 113.4, 112.1, 72.9, 55.2, 51.6, 46.8, 40.7, 39.1, 38.5, 38.2,
30.6, 25.0, 22.0, 21.5 ppm; IR (neat) ν 2927, 2833, 1607, 1498, 1464,
1435, 1279, 1257, 1241, 1153, 1038, 852 cmꢀ1; HRMS (ESI, m/z) calcd
for C18H24OS2 [M þ H]þ 321.1347, found 321.1348.
1
1:1 ratio. Rf = 0.70 (cyclohexane/EtOAc 95:5); H NMR (400 MHz,
CDCl3) δ 6.98 (m, 5H), 3.92 (s, 3H), 3.80 (s, 3H), 3.17 (m, 3H), 3.03 (m,
4H), 2.61 (m, 12H), 2.42 (m, 2H), 1.96 (m, 6H), 1.82 (s, 3H), 1.37 (s, 3H),
1.23 (d, J= 7.2 Hz, 6H), 1.20 ppm (d, J= 7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 155.1, 148.1, 138.4, 128.5, 123.9, 120.2, 60.6, 52.0, 39.1, 38.9, 38.6,
27.1, 26.9, 26.8, 26.2, 25.9, 25.6, 24.9, 24.1, 24.0, 20.4, 19.9 ppm.
Computational Details. All calculations were performed using
the B3LYP functional31 as implemented in the Gaussian03 software
package.32 Geometries were optimized with the 6-311þG(d) basis set
for S and Si and the 6-31G(d,p) basis set for the other atoms, and
3283
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The Journal of Organic Chemistry
ARTICLE
characterized with frequency calculations. Final energies were obtained
with the larger 6-311þG(2d,2p) basis set on all atoms and corrected for
zero-point effects obtained from the frequency calculations. The effect of
solvation in DCE was calculated using the conductor-like polarizable
continuum model (CPCM)33 with UAKS radii.
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’ ASSOCIATED CONTENT
Supporting Information. 1H NMR and 13C NMR spec-
S
b
tra of all compounds, crystallographic data of ketone 6 in CIF
format, and potential energy surface. This material is available
free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: baati@bioorga.u-strasbg.fr.
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(19) The trans diastereoselectivity of (()-5a was determined after
deprotection of the dithiolane moiety using PIFA leading to the
corresponding ketone trans-decalin 24 with a satisfactory yield of 84%.
The trans stereochemistry was determined by NMR analysis and
corroborated unambiguously by X-ray crystallography analysis. Supple-
mentary crystallographic data could be obtained from the Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif
with the deposition number CCDC 753095.
’ ACKNOWLEDGMENT
We acknowledge the Laboratoire Pierre Fabre (Plantes et
Industries) and the CNRS for financial support to S.G. A
postdoctoral fellowship from the Wenner-Gren Foundations
to S.S. is gratefully acknowledged. F.H. acknowledges financial
support from The Swedish Research Council (Grant Nos. 621-
2009-4736 and 622-2009-371) and computer time from the
PDC Center for High Performance Computing.
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