Enantioselective synthesis of bridgehead hydroxyl bicyclo[2.2.2]octane derivatives via asymmetric allylindation

Article abstract of DOI:10.1016/j.tetasy.2005.12.026

A recent new strategy for the transformation of mono-dioxolane protected 1,3-cyclohexadione into bridgehead hydroxyl bicyclo[2.2.2]octane derivatives, based on allylindation followed by ozonolysis and intramolecular aldol addition, was modified to include

Full text of DOI:10.1016/j.tetasy.2005.12.026

Tetrahedron: Asymmetry 17 (2006) 410–415
Enantioselective synthesis of bridgehead hydroxyl
bicyclo[2.2.2]octane derivatives via asymmetric allylindation
Viveca Thornqvist, Sophie Manner and Torbjo¨rn Frejd*
Division of Organic Chemistry, Kemicentrum, PO Box 124, SE-221 00 Lund, Sweden
Received 13 December 2005; accepted 28 December 2005
Available online 2 February 2006
Abstract—A recent new strategy for the transformation of mono-dioxolane protected 1,3-cyclohexadione into bridgehead hydroxyl
bicyclo[2.2.2]octane derivatives, based on allylindation followed by ozonolysis and intramolecular aldol addition, was modified to
include asymmetric allylindation. This enabled the first enantioselective synthesis of (1R,4R,6S)-endo-4-(tert-butyl-dimethyl-silyl-
oxy)-6-hydroxy-bicyclo[2.2.2]octan-2-one and (1S,4S,6R)-endo-4-(tert-butyl-dimethyl-silyloxy)-6-hydroxy-bicyclo[2.2.2]octan-2-
one in high enantiomeric excess. Issues concerning the non-reproducibility of the asymmetric allylindation were also addressed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
directly, without the need for subsequent oxidation and
Baker’s yeast reduction. The first step in our synthesis
towards 3 involves allylation of mono-protected 1,3-
cyclohexadione 1a to give 2a (Scheme 1). Accordingly,
an asymmetric version of this reaction would provide
directly enantioenriched 3.
Enantiomerically pure bicyclo[2.2.2]octanes are useful
chiral building blocks in asymmetric catalysis1 and
natural product synthesis.2 Recently we reported a
non-stereoselective synthesis of rac-endo-4-(tert-butyl-
dimethyl-silyloxy)-6-hydroxy-bicyclo[2.2.2]octan-2-one
3 (Scheme 1),3 which after oxidation yielded the corre-
sponding diketone.
The stereoselective introduction of an allyl group is often
achieved by the use of allylic organometallic reagents in
which the metal is coordinated to a chiral ligand.5 For
this purpose several different metals have been used with
success. Since we employed indium for the non-asym-
metric allylation of 1a, we found it interesting to con-
tinue the development of an asymmetric version of this
reaction using the same metal. Several examples of
asymmetric allylindations, involving In(0), have already
been described in the literature, in which the stereo-
selectivity has been achieved by employing substrate
To obtain bicyclic hydroxyketones, such as 3, in an
enantiomerically pure state, the corresponding diketone
can be asymmetrically reduced by Baker’s yeast. Several
examples have been reported in the literature on the
bioreduction of bicyclo[2.2.2]octane-2,6-dione and
analogues, giving mainly the endo-hydroxyketone in high
enantiomeric excess.4 In spite of this, it would be prefer-
able to obtain the optically active hydroxyketone 3
O
O
OH
Br
O
In,
O
4 steps
MeOH, 0 ˚C
O
O
OTBDMS
HO
endo-3
2a
1a
Scheme 1. Synthesis of rac-endo-3 (see Ref. 3).
*
Corresponding author. Tel.: +46 46 222 81 25; fax: +46 46 222 41 19; e-mail: torbjorn.frejd@organic.lu.se
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.026

V. Thornqvist et al. / Tetrahedron: Asymmetry 17 (2006) 410–415
411
controlled processes,6 catalytic asymmetric reactions,7
or chiral reagents in stoichiometric amounts.8 Most of
these methods are exemplified by allylation of alde-
hydes, but a few also include ketones (mainly conju-
gated), hydrazones, and aldimines as substrates. The
products are often obtained in high yields and ees.
when a new precipitate formed. 1H NMR spectra of
the precipitate indicated it to be the quaternary allylic
ammonium salt 4e (Fig. 2).
-
Br
N
For the asymmetric allylindation we became particularly
interested in a procedure, which was described by Loh
et al.8d–f They employed cinchona alkaloids (Fig. 1,
structures 4a–4d) as chiral promoters, which together
with indium powder and different allylic bromides
formed chiral non-racemic complexes. Unfortunately,
the described methodology proved irreproducible in
our hands, and, as will be discussed, extensive efforts
had to be made in order to establish optimal and repro-
ducible conditions.
OH
N
4e
Figure 2. Structure of quaternary allylic ammonium salt 4e.
In fact, it is known from the literature that the quinucli-
dine nitrogen of the cinchona alkaloids can be quaterna-
rized on reaction with an allylic halide in THF at rt.10
Thus, salt formation seemed to be favored over the for-
mation of the chiral complex.
R'
OH
9
R
N
Since sonication is known to activate metal surfaces and
has been used to activate indium metal for different
chemical transformations,11 this method was tested for
the complex formation, but did not lead to any improve-
ments (neither when run in THF or DCM). We then
tried to suppress the ammonium salt formation by add-
ing equimolar amounts of allyl bromide with regard to
the indium and chiral base (2 equiv), instead of excess
amounts, but this also failed. In a study reported by Sin-
garam et al.8a on the asymmetric allylindations of alde-
hydes using (1S,2R)-(+)-2-amino-1,2-diphenylethanol
as chiral promoter, they added 2 equiv of pyridine to
the reaction mixture, and were able to increase both
conversion and enantioselectivity. However, no progress
in reproducibility was achieved by applying this method-
ology to our system.
N
N
9
N
OH
4a R=H, (-)-cinchonidine
4c R=OMe, (-)-quinine
4b R'=H, (+)-cinchonine
4d R'=OMe, (+)-quinidine
Figure 1. Structures of cinchona alkaloids.
Herein we report the optimization of the asymmetric
allylation reaction employing In(0), together with cin-
chona alkaloids as chiral promoters. The improved pro-
tocol was subsequently applied to three different
cyclohexanone derivatives, differing in the functionaliza-
tion at the 3-position. Also, the first enantioselective
synthesis of both enantiomers of bridgehead hydroxyl
bicyclo[2.2.2]ocane derivative 3, starting from optically
active 2a, is described.
We now began to suspect that water, present to some
extent in the reaction mixture, might disturb the forma-
tion of the complex. The presence of water has been
observed by others to be unfavorable in this kind of reac-
tion.7,8f Azeotropically drying of the solids by distilling
off the THF three times, as according to the literature
procedure, did not seem to have any great effect on the
2. Results and discussion
The literature procedure for the asymmetric allylinda-
tion consisted of mixing indium powder (2 equiv) and
the chiral base (2 equiv) in a polar solvent, THF or
DCM.8e,f In the case of THF, the solvent was distilled
off three times to azeotropically remove water. After
this, the allylic bromide (6 equiv) was added and stirring
continued for approximately 1 h, after which a clear
solution (the chiral complex) formed. Hexane was then
added dropwise, and after adjustment of temperature,
the carbonyl compound (1 equiv) was added. Initial
attempts at the allylation of 1a according to the above
procedure, using allyl bromide together with (ꢀ)-cincho-
nidine 4a, progressed nicely in both THF–hexane (3:1)
and DCM–hexane (3:1). Compound 2a was obtained
in 79% ee and 85% yield at ꢀ78 ꢁC.9 However, on
repeating the experiment, it frequently failed. Com-
pletely clear reaction mixtures were not obtained and
the indium powder not consumed. This resulted in low
ee’s of 2a (10–20%) while the yields were also somewhat
reduced. In addition, we noticed that the reaction mix-
ture changed character after approximately 30 min,
˚
complex formation. However, the addition of 4 A MS
to the reaction mixture did produce the chiral complex
more frequently, but still not in a reproducible manner.
This indicated the dryness of the reaction mixture to be
an important factor. In fact, we noticed that the proce-
dure for drying the THF also affected the complex
formation. Drying of THF by passing it through an
alumina column appeared to be preferable, in our hands,
rather than distilling it from sodium/benzophenone.
Next, attempts were made to produce an allylic reagent
with increased reactivity by performing a Finkelstein
reaction in situ. This was done by adding either
Bu4N+ꢀI or NaI to the reaction mixture prior to the addi-
tion of the allyl bromide. In the case of NaI, the result
was the same as before, that is no clear solution was
obtained. However, in the case of Bu4N+ꢀI, a perfectly
clear solution formed within 10 min, but unfortunately
the allylic cinchonidinium salt 4e formed after another

412
V. Thornqvist et al. / Tetrahedron: Asymmetry 17 (2006) 410–415
30 min. Because of these observations, we came to con-
sider the complex formation to be dependent on the nat-
ure of the allylic reagent, and therefore the allyl bromide
was exchanged for allyl iodide. Thus, when allyl iodide
ingly, all of them yielded racemic 2a, showing the impor-
tance of the free 9-OH.
We also sought to address the importance of function-
alization of the 3-position of compound 1a. Thus, the
asymmetric allylation was extended to include other
3,3-disubstituted derivatives of cyclohexanone; com-
pound 1b14 bearing a dithiolane group, and compound
1c having two methyl substituents at the 3-position.
To investigate the effect of the bulkiness of the allylic
reagent, we also included 3-iodo-2-methyl-propene 5b15
(Table 1). In these attempts, 4a was used as a chiral
additive since the complex formed faster with 4a (2 h)
than with 4b (3 h). In the case of ketones 1b and 1c,
the reactions were too slow at ꢀ78 ꢁC and were there-
fore performed at ꢀ40 ꢁC. The ees and yields obtained
from the allylation of 1a was superior, compared to both
compounds 1b and 1c. Additionally, the bulkier allylic
reagent 5b resulted in products of both lower ees and
yields in most cases.
˚
was added to a mixture of indium, 4a and 4 A MS in
dry THF, a clear solution resulted within 2 min and
the indium powder consumed after two more hours.
This procedure was then tested repeatedly and finally
proved to be reproducible, thus yielding 2a with the
same high ee (79%) and yield (87%) as before. More-
over, it was found that addition of hexane to the reac-
tion mixture did not have any effect on the ee of 2a
and was thus excluded from subsequent reactions.
During our work, a study on a catalytic indium-medi-
ated allylation of hydrazones was published by Cook
et al.,7 in which they were able to use reduced amounts
of reagents (indium powder (1.1 equiv), chiral additive
(1.1 equiv), allyl iodide (1.65 equiv)). When applying
these same amounts to our system, the ee and yield
of 2a was the same as before (79% and 85%, respec-
tively).12
Homoallylic alcohols (ꢀ)-2a and (+)-2a were then used
for the synthesis of (ꢀ)-endo-3 and (+)-endo-3, respec-
tively (Scheme 2), which essentially followed the previ-
ously reported ‘racemic’ route.3 The last step in the
sequence consists of an aldol condensation, which, ex-
cept for the endo-isomer, also provides the exo-isomer
of 3 in a ratio of 85:15, respectively. Accordingly, (ꢀ)-
2a led to the formation of (ꢀ)-endo-3 and (+)-exo-3 in
79% ee (for both) and (+)-2a gave (+)-endo-3 and (ꢀ)-
exo-3 in 78% ee (for both). After a single recrystalliza-
tion from petroleum ether, the ee of both (ꢀ)-endo-3
and (+)-endo-3 could be raised to >98%. Unfortunately,
we were unable to find a suitable solvent system for the
recrystallization of the exo-enantiomers.
To test the potential of the other cinchona alkaloids,
allylation of 1a was also performed with bases 4b–4d,
of which 4b gave approximately the same high ee
(78%) as 4a, but the opposite enantiomer of 2a. How-
ever, both 4c and 4d gave lower ees of 2a, 55% and
50%, respectively. Furthermore, since it is unknown
how indium and the allyl groups are coordinated to
the cinchona alkaloids in the chiral complex, we found
it interesting to elucidate the significance of the presence
of the free hydroxyl group positioned at C9 in structures
4a–4d. Thus, this position was acetylated13 and the
derivatives tested in the allylation reaction. Interest-
Table 1. Results from the asymmetric allylation of ketones 1a–1c
In, 4a
THF, 4 Å MS
rt to -78 or -40 ˚C
R1
OH
R1
O
*
R2
R2
I or
I
R3
5a
5b
2a R1,R2 = -OCH2CH2O-, R3 = H
2b R1,R2 = -OCH2CH2O-, R3 = Me
2c R1,R2 = -SCH2CH2S-, R3 = H
2d R1,R2 = -SCH2CH2S-, R3 = Me
2e R1,R2 = Me, R3 = H
1a R1,R2 = -OCH2CH2O-
1b R1,R2 = -SCH2CH2S-
1c R1,R2 = Me
2f R1,R2,R3 = Me
Entry
Ketone
Allylic reagent
Product
T (ꢁC)
ee (%)
Yield (%)d
1
1a
1a
1a
1b
1b
1c
1c
5a
5a
5b
5a
5b
5a
5b
2a
2a
2b
2c
2d
2e
2f
ꢀ78
ꢀ78
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
79b
78b
71b
54c
23c
37b
38b
87
85
58
64
30
40
31
2a
3
4
5
6
7
a Compound 4b was used as chiral promoter.
b Determined by GC.
c Determined by HPLC.
d Isolated yields.

V. Thornqvist et al. / Tetrahedron: Asymmetry 17 (2006) 410–415
413
4. Experimental
TBDMSOTf
2,6-lutidine
CH2Cl2, 0 ˚C
OTBDMS
O
4.1. General
(-)-2a
O
95%
Materials were obtained from commercial suppliers and
used without further purification unless otherwise sta-
ted. Indium powder of quality: ꢀ100 mesh, 99.99%,
was used. THF was dried by passing it through an argon
pressurized column containing activated, neutral alumi-
(-)-6
PdCl2(CH3CN)2
acetone, 0 ˚C
90%
O
˚
num oxide and was stored over activated 4 A MS under
OTBDMS
OTBDMS
an atmosphere of argon. All moisture- and air-sensitive
reactions were carried out under an atmosphere of dry
argon using oven-dried glassware. Optical purities were
analyzed by GC on a b-DEX 120 column (30 m,
0.25 mm i.d., 0.25 lm stationary phase) or by HPLC
on an OD-H column (250 · 4.6 i.d., 5 lm). Optical rota-
tions were measured at 22 ꢁC and are given in
10ꢀ1 deg cm2 gꢀ1. CD-spectroscopic analyses were mea-
sured at 22 ꢁC. The NMR spectra were recorded at
400 MHz (1H) and at 100 MHz (13C) using benzene-d6
(C6H6 d 7.16 (1H) and 128.0 (13C)) as a solvent. The
melting points were not corrected. Chromatographic
separations were performed on normal phase silica gel
60 (0.035–0.070 mm). Thin-layer chromatography was
performed on precoated TLC glass plates with silica
gel 60 F254, 0.25 mm. After elution, the TLC plates were
sprayed with a solution of p-methoxybenzaldehyde
(26 mL), glacial acetic acid (11 mL), concentrated sulfu-
ric acid (35 mL), and 95% ethanol (960 mL) and the
compounds were visualized upon heating.
O
O3
heptane
O
-78 ˚C
8
(+)-7
Et3N, SiO2
heptane, rt
83%
HO
HO
O
O
TBDMSO
(+)-exo-3
15
OTBDMS
(-)-endo-3
85
:
>98% ee after one recrystallisation
Scheme 2. Synthesis of (ꢀ)-endo-3 and (+)-exo-3. (+)-endo-3 and (ꢀ)-
exo-3 were obtained from (+)-2 according to the same procedure (see
Ref. 3).
4.2. Representative procedure for asymmetric allylation of
ketones 1a–1c
The possibility of producing larger amounts of optically
active endo-3 (and exo-3) in one reaction sequence was
examined by performing the asymmetric indium allyla-
tion on 3 mmol scale (of 1a). At this scale, successful
complex formation required 4a to be added in small por-
tions over an extended period of time after the addition
of allyl iodide. The ee of (ꢀ)-2a dropped to 68%, but to
our satisfaction the yield was as high as before (85%),
and the ee could still be raised to >98% by a single
recrystallization from petroleum ether. In order to as-
sign the absolute configuration of compounds 3 and
their precursors (compounds 2a, 6, and 7), the CD spec-
tra of (ꢀ)-endo-3 and (+)-endo-3 were recorded and ana-
lyzed by applying the octant rule for the carbonyl
chromophore.16
Allyl iodide 5a or 3-iodo-2-methyl-propene 5b
˚
(1.65 equiv) was added to a mixture of 4 A MS
(100 mg/1.5 mL THF), indium powder (1.1 equiv), and
(ꢀ)-cinchonidine (1.1 equiv) in THF (1.5 mL/30 mg In)
at room temperature under vigorous stirring. After
approximately 5 min, a slightly yellow, clear solution
resulted, and after two additional hours, the indium
powder was consumed. The reaction mixture was cooled
to ꢀ78 ꢁC 1a or ꢀ40 ꢁC 1b and 1c. The ketone was then
added dropwise, and stirring was continued for 12 h at
the given temperature, whereafter the reaction was
quenched by adding 0.1 M HCl aqueous solution. The
water phase was extracted with EtOAc three times, the
collected organic phases were washed with brine, dried
over MgSO4, and concentrated at reduced pressure.
The resulting homoallylic alcohols were purified by col-
umn chromatography.
3. Conclusion
Reproducible conditions were developed for the asym-
metric indium-mediated allylation, including 4a or 4b
as chiral promoters, by exchanging allylic bromide for
4.3. (ꢀ)-(7R)-7-Allyl-1,4-dioxaspiro[4.5]decane-7-ol (ꢀ)-
2a
˚
allylic iodide, and by adding 4 A MS to the reaction mix-
ture. Under these conditions, tertiary homoallylic alco-
hols 2a–2f were obtained in moderate to good ees and
yields. Furthermore, bicyclic hydroxyketones (ꢀ)-endo-
3/(+)-exo-3 (79% ee) and (+)-endo-3/(ꢀ)-exo-3 (78%
ee) were obtained in four steps, starting from (ꢀ)-2
and (+)-2, respectively. The enantiomeric excess of the
endo-enantiomers of 3 was further increased to >98%
through a simple recrystallization from petroleum ether.
Compound (ꢀ)-2a was obtained as a colorless oil in 87%
yield and 79% ee. Rf = 0.16 (SiO2, heptane–EtOAc
22
85:15). ½aꢁD ¼ ꢀ19:7 (c 1.69, EtOH); IR (NaCl) 3526,
1
3074, 2885, 1639 cmꢀ1; H NMR (400 MHz, benzene-
d6) d 6.12 (ddt, J = 17.1, 10.1, 7.3 Hz, 1H), 5.11–5.03
(m, 2H), 3.99 (s, 1H), 3.40–3.27 (m, 4H), 2.32 (br ddAB
,
J = 7.0 Hz, JAB = 13.7 Hz, 1H), 2.21 (br ddAB
,
J = 7.5 Hz, JAB = 13.0 Hz, 1H), 1.89 (tq, J = 3.7,

414
V. Thornqvist et al. / Tetrahedron: Asymmetry 17 (2006) 410–415
13.5 Hz, 1H), 1.76 (tdAB, J = 2.5 Hz, JAB = 13.7 Hz,
1H), 1.65–1.60 (m, 2H), 1.50 (dAB, JAB = 13.7 Hz, 1H),
1.47–1.42 (m, 1H), 1.33 (dt, J = 4.4, 13.2 Hz, 1H), 1.04
(dt, J = 4.2, 13.3 Hz, 1H); 13C NMR (100 MHz, benz-
ene-d6) d 135.0, 117.3, 109.9, 72.2, 64.3, 63.9, 48.0,
43.9, 36.7, 35.0, 19.3. HRMS (FAB+): calcd for
C11H19O3 (M+H): 199.1334. Found: 199.1337. Anal.
Calcd for C11H18O3: C, 66.64; H, 9.15. Found: C,
66.51; H, 9.23. GC (b-DEX 120, 140 ꢁC isother-
mal) tmin = 30.2 min [(+)-enantiomer], tmaj = 31.1 min
[(ꢀ)-enantiomer].
4.7. (ꢀ)-7-(2-Methyl-allyl)-1,4-dithiaspiro[4.5]decane-7-
ol 2d
Compound 2d was obtained as a colorless oil in 30%
yield and 23% ee. Rf = 0.09 (SiO2, heptane–EtOAc
22
95:5). ½aꢁD ¼ ꢀ2:7 (c 1.08, CHCl3); IR (NaCl) 3462,
2934, 2860 cmꢀ1 1H NMR (400 MHz, benzene-d6) d
;
4.89–4.88 (m, 1H), 4.72–4.71 (m, 1H), 2.76–2.69 (m,
4H), 2.52 (s, 1H), 2.24 (tdAB, J = 2.4 Hz, JAB = 14.3 Hz,
1H), 2.20–2.14 (m, 1H), 2.08–1.94 (m, 3H), 1.90 (dAB
,
JAB = 14.3 Hz, 1H), 1.83 (s, 3H), 1.70 (dt, J = 3.6,
13.1 Hz, 1H), 1.59–1.56 (m, 1H), 1.44–1.39 (m, 1H),
0.93 (dt, J = 4.0, 13.4 Hz, 1H); 13C NMR (100 MHz,
benzene-d6) d 142.6, 114.8, 72.3, 66.7, 51.9, 51.3, 43.0,
39.1, 37.3, 36.7, 25.2, 21.8. HRMS (FAB+): calcd for
C12H20OS2 (M): 244.0956. Found: 244.0953. Anal.
Calcd for C12H20OS2: C, 58.97; H, 8.25. Found: C,
58.85; H, 8.18. HPLC (95:5 hexane–2-propanol,
0.5 mL/min, 254 nm) tmaj = 17.3 min [(ꢀ)-enantiomer],
tmin = 20.9 min [(+)-enantiomer]. The absolute configu-
ration was not determined.
4.4. (+)-(7S)-7-Allyl-1,4-dioxaspiro[4.5]decane-7-ol
(+)-2a
Compound (+)-2a was obtained as a colorless oil in 85%
22
yield and 78% ee. ½aꢁD ¼ þ19:8 (c 1.66, EtOH). GC (b-
DEX 120, 140 ꢁC isothermal) tmaj = 30.2 min ((+)-enan-
tiomer), tmin = 31.1 min [(ꢀ)-enantiomer]. For other
structural and analytical data, see compound (ꢀ)-2a.
4.5. (ꢀ)-7-(2-Methyl-allyl)-1,4-dioxaspiro[4.5]decane-
7-ol 2b
4.8. (ꢀ)-1-Allyl-3,3-dimethyl-cyclohexanol 2e
Compound 2b was obtained as a colorless oil in 58%
Compound 2e was obtained as a colorless oil in 40%
yield and 71% ee. Rf = 0.16 (SiO2, heptane–EtOAc
yield and 37% ee. Rf = 0.16 (SiO2, heptane–EtOAc
22
22
9:1). ½aꢁD ¼ ꢀ13:9 (c 0.90, CHCl3); IR (NaCl) 3524,
95:5). ½aꢁD ¼ ꢀ0:3 (c 1.13, CHCl3); IR (NaCl) 3462,
2947, 2887 cmꢀ1
;
1H NMR (400 MHz, benzene-d6) d
2934, 2866 cmꢀ1 1H NMR (400 MHz, benzene-d6) d
;
4.99–4.98 (m, 1H), 4.80–4.79 (m, 1H), 3.99 (s, 1H),
3.39–3.34 (m, 2H), 3.28–3.25 (m, 2H), 2.29 (dAB
5.81–5.71 (m, 1H), 5.05–4.96 (m, 2H), 1.97–1.94 (m,
2H), 1.89–1.80 (m, 1H), 1.46–1.32 (m, 3H), 1.30–1.25
(m, 1H), 1.20 (s, 3H), 1.04–0.97 (m, 3H), 0.87 (s, 3H),
0.69 (s, 1H); 13C NMR (100 MHz, benzene-d6) d
134.3, 118.4, 71.4, 50.1, 49.1, 39.7, 37.5, 34.3, 30.9,
27.3, 18.9. HRMS (FAB+): calcd for C13H25OSi
(M+SiMe2): 225.1675. Found: 225.1673. Anal. Calcd
for C11H20O: C, 78.51; H, 11.98. Found: C, 78.38; H,
12.08. GC (b-DEX 120, 140 ꢁC isothermal) tmaj = 7.1 -
min [(ꢀ)-enantiomer], tmin = 7.4 min [(+)-enantiomer].
The absolute configuration was not determined.
,
JAB = 13.2 Hz, 1H), 2.16 (dAB, JAB = 13.2 Hz, 1H),
2.04 (s, 3H), 1.91–1.82 (m, 2H), 1.75–1.71 (m, 1H),
1.65–1.61 (m, 1H), 1.51–1.43 (m, 2H), 1.36 (dt,
J = 4.4, 13.2 Hz, 1H), 1.03 (dt, J = 4.2, 13.4 Hz, 1H);
13C NMR (100 MHz, benzene-d6) d 143.4, 114.3,
110.0, 72.8, 64.3, 63.8, 51.2, 44.2, 37.3, 35.1, 25.0, 19.3.
HRMS (FAB+): calcd for C12H19O3 (MꢀH):
211.1334. Found: 211.1318. Anal. Calcd for C12H20O3:
C, 67.89; H, 9.50. Found: C, 67.97; H, 9.43. GC (b-
DEX 120, 140 ꢁC isothermal) tmin = 39.6 min [(+)-enan-
tiomer], tmaj = 40.9 min [(ꢀ)-enantiomer]. The absolute
configuration was not determined.
4.9. (+)-3,3-Dimethyl-1-(2-methyl-allyl)-cyclohexanol 2f
Compound 2f was obtained as a colorless oil in 31% yield
4.6. (ꢀ)-7-Allyl-1,4-dithiaspiro[4.5]decane-7-ol 2c
and 38% ee. Rf = 0.04 (SiO2, heptane–EtOAc 98:2).
22
½aꢁD ¼ þ1:4 (c 1.32, CHCl3); IR (NaCl) 3555, 3489,
Compound 2c was obtained as a colorless oil in 64%
2947 cmꢀ1 1H NMR (400 MHz, benzene-d6) d 4.88–
;
yield and 54% ee. Rf = 0.25 (SiO2, heptane–EtOAc
4.87 (m, 1H), 1.72 (br s, 1H), 1.94 (q, J = 12.7 Hz, 2H),
1.89–1.80 (m, 1H), 1.73 (s, 3H), 1.50–1.41 (m, 1H),
1.39–1.32 (m, 3H), 1.22 (s, 3H), 1.04–0.97 (m, 3H), 0.90
(s, 1H), 0.89 (s, 3H); 13C NMR (100 MHz, benzene-d6)
d 142.8, 114.8, 71.6, 53.1, 49.8, 39.6, 38.0, 34.6, 30.9,
27.1, 25.4, 19.0. HRMS (FAB+): calcd for C14H27OSi
(M+SiMe2): 239.1831. Found: 239.1841. Anal. Calcd
for C12H22O: C, 79.06; H, 12.16. Found: C, 78.88; H,
12.19. GC (b-DEX 120, 140 ꢁC isothermal) tmaj = 8.9
min [(+)-enantiomer], tmin = 9.1 min [(ꢀ)-enantiomer].
The absolute configuration was not determined.
22
85:15). ½aꢁD ¼ ꢀ10:8 (c 1.30, CHCl3); IR (NaCl) 3456,
2932, 2860 cmꢀ1 1H NMR (400 MHz, benzene-d6) d
;
5.91–5.80 (m, 1H), 5.04–4.95 (m, 2H), 2.77–2.69 (m,
4H), 2.47 (s, 1H), 2.18 (tdAB, J = 2.4 Hz, JAB = 14.4 Hz,
1H), 2.16–2.12 (m, 1H), 2.05–1.99 (m, 3H), 1.90 (dAB
,
JAB = 14.4 Hz, 1H), 1.69 (dt, J = 3.5, 13.0 Hz, 1H),
1.55–1.50 (m, 1H), 1.43–1.39 (m, 1H), 0.96 (dt,
J = 4.0, 13.2 Hz, 1H); 13C NMR (100 MHz, benzene-
d6) d 134.1, 118.2, 71.9, 66.7, 50.9, 48.7, 43.0, 39.1,
37.4, 36.3, 21.8. HRMS (FAB+): calcd for C11H18OS2
(M): 230.0799. Found: 230.0795. Anal. Calcd for
C11H18OS2: C, 57.35; H, 7.87. Found: C, 57.41; H,
7.81. HPLC (95:5 hexane–2-propanol, 0.5 mL/min,
254 nm) tmaj = 20.6 min [(ꢀ)-enantiomer], tmin = 28.0
min [(+)-enantiomer]. The absolute configuration was
not determined.
Acknowledgments
We thank the Swedish Science Council, The Crafoord
Foundation, The Royal Physiographic Society in Lund,

V. Thornqvist et al. / Tetrahedron: Asymmetry 17 (2006) 410–415
415
Asymmetry 2004, 15, 3823; (e) Khan, F. A.; Dash, J. Eur.
J. Org. Chem. 2004, 2692; (f) Miyabe, H.; Nishimura, A.;
Ueda, M.; Naito, T. Chem. Commun. 2002, 1454; (g) Shin,
J. A.; Cha, J. H.; Pae, A. N.; Choi, K. I.; Koh, H. Y.;
Kang, H. Y.; Cho, Y. S. Tetrahedron Lett. 2001, 42, 5489;
(h) Carda, M.; Castillo, E.; Rodriguez, S.; Murga, J.;
Marco, J. A. Tetrahedron: Asymmetry 1998, 9, 1117; (i)
Paquette, L. A.; Lobben, P. C. J. Org. Chem. 1998, 63,
5604.
The Research School in Medicinal Science at Lund Uni-
versity and the Knut and Alice Wallenberg Foundation
for economic support. We also thank Einar Nilsson for
obtaining mass spectral data.
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