Synthetic study toward 17-thiasteroids: synthesis of the 1-thiahydrinden-5-one subunit using a new annulation procedure and investigation of its reduction

Article abstract of DOI:10.1016/j.tet.2007.04.093

The enantioselective syntheses of ketones 6 and 7 featuring the CD subunit of 17-thiasteroid are described. The key bicyclic 1-thiahydrindenone (S)-5 was assembled in three steps from Michael adduct (S)-12 via β-keto ester 15 using a one-pot sequential process involving cleavage of both the ketal group and the tert-butyl ester group, decarboxylation, and finally intramolecular aldol condensation. Hydridoalkyl cuprate-induced conjugate reduction of 1-thiahydrindenone (S)-5 and its corresponding sulfone (S)-23 gave 1-thiahydrindanones 6 and 7, respectively, which display unexpectedly the unnatural cis-ring junctions.

Full text of DOI:10.1016/j.tet.2007.04.093

Tetrahedron 63 (2007) 7172–7177
Synthetic study toward 17-thiasteroids: synthesis of the
1-thiahydrinden-5-one subunit using a new annulation
procedure and investigation of its reduction
a
Michele Danet, Georges Morgant, Alain Tomas and Didier Desmaele
a
b
a,
*
ꢀ
€
a
´
Unite de Chimie Organique Associee au CNRS, IFR 141, Universite Paris-Sud, Faculte de Pharmacie,
´
´
´
´
^
5 rue J.-B. Clement, 92290 Chatenay-Malabry, France
´
4 avenue de l’Observatoire, 75270 Paris cedex 06, France
b
´
Laboratoire de Cristallographie et de RMN biologique, CNRS-UMR 8015, Universite Paris V, Faculte de Pharmacie,
Received 19 March 2007; revised 24 April 2007; accepted 26 April 2007
Available online 3 May 2007
Abstract—The enantioselective syntheses of ketones 6 and 7 featuring the CD subunit of 17-thiasteroid are described. The key bicyclic
1-thiahydrindenone (S)-5 was assembled in three steps from Michael adduct (S)-12 via b-keto ester 15 using a one-pot sequential process
involving cleavage of both the ketal group and the tert-butyl ester group, decarboxylation, and finally intramolecular aldol condensation.
Hydridoalkyl cuprate-induced conjugate reduction of 1-thiahydrindenone (S)-5 and its corresponding sulfone (S)-23 gave 1-thiahydrinda-
nones 6 and 7, respectively, which display unexpectedly the unnatural cis-ring junctions.
Ó 2007 Elsevier Ltd. All rights reserved.
COCH3
N
1. Introduction
O
S
H
H
Heterosteroids have attracted great interest, since it has been
recognized that the introduction of a heteroatom in the
steroidal framework brings about notable modifications in
its biological activities.1 Despite a recent revival of interest
for heterosteroids,2 there are only few reports on the syn-
thesis of 17-heterosteroids. Thus, in 1964 Rakhit and Gut
reported the synthesis of 17-azaprogesterone 13 and 17-
oxa-androstan-3-one 2 (Fig. 1).4 In 1980 Jogdeo and Bhide
described the synthesis of 17-thiaestratriene-17-dioxide 3
with the unnatural cis CD ring junction.5 Unfortunately, no
biological data were reported for these compounds. To the
best of our knowledge, 17-thiasteroids such as 17-thia-
estrone 4 and its corresponding sulfoxides have never been
synthesized.
H
H
H
H
O
O
H
1
2
O
O
S
H
H
H
H
H
H
MeO
O
MeO
3
4
O
O
S
S
S
O
O
H
H
7
5
6
Figure 1.
Herein, we report the asymmetric synthesis of 1-thiahydrin-
denone (S)-5 featuring the CD ring moiety of 17-thiasteroids
and our endeavors to reduce this system using the Tsuda–
Daniewski conjugate reduction protocol,6 leading to the
unexpected formation of ketones 6 and 7, which display
cis-fused ring junction.
2. Results and discussion
At the outset of our work we decided to target acid 8, since
C-8 carboxylic acid group is known to direct the stereochem-
ical outcome of the catalytic reduction of the D8(14)-double
bond (steroidal numbering) to the trans-fused hydrinda-
none.7 Keto acid 8 would be prepared from 5, which in
turn is readily available from 2-methyltetrahydrothiophen-
3-one 9, using the ‘deracemizing’ Michael addition pro-
cedure. Indeed, we recently disclosed that chiral imine 10
derived from (R)-1-phenylethylamine and 9 gave the
Keywords: Steroids and sterols; Michael reactions; Cerium and compounds;
Sulfur heterocycles; Reduction.
* Corresponding author. Fax: +33 (0) 146835752; e-mail: didier.desmaele@
u-psud.fr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.093

M. Danet et al. / Tetrahedron 63 (2007) 7172–7177
7173
corresponding Michael adducts 11 in 68% yield with a com-
plete regioselectivity and good enantiomeric excesses
(ee ꢀ95%) (Scheme 1).8
For example, the treatment of (S)-15 in standard acidic
conditions (3 N HCl/MeOH; acetone/PPTS;11 oxalic acid
impregnated SiO2;12 3 N HClO4;13 Amberlyst 1514) let the
substrate be unchanged. On the other hand, forcing the con-
ditions gave only a small amount of the desired keto ester 17,
along with diketone 16 and various undefined aldol products
arising from 16. In search for milder conditions to unmask
the carbonyl group, we tried to use the NaI/CeCl3$7H2O/
CH3CN mixture according to the procedure of Marcantoni
et al.15 To our surprise, when ketal 15 was subjected to
this reaction condition, the enone 5 was obtained in 92%
yield (Scheme 3). Formation of 5 could be best explained as-
suming a sequential process involving concomitant cleavage
of both the ketal group and the tert-butyl ester group, decarb-
oxylation with formation of the cerium enolate, and finally
intramolecular aldol condensation. Interestingly, the cleav-
age of tert-butyl ester with the NaI/CeCl3$7H2O mixture
in acetonitrile has been recently reported.16 In order to ex-
amine the scope of this method, we briefly investigated the
intermolecular condensation of aldehydes with tert-butyl
acetoacetate 20 in the presence of NaI/CeCl3$7H2O mixture,
reasoning that ketal hydrolysis step could be bypassed. Thus
exposure of a mixture of 3-phenylpropanal 19a and tert-
butyl acetoacetate 20 to these reaction conditions led to
the expected enone 21a, albeit in a low 23% yield. 4-Nitro-
benzaldehyde reacted similarly to give enone 21b in 14%
yields, whereas 4-methoxybenzaldehyde remained un-
changed. Attempts to improve the yield using various reac-
tion conditions failed. These results clearly established
that entropic factors were crucial for the success of the trans-
formation of 15 into 5, limiting the usefulness of this sequen-
tial process to intramolecular condensations, nevertheless
the mildness of this procedure may find further applications
to achieve aldol-dehydration sequence with sensitive sub-
strates in neutral conditions.
S
S
S
4
O
O
O
CO2H
8
5
9
Ph
H
Me
NH2
EWG
1)
2)
S
EWG
H3O+
S
9
N
O
Me
Ph
11
H
10
EWG = CO2CH3, SO2Ph, CN
60-70% yield
ee = 90-95%
Scheme 1.
However, although efficient with a great variety of electron
deficient olefins, this process failed with methyl vinyl ke-
tone, since large amounts of polyalkylated materials were
competitively formed. Therefore, an alternative synthetic
route to 5 was developed, starting from keto ester (S)-12.
Saponification of latter compound gave the corresponding
keto acid, which was then converted into enol lactone 13.
Treatment of 13 with LiCH2PO(OMe)2 furnished enone
(S)-5 with a moderate overall yield of ca. 40% from 12.8
Unfortunately, attempts to produce gram quantities of enone
5 according to this procedure encountered unexpected diffi-
culties due to the increasing formation of by-products on
scaling up. We thereby decided to access keto acid 8 directly
from ester (S)-12. Accordingly, the keto group of 12 was first
protected using the Noyori’s ketalization procedure9 and the
resulting ketal 14 was condensed with the sodium enolate of
tert-butyl acetate10 to provide b-keto ester 15 in 80% yield
(Scheme 2).
O
O
O
S
H+
S
t-BuO
16
O
+
MeO2C
S
O
S
a,b
15
O
O
O
O
O
O
12
S
13
t-BuO
OTMS
OTMS
TMSOTf
CeCl3.7H2O, NaI,
CH3CN, 80 °C, 8 h
92%
O
LiCH2PO(OMe)2
c
17
d
O
S
MeO2C
S
S
MMC
S
O
ONa
O
DMF, 2 h, 120 °C
45%
O
O
5
CO2R
Ot-Bu
e
14
5
8, R = H
18, R = CH3
O
O
O
O
S
t-BuO
t-BuO
O
O
20
RCHO
R
O
15
CeCl3.7H2O, NaI,
CH3CN, 80 °C, 8 h
19a-c
21a-c
Scheme 2. Reagents and conditions: (a) 3 N NaOH, THF, 4 h, 20 ꢁC, quan-
titative; (b) Ac2O, AcONa, 120 ꢁC, 2 h, 70%; (c) 2 equiv LiCH2PO(OMe)2,
THF, ꢂ78 ꢁC, 20 min, then H3O+, 57%; (d) 2 equiv (TMSOCH2)2,
0.2 equiv TMSOTf, CH2Cl2, ꢂ78 ꢁC, 30 min, then 16 h, 20 ꢁC, 89%; (e)
(i) 10 equiv CH3CO2t-Bu, 6 equiv NaHMDS, THF, ꢂ78 ꢁC, 1 h; (ii) 14,
ꢂ78 ꢁC, 1 h, then 2 h, 20 ꢁC; (iii) H3O+, 80%.
a: R = PhCHCH2-
b: R = p-NO2Ph-
c: R = p-OMePh-
0-23% yield
Scheme 3.
We next investigated the deprotection of the ketone group to
allow the cyclization of the future C-ring. However, this
seemingly easy task turned out to be extremely challenging.
Having secured an efficient access to unsaturated ketone 5,
attention was next given to the installation of the carboxylic
acid group at C-8. This task was achieved in a moderate 45%

7174
M. Danet et al. / Tetrahedron 63 (2007) 7172–7177
yield using magnesium methyl carbonate (MMC).17 We then
explored the crucial reduction of the D8(14)-double bond.7
Unfortunately all attempts to reduce this double bond by
catalytic hydrogenation, even in forced conditions starting
from keto acid 8 or from its corresponding methyl ester
18, met with failure probably due to poisoning of the catalyst
by the sulfur containing substrate. Since attempts at reduc-
ing 5 by catalytic hydrogenation were similarly unsuccessful
the sulfur atom was clearly implicated in these failures
(Scheme 3).
Tsuda–Daniewski procedure is unprecedented.6 Since the
only difference between the aforementioned examples and
enone 5 was the presence of the sulfur atom, we first invoked
as plausible explanation a complexation of the copper re-
agent by the sulfur atom anti to the bulky methyl group.
The resulting steric hindrance could impede another mole-
cule of reagent from complexing the double bond of 5 on
the bottom face. To test the validity of this assumption, we
examined the conjugated reduction of the sulfone (S)-23 ob-
tained in 73% yield from (S)-5 upon oxidation with mcpba.
Remarkably, treatment of 23 with DIBAL/n-BuCu in the
conditions previously used for 5, gave exclusively the
same cis-fused 1,1-dioxo-1-thiahydrindanone 7, albeit in a
modest 40% yield (Scheme 4).18
For this reason, we chose to explore the hydridoalkyl
cuprate-induced reduction of thiahydrindenone 5.6 This pro-
cedure offers an excellent solution to the longstanding
problem of the trans-fused hydrindanone synthesis. Thus,
the a,b-unsaturated ketone 5 was added to a 10-fold excess
of DIBAL/n-BuCu (from CuCN and n-BuLi) reagent in
HMPA at ꢂ50 ꢁC.6h,i Acidic work up afforded an 8:1 mix-
ture of the two isomeric ketones 6 and 22 in 55% yield.
The relative stereochemistry of the major isomer could not
be established by NMR spectroscopy, including NOE exper-
iments. Nevertheless, oxidation of 6 with mcpba produced
sulfone 7 as a colorless crystalline solid. Single crystal
X-ray diffraction analysis of 7 established unambiguously
the cis-ring junction of this material and confirmed the
(13S,14S) assignment of the absolute configuration on the
basis of the anomalous diffusion of the sulfur atom.
Since copper complexation is unlikely with the sulfone
group, we deduced that the stereochemical outcome of the
conjugated reduction should be attributed to an increasing
destabilization of the trans-fused 1-thiahydrindan in respect
to the corresponding carbon system due to the longer C–S
˚
bond length (1.80 A in 7) and increased angle strain. Thus,
assuming a late transition state partially reflecting the prod-
uct, this enhanced torsional strain might override the intrinsic
trend of the conjugate reducing process to give trans-
hydrindan systems. We shall pursue this intriguing phenom-
enon with further computational and experimental studies.
To our knowledge, the preferential formation of the thermo-
dynamically favorable cis-fused hydrindanone using the
3. Conclusions
In summary, we have successfully assembled in optically
active form the bicyclic enone (S)-5 in three steps with an
overall yield of 64% from Michael adduct (S)-12. The key
step was a new sequential process involving cleavage of
both the ketal group and the tert-butyl ester group of ketal
15, followed by decarboxylation, and finally intramolecular
aldol condensation, providing 1-thiahydrinden-5-one 5 in
92% yield. Hydridoalkyl cuprate-induced conjugate reduc-
tion of either (S)-5 or sulfone (S)-23 with DIBAL/n-BuCu
in HMPA gave unexpectedly cis-fused ketones 6 and 7,
respectively.
CuCN, n-BuLi,
DIBAL-H, THF,
HMPA, - 50 °C
S
S
S
+
O
55%
O
O
H
H
5
6
22
2 equiv. mcpba,
2 equiv. mcpba,
CH2Cl2, 1 h, 20 °C
65%
73%
CH2Cl2, 1 h, 20 °C
O
O
S
O
S
CuCN, n-BuLi,
DIBAL-H, THF,
HMPA, - 50 °C
O
O
O
40%
H
7
4. Experimental
23
4.1. General methods
€
Melting points were measured on a Buchi capillary tube
O
melting point apparatus and are uncorrected. IR spectra
were recorded from neat samples on a Fourier Transform
Bruker Vector 22 spectrometer. Only significant absorptions
are listed. Optical rotations were measured on a Perkin–
C13
C14
S
1
Elmer 241 polarimeter at 589 nm. The H and 13C NMR
O
spectra were recorded on a Bruker AC 200 P (200 and
1
50 MHz for H and 13C, respectively), a Bruker Avance-
C9
1
300 (300 and 75 MHz for H and 13C, respectively), or a
Bruker ARX 400 (400 and 100 MHz for 1H and 13C, respec-
tively) spectrometer. Recognition of methyl, methylene,
methine, and quaternary carbon nuclei in 13C NMR spectra
rests on the J-modulated spin-echo sequence. Mass spectra
were recorded on a Hewlett–Packard G 1019 A (70 eV) or on
a Bruker Esquire-LC. Analytical thin-layer chromatography
was performed on Merck silica gel 60F254 glass precoated
C8
O
X-ray crystal structure of sulfone 7
Scheme 4.

M. Danet et al. / Tetrahedron 63 (2007) 7172–7177
7175
plates (0.25 mm layer). Column chromatography was per-
formed on Merck silica gel 60 (230–400 mesh ASTM). Di-
ethyl ether and tetrahydrofuran (THF) were distilled from
sodium/benzophenone ketyl. Methanol and ethanol were
dried over magnesium and distilled. Benzene, toluene,
DMF, and CH2Cl2 were distilled from calcium hydride,
under a nitrogen atmosphere. Chemicals obtained from
commercial suppliers were used without further purification.
Elemental analyses were performed by the Service de micro-
ꢂ78 ꢁC. TMSOTf (1.0 g, 4.5 mmol) was added dropwise
and the mixture was stirred at ꢂ78 ꢁC. After 30 min, the
mixture was allowed to warm to 20 ꢁC and kept at this tem-
perature for 16 h. The reaction was quenched with aqueous
sodium bicarbonate (20 mL) and the mixture was extracted
with CH2Cl2 (4ꢃ20 mL). After drying over MgSO4, the
combined organic layers were concentrated. The crude prod-
uct was purified by silica gel chromatography (cyclohexane/
ethyl acetate/Et3N, 4:1:0.005) to give 5.03 g of ketal 14
(89%) as a colorless oil; [a]D ꢂ36.8 (c 5.4, EtOH); IR
(neat, cmꢂ1) 2950, 2885, 1733, 1435, 1373, 1308, 1218,
^
analyse, Centre d’Etudes Pharmaceutiques, Chatenay-
Malabry, France, with a Perkin–Elmer 2400 analyzer.
1
1169, 1069; H NMR (CDCl3, 300 MHz) d: 3.98–3.95 (m,
4.2. (R)-(2-Methyl-dihydrothiophen-3-ylidene)-
(1-phenyl-ethyl)-amine (10)
4H), 3.64 (s, 3H), 2.85–2.30 (m, 4H), 2.14 (t, J¼7.2 Hz,
2H), 2.12–1.90 (m, 2H), 1.28 (s, 3H); 13C NMR (CDCl3,
75 MHz) d: 174.1 (CO), 118.5 (C), 65.5 (CH2), 65.2
(CH2), 56.6 (C), 51.4 (CH3), 34.8 (CH2), 33.6 (CH2), 30.8
(CH2), 23.6 (CH2), 22.9 (CH3). Anal. Calcd for
C11H18O4S: C, 53.64; H, 7.37. Found: C, 53.99; H, 7.47.
˚
A mixture of 5 A molecular sieves (7.3 g), basic alumina
(1.8 g), and silica (0.9 g) was activated by heating for
a few minutes at 0.05 Torr with a free flame. After cooling,
freshly distilled cyclohexane (25 mL) and 2-methyltetra-
hydrothiophen-3-one (4.15 g, 35.7 mmol) were added under
inert atmosphere. The solution was degassed with azote, and
(R)-1-phenylethylamine (4.72 g, 39.0 mmol) was added.
After stirring for 6 days at room temperature, the mixture
was filtered, washed with anhydrous Et2O, and concentrated
to yield crude imine 10 as a pale yellow oil (7.8 g, quantita-
tive), which was used without further purification in the next
step; IR (neat, cmꢂ1) 1663, 1492, 1448.
4.5. (S)-5-(6-Methyl-1,4-dioxa-7-thiaspiro[4.4]non-
6-yl)-3-oxo-pentanoic acid tert-butyl ester (15)
A solution of tert-butyl acetate (23.2 g, 200 mmol) in an-
hydrous THF (10 mL) was added dropwise at ꢂ78 ꢁC to a
mixture of sodium hexamethyldisilazane (2 M in THF,
61 mL, 122 mmol) in THF (200 mL) under nitrogen. The re-
sulting mixture was stirred at ꢂ78 ꢁC for 1 h and a solution
of ketal 14 (5.0 g, 20.3 mmol) in THF (100 mL) was added
dropwise. The reaction mixture was stirred for 1 h at ꢂ78 ꢁC
and the temperature was then slowly raised to 20 ꢁC over
a 1 h period of time. A saturated aqueous NH4Cl solution
(200 mL) was then added and the solvent was removed un-
der reduced pressure. The aqueous residue was extracted
with diethyl ether (4ꢃ100 mL). After drying over MgSO4,
the combined organic layers were concentrated. The crude
product was purified by silica gel chromatography (cyclo-
hexane/ethyl acetate/Et3N, 4:1:0.005) to give 5.3 g of
keto ester 15 (80%) as a colorless oil; [a]D ꢂ35.9 (c 2.6,
EtOH); IR (neat, cmꢂ1) 2977, 2887, 1734, 1714, 1456,
4.3. (S)-3-(2-Methyl-3-oxo-tetrahydrothiophen-2-yl)-
propionic acid methyl ester (12)
To a solution of crude imine 10 (9.40 g, 42.9 mmol) in
distilled cyclohexane (5 mL), methyl acrylate (27 g,
0.31 mol) and few crystals of hydroquinone (35 mg,
0.3 mmol) were added. The resulting mixture was stirred
at 45 ꢁC for 70 h under nitrogen. The mixture was cooled
to room temperature and diluted with THF (300 mL). Aque-
ous acetic acid of 20% (50 mL) was then added and the
resulting mixture was stirred at 20 ꢁC for 3 h. The solvents
were removed under reduced pressure and 15 mL of 3 N
HCl was added. The mixture was extracted with Et2O
(4ꢃ25 mL), the organic layers were then washed with brine,
dried over MgSO4, filtered, and concentrated. The residue
was purified by column chromatography over silica gel (cy-
clohexane/ethyl acetate, 4:1) to yield keto ester 12 (5.8 g,
68% yield). Colorless oil, bp 80–85 ꢁC/0.1 Torr (oil bath);
[a]D ꢂ31 (c 13, EtOH); IR (neat, cmꢂ1) 2956, 1733, 1713,
1
1369, 1310, 1256, 1149; H NMR (CDCl3, 300 MHz) d:
3.88–3.82 (m, 4H), 3.25 (s, 2H), 2.70–2.46 (m, 4H), 2.04
(t, J¼7.3 Hz, 2H), 2.00–1.70 (m, 2H), 1.33 (s, 9H), 1.15
(s, 3H); 13C NMR (CDCl3, 75 MHz) d: 202.5 (CO), 166.0
(CO), 118.1 (C), 81.3 (C), 65.2 (CH2), 64.9 (CH2), 56.6
(C), 50.4 (CH2), 39.3 (CH2), 34.4 (CH2), 31.6 (CH2), 27.6
(3CH3), 23.3 (CH2), 23.1 (CH3). Anal. Calcd for
C16H26O5S: C, 58.16; H, 7.93. Found: C, 57.86; H, 8.09.
1
1436, 1349, 1248; H NMR (CDCl3, 200 MHz) d: 3.64 (s,
3H), 2.95–2.85 (m, 2H), 2.71–2.64 (m, 2H), 2.44–2.30 (m,
2H), 2.15–1.85 (m, 2H), 1.34 (s, 3H); 13C NMR (CDCl3,
50 MHz) d: 219.2 (C), 172.6 (C), 55.8 (C), 51.4 (CH3),
38.1 (CH2), 32.2 (CH2), 29.4 (CH2), 23.5 (CH3), 21.1
(CH2); MS (EI) m/z (%): 203 (M+1, 46), 202 (M, 55), 184
(23), 171 (15), 170 (42), 146 (34), 143 (30), 116 (25), 115
(37), 114 (100), 86 (76). Anal. Calcd for C9H14O3S: C,
53.44; H, 6.98. Found: C, 53.41; H, 7.01.
4.6. (S)-7a-Methyl-2,3,7,7a-tetrahydro-6H-benzo[b]-
thiophen-5-one (5)
A
mixture of keto ester 15 (530 mg, 1.6 mmol),
CeCl3$7H2O (1.0 g, 2.6 mmol), and sodium iodide (67 mg,
0.44 mmol) in acetonitrile (20 mL) was stirred at reflux
temperature for 16 h. After cooling, the mixture was con-
centrated under reduced pressure. The residue was taken
into 0.5 N HCl and the mixture was extracted with ethyl ace-
tate (3ꢃ20 mL). The combined organic layers were washed
with aqueous sodium thiosulfate and brine. After drying over
MgSO4, the organic layer was concentrated. The crude prod-
uct was purified by silica gel chromatography (cyclohexane/
ethyl acetate, 2:1) to give 248 mg of ketone 5 (92%) as a pale
yellow oil; [a]D +148 (c 1.5, EtOH); IR (neat, cmꢂ1) 2929,
4.4. (S)-3-(6-Methyl-1,4-dioxa-7-thiaspiro[4.4]non-
6-yl)-propionic acid methyl ester (14)
Keto ester 12 (4.65 g, 23.0 mmol) was taken into anhydrous
CH2Cl2 (80 mL), 1,2-bis(trimethylsilyloxy)ethane (9.5 g,
46.0 mmol) was added and the solution was cooled to

7176
M. Danet et al. / Tetrahedron 63 (2007) 7172–7177
2860, 1667, 1445, 1417, 1337, 1316, 1222, 1180; 1H NMR
(200 MHz, CDCl3) d: 5.65 (s, 1H), 3.05–2.72 (m, 4H),
2.50–2.10 (m, 4H), 1.51 (s, 3H); 13C NMR (50 MHz,
CDCl3) d: 197.6 (CO), 170.8 (C), 120.4 (CH), 51.6 (C),
36.8 (CH2), 35.1 (CH3), 33.6 (CH2), 27.0 (CH2), 26.6
(CH3). Anal. Calcd for C9H12OS: C, 64.24; H, 7.19. Found:
C, 64.01; H, 7.34.
(CH3); MS (+APCI) m/z (%): 201 (M+1, 100), 183 (33),
137 (82), 109 (45).
4.9. (7aS,cis)-7a-Methyl-1,1-dioxo-octahydrobenzo[b]-
thiophen-5-one (7)
Copper cyanide (895 mg, 10 mmol) was suspended in THF
(40 mL) and chilled to ꢂ20 ꢁC. A 2.0 M solution of
n-BuLi in hexanes (4.5 mL, 9.0 mmol) was added dropwise.
The brown solution was stirred at ꢂ20 ꢁC for 30 min, and
then the temperature was lowered to ꢂ50 ꢁC. A 1.1 M solu-
tion of DIBAL in hexanes (18 mL, 19.8 mmol) was added
slowly dropwise. The dark brown solution was allowed to
stir at ꢂ50 ꢁC for 1 h before the enone 23 (200 mg,
1.0 mmol) was added as a solution in 1:1 THF/HMPA
(15 mL). The temperature was raised to ꢂ20 ꢁC over the
next 10 min and then the mixture was allowed to stir at
ꢂ20 ꢁC for 1 h. The reaction was quenched with a solution
of 1:1 saturated aqueous NH4Cl and 3 M aqueous HCl
(50 mL) at ꢂ20 ꢁC and allowed to warm to ambient temper-
ature over 30 min. The mixture was filtered and extracted
with diethyl ether (4ꢃ20 mL). The organic layer was dried
over MgSO4, concentrated, and then washed sequentially
with 1 M aqueous HCl, water, and brine. The organic layer
was dried, filtered through silica gel, and evaporated to yield
a pale yellow oil. Purification by silica gel chromatography
eluting with cyclohexane/ethyl acetate, 4:1, gave pure
ketone 7 as a colorless crystals, 80 mg, 40%; [a]D +2ꢂ8.10
4.7. (S)-7a-Methyl-hexahydrobenzo[b]thiophen-
5-one (6)
Copper cyanide (2.15 g, 24 mmol) was suspended in THF
(100 mL) and chilled to ꢂ20 ꢁC. A 2.5 M solution of
n-BuLi in hexanes (8.65 mL, 21.6 mmol) was added drop-
wise. The brown solution was stirred at ꢂ20 ꢁC for
30 min, and then the temperature was lowered to ꢂ50 ꢁC.
A 1.1 M solution of DIBAL in hexanes (43 mL, 47 mmol)
was added slowly dropwise. The dark brown solution was
allowed to stir at ꢂ50 ꢁC for 1 h before the enone 5
(400 mg, 2.38 mmol) was added as a solution in 1:1 THF/
HMPA (36 mL). The temperature was raised to ꢂ20 ꢁC
over the next 10 min and then the mixture was allowed to
stir at ꢂ20 ꢁC for 1 h. The reaction was quenched with a so-
lution of 1:1 saturated aqueous NH4Cl and 3 M aqueous HCl
(100 mL) at ꢂ20 ꢁC and allowed to warm to ambient tem-
perature over 30 min. The mixture was filtered and extracted
with diethyl ether (4ꢃ50 mL). The organic layer was dried
over MgSO4, concentrated, and then washed sequentially
with 1 M aqueous HCl, water, and brine. The organic layer
was dried, filtered through silica gel, and evaporated to yield
a pale yellow oil. Purification by silica gel chromatography
eluting with cyclohexane/ethyl acetate, 4:1, gave pure ketone
6 as a colorless oil, 222 mg, 55%, bp 75 ꢁC/0.5 Torr (oil
bath); [a]D +44.5 (c 2.6, EtOH); IR (neat, cmꢂ1) 2948,
(c 2.7, CHCl3); mp 145 ꢁC (MeOH); IR (neat, cm
)
2968, 1703, 1471, 1453, 1417, 1292, 1161, 1131, 1095,
1
1040; H NMR (CDCl3, 300 MHz) d: 3.22 (ddd, J¼13.7,
9.9, 3.6 Hz, 1H), 3.09 (dt, J¼13.7, 9.1 Hz, 1H), 2.63 (dd, J¼
14.7, 5.7 Hz, 1H), 2.60–2.55 (m, 1H), 2.50–2.16 (m, 5H),
1.98 (dtd, J¼13.9, 4.8, 1.4 Hz, 1H), 1.82–1.70 (m, 1H),
1.55 (s, 3H); 13C NMR (CDCl3, 75 MHz) d: 208.0 (CO),
58.4 (C), 47.9 (CH2), 42.5 (CH), 41.5 (CH2), 36.5 (CH2),
27.9 (CH2), 24.3 (CH2), 18.1 (CH3). Crystal data: crystal
of size 0.19ꢃ0.20ꢃ0.22 mm. Orthorhombic, space group
1
2867, 1711, 1447, 1418, 1378, 1229; H NMR (CDCl3,
400 MHz) d: 3.00 (t, J¼6.7 Hz, 2H), 2.62–2.50 (m, 1H),
2.40–2.11 (m, 6H), 2.03–1.92 (m, 1H), 1.84–1.70 (m, 1H),
1.55 (s, 3H); 13C NMR (CDCl3, 75 MHz) d: 211.2 (CO),
54.1 (C), 50.6 (CH), 41.6 (CH2), 37.2 (CH2), 36.3 (CH2),
35.8 (CH2), 30.3 (CH3), 29.7 (CH2). Anal. Calcd for
C9H14OS: C, 63.48; H, 8.29. Found: C, 63.23; H, 8.43.
˚
P 21 21 21, Z¼4, a¼7.201(2), b¼7.399(7), c¼18.483(4) A,
a¼b¼g¼90 , V¼982.4(18) A , d¼1.160 g cmꢂ3, F(000)¼
3
ꢁ
˚
432, l¼0.710693 A (Mo Ka), m¼0.302 mmꢂ1; 6078 reflec-
˚
tions measured (–10 ꢄhꢄ10, 0ꢄkꢄ10, 0ꢄlꢄ25) on a Nonius
CAD4 diffractometer. The structure was solved with SIR92
and refined with CRYSTALS with hydrogen atoms riding.
Refinement converged to R(gt)¼0.0285 for the 1742 (119
parameters) reflections having Iꢀ3s(I), and wR(gt)¼0.0348,
goodness-of-fit S¼1.0986. Residual electron density: ꢂ0.14
4.8. (S)-7a-Methyl-1,1-dioxo-1,2,3,6,7,7a-hexahydro-
benzo[b]thiophen-5-one (23)
To an ice-cooled solution of enone 5 (672 mg, 4.0 mmol) in
CH2Cl2 (4 mL) was added dropwise a solution of mcpba
(70%, 2.0 g, 8.1 mmol) in CH2Cl2 (6 mL). The reaction mix-
ture was stirred for 1 h at 20 ꢁC. CH2Cl2 of 20 mL was added
and then the reaction mixture was filtered over a pad of
Celite, and the filtrate was washed with saturated aqueous
NaHSO3 and saturated aqueous NaHCO3. The organic layer
was dried and concentrated under reduced pressure. The
crude product was purified by silica gel chromatography
(cyclohexane/ethyl acetate, 1:1) to give 590 mg of sulfone
23 (73%) as a colorless oil; [a]D +27.9 (c 5.2, EtOH); IR
(neat, cmꢂ1) 2959, 1705 (weak), 1668, 1448, 1418, 1300,
3
˚
and 0.17 e A . Flack parameter¼0.07(12). Crystallographic
results have been deposited (CIF file) in the Cambridge
Crystallographic Data Centre, UK, and allocated the deposi-
tion number CCDC 625028.
Acknowledgements
We thank Dr. Jacqueline Mahuteau for NMR experiments
and Mrs. S. Mairesse-Lebrun for performing elemental
analyses.
1
1229, 1191, 1139; H NMR (CDCl3, 300 MHz) d: 6.02 (s,
1H), 3.41 (ddd, J¼14.1, 10.4, 7.8 Hz, 1H), 3.26 (ddd, J¼
14.1, 9.1, 5.3 Hz, 1H), 3.13–2.93 (m, 2H), 2.68–2.42 (m,
3H), 2.06 (m, 1H), 1.63 (s, 3H); 13C NMR (CDCl3,
75 MHz) d: 195.8 (CO), 159.5 (C), 127.0 (CH), 60.1 (C),
45.5 (CH2), 31.5 (CH2), 25.1 (CH2), 24.9 (CH2), 19.3
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