Asymmetric synthesis of thiadecalins via an organocatalytic triple cascade/sulfa-michael sequence

Article abstract of DOI:10.1055/s-0029-1218804

An efficient two-step asymmetric synthesis of highly substituted cis-configured thiadecalins and the corresponding hexahydrobenzothiophene core is described. Thiadecalin derivatives are known for their widespread biological activities, such as antimicrobi

Full text of DOI:10.1055/s-0029-1218804

PAPER
2271
Asymmetric Synthesis of Thiadecalins via an Organocatalytic Triple Cascade/
Sulfa-Michael Sequence
A
symmetric Synth
i
esisof
e
T
hiadecalin
t
s
er Enders,* Bertram Schmid, Nico Erdmann, Gerhard Raabe
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 5 May 2010
Dedicated to Professor Rolf Huisgen on the occasion of his 90th birthday
domino reaction leading to tetrasubstituted cyclohexene-
Abstract: An efficient two-step asymmetric synthesis of highly
substituted cis-configured thiadecalins and the corresponding
hexahydrobenzothiophene core is described. Thiadecalin deriva-
tives are known for their widespread biological activities, such as
carbaldehydes.8 In order to synthesize the potentially bio-
active thiadecalins 1 we envisaged extending the triple
cascade method by a subsequent intramolecular sulfa-
antimicrobial and neurotropic properties. The procedure is based on Michael addition9 via nucleophilic displacement of bro-
an organocatalytic triple cascade reaction followed by an intramo-
lecular sulfa-Michael addition. In this manner six consecutive ste-
mide 3 to form the sulfa-Michael precursor 2 (Scheme 1).
reocentres are controlled and the target molecules are obtained in
PG
S
Br
S
moderate yields, with virtually complete enantioselectivitiy (ee
>99%) and after recystallisation in diastereomeric ratios of >97:3.
The relative and absolute configuration was determined by NMR
spectroscopy and X-ray structure analysis.
∗
∗
∗
∗
∗
O
O
O
∗
R1
R2
R1
R2
R1
R2
NO2
NO2
NO2
Key words: organocatalysis, asymmetric synthesis, Michael addi-
tion, thiadecalins, domino reaction
1
2
3
EN
O
O
Br
6
triple
cascade
4
The research field of organocatalysis1 has developed rap-
idly since about the turn of the millennium and can now
be seen as a third pillar of asymmetric catalysis beside
metal and biocatalysis. Numerous basic organocatalytic
protocols for very efficient and highly stereoselective car-
bon–carbon and carbon–heteroatom bond formations are
now part of the strategic arsenal of synthetic chemistry
and can be used in the asymmetric total synthesis of natu-
ral products and bioactive compounds in general.
R2
EN
IM
NO2
R1
5
Scheme 1 Retrosynthetic analysis of the asymmetric thiadecalin
synthesis
Employing 5-bromopentanal (4), readily available
through DIBAL-H reduction of the commercially avail-
able bromo ester, in the cascade reaction with nitrostyrene
(5) and cinnamaldehyde (6) under diphenylprolinol TMS-
ether catalysis 7 gave the desired domino product 8 as a
3.8:1 diastereometric mixture of the a-nitro epimers and
with practically complete enantiomeric excess (ee >99%)
in 68% yield. The major diastereomer shown could be ob-
tained as a pure stereoisomer (dr >97:3, ee >99%) after re-
crystallisation in 54% yield (Scheme 2).
Thiadecalin derivatives have been studied intensively
with regard to their antimicrobial and antiphage properties
including the treatment of infected wounds.2 It has also
been shown that thiadecalins exhibit neutrotropic activi-
ty.3 The corresponding thiadecalin sulfonium salts
showed sedative properties during hexenal-induced sleep.
In addition, other thiadecalin derivatives are known to be
antigestagens and antiglucocorticoids.4 These compounds
are also mentioned in combination with the treatment of
psychosis and addictive behaviour. The antiglucocorti-
coids can be used to treat spontaneous or narcotic-induced
withdrawals, especially from heroin, morphine, metha-
done, cocaine, and their mixtures.5
Br
O
Ph
Ph
O
4
a)
N
Br
H
6
OTMS
O
7
NO2
Among the various subdisciplines of organocatalysis,
domino reactions6 enabling the highly stereoselective
construction of complex molecules in a single operation
have been studied intensively in the last few years.7 In
2006, our group reported an efficient three-component
54 %
5
NO2
8
dr 3.8:1
ee >99%
dr >97:3
ee >99%
after recrystallisation
Scheme 2 Triple domino reaction with 5-bromopentanal (4).
Reagents and conditions: a) 0.2 M toluene, 20 mol% 7, 24 h 0 °C,
then 48 h, r.t.
SYNTHESIS 2010, No. 13, pp 2271–2277
Advanced online publication: 27.05.2010
x
x.
x
x
.
2
0
1
0
DOI: 10.1055/s-0029-1218804; Art ID: Z11510SS
© Georg Thieme Verlag Stuttgart · New York

2272
D. Enders et al.
PAPER
The cyclohexenecarbaldehyde 8 thus obtained was then The scope of the novel asymmetric thiadecalin synthesis
converted into the more stable methyl ester 9 by Pinnick was demonstrated by variation of the substituents R1 and
oxidation followed by esterification with HCl/methanol. R2 (Tables 1 and 2). In addition, by shortening the chain
The displacement of the bromide with potassium thioace- length (n = 0) of the aldehyde 12 opened an entry to the
tate in DMF proceeded smoothly, affording an 8.5:1 dia- corresponding hexahydrobenzothiophene system as was
stereomeric mixture of the corresponding thioester 10. exemplified in the case of 14e.
The minor diastereomer could be easily removed by col-
umn chromatography. Deprotection of the thiol with po-
Table 1 Scope of the Domino Reaction
tassium carbonate in anhyd methanol provided the cis-
13 R1
R2
n
Yield drb
(%)a
ee
thiadecalin 11 via intramolecular sulfa-Michael addition
as a single stereoisomer in 62% yield after recrystallisa-
tion (Scheme 3).
(%)c
a
b
c
d
e
f
Ph
Ph
Ph
Ph
1
1
1
1
0
1
51 >97:3 (80:20)
45 >97:3 (95:5)
43 >97:3 (85:15)
60 >97:3
>99
>99
>99
>99
>99
>99
4-ClC6H4
4-MeOC6H4
O
O
Br
Br
OMe
a), b)
71%
4-methylfuran-2-yl Ph
NO2
NO2
Ph
Ph
Ph
H
57 >97:3 (80:20)
32 >97:3 (80:20)
8
9
dr >97:3
ee >99%
c)
78%
a Yield after recrystallisation.
b Diastereomeric ratio determined by NMR spectroscopy; dr of the
crude product is given in parentheses.
O
O
S
O
c The percentage of ee was determined by chiral stationary phase
HPLC.
S
OMe
OMe
d)
62%
NO2
10
NO2
dr >97:3
ee >99%
11
Table 2 Scope of the Thiadecalin Synthesis
14 R1
R2
n
Yield drb
(%)a
ee
(%)
Scheme 3 First route to thiadecalin 11. Reagents and conditions: a)
NaClO2, 2-methylbut-2-ene, buffer; b) SOCl2, MeOH; c) KSAc,
DMF; d) K2CO3, MeOH; recrystallisation.
a
b
c
d
e
f
Ph
Ph
Ph
Ph
1
1
1
1
0
1
57 >97:3 (90:10) >99
40 >97:3 (60:40) >99
52 >97:3 (88:12) >99
4-ClC6H4
4-MeOC6H4
With the first route to the thiadecalin 11 in hand, we then
shortened the protocol to a two-step version by employing
the thioester containing aldehyde 12 as a substrate in the
triple cascade. After optimisation, we were able to carry
out the sulfa-Michael addition with the enal domino prod-
ucts 13. The thiadecalins 14 were obtained with complete
enantioselectivity and in diastereomeric ratios ranging
from 85:15 to >97:3. To our delight, one recrystallisation
gave the virtually pure stereoisomers in moderate yields
(Scheme 4).
4-methylfuran-2-yl Ph
50 >97:3
57 >97:3 (80:20) >99
40 85:15 (70:30) >99
>99
Ph
Ph
Ph
H
a Yield after recrystallisation.
b Diastereomeric ratio determined by NMR; dr of the crude product is
given in parentheses.
O
The methylfuranyl group as R1 gave the best results for
the triple cascade reaction in terms of both yield and dia-
stereoselectivity. The yield for the subsequent sulfa-
Michael reaction was moderate, yet the diasteromeric ra-
tio was better than 97:3, even before recrystallisation. In
comparing the electron-donating and -withdrawing
groups at the phenyl ring of R1, no overall tendencies were
observed. For n = 0, the reaction proceeded smoothly with
57% yield for the triple cascade and the sulfa-Michael ad-
dition, respectively. Further variation on R2 was possible,
but led to lower yields and diastereomeric ratios. Al-
though a one-pot procedure for the two steps was feasible
and led to good overall yields, the main drawback was the
lack of diastereomeric excess obtained. For this reason the
two-step procedure with purification of the intermediates
13 was preferred.
Ph
Ph
S
O
O
O
N
H
OTMS
n
S
n
7
+
O
12
R2
a)
n = 0,1
R1
R2
NO2
6
R1
NO2
13
5
S
n
b)
O
R1
R2
NO2
14
Scheme 4 Optimised two-step route. Reagents and conditions: a)
20 mol% 7, toluene, 24 h, 0 °C, 48 h r.t.; b) K2CO3, MeOH.
Synthesis 2010, No. 13, 2271–2277 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Thiadecalins
2273
Mass spectra were measured on a Finnigan SSQ7000 (EI 70 eV)
spectrometer and high-resolution mass spectra on a Thermo Fisher
Scientific Orbitrap XL. IR spectra were recorded on a Perkin-Elmer
FT-IR Spectrum 100 using an ATR-Unit. 1H and 13C NMR spectra
were recorded at ambient temperature on Varian Mercury 300 or
Inova 400 spectrometers with TMS as an internal standard. Analyt-
ical HPLC was performed on a Hewlett-Packard 1100 Series instru-
ment using chiral stationary phases (Chiralcel OD, Chiralcel OJ,
Chiralpak AD, Chiralpak AS, Chiralcel IA).
The relative and absolute configuration of the thiadecalin
14b and the hexahydrobenzothiophene 14e was deter-
mined by 1H NMR spectroscopy (coupling constants) and
X-ray crystallography (Figures 1 and 2).
Organocatalytic Domino Reaction; General Procedure (GP 1)
Catalyst 7 (0.2 equiv) and nitroalkene 5 (1.0 equiv) were dissolved
in toluene (0.5 M with respect to 12) and cooled to 0 °C. Aldehyde
12 (1.0 equiv) was slowly added followed by a slow addition of the
a,b-unsaturated aldehyde 6 (1.0 equiv). The reaction was kept at
0 °C until TLC showed complete consumption of 12 (usually 24 h)
and then allowed to warm to r.t. The stirring was continued for 48
h. The domino product 13 was purified by column chromatography
and recrystallisation.
Figure 1 Determination of the relative and absolute configuration
of 14b (Ar = 4-ClC6H4) by 1H NMR and X-ray analysis
Sulfa-Michael Addition; General Procedure (GP 2)
The domino product 13 (1 equiv) was dissolved in anhyd MeOH
(0.02 M). Anhyd K2CO3 (1 equiv) was added and the suspension
stirred at r.t. until 13 was consumed (usually 20 min). Brine (1 mL
per 10 mg of 13) was added, followed by H2O (1 mL per 10 mg of
13), and the product was extracted with CH2Cl2 (3 × 1 mL per 10
mg of 13). The solvent was evaporated and the residue was recrys-
tallised.
Figure 2 Determination of the relative and absolute configuration
of 14e by 1H NMR and X-ray analysis
As shown in Figure 1, the 1H NMR coupling constants in-
dicate a chair conformation of the hexa-substituted cyclo-
hexane ring of the cis-thiadecalin 14b. This is also
confirmed for the crystalline stage by the corresponding
Röntgen structure. In the cis-configured hexahydroben-
zothiophene derivative 14e, however, the H NMR and
Röntgen data indicate a twist-boat conformation of the cy-
clohexane moiety (Figure 2).
Bromocarbaldehyde 8
The synthesis of 8 following GP 1 yielded 4.2 g (54%) of the main
diastereomer as colourless crystals; mp 122 °C; ee >99%; Rf = 0.38
(pentane–Et2O, 1:1); [a]D23 –1.1 (c 1, CHCl3).
IR (film): 1648, 1546, 1451, 1401, 1366, 1285, 1240, 1166, 887,
772, 754, 699, 614, 552 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.62 (m, 1 H), 1.79 (m, 1 H), 1.95
(m, 1 H), 2.08 (m, 1 H), 3.01 (dd, J = 10.6, 3.4 Hz, 1 H), 3.36 (m, 2
H), 3.41 (m, 1 H), 4.47 (s, 1 H), 4.87 (dd, J = 3.4, 1.6 Hz, 1 H), 6.99
(m, 2 H), 7.20 (m, 2 H), 7.42–7.27 (m, 7 H), 9.61 (s, 1 H).
1
In summary, we have developed a two-step organocatalyt-
ic asymmetric synthesis of functionalised, highly substi-
13C NMR (100 MHz, CDCl3): d = 29.6, 30.9, 32.7, 36.4, 42.9, 43.2,
92.3, 127.6, 127.7, 127.8, 128.1, 129.0, 129.1, 136.7, 137.6, 138.3,
tuted
cis-thiadecalins
and
the
corresponding
hexahydrobenzothiophene core. The novel entry is based 153.0, 191.5.
MS (EI): m/z = 427.0 (M+).
on our diphenylprolinol TMS-ether catalysed triple cas-
cade followed by an intramolecular sulfa-Michael addi-
tion. The target molecules are of pharmaceutical and
medicinal interest and bear six consecutive stereocentres
as part of a fully substituted cyclohexane ring. Besides
moderate overall yields, virtually complete enantiomeric
excesses (ee >99%) and after crystallisation, with one ex-
ception, diastereomeric ratios of >97:3 are obtained.
Anal. Calcd for C22H22BrNO3: C, 61.69; H, 5.18; N, 3.27. Found: C,
61.86; H, 4.76; N, 3.35.
Bromomethyl Ester 9
Compound 8 (4.0 g, 9.4 mmol) was dissolved in acetone (50 mL)
and cooled to 0 °C. After the addition of 2-methylbut-2-ene (6.60 g,
10 equiv), a solution of NaClO2 (2.13 g, 2.0 equiv) in H3PO4–aq
NaHCO3 buffer (15 mL, 1.25 M, pH 3.5) was added dropwise. The
reaction mixture was allowed to warm to r.t. and stirred until com-
pletion of the reaction (TLC). Acetone was evaporated and the res-
idue was treated with brine (40 mL). After extraction with EtOAc
(3 × 50 mL), the combined organic phases were evaporated and the
crude product was purified by flash chromatography (Et2O) yield-
ing the carboxylic acid in 3.38 g (81%) as a pale-brown solid. Most
of the carboxylic acid (3.24 g) was redissolved in MeOH (70 mL)
at 0 °C to obtain a 0.1 M solution. After the dropwise addition of
SOCl2 (3.47 g, 4.0 equiv), the solution was refluxed at 75 °C until
completion of the reaction (4 h). MeOH was evaporated, the residue
was treated with H2O (30 mL) and the product was extracted with
EtOAc (3 × 30 mL). The crude product was purified by flash chro-
matography yielding 2.94 g (88%) of yellow crystals; mp 137 °C;
All reactions were carried out under argon in flame-dried glassware.
Unless otherwise noted, all commercially available compounds
were used without further purification. Toluene was freshly distilled
under argon from Solvona® (Na on Celite). MeOH was freshly dis-
tilled under argon over Mg and I2. The catalyst was prepared ac-
cording to the previously described procedure.10 For the protocol to
prepare 5-bromopentanal (4), see ref.11 For preparative column
chromatography SIL G-25 UV254 from Macherey-Nagel, particle
size 0.040–0.063 mm (230–240 mesh, flash) was used. Visualisa-
tion of the developed TLC plates was performed with ultraviolet ir-
radiation (254 nm) or by staining with a KMnO4 solution. Optical
rotation values were measured on a Perkin-Elmer 241 polarimeter.
Microanalyses were performed with a Vario EL element analyser.
Synthesis 2010, No. 13, 2271–2277 © Thieme Stuttgart · New York

2274
D. Enders et al.
PAPER
ee >99%; dr >97:3; Rf = 0.58 (pentane–Et2O, 1:1); [a]D23 –20.1 (c 1,
IR (CHCl3): 2934, 2861, 1723, 1690, 1355, 1134, 958, 627 cm–1.
CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.66 (m, 4 H), 2.33 (s, 3 H), 2.47
(ddd, J = 7.2, 7.2, 1.5 Hz, 2 H), 2.88 (dd, J = 6.9, 6.9 Hz, 2 H), 9.77
(dd, J = 1.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.0, 28.6, 29.0, 30.6, 43.3, 195.7,
201.9.
IR (CHCl3): 2950, 1717, 1550, 1448, 1368, 1272, 758, 702 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.54 (m, 1 H), 1.73 (m, 1 H), 1.91
(m, 1 H), 2.97 (m, 1 H), 2.94 (dd, J = 10.4, 3.5 Hz, 1 H), 3.28 (m, 1
H), 3.35 (m, 2 H), 3.65 (s, 3 H), 4.52 (s, 1 H), 4.88 (dd, J = 3.5, 2.0
Hz, 1 H), 6.99 (m, 2 H), 7.23–7.42 (m, 8 H), 7.46 (d, J = 1.9 Hz, 1
H).
13C NMR (100 MHz, CDCl3): d = 29.6, 31.2, 32.9, 35.8, 42.5, 44.8,
52.0, 92.6, 127.4, 127.6, 127.7, 127.9, 128.9, 129.0, 137.0, 139.4,
143.2, 165.8.
Anal. Calcd for C7H12OS: C, 52.47; H, 7.55. Found: C, 52.20; H,
7.56.
Carbaldehyde 13a
The synthesis of 13a following GP 1 yielded 0.44 g (51%) of a co-
lourless solid; mp 163 °C; ee >99%; Rf = 0.40 (pentane–Et2O, 1:1);
[a]D23 –9.9 (c 1, CHCl3).
MS (EI): m/z = 457.1 (M+).
HRMS: m/z calcd for C23H24BrNO4: 457.0889; found: 457.0885.
IR (CHCl3): 1681, 1654, 1451, 1359, 1163, 1139, 1110, 953, 774,
754, 700 cm–1.
Methyl Ester 10
To a solution of 9 (0.50 g, 1.1 mmol) in DMF (6 mL) was added
KSAc (0.37 g, 3.3 mmol) in portions. After stirring for 2 h at r.t.,
brine (10 mL) was added, followed by H2O (300 mL). The product
was extracted with EtOAc (3 × 40 mL). Evaporation of the solvent
yielded a mixture of 2 diastereomers (dr = 8.5:1). Purification by
flash chromatography (pentane–Et2O, 2:1) yielded 0.39 g (78%) of
the major diastereomer as colourless crystals; mp 117 °C; Rf = 0.30
(pentane–Et2O, 2:1).
1H NMR (400 MHz, CDCl3): d = 1.50 (m, 1 H), 1.70 (m, 2 H), 1.82
(m, 1 H), 2.31 (s, 3 H), 2.82 (m, 2 H), 3.00 (dd, J = 10.6, 3.4 Hz, 1
H), 3.37 (m, 1 H), 4.46 (s, 1 H), 4.87 (dd, J = 3.4, 1.8 Hz, 1 H), 6.98
(m, 2 H), 7.19 (m, 2 H), 7.41–7.26 (m, 7 H), 9.60 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 26.6, 28.7, 30.6, 31.3, 36.7, 42.9,
43.2, 92.3, 127.6, 127.7, 127.8, 128.0, 129.0, 136.8, 137.5, 138.4,
153.3, 191.6, 195.3.
MS (EI): m/z = 423.4 (M+).
IR (CHCl3): 3027, 2919, 2852, 1717, 1691, 1549, 1452, 1437, 1366,
1272, 1232, 1133, 1110, 756, 702, 626 cm–1.
Anal. Calcd for C24H25NO4S: C, 68.06; H, 5.95; N, 3.31. Found: C,
68.15; H, 5.97; N, 3.29.
1H NMR (400 MHz, CDCl3): d = 1.45 (m, 1 H), 1.65 (m, 2 H), 1.80
(m, 1 H), 2.29 (s, 3 H), 2.82 (m, 2 H), 2.93 (dd, J = 10.3, 3.4 Hz, 1
H), 3.33 (m, 1 H), 3.64 (s, 3 H), 4.51 (s, 1 H), 4.87 (dd, J = 3.4, 2.2
Hz, 1 H), 6.98 (m, 2 H), 7.22–7.41 (m, 8 H), 7.45 (d, J = 2.2 Hz, 1
H).
13C NMR (100 MHz, CDCl3): d = 26.5, 28.8, 30.6, 31.6, 36.1, 42.5,
44.8, 51.9, 92.6, 127.2, 127.6, 127.7, 127.8, 128.8, 129.0, 137.1,
139.5, 143.4, 165.8, 195.3.
Carbaldehyde 13b
The synthesis of 13b following GP 1 yielded 0.935 g (45%) of a yel-
low solid; mp 132 °C; ee >99%; Rf = 0.45 (pentane–Et2O, 1:1);
[a]D23 –13.6 (c 1, CHCl3).
IR (CHCl3): 2947, 1677, 1544, 1362, 1136, 706 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.48 (ddt, J = 4.2, 6.7, 9.6 Hz, 1
H) 1.68 (m, 2 H), 1.81 (m, 1 H), 2.32 (m, 3 H), 2.83 (m, 2 H), 2.98
(dd, J = 3.4, 10.5 Hz, 1 H), 3.32 (m, 1 H), 4.46 (m, 1 H), 4.82 (dd,
J = 1.8 Hz, 3.4 Hz, 1 H), 7.19 (m, 10 H), 9.59 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 26.63, 28.77, 30.67, 31.34, 36.77,
42.83, 42.90, 92.11, 127.76–129.16, 133.99, 135.41, 137.55,
138.29, 152.85, 191.48, 195.37.
MS (EI): m/z = 453.1 (M+).
Anal. Calcd for C25H27NO5S: C, 66.20; H, 6.00; N, 3.09. Found: C,
65.87; H, 6.06; N, 3.02.
Thiadecaline Methyl Ester 11
The synthesis of 11 following GP 2 yielded 0.12 g (62%) of colour-
less crystals; mp 244 °C; Rf = 0.16 (pentane–Et2O, 3:1).
MS (CI): m/z = 458.2.
Anal. Calcd for C24H24ClNO4S: C, 62.94; H, 5.28; N, 3.06. Found:
C, 63.04; H, 5.25; N, 3.06.
IR (CHCl3): 1726, 1548, 1453, 1436, 1366, 1279, 1237, 1197, 1171,
909, 831, 760, 733, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.82 (m, 1 H), 1.93 (m, 2 H), 2.2
(m, 1 H), 2.36 (m, 1 H), 2.61 (m, 1 H), 2.79 (m, 1 H), 3.33 (dd,
J = 12.1, 11.9 Hz, 1 H), 3.46 (s, 3 H), 3.59 (dd, J = 6.4, 1.5 Hz, 1 H),
3.69 (dd, J = 11.9, 4.3 Hz, 1 H), 4.13 (dd, J = 12.3, 12.1 Hz, 1 H),
5.33 (dd, J = 12.3, 6.3 Hz, 1 H), 7.20–7.46 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 23.6, 28.0, 28.3, 37.7, 43.1, 45.7,
50.4, 51.9, 53.0, 87.3, 127.5, 128.0, 128.1, 128.9, 129.0, 138.0,
138.3, 172.7.
Carbaldehyde 13c
The synthesis of 13c following GP 1 yielded 4.28 g (43%) of the
major diastereomer as a yellow solid; ee >99%; Rf = 0.27 (pentane–
Et2O, 1:1); [a]D23 –4.5 (c 1, CHCl3).
IR (CHCl3): 1684, 1546, 1512, 1452, 1362, 1305, 1250, 1181, 1132,
1109, 1031, 954, 837, 759, 702 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.50 (m, 1 H), 1.69 (m, 2 H), 1.82
(m, 1 H), 2.32 (s, 3 H), 2.83 (m, 2 H), 2.95 (dd, J = 10.4, 3.5 Hz, 1
H), 3.30 (m, 1 H), 3.77 (s, 3 H), 4.44 (s, 1 H), 4.84 (dd, J = 3.5, 1.8
Hz, 1 H), 6.80 (m, 2 H), 6.90 (m, 2 H), 7.18 (m, 2 H), 7.40–7.27 (m,
4 H), 9.59 (s, 1 H).
MS (CI): m/z = 440.1 (M + C2H5 ), 412.1 (M + H+).
+
Anal. Calcd for C23H25NO4S: C, 67.13; H, 6.12; N, 3.40. Found: C,
66.89; H, 6.12; N, 3.27.
13C NMR (100 MHz, CDCl3): d = 26.6, 28.8, 30.6, 31.4, 37.0, 42.5,
42.8, 55.1, 92.4, 114.3, 127.6, 127.7, 128.8, 129.0, 137.5, 138.5,
153.4, 159.1, 191.6, 195.3.
S-(5-Oxopentyl) Ethanthioate 12 (n = 1)
Compound 4 (2.7 g, 16 mmol) was dissolved in DMF (30 mL) at
0 °C. After the addition of KSAc (4.5 g, 39 mmol), the solution was
stirred for 30 min. H2O (500 mL) was added and the mixture was
extracted with Et2O (3 × 50 mL). The solvent was evaporated and
the crude 12 (n = 1) was purified by flash chromatography (pen-
tane–Et2O, 3:1) to give 1.76 g (67%) of a colourless oil; Rf = 0.32
(pentane–Et2O, 2:1).
MS (EI): m/z = 453.3 (M+).
Anal. Calcd for C25H27NO5S: C, 66.20; H, 6.00; N, 3.09. Found: C,
66.01; H, 5.96; N, 3.07.
Synthesis 2010, No. 13, 2271–2277 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Thiadecalins
2275
Carbaldehyde 13d
13C NMR (100 MHz, CDCl3): d = 24.6, 26.8, 28.2, 36.1, 42.2, 42.8,
51.4, 53.4, 87.8, 127.8, 127.9, 128.0, 128.7, 128.8, 128.9, 137.7,
200.5.
The synthesis of 13d following GP 1 yielded 2.49 g (60%) of a pale-
red oil; ee >99%; Rf = 0.35 (pentane–Et2O, 2:1); [a]D23 24.1 (c 1,
CHCl3).
MS (EI): m/z = 382.2 (M+).
IR (film): 3360, 2920, 1689, 1551, 1451, 1362, 1218, 1135, 757,
625 cm–1.
Anal. Calcd for C22H23NO3S: C, 69.26; H, 6.08; N, 3.67. Found: C,
69.50; H, 5.98; N, 3.66.
1H NMR (400 MHz, CDCl3): d = 1.59 (m, 1 H) 1.72 (m, 1 H), 1.85
(m, 2 H), 2.19 (m, 3 H), 2.34 (m, 3 H), 2.90 (m, 2 H), 3.09 (dd,
J = 3.5, 10.1 Hz, 1 H), 3.20 (m, 1 H), 4.49 (s, 1 H), 5.01 (dd, J = 2.2,
3.4 Hz, 1 H), 5.86 (dd, J = 1.0, 3.1 Hz, 1 H), 5.98 (m, 1 H), 7.28 (m,
5 H), 9.55 (s, 1 H).
Thiadecaline 14b
The synthesis of 14b following GP 2 yielded 0.04 g (40%) of co-
lourless crystals, mp 126 °C; ee >99%; Rf = 0,40 (pentane–Et2O
1:1); [a]D23 –55.0 (c 1, CHCl3).
13C NMR (100 MHz, CDCl3): d = 13.6, 26.9, 28.9, 30.8, 32.0, 36.9,
37.6, 42.5, 89.8, 106.4, 108.4, 127.9, 128.0, 129.2, 137.5, 138.2,
148.2, 152.0, 152.7, 191.6, 195.5.
IR (CHCl3): 2926, 1720, 1546, 1369, 912, 835, 728, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.88 (m, 3 H), 2.17 (m, 1 H), 2.52
(m, 2 H), 2.82 (ddd, J = 3.0, 10.3, 13.5 Hz, 1 H), 3.39 (ddd, J = 2.4,
11.3, 10.3 Hz, 1 H), 3.58 (dd, J = 4.0, 10.3 Hz, 1 H), 3.70 (dd,
J = 3.6, 7.0 Hz, 1 H), 4.11 (dd, J = 12.2, 11.3 Hz, 1 H), 5.41 (dd,
J = 7.0, 12.2 Hz, 1 H), 7.29 (m, 9 H), 9.68 (d, J = 2.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.8, 26.5, 28.2, 36.2, 41.9, 42.6,
50.4, 53.5, 87.8, 128.0–130.2, 134.2, 136.3, 137.8, 200.8.
MS (CI): m/z = 428 (M + H+).
HRMS (EI): m/z calcd for C23H25NO5S: 427.1453. Found:
427.1436.
Carbaldehyde 13e
The synthesis of 13e following GP 1 yielded 2.40 g (57%) of the
major diastereomer as a yellow solid; mp 42 °C; ee >99%; Rf = 0.29
(pentane–Et2O, 2:1); [a]D23 –5.0 (c 1, CHCl3).
HRMS (EI): m/z calcd for C22H22ClNO3S: 369.1080 (M+ – NO2);
found: 369.1065 (M+ – NO2).
IR (CHCl3): 1684, 1546, 1365, 1131, 767, 699 cm–1.
Thiadecaline 14c
The synthesis of 14c following GP 2 yielded 0.51 g (52%) of the
major diastereomer as colourless needles; mp 156 °C; ee >99%;
Rf = 0.29 (pentane–Et2O, 1:1); [a]D23 –130.7 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.74 (m, 1 H), 1.87 (m, 1 H), 2.33
(s, 3 H), 3.01 (m, 3 H), 3.47 (m, 1 H), 4.48 (s, 1 H), 4.87 (dd, J = 1.7,
3.3 Hz, 1 H), 7.21 (m, 11 H), 9.63 (s, 1 H).
IR (CHCl3): 2917, 1717, 1609, 1548, 1511, 1455, 1368, 1250, 1180,
1109, 1032, 835, 812, 762, 700 cm–1.
13C NMR (100 MHz, CDCl3): d = 26.0, 30.6, 32.4, 36.3, 43.2, 43.0,
92.4, 127.8–129.2, 136.7, 137.7, 138.5, 152.8, 191.8, 195.2.
1H NMR (300 MHz, CDCl3): d = 1.81 (m, 1 H), 1.89 (m, 2 H), 2.17
(m, 1 H), 2.48 (m, 1 H), 2.52 (m, 1 H), 2.81 (ddd, J = 13.7, 11.3, 3.0
Hz, 1 H), 3.4 (ddd, J = 12.0, 11.0, 2.6 Hz, 1 H), 3.62 (m, 1 H), 3.64
(m, 1 H), 3.79 (s, 3 H), 4.13 (dd, J = 12.2, 12.0 Hz, 1 H), 5.38 (dd,
J = 12.2, 6.9 Hz, 1 H), 6.87 (m, 2 H), 7.32–7.20 (m, 7 H), 9.66 (d,
J = 2.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.6, 26.8, 28.1, 36.2, 42.3, 42.7,
50.7, 53.4, 55.1, 87.9, 114.1, 127.9, 128.9, 129.7, 129.8, 137.8,
159.0, 200.6.
Anal. Calcd for C23H23NO4S: C, 67.46; H, 5.66; N, 3.42. Found: C,
67.31; H, 5.87; N, 3.24.
Carbaldehyde 13f
The synthesis of 13f following GP 1 yielded 1.45 g (32%) of the ma-
jor diastereomer as a colourless oil; ee >99%; Rf = 0.27 (pentane–
Et2O, 2:1); [a]D23 –156.0 (c 1, CHCl3).
IR (CHCl3): 3025, 2921, 2852, 1682, 1548, 1371, 1134, 757, 627
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.57 (m, 2 H), 1.73 (m, 2 H), 2.32
(m, 3 H), 2.82 (m, 4 H), 3.12 (m, 1 H), 3.32 (dd, J = 4.0, 6.3 Hz, 1
H), 4.89 (dt, J = 4.0, 5.8 Hz, 1 H), 6.99 (td, J = 1.6, 3.2 Hz, 1 H),
7.06 (m, 2 H), 7.32 (m, 3 H), 9.59 (s, 1 H).
MS (EI): m/z = 411.2 (M+).
HRMS (EI): m/z calcd for C23H25NO4S: 411.1499, found: 411.1506.
Thiadecaline 14d
The synthesis of 14d following GP 2 yielded 0.045 g (50%) of a co-
lourless solid; mp 140 °C; ee >99%; Rf = 0.31 (pentane–Et2O, 2:1);
[a]D23 –153.0 (c 1, CHCl3).
IR (CHCl3): 2931, 1719, 1548, 1367, 1031, 791, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.88 (m, 3 H), 2.22 (m, 1 H), 2.33
(s, 3 H), 2.40 (m, 1 H), 2.66 (m, 1 H), 2.81 (m, 1 H), 3.37 (dt,
J = 3.5, 12.0 Hz, 1 H), 3.58 (m, 1 H), 3.80 (dd, J = 4.2, 12.2 Hz, 1
H), 4.04 (t, J = 12.0 Hz, 1 H), 5.21 (dd, J = 5.6, 12.3 Hz, 1 H), 5.90
(m, 1 H), 6.07 (d, J = 3.1 Hz, 1 H), 7.25 (m, 5 H), 9.56 (d, J = 3.5
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.8, 23.3, 27.3, 27.4, 35.9, 42.1,
43.7, 46.3, 52.9, 87.2, 106.3, 110.2, 128.0, 128.3, 129.0, 137.3,
149.2, 152.8, 200.4.
13C NMR (100 MHz, CDCl3): d = 24.1, 26.9, 28.9, 30.6, 32.6, 39.1,
47.2, 83.4, 127.5, 128.1, 128.9, 136.6, 137.0, 151.5, 192.0, 195.4.
MS (EI): m/z = 347 (M+).
HRMS (EI): m/z calcd for C18H21NO4S: 347.1191; found:
347.1187.
Thiadecaline 14a
The synthesis of 14a following GP 2 yielded 0.05 g (57%) of co-
lourless needles; mp 251 °C; ee >99%; Rf = 0.42 (pentane–Et2O,
1:1); [a]D23 –151.1 (c 1, CHCl3).
IR (CHCl3): 2930, 1720, 1544, 1496, 1452, 1367, 1333, 913, 828,
758, 736, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.82 (m, 1 H), 1.92 (m, 2 H), 2.19
(m, 1 H), 2.48 (m, 1 H), 2.56 (m, 1 H), 2.83 (m, 1 H), 3.42 (ddd,
J = 11.5, 10.8, 2.5 Hz, 1 H), 3.64 (dd, J = 10.8, 3.9 Hz, 1 H), 3.70
(dd, J = 6.9, 3.0 Hz, 1 H), 4.18 (dd, J = 12.1, 11.5 Hz, 1 H), 5.41
(dd, J = 12.1, 6.9 Hz, 1 H), 7.40–7.21 (m, 10 H), 9.68 (d, J = 2.5 Hz,
1 H).
MS (CI): m/z = 386 (M + H+).
+
HRMS (EI): m/z calcd for C21H23NO4S: 339.1419 (M – NO2 );
+
found: 339.1417 (M – NO2 ).
Synthesis 2010, No. 13, 2271–2277 © Thieme Stuttgart · New York

2276
D. Enders et al.
PAPER
Hexahydrobenzothiophene Derivative 14e
Chem. Soc. Rev. 2009, 38, 2178. (q) Enders, D.; Wang, C.;
Liebich, J. X. Chem. Eur. J. 2009, 15, 11058. (r) Merino,
P.; Marqués-Lopez, E.; Tejero, T.; Herrera, R. P. Synthesis
2010, 1.
The synthesis of 14e following GP 2 yielded 0.055 g (57%) of the
major diastereomer as a yellow solid; mp 166 °C; ee >99%; Rf = 0.3
(pentane–Et2O, 1:1); [a]D23 –139.0 (c 1, CHCl3).
(2) (a) Klimenko, S. K.; Stolbova, T. V.; Kulikova, L. K.; Shub,
G. M. Pharm. Chem. J. 2001, 35, 661. (b) Klimenko, S. K.;
Stolbova, T. V.; Kulikova, L. K.; Shub, G. M. Pharm. Chem.
J. 2001, 35, 370. (c) Klimenko, S. K.; Stolbova, T. V.;
Kulikova, L. K. Pharm. Chem. J. 2001, 35, 22.
(3) Klimenko, S. K.; Stolbova, T. V.; Makarov, V. V. Pharm.
Chem. J. 2002, 36, 583.
(4) Scheidges, C.; Ottow, E.; Neef, G.; Beier, S.; Elger, W.
German Patent DE 3820948 A1 19891221, 1989; Chem.
Abstr. 1989, 112, 198891.
IR (CHCl3): 1722, 1542, 1372, 767, 746, 703 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.46 (s, 1 H, J = 1.9 Hz), 7.29 (m,
10 H), 5.25 (dd, J = 6.0, 9.3 Hz, 1 H), 4.13 (dd, J = 7.4, 11.2 Hz, 1
H), 3.74 (dd, J = 9.3, 12.3 Hz, 1 H), 3.69 (t, J = 6.3, 6.0 Hz, 1 H),
3.22 (ddd, J = 1.9, 11.2, 12.3 Hz, 1 H), 3.09 (m, 1 H), 2.94 (ddd,
J = 3.6, 7.1, 10.7 Hz, 1 H), 2.86 (m, 1 H), 2.37 (dtd, J = 3.7, 6.1, 9.7
Hz, 1 H), 2.10 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 29.9, 35.8, 43.9, 44.6, 45.0, 46.6,
57.9, 92.2, 127.6, 128.2, 128.3, 129.0, 129.3, 137.2, 137.4, 201.1.
(5) (a) Oberlander, C.; Piazza, P. V. PCT Int. Appl. WO
9826783 A1 19980625, 1998; Chem. Abstr. 1998, 129,
50105. (b) Petit, F.; Philibert, D.; Ulmann, A. Eur. Pat. Appl.
EP 676203 A1 19951011, 1995; Chem. Abstr. 1995, 124,
22540.
(6) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Tietze, L. F.;
Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. (c) Pellissier, H.
Tetrahedron 2006, 62, 1619. (d) Pellissier, H. Tetrahedron
2006, 62, 2143. (e) Nicolaou, K. C.; Edmonds, D. J.; Bulger,
P. G. Angew. Chem. Int. Ed. 2006, 45, 7134; Angew. Chem.
2006, 118, 7292. (f) Chapman, C. J.; Frost, C. G. Synthesis
2007, 1. (g) Davies, H.; Sorensen, E. Chem. Soc. Rev. 2009,
38, 2969.
MS (EI): m/z = 367 (M+).
+
HRMS (EI): m/z calcd for C21H21NO3S: 321.1313 (M – NO2 ),
found: 321.1297(M – NO2 ).
+
Thiadecaline 14f
The synthesis of 14f following GP 2 yielded 0.032 g (40%) of the
major diastereomer as a colourless oil; ee >99%; Rf = 0.31 (pen-
tane–Et2O, 1:1); [a]D23 –178.0 (c 1, CHCl3).
IR (film): 2935, 2854, 1724, 1684, 1547, 1448, 1375, 910, 763, 731,
700 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.43 (m, 2 H), 1.59 (m, 2 H), 2.23
(m, 1 H), 2.52 (m, 2 H), 2.73 (m, 2 H), 2.87 (m, 1 H), 3.84 (m, 1 H),
4.20 (dd, J = 11.5, 11.5 Hz, 1 H), 4.74 (dt, J = 4.7, 11.5 Hz, 1 H),
7.30 (m, 5 H), 9.70 (s, 1 H).
(7) (a) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem.
Int. Ed. 2007, 46, 1570; Angew. Chem. 2007, 119, 1590.
(b) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037.
(c) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew.
Chem. Int. Ed. 2004, 43, 1272; Angew. Chem. 2004, 116,
1292. (d) Yang, J. W.; Fonseca, M. T. H.; List, B. J. Am.
Chem. Soc. 2005, 127, 15036. (e) Huang, Y.; Walji, A. M.;
Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 15051. (f) Marigo, M.; Schulte, T.; Franzén, J.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710.
(g) Enders, D.; Hüttl, M. R. M.; Runsink, J.; Raabe, G.;
Wendt, B. Angew. Chem. Int. Ed. 2007, 46, 467; Angew.
Chem. 2007, 119, 471. (h) Enders, D.; Narine, A. A.;
Benninghaus, T. R.; Raabe, G. Synlett 2007, 1667.
(i) Carlone, A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2007, 46, 1101; Angew. Chem. 2007,
119, 1119. (j) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard,
D. Angew. Chem. Int. Ed. 2007, 46, 4922; Angew. Chem.
2007, 119, 5010. (k) Zhao, G.-L.; Rios, R.; Vesley, J.;
Eriksson, L.; Córdova, A. Angew. Chem. Int. Ed. 2008, 47,
8468; Angew. Chem. 2008, 120, 5896. (l) Enders, D.; Hüttl,
M. R. M.; Raabe, G.; Bats, J. W. Adv. Synth. Catal. 2008,
350, 267. (m) Enders, D.; Wang, C.; Bats, J. W. Angew.
Chem. Int. Ed. 2008, 47, 7539; Angew. Chem. 2008, 120,
7649. (n) Kotame, P.; Hong, B.-C.; Liao, J.-H. Tetrahedron
Lett. 2009, 50, 704. (o) Zhang, F.-L.; Xu, A.-W.; Gong, Y.-
F.; Wei, M.-H.; Yang, X.-L. Chem. Eur. J. 2009, 15, 6815.
(p) Enders, D.; Krüll, R.; Bettray, W. Synthesis 2010, 567.
(q) Rueping, M.; Kuenkel, A.; Tato, F.; Bats, J. W. Angew.
Chem. Int. Ed. 2009, 48, 3699; Angew. Chem. 2009, 121,
3754. (r) Reyes, E.; Talavera, G.; Vicario, J. L.; Badia, D.;
Carrillo, L. Angew. Chem. Int. Ed. 2009, 48, 5701; Angew.
Chem. 2009, 121, 5811. (s) Zhu, D.; Lu, M.; Dai, L.; Zhong,
G. Angew. Chem. Int. Ed. 2009, 48, 6089; Angew. Chem.
2009, 121, 6205. (t) Wu, L.-Y.; Bencivenni, G.; Mancinelli,
M.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem.
Int. Ed. 2009, 48, 7196; Angew. Chem. 2009, 121, 7332.
(u) Alba, A.-N.; Companyo, X.; Viciano, M.; Rios, R. Curr.
Org. Chem. 2009, 13, 1432. (v) Enders, D.; Wang, C.; Bats,
13C NMR (100 MHz, CDCl3): d = 20.5, 25.9, 28.2, 29.5, 39.6, 42.2,
43.9, 51.6, 91.0, 127.7, 128.9, 137.0, 198.5.
HRMS (EI): m/z calcd for C16H19NO3S: 305.1086; found:
305.1087.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(priority program Organocatalysis) and the Fonds der Chemischen
Industrie (Kekulé stipend to N.E.). We thank the former Degussa
AG and BASF AG for the donation of chemicals. The collection of
the X-ray data of 14e by Dr. Dix, Bruker AXS GmbH, Karlsruhe is
gratefully acknowledged.
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