Desymmetrization and switching of stereoselectivity in direct organocatalytic Michael addition of ketones to 1,1-bis(phenylsulfonyl)ethylene

Article abstract of DOI:10.1002/ejoc.201201635

The organocatalytic desymmetrization was demonstrated for 4-substituted cyclohexanones by treatment with a vinyl sulfone in the presence of an organocatalyst. The desired Michael adducts were typically obtained in high chemical yields and high to excellent stereoselectivities (up to 97 % yield, 93 % ee). An efficient desymmetrization method was developed for the synthesis of enantiomeric products by using either camphor-derived pyrrolidine V or cinchonidine-derived primary amine VII as a catalyst. The absolute stereochemistry of the (2R,4R)-2-[2,2-bis(phenylsulfonyl)ethyl]-4- methylcyclohexanone (3a) and (2R,4R)-2-[2,2-bis(phenylsulfonyl)ethyl]-4-tert- butylcyclohexanone (3b) was confirmed by single-crystal X-ray structure analyses. The direct organocatalytic desymmetrization was demonstrated for 4-substituted cyclohexanones by treatment with a vinyl sulfone in CHCl ₃. The desired Michael adducts were obtained in high chemical yields and stereoselectivities (up to 97 % yield, 93 % ee). Enantiomeric products were obtained by using either a camphor-derived pyrrolidine or a cinchonidine-derived primary amine as a catalyst. Copyright

Full text of DOI:10.1002/ejoc.201201635

FULL PAPER
DOI: 10.1002/ejoc.201201635
Desymmetrization and Switching of Stereoselectivity in Direct Organocatalytic
Michael Addition of Ketones to 1,1-Bis(phenylsulfonyl)ethylene
Yan ming Chen,[a] Pei-Hsun Lee,[a] Jun Lin,[a] and Kwunmin Chen*[a]
Keywords: Synthetic methods / Michael addition / Organocatalysis / Asymmetric catalysis / Enantioselectivity
The organocatalytic desymmetrization was demonstrated for
4-substituted cyclohexanones by treatment with a vinyl sulf-
one in the presence of an organocatalyst. The desired
Michael adducts were typically obtained in high chemical
yields and high to excellent stereoselectivities (up to 97%
yield, 93%ee). An efficient desymmetrization method was
developed for the synthesis of enantiomeric products by
using either camphor-derived pyrrolidine V or cinchonidine-
derived primary amine VII as a catalyst. The absolute stereo-
chemistry of the (2R,4R)-2-[2,2-bis(phenylsulfonyl)ethyl]-4-
methylcyclohexanone (3a) and (2R,4R)-2-[2,2-bis(phenylsulf-
onyl)ethyl]-4-tert-butylcyclohexanone (3b) was confirmed by
single-crystal X-ray structure analyses.
previously studied by Alexakis.[4] Considerable efforts have
been directed to the development of the enantioselective ca-
Introduction
Recently, the use of small organic molecules to catalyze or- talysis of vinyl sulfones.[5] In recent years, desymmetrization
ganic reactions has been recognized as a powerful protocol has attracted much attention for the synthesis of chiral non-
for asymmetric synthesis, complemented by the use of en- racemic molecules.[6] The desymmetrization process results
zymes and transition-metal complexes.[1] In the emerging in the loss of one or more symmetry elements and converts
field of organocatalysis, the conjugate addition of carbon prochiral/meso molecules into optically active products. The
nucleophiles to electron-deficient Michael acceptors has be- use of catalytic desymmetrization represents a convenient
come one of the most efficient and reliable carbon–carbon protocol for the preparation of synthetically useful interme-
bond-forming reactions.[2] The sulfonyl group is a valuable diates. Transition-metal-mediated[7] and metal-free[8] enan-
functionality that can be used in organic reactions for nu- tioselective desymmetrizations have been documented. Ad-
merous chemical transformations.[3] The use of vinyl sulf- ditionally, the development of organocatalytic protocols for
ones as Michael acceptors in the presence of organocata- the asymmetric synthesis of both enantiomeric products is
lysts to form enantiomerically enriched products has been synthetically practical and worth pursuing.[9]
Figure 1. Chemical structures of various organocatalysts.
In our continued effort to develop new organocatalysts,
[a] Chemistry Department, National Taiwan Normal University,
we envision that the well-defined, rigid, bicyclic camphor
88 Sec. 4, Ting-Chow Rd., 116 Taipei, Taiwan
scaffold can serve as an efficient element of stereocon-
trol.[10] The assembly of a pyrrolidine and camphor frame-
work with an appropriate linker can yield a new class of
bifunctional organocatalysts (see Figure 1).
Fax: +886-2-29324249
E-mail: kchen@ntnu.edu.tw
Homepage: http://www.chem.ntnu.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201635.
Eur. J. Org. Chem. 2013, 2699–2707
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y. Chen, P.-H. Lee, J. Lin, K. Chen
FULL PAPER
In addition to the linker moiety, the pyrrolidine C-4 and NMR spectroscopy and then further verified by single-crys-
the C-2 atom in the camphor moiety can be functionalized tal X-ray structure analysis.[11,12]
to enhance hydrogen-bonding interactions in the transition
After the success of synthesizing organocatalyst V, its ef-
state. The installation of a thiourea moiety at the C-4 posi- ficacy in the Michael addition reaction was examined (see
tion of the pyrrolidine would provide an interesting influ- Table 1). 1,1-Bis(phenylsulfonyl)ethylene (2) and 4-methyl-
ence on an organocatalytic reaction. In this context, we re-
port the synthesis of a camphor-derived pyrrolidine that
contains a thiourea group at the C-4 position (i.e., V). The
Table 1. Optimization of the Michael reaction of 4-methylcyclohex-
anone (1a) with 1,1-bis(phenylsulfonyl)ethylene (2).[a]
direct desymmetrization of 4-substituted cyclohexanone
through an asymmetric Michael addition to 1,1-bis(phenyl-
sulfonyl)ethylene was examined. Both enantiomeric
Michael products were obtained with high stereoselectivi-
ties in reactions that were catalyzed by V or the cinchon-
idine-derived catalyst VII, respectively.
Entry
Catalyst
Solvent
t
%
dr[c]
%
[d] Yield[b]
ee[c]
Results and Discussion
1
2
3
4
5
6
7
8
V
V
hexane
toluene
CHCl3
CH2Cl2
EA
2
2
2
2
2
2
2
2
3
3
3
3
2
N.R.
54
75
41
28
32
20
40
17
–
–
89
88
90
90
87
80
17
54
53[d]
–
3:1
3:1
4:1
5:1
4:1
6:1
7:1
7:1
1:1
–
The design and synthesis of readily accessible, highly
stereoselective, and tunable asymmetric catalysts are always
desirable. We expect that organocatalyst V could be pre-
pared from the known l-proline-derived N-Boc-protected
tosylate 4 and (1S)-1-(mercaptomethyl)-7,7-dimethylbicy-
clo[2.2.1]heptan-2-one (5) as illustrated in Scheme 1.
Ketone sulfide 6 was obtained in 88% yield by treating the
N-Boc-protected tosyl prolinol 4 with 5 in the presence of
NaH as a base. The amino ketone sulfide 7 was obtained
through a three-step procedure with a favorable overall
chemical yield. By using a standard procedure, the thiourea
functionality was incorporated followed by a subsequent
deprotection to give V. The structure of organocatalyst V
V
V
V
V
ether
V
MeCN
MeOH
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
V
9
I
10
11
12
13
II
III
IV
VI
40
Ͻ10
35
5:1
2:1
77
40
50
[a] All reactions were carried out with 4-methylcyclohexanone (1a,
2.0 equiv.) and 1,1-bis(phenylsulfonyl)ethylene (2, 1.0 equiv.) with
the organocatalyst (20 mol-%) at ambient temperature. [b] Isolated
yield. [c] Determined by chiral AS-H HPLC analysis. [d] The major
was fully characterized by IR, HRMS, and 1H and 13C diastereomer.
Scheme 1. Synthesis of camphor-derived pyrrolidine containing the thiourea functionality (i.e., organocatalyst V).
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Eur. J. Org. Chem. 2013, 2699–2707

Organocatalytic Michael Addition
cyclohexanone (1a) were used as model substrates in the Table 3. Screening various cyclohexanones for Michael addition
with vinyl sulfone 2 catalyzed by V.[a]
Michael reaction that was catalyzed by V (20 mol-%) at am-
bient temperature. Screening the solvents revealed that
chloroform was the best option for the reaction. No reac-
tion (N.R.) occurred when nonpolar hexane was used (see
Table 1, Entry 1). The reactivity was slightly higher when
toluene was used (see Table 1, Entry 2). To our delight, the
desired product 3a was obtained with high enantio-
selectivity (90%ee) in halogenated solvents (see Table 1, En-
tries 3 and 4). The reactivities were lower when polar sol-
vents such as ethyl acetate (EA), ether, and MeCN were
used (see Table 1, Entries 5–7). Both the chemical yield and
the enantioselectivity were reduced when the reaction was
performed in methanol (see Table 1, Entry 8). The disrup-
tion of the hydrogen-bonding interactions might account
for this result. Next, the organocatalysts were screened. In
CH2Cl2, catalysts I, II, and IV yielded the desired product
with modest enantioselectivity and chemical yield (see
Table 1, Entries 9, 10, and 12), but sulfonamide catalyst III
yielded only a trace amount of the Michael adduct (see
Table 1, Entry 11). A drop in stereoselectivity was observed
when catalyst VI, with the C-4 amino group, was utilized
(see Table 1, Entry 13), which indicates the importance of
the thiourea functionality in the asymmetric Michael reac-
tion. Two diastereomeric products were obtained, but they
were inseparable by flash column chromatography. The dia-
stereomeric ratios and enantioselectivity of the stereoiso-
1
mers were determined by H NMR and HPLC analyses.
Various acidic and basic additives were then investigated
to improve the reaction further. Comparable results with
improved reactivities were obtained when the reaction was
carried out in the presence of PhCO2H, acetic acid, and
para-toluenesulfonic acid (p-TsOH, see Table 2, Entries 2–
4). The reactivity decreased when trifluoroacetic acid (TFA)
Table 2. Screening of additives in the asymmetric Michael addition
reaction.[a]
Entry Additive
t
[d]
%
dr[c]
%
Yield[b]
ee[c,d]
1
2
3
4
5
6
–
2
1
1
1
1
1
1
1
75
95
87
82
17
trace
62
89
3:1
3:1
3:1
5:1
2:1
–
88
88
89
87
15
–
PhCO2H
acetic acid
p-TsOH
TFA
NEt3
imidazole
PhCO2H
7
3:1
3:1
89
90
8[e]
[a] All reactions were carried out with 4-methylcyclohexanone (1a,
2.0 equiv.) and 1,1-bis(phenylsulfonyl)ethylene (2, 1.0 equiv.), addi-
tive (20 mol-%), and organocatalyst V (20 mol-%) at ambient tem-
perature. [b] Isolated yield. [c] Determined by chiral HPLC analy-
sis. [d] The ee value reported corresponds to the major dia-
stereomer. [e] The reaction was carried out from 0 °C to ambient
temperature.
[a] All reactions were carried out with cyclohexanones 1a–1j
(2.0 equiv.) and 1,1-bis(phenylsulfonyl)ethylene (2, 1.0 equiv.) with
organocatalyst V (20 mol-%) at ambient temperature. [b] Isolated
yield. [c] Determined by chiral HPLC analysis. [d] The ee value re-
ported corresponds to the major diastereomer. [e] The major dia-
stereomer.
Eur. J. Org. Chem. 2013, 2699–2707
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Y. Chen, P.-H. Lee, J. Lin, K. Chen
FULL PAPER
was used as an acidic additive. This is perhaps caused by with cinchonidine-derived catalyst VII at ambient tempera-
the protonation of the secondary amine, which then ham- ture. The product was obtained in good chemical yield with
pers the enamine formation (see Table 2, Entry 5). The use the high enantioselectivity of 92%ee. This result is compar-
of a basic additive failed to improve the reaction results (see able to that previously reported. However, the absolute
Table 2, Entries 6 and 7).
stereochemistry of the major product was determined to
Under the optimized reaction conditions, the scope of have the (2S,4S) configuration, which is the enantiomer of
the methodology was investigated with 4-alkyl- or 4-aryl- the product obtained when organocatalyst V was used. The
substituted cyclohexanones 1 and 1,1-bis(phenylsulfonyl)- use of structurally related catalysts resulted in low reactivity
ethylene (2) in the presence of 20 mol-% of catalyst V in (VIII afforded Ͻ10% chemical yield) or low stereoselectivi-
CHCl3 at ambient temperature (see Table 3). A broad range
of cyclohexanones 1a–1j were investigated to evaluate the
Table 4. Screening various cyclohexanones for Michael addition to
general utility of this asymmetric transformation. As pre-
sented in Table 3, the asymmetric desymmetrization process
proceeded smoothly when 4-substituted cyclohexanones
1a–1d were used to form the corresponding Michael ad-
ducts in high chemical yields and with high enantio-
selectivities (see Table 3, Entries 1–4). The use of 3-methyl-
cyclohexanone (1f) provided the product with moderate
selectivity (see Table 3, Entry 6). The two major dia-
stereomers (2:1.3) were believed to be the 2,3- and 2,5-re-
gioisomer with the two substituents located in the equato-
rial position. The use of a 2-methyl-substituted cyclohexan-
one gave trace amounts of the product (see Table 3, En-
try 7). Moderate yields were obtained when cycloheptanone
was employed (see Table 3, Entry 8). However, high chemi-
cal yields and high enantioselectivities were obtained when
tetrahydrothiopyran-4-one and tetrahydropyran-4-one were
used (see Table 3, Entries 9 and 10). The structures of the
Michael products were determined by the analysis of the
1,1-bis(phenylsulfonyl)ethylene (2) catalyzed by VII.[a]
1
IR, HRMS, and H and 13C NMR spectroscopic data. The
absolute stereochemistry of the two products (2R,4R)-3a
and (2R,4R)-3b was further confirmed by single-crystal X-
ray structure analyses (space groups are P 21/n and P 21/c,
respectively).[12]
The enantioselective Michael addition of 4-methylcyclo-
hexanone (1a, 10 equiv.) to 1,1-bis(phenylsulfonyl)ethylene
(2, 1 equiv.) catalyzed by cinchonidine-derived primary
amine VII has been reported.[13] However, careful examina-
tion of the HPLC chromatography results from this study
reveals that a different stereoisomer was obtained when or-
ganocatalyst VII was used. To clarify this discrepancy, our
protocol was expanded, and various quinine and cinchon-
idine-derived organocatalysts (i.e., VII–X) were systemati-
cally screened (see Figure 2).
[a] All reactions were carried out with cyclohexanones 1a–1e and
1h–1j (2.0 equiv.) and 1,1-bis(phenylsulfonyl)ethylene (2, 1.0 equiv.)
with organocatalyst VII (20 mol-%) at ambient temperature.
[b] Isolated yield. [c] Determined by chiral HPLC analysis. [d] The
Figure 2. Chemical structures of organocatalysts VII–X.
The addition of 4-methylcyclohexanone (1a) and 1,1-bis-
(phenylsulfonyl)ethylene (2) in CHCl3 was first conducted ee value reported corresponds to the major diastereomer.
2702 Eur. J. Org. Chem. 2013, 2699–2707
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Organocatalytic Michael Addition
ties (IX afforded 39% yield, dr 6:1, 61%ee; X afforded 40% organocatalyst V effectively catalyzed the Michael reaction
yield, dr 1:1, 40%ee). Therefore, catalyst VII was used for between cyclohexanones 1a–1j and 1,1-bis(phenylsulfonyl)-
the asymmetric Michael additions to produce enantiomer- ethylene (2). The enantiomeric products were obtained with
ically enriched ketosulfones (see Table 4). A series of cyclo- high to excellent levels of stereoselectivity when the cin-
hexanones were employed, and comparable chemical yields chonidine-derived catalyst VII was used. This methodology
and stereoselectivities were typically obtained (up to 96% has proven to be effective for the purpose of asymmetric
chemical yield, 94%ee). The diastereomeric ratios in En- desymmetrization in the preparation of nonracemic chiral
tries 1–4 of Tables 3 and 4 ranged from 4:1 to 1:2. This may molecules. The asymmetric desymmetrization protocol is
indicate that the 2,4-substituents are located in the axial actively under investigation in our laboratory.
and equatorial positions, respectively.
Although the mechanisms for the reactions in this study
Experimental Section
remain to be defined, two reaction modes are proposed and
described in Scheme 2. The initial reaction of the camphor-
derived pyrrolidine catalyst V with 4-methylcyclohexanone
gave the nucleophilic enamine, as the vinyl sulfone, acting as
the Michael acceptor, was activated by the thiourea moiety
through a hydrogen-bonding interaction. This activation
was followed by the addition of the nucleophilic enamine
from the si face to the electrophilic component to generate
the desired product 3a. On the other hand, catalysis of the
reaction by the cinchonidine-derived primary amine cata-
lyst VII may also involve hydrogen-bonding interactions.
The favored enamine was formed from the primary amino
group of the catalyst and 4-methylcyclohexanone with the
methyl group away from the 1,1-bis(phenylsulfonyl)ethylene
(2). The bicyclic moiety selectively shielded the approach of
the Michael acceptor. The conjugate addition occurred
from the re face of the nucleophile to give the observed
stereochemistry of Michael adduct 4a.
General Remarks: Chemicals and solvents were purchased from
commercial suppliers and used as received. The cyclohexanones
and 1,1-bis(phenylsulfonyl)ethylene were purchased from Sigma–
Aldrich and used as received. IR spectra were recorded with a Per-
kin–Elmer 500 spectrometer. The H and 13C NMR spectroscopic
1
data were recorded with a Bruker Avance 400 (400 MHz) or Bruker
Avance 500 (500 MHz) spectrometer. Chemical shifts are reported
in δ (ppm) and referenced to TMS as an internal standard for H
1
NMR spectroscopy and to deuterated chloroform (δ = 77.0 ppm)
as an internal standard for 13C NMR spectroscopy. The abbrevi-
ations for the multiplicities of the NMR spectra are s (singlet), d
(doublet), t (triplet), q (quartet), m (multiple), dd (doublet of doub-
let), and br. s (broad singlet). The coupling constants are reported
in Hertz (Hz). All high resolution mass spectra were obtained with
a Finnigan/MAT 95XL-T spectrometer. The X-ray diffraction mea-
surements were carried out at 200 K with a KAPPA APEX II CCD
area detector system equipped with a graphite monochromator and
a Mo-Kα fine-focus sealed tube (k = 0.71073 Å). Merck precoated
TLC plates (Merck 60 F254) were used for thin layer chromatog-
raphy, and compounds were visualized under UV light at 254 nm.
Solutions were evaporated to dryness under reduced pressure with
a rotary evaporator, and the residues were purified by flash column
chromatography on silica gel (230–400 mesh) with the indicated el-
uents. The enantiomeric excess value for a product was determined
by chiral-phase HPLC analysis.
Synthesis of Catalyst V
tert-Butyl (2S,4R)-2-[({[(1S,4S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]-
heptan-1-yl]methyl}thio)methyl]-4-hydroxypyrrolidine-1-carboxylate
(6): To a solution of NaH (2.69 g, 67.30 mmol) were added sequen-
tially a solution of 4 (5.00 g, 13.46 mmol) in tetrahydrofuran (THF,
20 mL) and 5 (2.98 g, 16.51 mmol) dropwise at ambient tempera-
ture. The reaction mixture was stirred for 3 h and then quenched
with H2O (10 mL). The mixture was extracted with CH2Cl2
(2ϫ50 mL). The combined organic layers were washed with brine,
dried with anhydrous MgSO4, and filtered. Purification by flash
column chromatography (hexanes/EtOAc, 2:1) gave the coupled
product (88% yield) as a viscous liquid. [α]2D0 = –18.0 (c = 1.00,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.45–4.41 (m, 1 H),
4.19–4.11 (m, 1 H), 3.61–3.43 (m, 2 H), 2.92 (d, J = 12.8 Hz, 1 H),
2.87 (d, J = 12.8 Hz, 1 H), 2.72–2.67 (m, 1 H), 2.57 (d, J = 12.0 Hz,
1 H), 2.36 (dq, J = 4.7, 2.6 Hz, 1 H), 2.15–1.95 (m, 6 H), 1.86 (d,
J = 18.3 Hz, 1 H), 1.84–1.51 (m, 1 H), 1.39 (s, 9 H), 1.04 (s, 3 H),
0.90 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 216.9, 154.3,
79.5, 68.4, 60.5, 55.4, 54.6, 47.4, 43.1, 42.7, 38.7, 37.7, 29.7, 28.1,
Scheme 2. Plausible reaction mechanisms.
26.4, 26.3, 19.9, 19.8 ppm. IR (CH Cl ): ν = 3424, 3055, 2959,
˜
2
2
Conclusions
2878, 1742, 1668, 1407 cm–1. HRMS (EI): calcd. for C20H33NO4S
383.2130; found 383.2138.
In summary, a new camphor-derived pyrrolidine organo-
catalyst that contains a thiourea group at the C-4 position
tert-Butyl (2S,4R)-2-[({[(1S,4S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]-
was successfully synthesized. This study demonstrated that heptan-1-yl]methyl}thio)methyl]-4-[(methylsulfonyl)oxy]pyrrolidine-
Eur. J. Org. Chem. 2013, 2699–2707
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Y. Chen, P.-H. Lee, J. Lin, K. Chen
FULL PAPER
1-carboxylate: To a solution of ketosulfide 6 (2.50 g, 6.50 mmol) in
tert-Butyl (2S,4S)-2-[({[(1S,4S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]-
CH2Cl2 (10 mL) were added Et3N (1.8 mL, 13 mmol) and meth-
heptan-1-yl]methyl}thio)methyl-]-4-(3-phenylthioureido)pyrrolidine-
anesulfonyl chloride (MsCl, 0.75 mL, 9.77 mmol) dropwise at 0 °C. 1-carboxylate: A solution of compound 7 (1.0 g, 2.6 mmol) in
After stirring for 1 h, the reaction mixture was quenched with H2O
(5.0 mL), and the resulting solution was adjusted to pH = 9–10
with an aqueous solution of NaHCO3 (1.0 m). The reaction mixture
was then extracted with CH2Cl2 (2ϫ50 mL). The combined or-
ganic layers were washed with brine, dried with anhydrous MgSO4,
and filtered. Purification by flash column chromatography (hex-
anes/EtOAc, 2:1) gave the product (97% yield) as a viscous liquid.
CH2Cl2 (10 mL) was treated with PhNCS (0.34 mL, 2.88 mmol)
dropwise at ambient temperature. After stirring for 2 h, the reaction
mixture was quenched with H2O, and the resulting solution was
adjusted to pH = 9–10 with an aqueous solution of NaHCO3
(1.0 m). The reaction mixture was then extracted with CH2Cl2. The
combined organic layers were washed with brine, dried with anhy-
drous MgSO4, and filtered. Purification by flash column
chromatography (hexanes/EtOAc, 2:1) gave the product (76 %
yield) as a viscous liquid. [α]2D0 = –11.9 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.50 (br. s, 1 H, NH), 7.43–7.35 (m, 2 H),
7.35–7.23 (m, 3 H), 7.30 (br. s, 1 H, NH), 5.07–4.97 (m, 1 H), 4.15–
3.94 (m, 2 H), 3.35–3.00 (m, 2 H), 2.80–2.70 (m, 2 H), 2.65–2.45
(m, 2 H), 2.34 (ddd, J = 2.9, 4.5, 18.4 Hz, 1 H), 2.06 (t, J = 4.3 Hz,
1 H), 2.02–1.93 (m, 1 H), 1.93–1.78 (m, 3 H), 1.50–1.40 (m, 1 H),
1
[α]2D0 = –17.8 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
5.19 (s, 1 H), 4.30–4.10 (m, 1 H), 4.02–3.78 (m, 1 H), 3.64–3.49 (m,
1 H), 3.03 (s, 3 H), 2.95–2.75 (m, 2 H), 2.83 (d, J = 12.8 Hz, 1 H),
2.62–2.30 (m, 3 H), 2.30–2.18 (m, 1 H), 2.10–1.90 (m, 3 H), 1.84
(d, J = 18.4 Hz, 1 H), 1.55–1.40 (m, 1 H), 1.45 (s, 9 H), 1.40–1.30
(m, 1 H), 0.98 (s, 3 H), 0.85 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 217.0, 154.0, 80.4, 78.8, 60.8, 55.4, 52.5, 47.7, 43.4,
43.0, 38.6, 38.0, 36.7, 31.5, 30.2, 28.3, 26.7, 20.1, 20.0 ppm. IR 1.45 (s, 9 H), 1.40–1.30 (m, 1 H), 0.98 (s, 3 H), 0.88 (s, 3 H) ppm.
(CH Cl ): ν = 2968, 2887, 1741, 1693, 1479, 1398 cm–1. HRMS
13C NMR (100 MHz, CDCl3): δ = 217.6, 180.5, 154.2, 136.9, 129.7,
˜
2
2
(EI): calcd. for C21H35NO6S2 461.1906; found 461.1908.
126.6, 124.8, 79.9, 61.0, 56.4, 52.9, 47.8, 43.5, 43.1, 38.4, 35.5, 30.3,
28.4, 27.2, 26.7, 25.3, 20.4, 19.8 ppm. IR (CH Cl ): ν = 3461, 3336,
˜
2
2
tert-Butyl (2S,4S)-4-Azido-2-[({[(1S,4S)-7,7-dimethyl-2-oxobicy-
clo[2.2.1]heptan-1-yl]methyl}thio)methyl]pyrrolidine-1-carboxylate:
To a solution of the previously prepared mesylate compound
(2.58 g, 5.59 mmol) in dimethyl sulfoxide (DMSO, 10 mL) was
added NaN3 (1.80 g, 28 mmol). The resulting mixture was heated
to 65 °C for 1 h. The reaction mixture was quenched with H2O,
and the resulting solution was then extracted with diethyl ether.
The combined organic layers were washed with brine, dried with
anhydrous MgSO4, and filtered. Purification by flash column
chromatography (hexanes/EtOAc, 5:1) gave the product (86 %
yield) as a viscous liquid. [α]2D0 = –7.5 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 4.18–3.95 (m, 2 H), 3.75–3.60 (m, 1 H),
3.40–3.25 (m, 1 H), 3.10–2.85 (m, 1 H), 2.89 (d, J = 12.8 Hz, 1 H),
2.70 (dd, J = 10.2, 13.2 Hz, 1 H), 2.60–2.50 (m, 1 H), 2.40–2.22
(m, 2 H), 2.22–2.13 (m, 1 H), 2.08–1.92 (m, 3 H), 1.84 (d, J =
18.3 Hz, 1 H), 1.55–1.40 (m, 1 H), 1.46 (s, 9 H), 1.40–1.33 (m, 1
H), 1.03 (s, 3 H), 0.88 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 216.8, 153.8, 80.1, 60.7, 58.8, 56.2, 51.7, 47.6, 43.3, 42.9, 38.2,
2967, 2885, 2081, 1738, 1661, 1531, 1476, 1392 cm–1. HRMS
(FAB+): calcd. for C27H40O3N3S2 [MH]+ 518.2511; found
518.2507.
1-{(3S,5S)-5-[({[(1S,4S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-
yl]methyl}thio)methyl]pyrolidin-3-yl}-3-phenylthiourea (V): To a
solution of the C-4-substituted thiourea ketosulfide (0.5 g,
0.97 mmol) in CH2 Cl2 (5 mL) was added TFA (1.8 mL,
24.23 mmol) dropwise at ambient temperature. After stirring for
6 h, the reaction mixture was quenched with H2O, and the resulting
solution was adjusted to pH = 9–10 with an aqueous solution of
NaHCO3 (1.0 m). The reaction mixture was then extracted with
CH2Cl2. The combined organic layers were washed with brine,
dried with anhydrous MgSO4, and filtered. Purification by flash
column chromatography (hexanes/EtOAc, 2:1) gave V (99% yield)
as a white solid; m.p. 81.6–82.5 °C. [α]2D0 = +1.8 (c = 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 8.57 (br. s, 1 H), 7.41–7.36 (m,
2 H), 7.31–7.28 (m, 2 H), 7.22 (t, J = 7.1 Hz, 1 H), 7.07–6.96 (m,
1 H), 4.90 (br. s, 1 H), 3.40–3.29 (m, 1 H), 3.11 (dd, J = 10.9,
6.0 Hz, 1 H), 3.07–2.97 (m, 1 H), 2.80 (dd, J = 4.4, 13.5 Hz, 1 H),
2.76 (d, J = 12.9 Hz, 1 H), 2.58 (dd, J = 13.3, 6.9 Hz, 1 H), 2.60–
2.45 (m, 1 H), 2.48 (d, J = 13.1 Hz, 1 H), 2.45–2.30 (m, 2 H), 2.06
(t, J = 3.7 Hz, 1 H), 2.03–1.84 (m, 2 H), 1.84 (d, J = 18.4 Hz, 1
H), 1.52–1.22 (m, 4 H), 0.99 (s, 3 H), 0.87 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 218.9, 180.9, 137.5, 129.2, 126.2, 124.6,
61.2, 59.1, 53.6, 51.6, 48.0, 43.6, 43.1, 36.4, 32.1, 29.2, 27.4, 26.8,
35.1, 29.6, 28.3, 26.7, 26.5, 20.1 (2ϫ) ppm. IR (CH Cl ): ν = 2965,
˜
2
2
2889, 2103, 1742, 1694, 1477, 1366 cm–1. HRMS (EI) m/z: calcd.
for C20H32N4O3S 408.2195; found 408.2203.
tert-Butyl (2S,4S)-4-Amino-2-[({[(1S,4S)-7,7-dimethyl-2-oxobicy-
clo[2.2.1]heptan-1-yl]methyl}thio)methyl]pyrrolidine-1-carboxylate
(7): To a solution of the previously prepared azido compound
(1.7 g, 4.16 mmol) in THF (10 mL) was added PPh3 (1.2 g,
4.58 mmol) portionwise. The reaction mixture was heated at reflux
for 4 h and then was quenched with H2O. To the resulting solution
was added aqueous HCl (1.2 n solution, 25.0 mL), and the pH was
adjusted with an aqueous solution of NaOH (1.0 m, 30.0 mL) to
pH = 8–9. The reaction mixture was then extracted with EtOAc.
The combined organic layers were washed with brine, dried with
anhydrous MgSO4, and filtered. Purification by flash column
chromatography (hexanes/EtOAc, 5:1) gave compound 7 (83 %
yield) as a viscous liquid. [α]2D0 = –6.5 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 4.10–3.90 (m, 1 H), 3.90–3.62 (m, 1 H),
3.55–3.47 (m, 1 H), 3.20–2.80 (m, 5 H), 2.88 (d, J = 12.8 Hz, 1 H),
2.65–2.53 (m, 2 H), 2.45–2.30 (m, 2 H), 2.10–1.93 (m, 2 H), 1.86
(d, J = 18.3 Hz, 1 H), 1.77–1.69 (m, 1 H), 1.47 (s, 9 H), 1.43–1.32
(m, 1 H), 1.04 (s, 3 H), 0.90 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 217.1, 154.3, 79.6, 60.9, 56.8, 55.0, 50.0, 47.8, 43.5,
43.1, 39.5, 38.6, 30.0, 28.5, 26.9, 26.8, 20.2 (2ϫ) ppm. IR (CH2Cl2):
20.2, 19.6 ppm. IR (CH Cl ): ν = 3424, 3055, 2959, 2089, 1735,
˜
2
2
1676, 1616, 1543, 1498, 1318, 1200 cm–1. HRMS (FAB+): calcd.
for C22H32ON3S2 [MH]+ 418.1987; found 418.1984.
Crystal Structure Data of V at 200(2) K: C44H64Cl2O2N6S4, M =
908.15 gmol–1, monoclinic, C2, a = 31.545(6) Å, b = 8.3641(18) Å,
c = 19.695(4) Å, α = 90.00°, β = 110.966(9)°, γ = 90.00°, V =
4852.4(17) Å3, F(000) = 1936, λ (Mo-Kα) = 0.71073 Å, Z = 4, D =
1.243 gcm–3, 15677 reflections, 1 restraint, 523 parameters, R =
0.2356, wR2 = 0.1786 for all data.[12]
General Procedure: To a mixture of 1-{(3S,5S)-5-[({[(1S,4S)-7,7-di-
methyl-2-oxobicyclo[2.2.1]heptan-1-yl]methyl}thio)methyl]pyrrol-
idin-3-yl}-3-phenylthiourea (V, 5.4 mg, 0.01 mmol), benzoic acid
(1.6 mg, 0.01 mmol), and 1,1-bis(phenylsulfonyl)ethylene (2, 20 mg,
0.06 mmol) in anhydrous chloroform (0.04 mL) in a vial at ambient
temperature was added cyclohexanone 1 (14.8 μL, 0.12 mmol). The
vial was then sealed, and the reaction mixture was stirred at ambi-
ν = 3431, 2966, 2888, 2096, 1738, 1679, 1477, 1400 cm–1. HRMS
˜
(EI): calcd. for C20H34N2O3S 382.2290; found 382.2292.
2704
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2699–2707

Organocatalytic Michael Addition
ent temperature for 24 h. To the reaction mixture was added
analysis (Chiralcel AS-H, λ = 220 nm, 15% iPrOH/hexanes, flow
EtOAc/H2O. The organic layer was separated, dried with anhy- rate: 1.0 mLmin–1): tR = 21.5 min (major), tR = 52.8 min (minor).
drous Na2SO4, filtered, and concentrated in vacuo. Purification by
flash column chromatography (ethyl acetate/hexanes, 1:2) afforded
the desired adducts 3a–3j and the desired adducts 4a–4e and 4h–
4j.
2-[2,2-Bis(phenylsulfonyl)ethyl]-4-phenylcyclohexanone [(2R,4R)-3c]:
Viscous liquid (75% yield, 88%ee). 1H NMR (400 MHz, CDCl3,
mixture): δ = 1.88–2.13 (m, 2 H), 2.16–2.21 (m, 4 H), 2.39–2.43 (m,
2 H), 2.78–2.83 (m, 1 H), 3.11–3.14 (m, 0.75 H, major), 3.32–3.38
(m, 0.25 H, minor), 4.77 (dd, J = 7.7, 2.8 Hz, 0.72 H, major), 5.01
(dd, J = 9.3, 3.8 Hz, 0.28 H, minor),7.18–7.39 (m, 5 H), 7.49–7.69
(m, 6 H), 7.84–7.96 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 26.47, 26.75, 31.79, 34.80, 37.04, 38.26, 38.38, 41.59, 41.72,
43.07, 45.61, 46.66, 80.35, 80.67, 126.62, 126.69, 126.82, 128.47,
128.68, 128.78, 129.14, 129.31, 129.41, 129.48, 129.78, 130.14,
134.46, 134.51, 134.56, 134.62, 137.77, 137.93, 143.36, 212.61 ppm.
HRMS (ESI): calcd. for C26H26O5S2 [M + Na]+ 505.1120; found
505.1135. HPLC analysis (Chiralcel AS-H, λ = 220 nm, 15 %
iPrOH/hexanes, flow rate: 1.0 mLmin–1): tR = 81.7 min (major), tR
= 61.8 min (minor).
2-[2,2-Bis(phenylsulfonyl)ethyl]-4-methylcyclohexanone [(2R,4R)-
3a]: White solid (95% yield, 88%ee); m.p. 183.5–185.1 °C. [α]2D0
=
1
–16.0 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3, mixture): δ
= 0.97 (d, J = 5.2 Hz, 1.2 H, minor), 1.12 (d, J = 6.8 Hz, 1.8 H,
major), 1.58–1.64 (m, 3 H), 1.98–2.28 (m, 3 H), 2.35–2.60 (m, 3
H), 2.96–3.02 (m, 0.64 H, major), 3.11–3.18 (m, 0.36 H, minor),
4.85–4.87 (m, 0.62 H, major), 4.98–5.00 (m, 0.38 H, minor), 7.54–
7.59 (m, 4 H), 7.66–7.71 (m, 2 H), 7.89–7.96 (m, 4 H) ppm. 13C
NMR (100 MHz, CDCl3, mixture): δ = 18.89 (major), 21.04
(minor), 26.47 (major), 26.73 (minor), 31.81 (minor), 33.27 (major),
35.70 (minor), 37.62 (major), 40.04 (major), 41.31 (minor), 42.76
(minor), 43.89 (major), 46.25 (minor), 80.52 (major), 80.71 (minor),
129.0, 129.08, 129.10, 129.26, 129.34, 129.54, 129.74, 134.39,
134.43, 134.56, 137.98 (minor), 138.01 (major), 212.04 (minor),
213.07 (major) ppm. HRMS (ESI): calcd. for C21H24O5S2 [M +
Na]+ 443.0963; found 443.0977. HPLC analysis (Chiralcel AS-H, λ
= 220 nm, 15 % iPrOH/hexanes, flow rate: 1.0 mL min–1): tR
(major) = 51.1 min (major), tR = 38.5 min (minor).
(2S,4S)-4c: Viscous liquid (88 % yield, 94 % ee). HRMS (ESI):
calcd. for C26H26O5S2 [M + Na]+ 505.1120; found 505.1134. HPLC
analysis (Chiralcel AS-H, λ = 220 nm, 15% iPrOH/hexanes, flow
rate: 1.0 mLmin–1): tR = 66.1 min (major), tR = 87.2 min (minor).
Ethyl 3-[2,2-Bis(phenylsulfonyl)ethyl]-4-oxocyclohexanecarboxylate
[(1R,3R)-3d]: Viscous liquid (55 % yield, 86 % ee). 1H NMR
(500 MHz, CDCl3, mixture): δ = 1.27 (t, J = 7.0 Hz, 1.27 H,
minor), 1.33 (t, J = 7.0 Hz, 1.73 H, major), 1.46–1.59 (m, 1 H),
1.74–2.01 (m, 3 H), 2.38–2.45 (m, 5 H), 2.77–2.82 (m, 0.7 H,
major), 3.19–3.26 (m, 0.3 H, minor), 4.14–4.15 (m, 0.6 H, minor),
4.24–4.27 (m, 1.4 H, major), 4.89–4.91 (m, 0.72 H, major), 5.01–
5.03 (m, 0.28 H, minor), 7.55–7.60 (m, 4 H), 7.67–7.71 (m, 2 H),
7.88–7.98 (m, 4 H) ppm. 13C NMR (125 MHz, CDCl3, mixture): δ
= 14.41, 14.25, 26.05 (major), 26.44 (minor), 28.29 (major), 29.68
(minor), 34.73 (major), 36.21 (minor), 38.44 (major), 38.71 (major),
40.37 (minor), 41.80 (minor), 44.07 (major), 45.59 (minor), 60.88
(minor), 61.15 (major), 79.01 (minor), 80.68 (major), 128.43,
129.03, 129.08, 129.13, 129.18, 129.27, 129.73 129.88, 130.08,
134.38, 134.49, 134.60, 134.67, 137.38, 137.81, 137.88, 138.23,
173.42, 210.44 (minor), 211.22 (major) ppm. HRMS (ESI): calcd.
for C23H26O7S2 [M + Na]+ 501.1018; found 501.1032. HPLC analy-
sis (Chiralcel AS-H, λ = 220 nm, 15% iPrOH/hexanes, flow rate:
1.0 mLmin–1): tR = 69.7 min (major), tR = 59.1 min (minor).
Crystal Structure Data of 3a at 200(2) K: C21H24O5S2, M =
420.52 g mol–1, monoclinic, P 21/n, a = 10.6461(11) Å, b =
18.590(2) Å, c = 11.3438(12) Å, α = 90.00°, β = 116.380(7)°, γ =
90.00°, V = 2011.3(4) Å3, F(000) = 888, λ (Mo-Kα) = 0.71073 Å, Z
= 4, D = 1.389 gcm–3, 13321 reflections, 0 restraints, 253 param-
eters, R = 0.2067; wR2 = 0.3423 for all data.[12]
(2S,4S)-4a: Viscous liquid (73% yield, 92%ee). [α]2D0 = +16.7 (c =
1.00, CHCl3). HRMS (ESI): calcd. for C21H24O5S2 [M + Na]+
443.0963; found 443.0974. HPLC analysis (Chiralcel AS-H, λ =
220 nm, 15 % iPrOH/hexanes, flow rate: 1.0 mL min–1): tR
35.7 min (major), tR = 47.93 min (minor).
=
2-[2,2-Bis(phenylsulfonyl)ethyl]-4-(tert-butyl)-cyclohexanone
[(2R,4R)-3b]: White solid (85% yield, 86%ee); m.p. 127.2–128.1 °C.
1H NMR (500 MHz, CDCl3, mixture): δ = 0.91 (s, 3 H), 0.93 (s, 6
H), 1.27–1.55 (m, 3 H), 1.64–1.67 (m, 2 H), 1.93–1.95 (m, 1 H),
2.23–2.36 (m, 2 H), 2.62–2.67 (m, 1 H), 2.74–2.80 (m, 0.66 H,
major), 3.09–3.14 (m, 0.34 H, minor) 4.78–4.80 (m, 0.67 H, major),
5.05–5.07 (m, 0.33 H, minor), 7.54–7.56 (m, 4 H), 7.67–7.72 (m, 2
H), 7.86–7.97 (m, 4 H) ppm. 13C NMR (125 MHz, CDCl3, mix-
ture): δ = 25.01, 26.77 (minor), 26.88 (major), 27.23 (minor), 27.57
(minor), 28.61 (major), 31.27 (major), 32.57 (minor), 35.90 (major),
38.57 (major), 41.39 (minor), 41.76 (major), 45.71 (major), 46.79
(minor), 80.59 (major), 80.72 (minor), 129.02, 129.10, 129.13,
129.14, 129.28, 129.39, 129.40, 129.69, 130.15, 133.62, 134.40,
134.48, 134.54, 137.57, 138.06 (minor), 138.18 (major), 212.75
(minor), 214.53 (major) ppm. HRMS (ESI): calcd. for C24H30O5S2
[M + Na]+ 485.1432; found 485.1446. HPLC analysis (Chiralcel
AS-H, λ = 220 nm, 15% iPrOH/hexanes, flow rate: 1.0 mLmin–1):
tR = 51.2 min (major), tR = 22.0 min (minor).
(1S,3S)-4d: Viscous liquid (96 % yield, 80 % ee). HRMS (ESI):
calcd. for C23H26O7S2 [M + Na]+ 501.1018; found 501.1028. HPLC
analysis (Chiralcel AS-H, λ = 220 nm, 15% iPrOH/hexanes, flow
rate: 1.0 mLmin–1): tR = 60.0 min (major), tR = 72.0 min (minor).
2-[2,2-Bis(phenylsulfonyl)ethyl]cyclohexanone [(R)-3e]: Viscous li-
1
quid (73% yield, 81%ee). H NMR (500 MHz, CDCl3): δ = 1.25–
1.30 (m, 2 H), 1.60–1.86 (m, 3 H), 1.93–2.11 (m, 2 H), 2.29–2.34
(m, 2 H), 2.50–2.52 (m, 1 H), 3.07–3.10 (m, 1 H), 4.98 (q, J =
4.0 Hz, 1 H), 7.54–7.58 (m, 4 H), 7.66–7.71 (m, 2 H), 7.89–7.95 (m,
4 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 24.94, 26.46, 27.75,
34.73, 41.97, 47.31, 80.70, 128.99, 129.06, 129.23, 129.69, 134.37,
134.55, 137.98, 138.04, 212.26 ppm. HRMS (ESI): calcd. for
C20H22O5S2 [M + Na]+ 429.0801; found 429.0818. HPLC analysis
(Chiralcel AS-H, λ = 220 nm, 30 % iPrOH/hexanes, flow rate:
1.0 mLmin–1): tR = 28.0 min (major), tR = 21.3 min (minor).
Crystal Structure Data of 3b at 200(2) K: C24H30O5S2, M =
462.60 g mol–1; monoclinic, P 21/c, a = 13.0368(17) Å, b =
15.1059(19) Å, c = 12.1816(13) Å, α = 90.00°, β = 102.527(5)°, γ =
90.00°, V = 2341.8(5) Å3, F(000) = 984, λ (Mo-Kα) = 0.71073 Å, Z
= 4, D = 1.312 gcm–3, 14519 reflections, 1 restraint, 270 param-
eters, R = 0.2277, wR2 = 0.4544 for all data.[12]
(S)-4e: Viscous liquid (89% yield, 85%ee). HRMS (ESI): calcd. for
C20H22O5S2 [M + Na]+ 429.0801; found 429.0820. HPLC analysis
(Chiralcel AS-H, λ = 220 nm, 30 % iPrOH/hexanes, flow rate:
1.0 mLmin–1): tR = 27.4 min (major), tR = 36.7 min (minor).
(2S,4S)-4b: Viscous liquid (86 % yield, 91 % ee). HRMS (ESI): (2S,3R)-2-[2,2-Bis(phenylsulfonyl)ethyl]-3-methylcyclohexanone (3f):
calcd. for C24H30O5S2 [M + Na]+ 485.1432; found 485.1446; HPLC Viscous liquid (72% yield, 78%ee). 1H NMR (400 MHz, CDCl3,
Eur. J. Org. Chem. 2013, 2699–2707
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2705

Y. Chen, P.-H. Lee, J. Lin, K. Chen
FULL PAPER
mixture): δ = 0.94 (d, J = 7.04 Hz, 1.56 H, major), 1.01 (d, J = found 431.0598. HPLC analysis (Chiralcel AS-H, λ = 220 nm, 40%
6.32 Hz, 1.13 H, minor), 1.07–1.09 (d, J = 5.76 Hz, 0.31 H, minor),
1.53–1.58 (m, 3 H), 1.92–2.32 (m, 4 H), 2.44–2.49 (m, 2 H), 2.58–
2.96 (m, 1 H), 4.88 (dd, J = 5.2, 3.6 Hz, 0.6 H, major), 4.90 (dd, J
= 5.6, 3.6 Hz, 0.32 H, minor), 4.97 (dd, J = 8.0, 2.8 Hz, 0.08 H,
minor), 7.54–7.58 (m, 4 H), 7.67–7.69 (m, 2 H), 7.87–7.95 (m, 4
H) ppm. 13C NMR (100 MHz, CDCl3, mixture): δ = 19.22, 22.22,
26.41, 29.73, 30.14, 32.23, 33.65, 33.70, 35.63, 46.50, 47.05, 47.98,
50.21, 80.72 (major), 80.85 (minor), 81.31 (minor), 128.93, 129.00,
129.04, 129.10, 129.29, 129.33, 129.68, 129.77, 129.89, 134.39,
134.53, 138.10, 138.17, 212.62 (minor), 212.42 (major) ppm.
HRMS (ESI): calcd. for C21H24O5S2 [M + Na]+ 443.0963; found
443.0977. HPLC analysis (Chiralcel AD-H, λ = 220 nm, 8 %
iPrOH/hexanes, flow rate: 1.0 mLmin–1): tR = 59.2 min (major), tR
= 64.5 min (minor).
iPrOH/hexanes, flow rate: 1.0 mLmin–1): tR = 26.5 min (major), tR
= 39.9 min (minor).
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the HPLC chromatograms of all products and H
and 13C NMR spectra of 6, 7 and V.
Acknowledgments
The authors thank the National Science Council of the Republic
of China (NSFC) (grant number NSC 99-2113-M-003-002-MY3)
and the National Taiwan Normal University (grant number 100-
d-06) for financial support of this work.
2-[2,2-Bis(phenylsulfonyl)ethyl]cycloheptanone [(R)-3h]: Viscous li-
quid (50% yield, 51%ee). [α]2D0 = –6.6 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.20–1.29 (m, 2 H), 1.44–1.55 (m, 2 H),
1.62–1.73 (m, 4 H), 1.74–2.16 (m, 1 H), 2.38–2.48 (m, 3 H), 3.17–
3.21 (m, 1 H), 4.79–4.82 (m, 1 H), 7.52–7.58 (m, 4 H), 7.66–7.71
(m, 2 H), 7.69–7.95 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 23.75, 27.91, 28.61, 29.01, 32.16, 42.96, 48.58, 80.50, 129.05,
129.12, 129.25, 129.66, 134.38, 134.56, 138.02, 138.24, 214.86 ppm.
HRMS (ESI): calcd. for C21H24O5S2 [M + Na]+ 443.0963; found
443.0966. HPLC analysis (Chiralcel AD-H, λ = 220 nm, 15 %
iPrOH/hexanes, flow rate: 1.0 mLmin–1): tR = 44.6 min (major), tR
= 39.8 min (minor).
(S)-4h: Viscous liquid (56% yield, 66%ee). [α]2D0 = +6.9 (c = 1.00,
CHCl3). HRMS (ESI): calcd. for C21H24O5S2 [M + Na]+ 443.0963;
found 443.0956. HPLC analysis (Chiralcel AD-H, λ = 220 nm,
15 % iPrOH/hexanes, flow rate: 1.0 mL min–1): tR = 42.3 min
(major), tR = 47.3 min (minor).
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3-[2,2-Bis(phenylsulfonyl)ethyl]dihydro-2H-thiopyran-4(3H)-one
[(R)-3i]: Viscous liquid (78% yield, 86%ee). [α]2D0 = –11.3 (c = 1.00,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 2.01–2.07 (m, 1 H),
2.61–2.73 (m, 4 H), 2.90–2.93 (m, 3 H), 3.38–3.43 (m, 1 H), 4.83–
4.86 (m, 1 H), 7.55–7.59 (m, 4 H), 7.66–7.70 (m, 2 H), 7.87–7.95
(m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.21, 30.84,
36.25, 44.06, 49.87, 80.47, 129.11, 129.15, 129.32, 129.67, 134.51,
134.70, 137.82, 209.42 ppm. HRMS (ESI): calcd. for C19H20O5S3
[M + Na]+ 447.0371; found 447.0378. HPLC analysis (Chiralcel
AS-H, λ = 220 nm, 40% iPrOH/hexanes, flow rate: 1.0 mLmin–1):
tR = 46.5 min (major), tR = 32.1 min (minor).
(S)-4i: Viscous liquid (90% yield, 93%ee). [α]2D0 = –11.7 (c = 1.00,
CHCl3). HRMS (ESI): calcd. for C19H20O5S3 [M + Na]+ 447.0371;
found 447.0370. HPLC analysis (Chiralcel AS-H, λ = 220 nm, 40%
iPrOH/hexanes, flow rate: 1.0 mLmin–1): tR = 33.6 min (major), tR
= 49.2 min (minor).
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3-[2,2-Bis(phenylsulfonyl)ethyl]dihydro-2H-pyran-4(3H)-one [(S)-3j]:
Viscous liquid (97% yield, 88%ee). [α]2D0 = –17.4 (c = 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.89–1.93 (m, 1 H), 2.30–2.35
(m, 1 H), 2.47–2.60 (m, 2 H), 3.25–3.33 (m, 2 H), 3.66–3.99 (m, 1
H), 4.13–4.20 (m, 2 H), 4.93–4.97 (m, 1 H), 7.54–7.59 (m, 4 H),
7.66–7.68 (m, 2 H), 7.70–7.95 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.19, 42.22, 42.77, 48.23, 67.70, 68.49, 72.32, 80.29,
129.06, 129.10, 129.28, 129.35, 129.57, 134.49, 134.66, 137.64,
137.69, 207.61 ppm. HRMS (ESI): calcd. for C19H20O6S2 [M +
Na]+ 431.0599; found 431.0602. HPLC analysis (Chiralcel AS-H, λ
= 220 nm, 40 % iPrOH/hexanes, flow rate: 1.0 mL min–1): tR
39.2 min (major), tR = 26.2 min (minor).
=
(R)-4j: Viscous liquid (92% yield, 77%ee). [α]2D0 = +16.5 (c = 1.00,
CHCl3). HRMS (ESI): calcd. for C19H20O6S2 [M + Na]+ 431.0599;
2706
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Eur. J. Org. Chem. 2013, 2699–2707

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contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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Received: December 4, 2012
Published Online: March 8, 2013
Eur. J. Org. Chem. 2013, 2699–2707
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2707