Enantioselective conjugate addition of thiols to cyclic enones and enals catalyzed by chiral N,N'-dioxide-cadmium iodide complex

Article abstract of DOI:10.1016/S0040-4020(00)00914-5

Chiral N,N'-dioxide-cadmium iodide complex has been shown to catalyze enantioselective conjugate additions of thiols to cyclic enones and enals. The sulfides are generated in high yields and in good enantioselectivities up to 78% ee using 1 mol% of the chiral catalyst. The present reaction provides the first example of utilizing a cadmium complex as a catalyst in enantioselective reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00914-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9589±9594
Enantioselective Conjugate Addition of Thiols to Cyclic Enones
and Enals Catalyzed by Chiral N,N0-Dioxide±Cadmium
Iodide Complex
*
Makoto Saito, Makoto Nakajima and Shunichi Hashimoto
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 13 September 2000; accepted 2 October 2000
AbstractÐChiral N,N0-dioxide±cadmium iodide complex has been shown to catalyze enantioselective conjugate additions of thiols to
cyclic enones and enals. The sul®des are generated in high yields and in good enantioselectivities up to 78% ee using 1 mol% of the chiral
catalyst. The present reaction provides the ®rst example of utilizing a cadmium complex as a catalyst in enantioselective reaction. q 2000
Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
The design of chiral ligands plays a key role in the
development of enantioselective reactions. Many recent
studies have therefore focused on the development of
novel chiral ligands for metal-catalyzed reactions. Although
N-oxide is now known to be a unique functional group,
possessing a notable electron-donating property, which
allows it to form complexes with a variety of metals,1
there have been few attempts to employ N-oxides as chiral
ligands.2 We have recently reported an enantioselective
allylation of aldehydes with allyltrichlorosilanes utilizing
chiral N,N0-dioxide 1 as a catalyst, in which the electron-
donating property of N-oxide played a pivotal role.3c As part
of our program directed at the development of N-oxide-
mediated reaction,3 herein we describe a detail of an
enantioselective conjugate addition of thiols to enones and
enals catalyzed by chiral N,N0-dioxide±cadmium iodide
complex (Eq. (1)).4
Since the ®rst enantioselective conjugate addition of thiols
catalyzed by cinchona alkaloid was reported,5a several
chiral amine-catalyzed reactions have been discussed.5
The recent discovery of a lithium thiolate complex of
amino bisether,6 heterobimetallic complex,7 or nickel
oxazoline complex8 as the catalysts for the enantioselective
conjugate addition has received considerable attention, due
to their high ef®cacy.
Recently, we described the optical resolution of 1 through
the formation of a hydrogen-bonding complex between 1
and optically active binaphthol.3a This prompted our
hypothesis that thiophenol forms a hydrogen-bonding
complex with 1, which is expected to control the nucleo-
philicity and steric accessibility of thiophenol in its enantio-
selective conjugate addition to electron-de®cient ole®n. To
test this hypothesis, we initially employed 10 mol% of 1 as a
ꢀ1†
Keywords: asymmetric reactions; cadmium and compounds; N-oxides; sul®des.
* Corresponding author. Tel.: 181-11-706-3766; fax: 181-11-706-4981; e-mail: nakajima@pharm.hokudai.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00914-5
Tetrahedron ± Own style ± Own refs ±
te6014
am
lden
AUTOPAGINATION 2 16-11-2000 10:55
A

9590
M. Saito et al. / Tetrahedron 56 (2000) 9589±9594
Table 1. Enantioselective conjugate addition of thiophenol to 2 with 1 and
various metal salts
various metal chlorides surveyed, addition of cadmium
chloride yielded the corresponding sul®de quantitatively
with 30% ee (entry 8). Further investigation revealed that
cadmium iodide was the optimal additive, affording the
sul®de in 57% ee (entry 10). Enantioselectivity increased
up to 78% when the reaction was performed in toluene,
whereas polar solvents decreased enantioselectivity (tetra-
hydrofuran: 99%, 0% ee; acetonitrile: 97%, 33% ee).
Stoichiometric studies using 1 mol% of cadmium iodide
revealed that equimolar amounts of 1 and cadmium iodide
are suf®cient for optimum enantioselectivity (Table 2, entry
2). The reaction was promoted by cadmium iodide in the
absence of N-oxide to produce the sul®de in 96% yield
(entry 4). These results suggest that a 1:1 complex of 1
and cadmium iodide9 functions as a catalyst in this enantio-
selective addition. This is the ®rst example of an enantio-
Entry
MXn
Conversion, %a
ee, %b
1
2
3
4
5
6
7
8
9
10
CuCl
ZnCl2
PdCl2
AgCl
SnCl2
HgCl
BiCl3
CdCl2
CdBr2
CdI2
.95
.95
.95
80
.95
.95
.95
.95
.95
.95
16
7
9
19
7
13
8
30
46
57
selective reaction utilizing
exhibiting a distinctive binding to N-oxide.
a
cadmium compound,10
a Determined by NMR measurement.
b Determined by HPLC analysis employing Daicel Chiralpak AD.
Table 3 summarizes the conjugate addition of various thiols
to 2 under optimized conditions. Introduction of one or two
methyl groups into ortho-position of thiophenol decreased
both chemical yield and enantioselectivity, probably due to
the steric hindrance (entries 2, 3). It is surprising that the
reaction of 4-substituted thiophenols (entries 4±7), except
for 4-methoxybenzenethiol (entry 7) gave low selectivity as
compared to that of thiophenol (entry 1), though the steric
environment around the reaction center seems quite similar.
Benzyl mercaptan (entry 8) also gave lower reactivity and
selectivity.
Table 2. Stoichiometric study in enantioselective conjugate addition of
thiophenol to 2 (2 (1 mmol) CdI2 (10 mmol) PhSH (2 mmol), toluene, rt)
Entry
Mol% of 1
Time, h
Yield, %a
ee, %b
1
2
3
4
2
1
0.5
0
6
6
4
1
96
96
97
96
78
78
34
±
a Isolated yield.
b Determined by HPLC analysis employing Daicel Chiralpak AD.
The scope of the acceptor in the conjugate addition was then
investigated (Table 4). Slight modi®cations of the substrate
strongly in¯uenced enantioselectivity. 2-Cyclohepten-1-one
4 (entry 2) gave an enantioselectivity comparable to that of
2 (entry 1), while 2-cyclopenten-1-one 5 (entry 3) demon-
strated low selectivity. Introduction of substituent into 3- or
4-position of cyclohexenone resulted in decline in both
chemical yield and enantioselectivity, probably for the
steric reason (entries 4, 5).
catalyst in the conjugate addition of thiophenol to 2-cyclo-
hexen-1-one (2) in dichloromethane. The reaction produced
a signi®cant yield of the corresponding sul®de 3a, although
the observed enantioselectivity was quite low (rt, 24 h, 35%,
12% ee).
To enhance the reactivity and enantioselectivity, we used
10 mol% metal salt as an additive expected to coordinate
with carbonyl oxygen. Table 1 shows some representative
results using various metal salts which gave the sul®de 3a in
high yield with observable enantioselectivity. Among
While attempts to employ acyclic conjugate ketones as the
substrate such as chalcone were unsuccessful (30%, 10%
Table 3. Enantioselective conjugate addition of thiols to 2 catalyzed by 1±CdI2 complex
d
Entry
R
Time, h
Product
Yield, %a
ee, %b
Con®gnc
[a]D
1
2
3
4
5
6
7
8
Ph
6
3a
3b
3c
3d
3e
3f
96
28
8
74
78
98
91
48
78
29
33
29
40
24
58
40
S
±
±
S
S
S
S
S
268.7
225.5
226.0
223.7
230.8
219.8
243.2
243.1
2-MeC6H4
2,6-Me2C6H3
4-MeC6H4
4-tBuC6H4
4-ClC6H4
24
48
12
12
3
4-MeOC6H4
PhCH2
6
12
3g
3h
a Isolated yield.
b Determined by HPLC analysis employing Daicel Chiralpak AD.
c Con®guration assignment by comparison to literature5b values of optical rotations.
d c 1, CHCl3.
Tetrahedron ± Own style ± Own refs ±
te6014
am
lden
AUTOPAGINATION 2 16-11-2000 10:55
A

M. Saito et al. / Tetrahedron 56 (2000) 9589±9594
9591
Table 4. Enantioselective conjugate addition of thiols to enones catalyzed by 1±CdI2 complex
c
Entry
Enone
n
R1
R2
Time, h
Product
Yield, %a
ee, %b
[a]D
1
2
3
4
5
2
4
5
6
7
2
3
1
2
2
H
H
H
Me
H
H
H
H
H
Me
6
24
4
48
48
3a
8
9
10
11
96
68
94
43
79
78
61
21
10
26
268.7
227.2
11.8
24.2
229.0
a Isolated yield.
b Determined by HPLC analysis employing Daicel Chiralpak AD or AS.
c c 1, CHCl3.
Table 5. Enantioselective conjugate addition of thiophenol to enals catalyzed by 1±CdI2 complex
Time, ha
Product
Yield, %b
ee, %c
[a]D
d
Entry
Enal
R
1
2
3
4
5
6
7
12
13
14
15
16
17
18
Me
Et
12
12
24
24
24
48
48
19
20
21
22
23
24
25
89
91
66
80
76
67
34
69e
70
65
63
52
39
9
124.9
114.0
116.4
124.8
15.2
Pr
iPr
PhCH2
tBu
Ph
18.3
219.9
a Reaction time of conjugate addition.
b Isolated yield of alcohol.
c Determined by HPLC analysis employing Daicel Chiralcel OD.
d c 1, CHCl3.
e Absolute con®guration was determined to be S by comparison to the values of optical rotation of 19 prepared from methyl 3-phenylthiobutanoate.6a
ee), the reaction of acyclic conjugate aldehydes afforded the
corresponding sul®des in high chemical yields and with
enantioselectivities up to 70% ee after conversion to the
corresponding alcohol (Table 5). Aliphatic enals (entries
1±6) except for 17 having bulky tert-butyl group (entry 6)
gave almost the same degree of enantioselectivities, while
conjugate enal 18 (entry 7) gave unsuccessful result. The
mildness of the reaction conditions allows the enantio-
selective conjugate addition of thiols to enals, a reaction
never previously reported due to the lability of aldehydes.
complex to carbon±carbon double bond. To examine the
in¯uence of ligand purity on the enantioselectivity, we
carried out a series of conjugate addition of thiophenol to
2 with mixtures of the (R)- and (S)-1. When the enantios-
electivity of the product was plotted against the optical
purity of 1, a slight nonlinear effect11 was observed as can
be seen in Fig. 1. These results imply the possibility of the
aggregation of the N,N0-dioxide±cadmium iodide complex,
though the detail is not clear.
To gain an insight into the reaction mechanism, we
examined the in¯uence of enantioselectivity by the stereo-
chemistry of the carbon±carbon double bond in enal.
Surprisingly, addition of thiophenol to a 1:1 mixture of
(E)- and (Z)-2-pentenal exhibited the same sense and degree
of enantioselectivity (86%, 68% ee) as (E)-2-pentenal 13
(Table 5, entry 2) without observable isomerization of the
starting ole®n. We next investigated several additives to the
reaction of 2 and thiophenol in toluene. Addition of cyclo-
hexanone (1.0 equiv.) in¯uenced neither chemical yield nor
enantioselectivity (92%, 74% ee) of the reaction. The addi-
tion of cyclohexene (1.0 equiv.), however, dramatically
reduced enantioselectivity (92%, 45% ee). These results
suggest the importance of the coordination of cadmium
Figure 1. Nonlinear effect in the conjugate addition of thiophenol to 2
catalyzed by 1±CdI2 complex
Tetrahedron ± Own style ± Own refs ±
te6014
am
lden
AUTOPAGINATION 2 16-11-2000 10:56
A

9592
M. Saito et al. / Tetrahedron 56 (2000) 9589±9594
Conclusions
ee. HPLC: tR (1), 9.0 min, (2), 10.0 min (Daicel Chiralpak
1
AD, 1.0 mL/min, hex/IPAˆ99:1). H NMR: d 1.58±1.86
We have demonstrated the effectiveness of a chiral N,N0-
dioxide±cadmium iodide complex as a catalyst for enantio-
selective conjugate addition of thiols. Cyclic enones and
enals can be employed as acceptors, utilizing 1 mol%
catalyst loadings, to afford the sul®des in high yields and
with good enantioselectivities of up to 78% ee. The present
reaction provides the ®rst example of utilizing cadmium
complex in enantioselective reaction.
(m, 2H), 2.01±2.20 (m, 2H), 2.25±2.48 (m, 3H), 2.52 (s.
6H), 2.53±2.64 (m, 1H), 3.12±3.24 (m, 1H). 3.34±3.46 (m,
1H), 7.08±7.13 (m, 3H).
(S)-3-[(4-Methylphenyl)thio]-cyclohexanone (3d).5h [a]D24ˆ
20
25
223.7 (c 1.2, CHCl3), [a] ˆ217.2 (c 1.9, benzene) for
577
29% ee (lit. 5h; [a] ˆ233.2 (c 2.1, benzene) for (S)-3d
578
47% ee). HPLC: tR (S), 8.0 min, (R), 9.5 min (Daicel
1
Chiralpak AD, 1.0 mL/min, hex/IPAˆ9:1). H NMR: d
1.64±1.80 (m, 2H), 2.05±2.21 (m, 2H), 2.23±2.41 (m,
3H), 2.34 (s, 3H), 2.62±2.72 (m, 1H), 3.28±3.41 (m, 1H),
7.13 (d, 2H, Jˆ8.3 Hz), 7.33 (d, 2H, Jˆ8.3 Hz).
Experimental
General
(S)-3-[(4-tert-butylphenyl)thio]-cyclohexanone
(3e).5b
[a]2D4ˆ230.8 (c 1.4, CHCl3), [a] ˆ234.6 (c 1.6, CCl4)
24
Melting points were measured using a BuÈchi 535 melting
point apparatus and were not corrected. Optical rotations
were obtained on a JASCO P-1030 digital polarimeter. H
577
21
for 40% ee (lit. 5b; [a] ˆ147 (c 1, CCl4) for (R)-3e
578
1
62% ee). HPLC: tR (S), 6.0 min, (R), 7.0 min (Daicel
NMR and 13C NMR spectra were recorded on a JEOL
EX-270 (1H, 270 MHz; 13C, 68 MHz) spectrometer in
deuteriochloroform. Chemical shift values are expressed
in ppm relative to internal tetramethylsilane. Coupling
constants (J) are reported in Hertz (Hz). Abbreviations
are as follows: s, singlet; d, doublet; t, triplet; q, quar-
tet; m, multiplet, br, broad. Infrared spectra (IR) were
recorded on a JASCO FT/IR-5300 spectrometer. Mass
spectra were obtained on a JEOL JMS-FABmate spec-
trometer by electron impact (EI) with ionization voltage of
70 eV.
1
Chiralpak AD, 1.0 mL/min, hex/IPAˆ9:1). H NMR: d
1.31 (s, 9H), 1.61±1.82 (m, 2H), 2.07±2.22 (m, 2H),
2.24±2.43 (m, 3H), 2.64±2.72 (m, 1H), 3.32±3.41 (m,
1H), 7.30±7.40 (m, 4H).
(S)-3-[(4-Chlorophenyl)thio]-cyclohexanone (3f).5b Mp
56.0±57.08C. [a]2D5ˆ219.8 (c 1.2, CHCl3), [a] ˆ221.8
25
577
21
(c 1.6, CCl4) for 24% ee (lit. 5b; [a] ˆ131 (c 1, CCl4) for
578
(R)-3f 35% ee). HPLC: tR (S), 13.0 min, (R), 14.5 min
(Daicel Chiralpak AD, 1.0 mL/min, hex/IPAˆ19:1). 1H
NMR: d 1.61±1.82 (m, 2H), 2.08±2.22 (m, 2H), 2.26±
2.45 (m, 3H), 2.63±2.74 (m, 1H), 3.34±3.46 (m, 1H), 7.29
(d, 2H, Jˆ8.6 Hz), 7.36 (d, 2H, Jˆ8.6 Hz).
Enantioselective conjugate addition of thiols to enones
(S)-3-[(4-Methoxyphenyl)thio]-cyclohexanone
(3g).5b
Thiol (2.0 mmol) in toluene (1 mL) was added to a stirred
solution of enone (1.0 mmol), N-oxide 1 (3.2 mg, 10 mmol)
and cadmium iodide (3.6 mg, 10 mmol) in toluene (7 mL)
and stirred at rt. The reaction mixture was diluted in toluene
and successively washed with aq. NaOH and brine. The
solvent was evaporated and the residue was chromato-
graphed on silica gel column (eluent, toluene/AcOEt) to
afford the corresponding sul®de. N-Oxide 1 was recovered
by elution with 10% ethanol in dichloromethane without a
loss of optical purity. The enantiomeric excess of the
product was determined by chiral HPLC.
[a]2D5ˆ243.2 (c 1.2, CHCl3), [a] ˆ250.8 (c 1.1, CCl4)
25
577
21
for 58% ee (lit. 5b; [a] ˆ143 (c 1, CCl4) for (R)-3g 50%
578
ee). HPLC: tR (S), 11.5 min, (R), 15.0 min (Daicel Chiralpak
AD, 1.0 mL/min, hex/IPAˆ9:1). 1H NMR: d 1.61±1.78 (m,
2H), 2.05±2.20 (m, 2H), 2.25±2.39 (m, 3H), 2.59±2.68 (m,
1H), 3.18±3.41 (m, 1H), 3.81 (s, 3H), 6.87 (d, 2H,
Jˆ8.6 Hz), 7.40 (d, 2H, Jˆ8.6 Hz).
(S)-3-[(Phenylmethyl)thio]-cyclohexanone (3h).7b [a]D24ˆ
243.1 (c 1.3, CHCl3) for 40% ee (lit. 7b; [a]2D7ˆ149.0 (c
0.93, CHCl3) for (R)-3h 52% ee). HPLC: tR (R), 8.5 min,
(S), 10.0 min (Daicel Chiralpak AD, 1.0 mL/min, hex/
(S)-3-(Phenylthio)-cyclohexanone (3a).5b [a]D23ˆ268.7 (c
21
1
24
1.1, CHCl3), [a] ˆ272.7 (c 1.1, CCl4) for 78% ee (lit. 5b;
577
IPAˆ9:1). H NMR: d 1.61±1.78 (m, 2H), 2.04±2.18 (m,
2H), 2.31±2.43 (m, 3H), 2.64±2.71 (m, 1H), 2.88±3.01 (m,
1H), 3.75 (d, 1H, Jˆ13.8 Hz), 3.77 (d, 1H, Jˆ13.8 Hz),
7.18±7.32 (m, 5H).
[a] ˆ153 (c 1, CCl4) for (R)-3a 54% ee). HPLC: tR (S),
578
8.5 min, (R), 10.0 min (Daicel Chiralpak AD, 1.0 mL/min,
1
hex/IPAˆ9:1). H NMR: d 1.59±1.82 (m, 2H), 2.07±2.22
(m, 2H), 2.24±2.43 (m, 3H), 2.64±2.77 (m, 1H), 3.39±3.45
(m, 1H), 7.26±7.36 (m, 3H), 7.39±7.45 (m, 2H).
(2)-3-(Phenylthio)-cycloheptanone (8). [a]2D4ˆ227.2 (c
1.1, CHCl3) for 61% ee. HPLC: tR (1), 15.0 min, (2),
23.0 min (Daicel Chiralpak AS, 1.0 mL/min, hex/
(2)-3-[(2-Methylphenyl)thio]-cyclohexanone
(3b).5j
1
IPAˆ9:1). IR: (neat) 1701 cm21. H NMR: d 1.48±1.64
[a]2D4ˆ225.5 (c 0.9, CHCl3) for 29% ee. HPLC: tR (1),
14.0 min, (2), 16.0 min (Daicel Chiralpak AD, 1.0 mL/
min, hex/IPAˆ99:1). 1H NMR: d 1.61±1.84 (m, 2H),
2.08±2.22 (m, 2H), 2.29±2.46 (m, 3H), 2.43 (s, 3H),
2.65±2.72 (m, 1H), 3.36±3.49 (m, 1H), 7.11±7.25 (m,
3H), 7.36±7.41 (m, 1H).
(m, 1H), 1.65±1.79 (m, 2H), 1.80±2.04 (m, 2H), 2.10±
2.21 (m, 1H), 2.42±2.64 (m, 2H), 2.72 (dd, 1H, Jˆ9.6,
14.9 Hz), 2.79 (ddd, 1H, Jˆ1.3, 3.6, 14.9 Hz), 3.41 (ddt,
1H, Jˆ2.6, 3.0, 9.6 Hz), 7.24±7.35 (m, 3H), 7.38±7.43
(m, 2H). 13C NMR: d 23.9, 28.1, 36.9, 44.0, 44.2, 49.5,
127.5, 129.1, 132.5, 134.1, 221.4. MS: m/z 220(M1), 111,
110(bp). Anal. Calcd for C13H16OS: C, 70.87; H, 7.32.
Found: C, 70.89; H, 7.28.
(2)-3-[(2,6-Dimethylphenyl)thio]-cyclohexanone (3c).5j
Mp 91.0±92.08C. [a]D24ˆ226.0 (c 0.9, CHCl3) for 33%
Tetrahedron ± Own style ± Own refs ±
te6014
am
lden
AUTOPAGINATION 2 16-11-2000 10:56
A

M. Saito et al. / Tetrahedron 56 (2000) 9589±9594
9593
(1)-3-(Phenylthio)-cyclopentanone (9).7a [a]D23ˆ11.8 (c
1.3, CHCl3) for 21% ee. HPLC: tR (1), 12.5 min, (2),
14.0 min (Daicel Chiralpak AD, 1.0 mL/min, hex/
CHCl3) for 70% ee. HPLC: tR (2), 7.5 min, (1), 10.0 min
(Daicel Chiralcel OD, 1.0 mL/min, hex/IPAˆ9:1). IR:
1
(neat) 3347 cm21. H NMR: d 1.04 (t, 3H, Jˆ7.3 Hz),
1
IPAˆ19:1). H NMR: d 1.96±2.09 (m, 1H), 2.16±2.55
1.57 (br, 1H), 1.59±1.97 (m, 4H), 3.15±3.25 (m, 1H),
3.76±3.93 (m, 2H), 7.20±7.33 (m, 3H), 7.41±7.44 (m,
2H). 13C NMR: d 11.2, 27.9, 36.8, 47.9, 60.7, 126.8,
128.9, 132.1, 135.1. MS: m/z 196(M1), 110(bp). Anal.
Calcd for C11H16OS: C, 67.30; H, 8.22. Found C, 67.05;
H, 8.27.
(m, 4H), 2.61 (dd, 1H, Jˆ7.3, 18.5 Hz), 3.84±3.93 (m,
1H), 7.20±7.37 (m, 3H), 7.39±7.45 (m, 2H).
(2)-3-Methyl-3-(phenylthio)-cyclohexanone (10). [a]2D2ˆ
24.2 (c 1.1, CHCl3) for 10% ee. HPLC: tR (2), 8.5 min,
(1), 9.5 min (Daicel Chiralpak AD, 1.0 mL/min, hex/
1
IPAˆ19:1). IR: (neat) 1711 cm21. H NMR: d 1.29 (s,
(1)-3-(Phenylthio)-1-hexanol (21). [a]2D3ˆ116.4 (c 1.1,
CHCl3) for 65% ee. HPLC: tR (2), 7.0 min, (1), 8.0 min
(Daicel Chiralcel OD, 1.0 mL/min, hex/IPAˆ9:1). IR:
3H), 1.80±1.99 (m, 3H), 2.12±2.39 (m, 3H), 2.33 (d, 1H,
Jˆ13.9 Hz), 2.51 (d, 1H, Jˆ13.9 Hz), 7.31±7.43 (m, 3H),
7.50±7.54 (m, 2H). 13C NMR: d 22.1, 28.5, 36.8, 40.4, 51.8,
53.2, 128.7, 129.2, 130.3, 137.8, 209.0. MS: m/z 220(M1),
111(bp). Anal. Calcd for C13H16OS: C, 70.87; H, 7.32.
Found C, 70.91; H, 7.35.
1
(neat) 3358 cm21. H NMR: d 0.94 (t, 3H, Jˆ7.1 Hz),
1.45±1.62 (m, 5H), 1.72±1.91 (m, 2H), 3.21±3.28 (m,
1H), 3.76±3.91 (m, 2H), 7.18±7.33 (m, 3H), 7.40±7.45
(m, 2H). 13C NMR: d 13.9, 20.0, 37.3, 37.4, 46.1, 60.7,
126.8, 128.8, 132.1, 135.1. MS: m/z 210(M1), 110(bp).
Anal. Calcd for C12H18OS: C, 68.52; H, 8.63. Found C,
68.31; H, 8.64.
(2)-4,4-Dimethyl-3-(phenylthio)-cyclohexanone
(11).
Mp 61.58C. [a]2D5ˆ229.0 (c 1.1, CHCl3) for 26% ee.
HPLC: tR (1), 8.5 min, (2), 9.5 min (Daicel Chiralpak
AD, 1.0 mL/min, hex/IPAˆ40:1). IR: (neat) 1705 cm21
.
(1)-4-Methyl-3-(phenylthio)-1-pentanol (22). [a]2D3ˆ
124.8 (c 1.1, CHCl3) for 63% ee. HPLC: tR (2), 6.0 min,
(1), 8.0 min (Daicel Chiralcel OD, 1.0 mL/min, hex/
1H NMR: d 1.22 (s, 3H), 1.28 (s, 3H), 1.64 (ddd, 1H,
Jˆ5.3, 12.5, 13.9 Hz), 1.90 (ddd, 1H, Jˆ4.6, 6.3,
13.9 Hz), 2.30 (dddd, 1H, Jˆ1.3, 4.6, 5.3, 15.2 Hz), 2.45
(ddd, 1H, Jˆ6.3, 12.5, 15.2 Hz), 2.54 (dd, 1H, Jˆ10.6,
15.2 Hz), 2.63 (ddd, 1H, Jˆ1.3, 5.3, 15.2 Hz), 3.17 (dd,
1H, Jˆ5.3, 10.6 Hz), 7.20±7.33 (m, 3H), 7.38±7.43 (m,
2H). 13C NMR: d 21.0, 29.0, 34.6, 37.8, 38.6, 45.4, 57.6,
127.4, 129.0, 132.7, 134.6, 208.9. MS: m/z 234(M1), 125,
110(bp). Anal. Calcd for C14H18OS: C, 71.75; H, 7.74.
Found C, 71.77; H, 7.74.
1
IPAˆ9:1). IR: (neat) 3354 cm21. H NMR: d 0.99 (d, 3H,
Jˆ6.6 Hz), 1.02 (d, 3H, Jˆ6.6 Hz), 1.58 (br, 1H), 1.63±1.79
(m, 1H), 1.87±2.04 (m, 2H), 3.21 (dt, 1H, Jˆ4.0, 10.6 Hz),
3.78±3.93 (m, 2H), 7.16±7.31 (m, 3H), 7.40±7.44 (m, 2H).
13C NMR: d 19.1, 19.2, 32.3, 34.5, 53.6, 61.2, 126.5, 128.9,
131.2, 136.7. MS: m/z 210(M1), 167, 137, 123, 110(bp).
Anal. Calcd for C12H18OS: C, 68.52; H, 8.63. Found C,
68.48; H, 8.62.
(1)-4-Phenyl-3-(phenylthio)-1-butanol (23). [a]2D2ˆ15.2
(c 1.3, benzene) for 52% ee. HPLC: tR (2), 10.0 min, (1),
11.5 min (Daicel Chiralcel OD, 1.0 mL/min, hex/IPAˆ9:1).
IR: (neat) 3356 cm21. 1H NMR: d 1.55 (br, 1H), 1.67±1.77
(m, 1H), 1.87±1.94 (m, 1H), 2.80 (dd, 1H, Jˆ8.2, 13.9 Hz),
3.03 (dd, 1H, Jˆ5.9, 13.9 Hz), 3.46±3.52 (m, 1H), 3.77±
3.85 (m, 1H), 7.15±7.34 (m, 8H), 7.37±7.44 (m, 2H). 13C
NMR: d 36.3, 42.1, 47.7, 60.7, 126.5, 127.1, 128.4, 129.0,
129.3, 132.3, 134.8, 139.0. MS: m/z 258(M1), 167, 137,
123, 91(bp). Anal. Calcd for C16H18OS: C, 74.38; H, 7.02.
Found C, 74.36; H, 7.18.
Enantioselective conjugate addition of thiophenol to enal
Thiol (2.0 mmol) in toluene (1 mL) was added to a stirred
solution of enal (1.0 mmol), 1 (3.2 mg, 10 mmol) and
cadmium iodide (3.6 mg, 10 mmol) in toluene (7 mL) and
stirred at rt. The reaction mixture was diluted with toluene
and successively washed with 15% NaOH aq, satd NH4Cl
aq and brine. The solvent was evaporated and the residue
was dissolved in MeOH (4 mL). Sodium borohydride
(30 mg) was added to the solution and the mixture was
stirred for 10 min. The reaction was quenched with brine
and the mixture was extracted with AcOEt. The organic
layer was washed with brine and evaporated. The residue
was puri®ed by silica gel column chromatography (eluent,
hexane/AcOEt) to give the corresponding alcohol. N-Oxide
1 was quantitatively recovered by further elution with 10%
EtOH in CHCl3 without any loss of optical purity.
(1)-4,4-Dimethyl-3-(phenylthio)-1-pentanol (24). [a]2D2ˆ
18.3 (c 1.1, CHCl3) for 39% ee. HPLC: tR (2), 6.0 min,
(1), 7.5 min (Daicel Chiralcel OD, 1.0 mL/min, hex/
1
IPAˆ9:1). IR: (neat) 3360 cm21. H NMR: d 1.04 (s, 9H),
1.53 (br, 1H), 1.57±1.72 (m, 1H), 2.08±2.21 (m, 1H), 3.07
(dd, 1H, Jˆ2.6, 11.9 Hz), 3.88±3.93 (m, 2H), 7.14±7.19 (m,
1H), 7.24±7.32 (m, 2H), 7.42±7.47 (m, 2H). 13C NMR: d
27.8, 34.5, 36.2, 59.7, 61.5, 126.0, 128.9, 130.4, 138.7. MS:
m/z 224(M1), 167, 137(bp), 123, 110, 97. Anal. Calcd for
C13H20OS: C, 69.59; H, 8.98. Found C, 69.80; H, 9.02.
(S)-3-(Phenylthio)-1-butanol (19). [a]2D3ˆ124.9 (c 1.2,
CHCl3) for 69% ee. HPLC: tR (R), 7.5 min, (S), 9.0 min
(Daicel Chiralcel OD, 1.0 mL/min, hex/IPAˆ9:1). IR
1
(neat) 3355 cm21. H NMR: d 1.33 (d, 3H, Jˆ6.6 Hz),
1.57 (br, 1H), 1.73±1.93 (m, 2H), 3.31±3.48 (m, 1H),
3.73±3.91 (m, 2H), 7.21±7.33 (m, 3H), 7.41±7.44 (m,
2H). 13C NMR: d 21.0, 39.2, 40.4, 60.6, 127.0, 128.8,
132.2, 134.7. MS: m/z 182(M1), 137, 110(bp). Anal.
Calcd for C10H14OS: C, 65.89; H, 7.74. Found C, 65.63;
H, 7.80.
(2)-3-Phenyl-3-(phenylthio)-1-propanol (25). Mp 54.0±
55.08C. [a]2D2ˆ219.9 (c 1.2, CHCl3) for 9% ee. HPLC:
tR (2), 13.0 min, (1), 14.0 min (Daicel Chiralcel OD,
1.0 mL/min, hex/IPAˆ9:1). IR: (nujol) 3358 cm21
.
1H
NMR: d 1.53 (br, 1H), 2.07±2.31 (m, 2H), 3.60 (ddt, 1H,
Jˆ2.0, 5.7, 11.2 Hz), 3.76 (ddt, 1H, Jˆ1.3, 5.9, 11.2 Hz),
4.36 (dd, 1H, Jˆ7.3, 7.9 Hz), 7.18±7.39 (m, 10H). 13C
(1)-3-(Phenylthio)-1-pentanol (20). [a]2D2ˆ114.0 (c 1.1,
Tetrahedron ± Own style ± Own refs ±
te6014
am
lden
AUTOPAGINATION 2 16-11-2000 10:56
A

9594
M. Saito et al. / Tetrahedron 56 (2000) 9589±9594
5. (a) Helder, R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H.
Tetrahedron Lett. 1977, 25, 2181±2182. (b) Hiemstra, H.;
Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417±430. (c) J.
Gawronski, J.; Gawronska, K.; Wynberg, H. J. Chem. Soc.,
Chem. Commun. 1981, 307±308. (d) Kobayashi, N.; Iwai, K.
J. Am. Chem. Soc. 1978, 100, 7071±7072. (e) Mukaiyama, T.;
Ikegawa, A.; Suzuki, K. Chem. Lett. 1981, 165±168. (f) Suzuki,
K.; Ikegawa, A.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1982, 55,
3277±3282. (g) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985,
NMR: d 38.8, 50.2, 60.5, 127.21, 127.24, 127.8, 128.5,
128.7, 132.5, 134.6, 141.7. MS: m/z 244(M1), 135,
105(bp), 91. Anal. Calcd for C15H16OS: C, 73.73; H, 6.60.
Found C, 73.61; H, 6.43.
Acknowledgements
This work was partly supported by a Grant-in-Aid for
Scienti®c Research from the Ministry of Education,
Science, Sports and Culture of Japan and Otsuka Chemical
Award in Synthetic Organic Chemistry, Japan. The authors
thank the Japan Society for the Promotion of Science for
Research Fellowships for Young Scientists (to M. S.).
Â
363±366. (h) Hodge, P.; Khoshdel, E.; Waterhouse, J.; Frechet,
J. M. J. J. Chem. Soc., Perkin Trans. 1 1985, 2327±2331.
(i) Kumar, A.; Salunkhe, R. V.; Rane, R. A.; Dike, S. Y.
J. Chem. Soc., Chem. Commun. 1991, 485±486. (j) Ito, A.;
Konishi, K.; Aida, T. Tetrahedron Lett. 1996, 37, 2585±2588.
6. (a) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J. Am.
Chem. Soc. 1997, 119, 12974±12975. (b) Tomioka, K.; Okuda, M.;
Nishimura, K.; Manabe, S.; Kanai, M.; Nagaoka, Y.; Koga, K.
Tetrahedron Lett. 1998, 39, 2141±2144.
References
1. Karayannis, N. M.; Pytlewski, L. L.; Mikulski, C. M. Coord.
Chem. Rev. 1973, 11, 93±159.
7. (a) Manickam, G.; Sundararajan, G. Tetrahedron: Asymmetry
1997, 13, 2271±2278. (b) Emori, E.; Arai, T.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1998, 120, 4043±4044.
2. (a) Diana, M. B.; Marchetti, M.; Melloni, G. Tetrahedron:
Asymmetry 1995, 6, 1175±1179. (b) O'Neil, I. A.; Turner, C. D.;
È
Kalindjian, S. B. Synlett 1997, 777±780. (c) Dyker, G.; Holzer, B.;
Henkel, G. Tetrahedron: Asymmetry 1999, 10, 3297±3307.
8. Kanemasa, S.; Oderaotoshi, Y.; Wada, E. J. Am. Chem. Soc.
1999, 121, 8675±8676.
È
(d) Derdau, V.; Laschat, S.; Hupe, E.; Konig, W. A.; Dix, I.;
9. Nieuwenhuyzen, M.; Robinson, W. T.; Wilkins, C. J.
Polyhedron 1991, 10, 2111±2121.
Jones, P. G. Eur. J. Inorg. Chem. 1999, 1001±1007. (e) Miura,
K.; Katsuki, T. Synlett 1999, 783±785.
10. The application of cadmium iodide as a catalyst: (a) Prajapati,
D.; Sandhu, J. S. J. Chem. Soc., Perkin Trans. 1 1993, 739±740.
(b) Baruah, B.; Boruah, A.; Prajapati, D.; Sandhu, J. S.
Tetrahedron Lett. 1997, 38, 1449±1450. (c) Laskar, D. D.;
Prajapati, D.; Sandhu, J. S. Chem. Lett. 1999, 1283±1284.
11. Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. Engl. 1998,
37, 2922±2959.
3. (a) Nakajima, M.; Sasaki, Y.; Shiro, M.; Hashimoto, S.
Tetrahedron: Asymmetry 1997, 8, 341±344. (b) Nakajima, M.;
Sasaki, Y.; Iwamoto, H.; Hashimoto, S. Tetrahedron Lett. 1998,
39, 87±88. (c) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S.
J. Am. Chem. Soc. 1998, 120, 6419±6420. (d) Nakajima, M.; Saito,
M.; Hashimoto, S. Chem. Pharm. Bull. 2000, 48, 306±307.
4. Saito, M.; Nakajima, M.; Hashimoto, S. Chem. Commun. 2000,
1851±1852.
Tetrahedron ± Own style ± Own refs ±
te6014
am
lden
AUTOPAGINATION 2 16-11-2000 10:56
A