Enantioselective Reaction of α-Lithiated Dithioacetals Using Chiral Bis(oxazoline)s: New Chiral Formyl Anion Equivalents

Article abstract of DOI:10.1021/jo035558e

The enantioselective reaction of various α-lithiated dithioacetals with aldehydes or a ketone in the presence of bis(oxazoline)s was examined. Among them, unsymmetrical dithioacetals were found to be the best choice for attaining high enantioselectivity. The reaction of lithiated tert-butylthio-(2-pyridylthio)methane with aldehydes proceeded with good diastereoselectivity as well as with good enantioselectivity. The enantioselective reaction was shown to proceed through dynamic thermodynamic resolution. Mercury(II) chloride effected hydrolysis of the dithioacetal moiety of the products to 2-hydroxyaldehydes, which were directly reduced to give the optically active 1,2-diols.

Full text of DOI:10.1021/jo035558e

En a n tioselective Rea ction of r-Lith ia ted Dith ioa ceta ls Usin g
Ch ir a l Bis(oxa zolin e)s: New Ch ir a l F or m yl An ion Equ iva len ts
Shuichi Nakamura, Yuji Ito, Libo Wang, and Takeshi Toru*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya 466-8555, J apan
toru@nitech.ac.jp
Received October 21, 2003
The enantioselective reaction of various R-lithiated dithioacetals with aldehydes or a ketone in the
presence of bis(oxazoline)s was examined. Among them, unsymmetrical dithioacetals were found
to be the best choice for attaining high enantioselectivity. The reaction of lithiated tert-butylthio-
(2-pyridylthio)methane with aldehydes proceeded with good diastereoselectivity as well as with
good enantioselectivity. The enantioselective reaction was shown to proceed through dynamic
thermodynamic resolution. Mercury(II) chloride effected hydrolysis of the dithioacetal moiety of
the products to 2-hydroxyaldehydes, which were directly reduced to give the optically active 1,2-
diols.
In tr od u ction
enantioselective reaction using lithiated dithioacetals,
because there was no systematic study of this kind of
asymmetric syntheses. We have previously reported
highly enantioselective lithiation-substitution reactions
of benzyl sulfides in the presence of bis(oxazoline)s.9,10
Herein we report an enantioselective reaction of a variety
of lithiated dithioacetals with various aldehydes.
The study of chiral formyl anion equivalents is of vital
interest. Intensive studies have so far been focused
mainly on diastereoselective reactions employing dithio-
acetals,1 hemithioacetals,2 1,3-dioxolanes,3 1,3-oxazo-
lidines,4 oxazolidinones,5 and formaldehyde hydrazones6
as chiral auxiliaries. The enantioselective version should
be a very desirable yet challenging subject of study for
developing formyl anion equivalents as an efficient tool
for asymmetric synthesis. Enantioselective reactions of
N,O-acetals7 and 1,3-dithiane have been previously de-
scribed.8 These reactions show good enantioselectivity
only when benzaldehyde is used as an electrophile,
inasmuch as much poorer enantioselectivity results with
other aldehydes.8 We focused on a detailed study of the
Rea ction s of Lith ia ted Dith ioa ceta ls. Initially, we
examined the reaction of lithiated symmetrical dithio-
acetals 1-6. Dithioacetals 1-6 were lithiated with n-
BuLi in the presence of bis(oxazoline)s 7 and subse-
quently reacted with benzaldehyde. The results are
shown in Table 1. Treatment of bis(phenylthio)methane
1 with 1.2 equiv of n-BuLi and 1.25 equiv of bis-
(oxazoline)-iPr 7a in cumene for 30 min at -78 °C,
followed by the addition of benzaldehyde (1.3 equiv) gave
the product 8 in high yield but with low enantioselectivity
(entry 1). Bis(oxazoline)-tBu 7b slightly improved the
enantioselectivity (entry 2). Dithioacetals such as 1,3-
dithiane 2, bis(tert-butylthio)methane 3, and bis(2,4,6-
trimethylphenylthio)methane 4 are not acidic enough to
give the product in high yield (entries 4-6), whereas bis-
(2-pyridylthio)methane 5 and bis(2-quinolylthio)methane
6 gave the products 12 and 13 in high yields, respectively,
but again with low enantioselectivities (entries 7 and 8).11
We concluded from these results that symmetrical dithio-
acetals were not the proper choice for the enantioselective
(1) (a) Colombo, L.; Gennari, C.; Scolastico, C.; Guanti, G.; Narisano,
E. J . Chem. Soc., Perkin Trans. 1 1981, 1278-1283. (b) Colombo, L.;
Gennari, C.; Resnati, G.; Scolastico, C. J . Chem. Soc., Perkin Trans. 1
1981, 1284-1286. (c) Colombo, L.; Gennari, C.; Resnati, G.; Scolastico,
C. Synthesis 1981, 74-76. (d) Delogu, G.; Lucchi, O. D.; Maglioli, P.
J . Org. Chem. 1991, 56, 4467-4473. (e) Aggarwal, V. K.; Franklin, R.;
Maddock, J .; Evans, G. R.; Thomas, A.; Mahon, M. F.; Molloy, K. C.;
Rice, M. J . J . Org. Chem. 1995, 60, 2174-2182.
(2) (a) Lynch, J . E.; Eliel, E. L. J . Am. Chem. Soc. 1984, 106, 2943-
2948. (b) Kaulen, J . Angew. Chem., Int. Ed. Engl. 1989, 28, 462-463.
(3) Colombo, L.; Giacomo, M. D.; Brusotti, G.; Delogu, G. Tetrahe-
dron Lett. 1994, 35, 2063-2066.
(4) Colombo, L.; Giacomo, M. D.; Brusotti, G.; Milano, E. Tetrahe-
dron Lett. 1995, 36, 2863-2866.
(5) (a) Gaul, C.; Seebach, D. Org. Lett. 2000, 2, 1501-1504. (b) Gaul,
C.; Scha¨rer K.; Seebach, D. J . Org. Chem. 2001, 66, 3059-3073. (c)
Gaul, C.; Arvidsson, P. I.; Bauer, W.; Gawley, R. E.; Seebach, D.
Chem.sEur. J . 2001, 7, 4117-4125. (d) Gaul, C.; Seebach, D. Helv.
Chim. Acta 2002, 85, 772-787. (e) Gawley, R. E.; Campagna, S. A.;
Santiago, M.; Ren, T. Tetrahedron: Asymmetry 2002, 13, 29-36.
(6) Pareja, C.; Martin-Zamora, E.; Ferna´ndez, R.; Lassaletta, J . M.
J . Org. Chem. 1999, 64, 8846-8854.
(7) Kise, N.; Urai, T.; Yoshida, J . Tetrahedron: Asymmetry 1998,
9, 3125-3128.
(8) Kang. J .; Kim, J . I.; Lee, J . H. Bull. Korean Chem. Soc. 1994,
15, 865-868. For the enantioselective reaction of symmetrical dithio-
acetals with R,â-unsaturated esters, see: Tomioka, K.; Sudani, M.;
Shinmi, Y.; Koga, K. Chem. Lett. 1985, 329-332.
(9) (a) Nakamura, S.; Nakagawa, R.; Watanabe, Y.; Toru, T. Angew.
Chem., Int. Ed. 2000, 39, 353-355. (b) Nakamura, S.; Nakagawa, R.;
Watanabe, Y.; Toru, T. J . Am. Chem. Soc. 2000, 122, 11340-11347.
(c) Nakamura, S.; Furutani, A.; Toru, T. Eur. J . Org. Chem. 2002,
1690-1695. For the allyl carbanion, see: Nakamura, S.; Kato, T.;
Nishimura, H.; Toru, T. Chirality 2003, in press.
(10) Toru, T.; Nakamura, S. In Organolithiums in Enantioselective
Synthesis; Hodgson, D. M., Ed.; Springer: New York, 2003; Vol. 5, pp
177-216.
(11) Intramolecular coordination of the pyridyl or quinolyl nitrogen
atom to the lithium ion promotes deprotonation.
10.1021/jo035558e CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/06/2004
J . Org. Chem. 2004, 69, 1581-1589
1581

Nakamura et al.
TABLE 1. En a n tioselective Rea ction of Sym m etr ica l
Dith ioa ceta ls w ith Ben za ld eh yd e
TABLE 2. En a n tioselective Rea ction of Va r iou s
Un sym m etr ica l Dith ioa ceta ls w ith Ben zop h en on e in th e
P r esen ce of Bis(oxa zolin e)s 7
dithioacetal
bis(oxazoline) time
yield eea
(min) product (%) (%)
entry
R
7
1
2
3
4
5
6
7
8
9
10
11
12
13
tBu
tBu
tBu
tBu
iPr
Me
Me
Ph
Ph
Mes 18
Mes 18
Tip
Tip
14
14
14
14
15
16
16
17
17
7a
7b
7c
7c
7c
7a
7c
7a
7c
7a
7c
7a
7c
60
60
60
15
15
60
15
60
15
60
15
60
15
20
20
20
20
21
22
22
23
23
24
24
25
25
73
53
86
80
92
73
80
79
75
99
47
76
81
61
68
61
68
68
40
42
dithioacetal
3b
bis(oxazoline)
yield eea
18b
60b
57b
29b
71b
entry
R
7
product
(%)
(%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
1
1
1
2
3
4
5
6
7a
7b
7c
7a
7a
7a
7a
7a
8
8
8
9
10
11
12
13
73
99
55
0
14
8
24
33
6
19
19
-(CH2)3-
tBu
5
a
Determined by HPLC analysis using Chiralpak AD-H unless
b
Mes
2-Py
2-Quinolyl
9
otherwise noted. Determined by HPLC analysis using Chiralcel
OD-H.
95
87
5b
4
a
Determined by HPLC analysis using Chiralpak AD-H unless
24 with good enantioselectivity (entries 10 and 11). The
reaction of dithioacetal 19 having a bulkier 2,4,6-triiso-
propylphenylthio group in the presence of 7c afforded 25
with high enantioselectivity (entry 13).
b
otherwise noted. Determined by HPLC analysis using Chiralcel
OD-H.
reaction with aldehydes and next examined the reaction
using unsymmetrical dithioacetals.
The reaction of dithioacetals 14-16 and 19 with
various aldehydes in the presence of 7c was examined,
and the results are shown in Table 3. Treatment of
unsymmetrical dithioacetals 14 with 1.2 equiv of n-BuLi
and 1.25 equiv of 7c in cumene for 30 min at -78 °C,
followed by the addition of benzaldehyde (1.3 equiv), gave
the product 26 in 91% yield in an anti/syn ratio of 83:17
(entry 1). Diastereomers of 26 could be easily separated
by column chromatography, and the optical purities of
anti- and syn-26 were found to be 85 and 76% ee,
respectively, by HPLC analysis using Chiralpak AD-H.15
Methylthio- and isopropylthio(2-pyridylthio)methanes 15
and 16 showed low diastereoselectivity but high enanti-
oselectivity (entries 2 and 3). Expecting a highly enan-
tioselective result as in the case of Table 2, entry 13, we
examined the reaction of the dithioacetal 19 having a
bulky substituent, 2,4,6-triisopropylphenyl group; unfor-
tunately, the anti and syn isomers could not be separated
(entry 4).16 A mixture of 14, n-BuLi, and 7c was stirred
for 15 min at -78 °C and then cooled to -95 °C.
Benzaldehyde was added at this temperature to give the
product 26 with substantially the same enantioselectivity
as that obtained in the reaction performed at -78 °C but
with slightly higher diastereoselectivity (entries 1 vs 5).
Thus, the reaction of 14 with various aromatic aldehydes
such as 2,4,6-trimethylbenzaldehyde, 2-naphthaldehyde,
We chose a pyridyl group as one of the substituents in
unsymmetrical dithioacetals, because we have previously
succeeded in a highly enantioselective reaction of the
R-(2-pyridylthio) carbanion involving intramolecular co-
ordination of the pyridyl nitrogen to the lithium ion.9,12
To optimize the reaction conditions, the reaction of alkyl-
or arylthio(2-pyridylthio)methanes 14-19 with benzophe-
none was examined under various conditions (Table 2).
The reaction of lithiated tert-butylthio(2-pyridylthio)-
methane Li-14 with benzophenone in the presence of bis-
(oxazoline)s 7 as chiral ligands gave the product 20 with
good enantioselectivities (entries 1-4). Interestingly, the
enantioselectivity of 20 using 7c depends on the time for
lithiation, shorter lithiating times giving higher enanti-
oselectivity (entries 3 vs 4).13 This is probably because
bis(oxazoline)-Ph 7c is partially isomerized to the meso-
isomer during lithiation.14 Isopropylthio(2-pyridylthio)-
methane 15 afforded 21 with good enantioselectivity
(entry 5). Introduction of a methylthio group as a less
hindered substituent lowered the enantioselectivity (en-
tries 6 and 7). Phenylthio(2-pyridylthio)methane 17
showed low enantioselectivity (entries 8 and 9), whereas
2,4,6-trimethylphenylthio(2-pyridylthio)methane 18 gave
(12) Methylthio(phenylthio)methane and tert-butylthio(phenylthio)-
methane afforded products with low ee (20-30% ee). tert-Butylthio-
(2-imidazolylthio)methane showed good enantioselectivity, but the
product could not be converted to the aldehyde in good yield.
(13) Enantioselectivity of the reaction with other bis(oxazoline)s was
not affected by the lithiating time.
(14) Formation of a small amount of the meso-isomer of 7c was
detected in the reaction of n-BuLi and 7c in cumene for 30 min at
-78 °C.
(15) Enantioselective reaction in the presence of (-)-sparteine
afforded the product in 70% yield in a diastereomer ratio of 75:25 but
with 7% ee for the major isomer.
(16) We observed that diastereomers formed in the reaction of
alkylthio(2-pyridylthio)methanes could be separated by column chro-
matography more easily than those from arylthio(2-pyridylthio)-
methanes.
1582 J . Org. Chem., Vol. 69, No. 5, 2004

Enantioselective Reaction of R-Lithiated Dithioacetals
TABLE 3. En a n tioselective Rea ction of Un sym m etr ica l Dith ioa ceta ls 14-16 a n d 19 w ith Va r iou s Ald eh yd es in th e
P r esen ce of 7c
dithioacetal
R
ee (%)b
diastereomer ratioa
anti:syn
entry
R′CHO
temp
product
yield (%)
anti
syn
1
2
3
4
5
6
7
8
9
tBu
14
15
16
19
14
14
14
14
14
14
14
14
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
-78
-78
-78
-78
-95
-95
-95
-95
-95
-95
-95
-95
26
27
28
29
26
30
31
32
33
34
35
36
91
85
99
69
93
83
92
65
91
57
63
71
83:17
65:35
60:40
67:33
86:14
90:10
80:20
81:19
85:15
63:37
68:32
55:45
85
84
72
c
85
85
83
75
88
80
81
84
76
c
60
c
73
69
69
55
71
65
64
70
iPr
Me
Tip
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
MesCHO
2-NaphCHO
p-MeOC6H4CHO
p-ClC6H4CHO
iPrCHO
10
11
12
c-HexCHO
tBuCHO
a
b
Determined by the 1H NMR analysis. Determined by the HPLC analysis using Chiralpak AD-H. c Enantiomers were not separable
by the HPLC analysis using chiral columns.
SCHEME 1
4-methoxybenzaldehyde, and 4-chlorobenzaldehyde was
carried out at -95 °C, giving products 30-33 with high
diastereoselectivities and high enantioselectivities (en-
tries 6-9). The reaction with 2-methylpropanal, cyclo-
hexanecarbaldehyde, or 2,2-dimethylpropanal also af-
forded products 34-36 with high enantioselectivities
(entries10-12).17 It should be noted that high enantiose-
lectivity was achieved in the reaction with such aliphatic
aldehydes, since only poor or no results have so far been
reported in enantioselective reactions of formyl anion
equivalents.7,8 Thus, the present reaction provides a
generally acceptable method for the highly enantioselec-
tive reaction with aromatic as well as aliphatic aldehydes.
The relative stereochemistry of anti-26 was confirmed
by X-ray analysis (see Supporting Information), and the
absolute configuration of 26 was determined after trans-
formation to the known diol as shown in the next section.
From the above results, the relative stereochemistry of
major isomers 30-36 was tentatively assigned as anti.
P r ep a r a tion of Ch ir a l Diols. Major diastereomers
26, 30, and 31 were reacted with acetic anhydride in
pyridine in the presence of 4-N,N-(dimethylamino)pyri-
dine at room temperature to give 37, 38, and 39,
respectively, which were then treated with HgCl2 in CH3-
CN/H2O at room temperature (Scheme 1).18 The formed
acetoxyaldehydes were treated, without purification, with
LiAlH4 in Et2O at 0 °C to give known chiral diols 40-
42.19,20 Optical purities of 40 and 41 were determined by
comparison with the values of specific rotation with those
(18) Meyers, A. I.; Comins, D. L.; Roland, D. M.; Henning, R.;
Shimizu, K. J . Am. Chem. Soc. 1979, 101, 7104-7105.
(19) Ko, K.-Y.; Park, J .-Y. Tetrahedron Lett. 1997, 38, 407-410.
(20) Sharpless oxidation is another choice for the preparation of
chiral dihydroxyethanes, but it shows only moderate enantioselectivity
for terminal olefins, see: (a) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483-2547. (b) Andrus, M. B.;
Lepore, S. D.; Sclafani, J . A. Tetrahedron Lett. 1997, 38, 4043-4046.
(17) Enantiomeric products obtained in the reaction with 1-pentanal
were not separable by HPLC analysis using various chiral columns.
J . Org. Chem, Vol. 69, No. 5, 2004 1583

Nakamura et al.
TABLE 4. Tem p er a tu r e Dep en d en ce of
En a n tioselective Rea ction of 14 w ith Ben za ld eh yd e
ee (%)
anti syn
diastereomer ratio
anti:syn
entry T1 (°C) T2 (°C) yield (%)
1
2
3
4
5
6
-30
-50
-78
-78
-95
-78
-30
-50
-78
-95
-95
-78a
87
80
91
93
88
47
78:22
79:21
83:17
86:14
84:16
76:24
75
78
85
85
19
76
65
65
76
73
8
F IGURE 1. Optimized structures and energies of diastereo-
meric complexes of (R)- and (S)-Li-14 with bis(oxazoline)-Ph
7c.
55
plexes.25,26 Furthermore, the reaction with an insufficient
amount of benzaldehyde resulted in slightly lower enan-
tioselectivity in comparison with that obtained in the
reaction using a stoichiometric amount of benzaldehyde
(entry 6), and thus the minor diastereomeric complex,
which gives the minor enantiomer, would have slightly
lower activation energy in the reaction with an electro-
phile.
a
PhCHO (0.2 equiv) was used.
reported.21-23 The optical purity of the product 42 was
determined by the HPLC analysis using Chiralcel
OD-H. Their stereochemistry was determined to be R by
the sign of specific rotation. From these results, the
absolute stereochemistry of the major diastereomers of
dithioacetals 26, 30, and 31 was determined to be
(1R,2S).
The diastereomeric complexes of lithiated 14 with 7c
were estimated by the MO calculation using MOPAC 93/
PM327 and Gaussian 98 HF/3-21+G* methods.28 The
relative energies of the optimized structures obtained by
the calculation are depicted in Figure 1. Both calculations
showed that the (R)-Li-14-bis(oxazoline)-Ph complex was
more stable than the (S)-Li-14-bis(oxazoline)-Ph complex,
where the lithium ion was coordinated with a pyridyl
nitrogen as well as two nitrogens of the bis(oxazoline),
giving the fully coordinated lithium complex. In the most
stable (R)-Li-14-bis(oxazoline)-Ph 7c complex, the S-CtBu
bond is arranged anti to the C-Li bond by the stabilizing
Rea ction Mech a n ism . To define the enantio-deter-
mining step in the reaction of R-lithiated dithioacetals,
we studied the temperature dependence of the stereo-
chemical outcome in the reaction of R-lithiated tert-
butylthio-(2-pyridylthio)methane 14 with benzaldehyde
(Table 4). Reaction with benzaldehyde performed at -30
and -50 °C slightly lowered the enantioselectivity in
comparison with the result performed at -78 °C (entries
1 and 2 vs entry 3). The enantioselectivity was lowered
when deprotonation was carried out at -95 °C (entry 5),
whereas deprotonation at -78 °C followed by the reaction
with benzaldehyde at -95 °C showed substantially the
same enantioselectivity as that obtained in the reaction
performed at -78 °C at both reaction steps (entries 3 vs
4). These results indicate that the diastereomeric com-
plexes derived from lithiated 14 and the bis(oxazoline)
7c are configurationally stable at temperatures lower
than -78 °C at least on the time scale of the reaction
with an aldehyde.24 Thus, the enantioselective reaction
of lithiated 14 would proceed through a dynamic ther-
modynamic resolution pathway at -78 °C, where the
enantiomeric excess of the product reflects the ratio of
the two diastereomeric Li-14-bis(oxazoline)-Ph com-
(25) For review, see: Organolithiums in Enantioselective Synthesis;
Hodgson, D. M., Ed.; Springer: New York, 2003; Vol. 5.
(26) (a) Gallagher, D. J .; Du, H.; Long, S. A.; Beak, P. J . Am. Chem.
Soc. 1996, 118, 11391-11398. (b) Faibish, N. C.; Park, Y. S.; Lee, S.;
Beak, P. J . Am. Chem. Soc. 1997, 119, 11561-11570. (c) Thayumana-
van, S.; Basu, A.; Beak, P. J . Am. Chem. Soc. 1997, 119, 8209-8216.
(c) Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J .; Beak, P. J . Am.
Chem. Soc. 1999, 121, 9522-9530.
(27) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209-220. For the
lithium parameter for PM3, see: Anders, E.; Koch, R.; Freunscht, P.
J . Comput. Chem. 1993, 14, 1301-1312.
(28) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.6; Gaussian, Inc.: Pittsburgh, PA,
1998.
(21) Matsumoto, M.; Watanabe, N.; Kobayashi, H.; Azami, M.;
Ikawa, H. Tetrahedron Lett. 1997, 38, 411-414.
(22) Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1999, 10,
1843-1846.
(23) Miao, G.; Rossiter, B. E. J . Org. Chem. 1995, 60, 8424-8427.
(24) Another reaction pathway in which the reaction at -95 °C
proceeds through an incompletely coordinated intermediate is ruled
out, since the lithiation of 14 without 7c hardly proceeds at this
temperature.
1584 J . Org. Chem., Vol. 69, No. 5, 2004

Enantioselective Reaction of R-Lithiated Dithioacetals
effect of the n - σ* negative hyperconjugation,5c,29,30
which was estimated to be 13.0 kcal/mol by the NBO
calculations.31,32 The anti conformation of the Li-C-S-
CtBu bond would play an important role in controlling the
face of approach of the aldehyde to the C-Li bond. The
aldehyde approaches the carbanionic center avoiding
steric interaction with the tert-butyl group to give the
anti isomer predominantly. In the (R)-Li-14 complex, an
electrophile such as benzophenone or benzaldehyde ap-
proaches the reaction site from the side opposite the C-Li
bond to form the product with inversion of configura-
tion.33 This stereochemical course is in accord with that
in the reaction of lithiated benzyl 2-pyridyl sulfide and
lithiated benzyl 2-quinolyl sulfide9 as well as that in the
reaction of chiral R-thiobenzyllithium derived from chiral
thiocarbamates.34
trated under reduced pressure to give the crude product, which
was purified by column chromatography (silica gel 70 g,
hexane) to give 4 (1.74 g, 44%): mp 57-58 °C; H NMR (200
1
MHz, CDCl3) δ 2.25, (s, 6H), 2.40 (s, 12H), 3.77 (s, 2H), 6.89
(s, 4H); 13C NMR (50 MHz, CDCl3) δ 21.7, 22.5, 42.5, 129.3,
130.3, 138.8, 143.2; IR (KBr) 2948, 2915, 1602, 1461, 1199,
850, 730 cm-1, EIMS m/z 316 (M+), 165, 119, 91; Anal. Calcd
for C19H24S2: C, 72.10; H, 7.64. Found: C, 72.06; H, 7.74.
Bis(2-qu in olylth io)m eth a n e (6): mp 133-134 °C; 1H
NMR δ 5.39 (s, 2H), 7.17-8.02 (m, 12H); 13C NMR δ 30.3,
120.6, 125.1, 125.8, 127.3, 127.9, 129.4, 135.2, 147.8, 157.6;
IR (KBr) 3051, 2984, 2922, 1592, 1419, 1292, 1137, 1088, 818,
745 cm-1; EIMS m/z 334 (M+) 174, 128, 101; Anal. Calcd for
C
19H14N2S2: C, 68.23; H, 4.22; N, 8.38. Found: C, 68.23; H,
4.26; N, 8.38.
Typical P r ocedu r e for Reaction of Sym m etr ical Dith io-
a ceta ls w ith Ben za ld eh yd e in th e P r esen ce of Ch ir a l
Liga n d s: 2,2-Bis(p h en ylth io)-1-p h en yleth a n ol (8). n-BuLi
(0.095 mL, 1.53 mol/L solution in hexane, 0.148 mmol) was
added to a solution of bis(phenylthio)methane 1 (29 mg, 0.12
mmol) in cumene (0.5 mL) at -78 °C, and the solution was
stirred for 10 min. A solution of bis(oxazoline)-Ph 7c (51 mg,
0.154 mmol) in cumene (0.2 mL) was then added. After stirring
for 15 min, benzaldehyde (0.02 mL, 0.160 mmol) was added
and the reaction mixture was stirred for 30 min. Saturated
aqueous NH4Cl was then added to the reaction mixture, and
the aqueous layer was extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure to give the
crude product, which was purified by column chromatography
(silica gel 20 g, hexane/ethyl acetate ) 97:3) to give 8 (23 mg,
55%). The enantiomeric excess was determined by the HPLC
analysis using Chiralpak AD-H: 1H NMR δ 3.24 (d, J ) 2.1
Hz, 1H), 3.98 (d, J ) 2.1 Hz, 1H), 4.72 (s, 1H), 7.20-7.40 (m,
15H); 13C NMR δ 68.3, 74.3, 126.5, 127.7, 127.8, 128.6, 128.8,
132.6, 133.5, 139.3; IR (neat) 3447, 3058, 1581, 1452, 1187,
848, 726 cm-1; EIMS m/z 338 (M+), 231, 153, 122, 91; Anal.
Calcd for C20H18OS2: C, 70.97; H, 5.36. Found: C, 71.08; H,
5.52. HPLC (Daicel Chiralpak AD-H, hexane/iPrOH 95/5, 0.5
mL/min) tR 13.2 and 19.2 min (6% ee).
Su m m a r y
We have demonstrated a highly enantioselective reac-
tion of lithiated unsymmetrical dithioacetals, especially
those having a 2-pyridyl group, not only with aromatic
aldehydes but also with aliphatic aldehydes. The reaction
was shown to proceed through a dynamic thermodynamic
resolution pathway with inversion of configuration of the
carbanion. The present enantioselective reaction together
with deprotection and reduction provides an efficient
method for the preparation of chiral diols.
Exp er im en ta l Section
Typ ica l P r oced u r e for th e P r ep a r a tion of Sym m etr i-
cal Dith ioacetals: Bis(2,4,6-tr im eth ylph en ylth io)m eth an e
(4). A solution of 2,4,6-trimethylbenzenethiol (3.8 g, 24.9 mmol)
and DBU (4.1 mL, 27.4 mmol) in dibromomethane (3.9 mL)
was stirred at room temperature for 4 h. Aqueous NH4Cl was
added to the reaction mixture, and the aqueous layer was
extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried over Na2SO4, filtered, and concen-
2,2-Bis(ter t-bu tylth io)-1-p h en yleth a n ol (10): mp 67-68
1
°C; H NMR δ 1.17 (s, 9H), 1.43 (s, 9H), 3.26 (d, J ) 3.6 Hz,
1H), 4.11 (d, J ) 3.6 Hz, 1H), 5.02 (s, 1H), 7.25-7.46 (m, 5H);
13C NMR δ 31.2, 31.8, 75.7, 116.5, 126.7, 127.2, 127.4, 139.9;
(29) (a) Epiotis, N. D.; Yates, R. L.; Bernardi, F.; Wolfe, S. J . Am.
Chem. Soc. 1976, 98, 5435-5439. (b) Lehn, J .-M.; Wipff, G. J . Am.
Chem. Soc. 1976, 98, 7498-7505. (c) Lehn, J .-M.; Wipff, G.; Demun-
ynck, J . Helv. Chim. Acta 1977, 60, 1239-1246. (d) Schleyer, P. R.;
Clark, T.; Kos, A. J .; Spitznagel, G. W.; Rohde, C.; Arad, D.; Houk, K.
N.; Rondan, N. G. J . Am. Chem. Soc. 1984, 106, 6467-6475. (e) Wiberg,
K. B.; Castejon, H. J . Am. Chem. Soc. 1994, 116, 10489-10497. (f)
Cuevas, G.; J uaristi, E. J . Am. Chem. Soc. 1997, 119, 7545-7549.
(30) Previously reported X-ray structures of lithiated thioethers or
thioacetals show that the C-Li bond is always in an antiperiplanar
orientation to the S-C bond; see: (a) Amstutz, R.; Seebach, D.; Seiler,
P.; Schweizer, B.; Dunitz, J . D. Angew. Chem., Int. Ed. Engl. 1980,
19, 53-54. (b) Amstutz, R.; Dunitz, J . D.; Seebach, D. A ngew. Chem.,
Int. Ed. Engl. 1981, 20, 465-466. (c) Amstutz, R.; Laube, T.; Schweizer,
B.; Seebach, D.; Dunitz, J . D. Helv. Chim. Acta 1984, 67, 224-236. (d)
Seebach, D.; Maetzke, T.; Haynes, R. K.; Paddon-Row, M. N.; Wong,
S. S. Helv. Chim. Acta 1988, 71, 299-311. (e) Zarges, W.; Marsch, M.;
Harms, K.; Koch, W.; Frenking, G.; Boche, G. Chem. Ber. 1991, 124,
543-549. (f) Becke, F.; Heinemann, F. W.; Steinborn, D. Organome-
tallics 1997, 16, 2736-2739.
(31) Glendening, E. D.; Reed, A. E.; Carpenter, J . E.; Weinhold, F.
NBO Ver. 3.1. See also: (a) Reed, A. E.; Weinstock, R. B.; Weinhold,
F. J . Chem. Phys. 1985, 83, 735-746. (b) Reed, A. E.; Curtiss, L. A.;
Weinhold, F. Chem. Rev. 1988, 88, 899-926.
(32) (a) Salzner, U.; Schleyer, P. R. J . Org. Chem. 1994, 59, 2138-
2155. (b) Cortes, F.; Tenorio, J .; Collera, O. Cuevas, G. J . Org. Chem.
2001, 66, 2918-2924. (c) Hete´nyi, A.; Martinek, T. A.; La´za´r, L.; Zala´n,
Z.; Fu¨lo¨p, F. J . Org. Chem. 2003, 68, 5707-5705.
IR (KBr) 3390, 2960, 1460, 1364, 1157, 1055, 851, 730 cm-1
;
EIMS m/z 298 (M+), 209, 191, 135, 107. Anal. Calcd for
16H26OS2: C, 64.38; H, 8.78. Found: C, 64.14; H, 8.66. HPLC
C
(Daicel Chiralpak AD-H, hexane/iPrOH 98/2, 0.5 mL/min) tR
28.3 and 43.8 min (5% ee).
1-P h en yl-2,2-bis(2,4,6-tr im eth ylph en ylth io)eth an ol (11):
1
mp 48-49 °C; H NMR δ 2.16 (s, 6H), 2.22 (s, 6H), 2.24, (s,
3H), 2.25 (s, 3H), 3.24 (d, J ) 2.1 Hz, 1H), 3.98 (d, J ) 2.1 Hz,
1H), 4.72 (s, 1H), 6.85 (s, 2H), 6.89 (s, 2H), 7.20-7.40 (m, 5H);
13C NMR δ 21.0, 21.2, 21.6, 21.6, 67.9, 74.4, 126.3, 127.1, 127.5,
127.8, 128.9, 129.3, 138.6, 138.8, 139.9, 142.8, 143.5; IR (KBr)
3526, 2919, 1453, 1186, 851, 729 cm-1; EIMS m/z 405 (M+
-
OH), 315, 271, 151, 119, 91. Anal. Calcd for C26H30OS2: C,
73.89; H, 7.15. Found: C, 73.75; H, 7.22. HPLC (Daicel
Chiralpak AD-H, hexane/iPrOH 95/5, 0.5 mL/min) tR 14.5 and
21.0 min (9% ee).
1-P h en yl-2,2-bis(2-p yr id ylth io)eth a n ol (12). 1H NMR δ
2.05 (s, 1H), 5.48 (d, J ) 3.6 Hz, 1H), 6.15 (d, J ) 3.6 Hz, 1H),
7.00-7.80 (m, 11H), 8.40-8.55 (m, 2H); 13C NMR δ 56.8, 76.3,
120.0, 122.8, 126.4, 127.2, 127.6, 136.2, 136.2, 141.9, 148.5,
148.7, 156.1, 156.9; IR (KBr) 3396, 3061, 2850, 1730, 1577,
1281, 1121, 854, 757 cm-1; EIMS m/z 340 (M+), 233, 211, 122,
76. Anal. Calcd for C18H16N2OS2: C, 63.50; H, 4.74; N, 8.23.
Found: C, 63.57; H, 4.83; N, 8.10. HPLC (Daicel Chiralcel OD-
H, hexane/iPrOH 80/20, 0.5 mL/min) tR 31.0 and 37.2 min (5%
ee).
(33) It can be reasonably assumed that the (R)-Li-13 complex
affords the product with inversion of the configuration because the
HOMO lobe of the carbanionic center significantly expands in the
direction opposite the C-Li bond (HF/3-21+G*).
(34) Stratmann, O.; Kaiser, B.; Fro¨hlich, R.; Meyer, O.; Hoppe, D.
Chem.sEur. J . 2001, 7, 423-435.
1-P h en yl-2,2-b is(2-qu in olylt h io)et h a n ol (13): mp 61-
62 °C; 1H NMR δ 1.40-1.80 (br, 1H), 5.64 (d, J ) 3.2 Hz, 1H),
J . Org. Chem, Vol. 69, No. 5, 2004 1585

Nakamura et al.
6.62 (d, J ) 3.2 Hz, 1H), 7.14-8.03 (m, 17H); 13C NMR δ 56.4,
120.7, 120.8, 125.6, 125.8, 125.9, 126.4, 127.2, 127.4, 127.7,
129.8, 135.8, 142.1, 147.3, 157.8; IR (KBr) 3410, 3059, 2920,
1591, 1496, 1137, 1088, 816, 749 cm-1; EIMS m/z 440 (M+),
307, 196, 168,124, 77. Anal. Calcd for C26H20N2OS2: C, 70.88;
H, 4.58; N, 6.36. Found: C, 70.86; H, 4.81; N, 6.14. HPLC
(Daicel Chiralcel OD-H, hexane/iPrOH 98/2, 0.9 mL/min) tR
52.5 and 57.8 min (1% ee).
Typ ica l P r oced u r e for th e Rea ction of Un sym m etr ica l
Dith ioa ceta ls w ith Electr op h iles. 2-(ter t-Bu tylth io)-1,1-
d ip h en yl-2-(2-p yr id ylth io)eth a n ol (20). n-BuLi (0.055 mL,
1.49 mol/L solution in hexane, 0.078 mmol) was added at -78
°C to a solution of 14 (14 mg, 0.065 mmol) in cumene (0.5 mL),
and the solution was stirred for 10 min. A solution of 7c (27
mg, 0.081 mmol) in cumene (0.2 mL) was then added. After
the reaction mixtre was stirred for 15 min, a solution of
benzophenone (15 mg, 0.084 mL) in cumene (0.1 mL) was
added and the reaction mixture was stirred for an additional
30 min. Saturated aqueous NH4Cl was then added to the
reaction mixture, and the aqueous layer was extracted with
CH2Cl2. The combined organic extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure to give the crude product which was purified
by column chromatography (silica gel 15 g, hexane/ethyl
acetate ) 98:2) to give 20 (18 mg, 70%). The enantiomeric
excess was determined by HPLC analysis using Chiralpak
AD-H: mp 128-129 °C; [R]20D -9.76 (c 0.444, CHCl3, 61% ee);
1H NMR δ 1.21 (s, 9H), 5.60 (s, 1H), 6.73 (s, 1H), 7.00-8.45
(m, 14H); 13C NMR δ 30.6, 45.4, 59.8, 82.8, 120.1, 123.3, 126.7,
127.2, 127.5, 127.8, 136.5, 136.7, 146.3, 148.5, 157.7; IR (KBr)
Typ ica l P r oced u r e for P r ep a r a tion of Un sym m etr ica l
Dith ioacetals: ter t-Bu tylth io(2-pyr idylth io)m eth an e (14).
To a solution of 2-pyridinethiol (365 mg, 3.28 mmol) and DBU
(0.52 mL, 3.61 mmol) in acetonitrile (5 mL) was added
bromochloromethane (4.5 mL, 32.8 mL) at room temperature.
The resulting solution was stirred at room temperature for 2
h. The reaction mixture was concentrated under reduced
pressure to afford the crude product containing mainly chlo-
romethyl 2-pyridyl sulfide. To a solution of the crude product
in acetonitrile (10 mL) was added 1,1-dimethylethanethiol
(0.44 mL, 4.92 mmol) and DBU (0.76 mL, 5.24 mmol) at room
temperature, and the reaction mixture was stirred for 3 h.
Aqueous NH4Cl was added to the reaction mixture, and the
aqueous layer was extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure to give the
crude product, which was purified by column chromatography
(silica gel 30 g, hexane/ethyl acetate ) 98:2) to give 14 (497
mg, 71%): 1H NMR δ 1.41 (s, 9H), 4.40 (s, 2H), 6.98-8.47 (m,
4H); 13C NMR δ 29.8, 30.9, 119.7, 122.2, 136.0, 149.5; IR (neat)
3044, 2960, 2862, 1577, 1454, 1414, 1281, 1122, 1042, 757
3456, 2965, 1573, 1454, 1363, 1119, 1049, 802, 750, 701 cm-1
;
EIMS m/z 378 (M+ - OH), 319, 212, 182, 155, 111, 56. Anal.
Calcd for C23H25NOS2: C, 69.83; H, 6.37; N, 3.54. Found: C,
69.62; H, 6.59; N, 3.53. HPLC (Daicel Chiralpak AD-H, hexane/
iPrOH 90/10, 1.0 mL/min) tR 8.4 (S) and 16.5 (R) min (61%
ee).
2-Isop r op ylt h io-1,1-d ip h e n yl-2-(2-p yr id ylt h io)e t h a -
cm-1; EIMS m/z 213 (M+), 156, 112, 57. Anal. Calcd for C10H15
-
1
n ol (21): mp 101 °C; [R]20 26.2 (c 0.202, CHCl3, 68% ee); H
D
NS2: C, 56.30; H, 7.09; N, 6.56. Found: C, 56.46; H, 7.07; N,
6.42.
NMR δ 1.15 (d, J ) 6.6 Hz, 3H), 1.25 (d, J ) 6.6 Hz, 3H), 2.91
(sep, J ) 6.6 Hz, 1H), 5.75 (s, 1H), 6.58 (s, 1H), 6.99-8.45 (m,
14H); 13C NMR δ 22.8, 23.3, 36.7, 61.9, 120.1, 123.5, 126.4,
126.7, 127.3, 127.4, 136.2, 144.0, 145.9, 148.2, 155.4; IR (KBr)
Isop r op ylth io(2-p yr id ylth io)m eth a n e (15).36 1H NMR δ
1.31 (d, J ) 3.3 Hz, 6H), 3.17 (sep, J ) 3.3 Hz, 1H), 4.39 (s,
2H), 6.95-8.42 (m, 4H): 13C NMR δ 23.2, 32.0, 35.2, 119.5,
122.1, 135.7, 149.1, 157.6; IR (neat) 2958, 2923, 1577, 1453,
1415, 1122, 758 cm-1; EIMS m/z 199 (M+), 156, 123, 112, 77.
Anal. Calcd for C9H13NS2: C, 54.23; H, 6.57; N, 7.02. Found:
C, 54.16; H, 6.75; N, 7.05.
3456, 2965, 1573, 1454, 1363, 1119, 1049, 802, 750, 701 cm-1
;
EIMS m/z 364 (M+ - OH), 320, 241, 199, 156, 124, 77. Anal.
Calcd for C22H23NOS2: C, 69.26; H, 6.08; N, 3.67. Found: C,
69.08; H, 6.19; N, 3.67. HPLC (Daicel Chiralcel OD-H, hexane/
iPrOH 97/3, 0.5 mL/min) tR 14.1 (S) and 17.9 (R) min (68%
ee).
Meth ylth io(2-p yr id ylth io)m eth a n e (16).37 1H NMR δ
2.24 (s, 3H), 4.36 (s, 2H), 6.98-8.47 (m, 4H); IR (neat) 3044,
2980, 2913, 1576, 1414, 1207, 1122, 985, 756 cm-1; EIMS m/z
171 (M+), 156, 123, 112, 77, 61.
2-Meth ylth io-1,1-diph en yl-2-(2-pyr idylth io)eth an ol (22):
mp 96-97 °C; [R]20 -38.1 (c 0.340, CHCl3, 42% ee); 1H NMR
D
δ 2.12 (s, 3H), 5.63 (s, 1H), 6.75 (s, 1H), 7.00-8.49 (m, 14H);
13C NMR δ 16.8, 65.4, 81.1, 120.4, 123.9, 126.3, 126.6, 127.7,
128.4, 136.7, 144.7, 146.5, 148.6, 156.9; IR (KBr) 3440, 3031,
2817, 1589, 1468, 1134, 1074, 740, 700 cm-1; EIMS m/z 353
(M+), 288, 213, 171, 124, 77; Anal. Calcd for C20H19NOS2: C,
67.96; H, 5.42; N, 3.96. Found: C, 67.92; H, 5.56; N, 4.15.
HPLC (Daicel Chiralpak AD-H, hexane/iPrOH 95/5, 0.5 mL/
min) tR 22.6 (R) and 30.4 (S) min (42% ee).
P h en ylth io(2-p yr id ylth io)m eth a n e (17): mp 35-36 °C;
1H NMR δ 4.72 (s, 2H), 6.95-8.45 (m, 9H); 13C NMR δ 35.6,
119.6, 122.3, 126.6, 128.6, 130.4, 135.1, 135.8, 149.1, 156.0;
IR (KBr) 3037, 2987, 1577, 1453, 1411, 1208, 1122, 800, 730
cm-1; EIMS m/z 233 (M+), 124, 77. Anal. Calcd for C12H11NS2:
C, 61.76; H, 4.75; N, 6.00. Found: C, 61.86; H, 4.77; N, 6.01.
2-P yr id ylth io(2,4,6-tr im eth ylp h en ylth io)m eth a n e (18):
mp 34-35 °C; 1H NMR δ 2.25 (s, 3H), 2.52 (s, 6H), 4.45 (s,
2H), 6.91 (s, 2H), 6.95-8.46 (m, 4H); 13C NMR δ 21.1, 22.2,
36.6, 77.6, 119.5, 122.2, 128.6, 135.6, 138.3, 143.0, 149.0, 157.2,
167.6; IR (KBr) 2994, 2914, 1577, 1452, 1160, 1124, 849, 726
cm-1; EIMS m/z 275 (M+), 228, 195, 164, 123, 76, 50. Anal.
Calcd for C15H17NS2: C, 65.41; H, 6.22; N, 5.09. Found: C,
65.50; H, 6.26; N, 5.27.
2-P yr id ylt h io(2,4,6-t r iisop r op ylp h en ylt h io)m et h a n e
(19): mp 65-66 °C; 1H NMR δ 1.23 (d, J ) 6.8 Hz, 12H), 1.24
(d, J ) 7.0 Hz, 6H), 2.86 (sep, J ) 7.0 Hz, 1H), 3.97 (sep, J )
6.8 Hz, 2H), 4.42 (s, 2H), 7.01 (s, 2H), 6.95-8.43 (m, 4H); 13C
NMR δ 23.7, 24.3, 31.1, 34.1, 37.7, 119.2, 121.2, 121.9, 127.3,
135.4, 148.2, 149.3, 152.6, 156.8; IR (KBr) 2961, 2865, 1577,
1453, 1148, 878, 725 cm-1; EIMS m/z 359, 233, 191, 149, 124,
77. Anal. Calcd for C21H29NS2: C, 70.14; H, 8.13; N, 3.90.
Found: C, 70.18; H, 8.24; N, 3.91.
1,1-Diph en yl-2-ph en ylth io-2-(2-pyr idylth io)eth an ol (23).
1
[R]20 33.1 (c 0.226, CHCl3, 18% ee); H NMR δ 5.30 (s, 1H),
D
5.95 (s, 1H), 7.04-8.28 (m, 19H); 13C NMR δ 67.5, 81.5, 120.6,
124.4, 126.2, 126.4, 126.9, 128.7, 132.7, 135.0, 136.8, 144.9,
146.7, 148.6, 156.4; IR (KBr) 3056, 2824, 1583, 1456, 1413,
804, 729 cm-1; EIMS m/z 398 (M+ - OH), 288, 233, 167, 124,
77. Anal. Calcd for C25H21NOS2: C, 72.26; H, 5.09; N, 3.37.
Found: C, 72.16; H, 5.27; N, 3.28. HPLC (Daicel Chiralpak
AD-H, hexane/iPrOH 90/10, 0.5 mL/min) tR 14.2 (S) and 17.8
(R) min (18% ee).
1,1-Dip h en yl-2-(2-p yr id ylth io)-2-(2,4,6-tr im eth ylp h en -
ylth io)eth a n ol (24): mp 129-130 °C; [R]20 17.8 (c 0.188,
D
1
CHCl3, 57% ee); H NMR δ 2.11 (s, 3H), 2.23 (s, 6H), 5.27 (s,
1H), 6.26 (s, 1H), 6.64 (s, 2H), 6.88-8.29 (m, 14H); 13C NMR
δ 22.1, 65.8, 81.2, 119.6, 123.0, 126.0, 126.1, 126.6, 126.8, 127.4,
127.6, 127.9, 128.2, 135.5, 138.1, 143.6, 147.7; IR (KBr) 3064,
1582, 1456, 1123, 852, 699 cm-1; EIMS m/z 440 (M+ - OH),
306, 275, 195, 167, 124, 91. Anal. Calcd for C28H27NOS2: C,
73.49; H, 5.95; N, 3.06. Found: C, 73.53; H, 6.10; N, 2.99.
HPLC (Daicel Chiralcel OD-H, hexane/iPrOH 90/10, 0.5 mL/
min) tR 44.9 (S) and 50.7 (R) min (57% ee).
(35) Ono, N.; Miyake, H.; Saito, T.; Kaji, A. Synthesis 1980, 952-
953.
(36) Reich, H. J .; Sikorski, W. H.; Gudmundsson, B. O¨ .; Dykstra,
R. R. J . Am. Chem. Soc. 1998, 120, 4035-4036.
(37) Erian, A. W.; Konno, A.; Fuchigami, T. J . Org. Chem. 1995,
60, 7654-7659.
1586 J . Org. Chem., Vol. 69, No. 5, 2004

Enantioselective Reaction of R-Lithiated Dithioacetals
1,1-Diph en yl-2-(2-pyr idylth io)-2-(2,4,6-tr iisopr opylph en -
1-P h en yl-2-(2-pyr idylth io)-2-(2,4,6-tr iisopr opylph en ylth -
ylth io)eth a n ol (25): [R]20 95.8 (c 0.352, CHCl3, 71% ee); 1H
io)eth a n ol (29). An inseparable diastereomeric mixture of
D
1
NMR δ 0.97 (d, J ) 7.0 Hz, 6H), 1.03 (d, J ) 7.0 Hz, 6H), 1.14
(d, J ) 7.0 Hz, 6H), 2.74 (sep, J ) 7.0 Hz, 1H), 3.32 (br, 2H),
29: mp 124-125 °C; H NMR δ 0.92-1.23 (m, 18H), 1.62 (s,
1H), 2.79 (sep, J ) 6.6 Hz, 1H (major)), 3.10-3.30 (m, 2H
(major), 1H (minor)), 3.67 (sep, J ) 6.4 Hz, 2H (minor)), 4.58
(d, J ) 5.8 Hz, 1H (minor)), 4.62 (d, J ) 1.8 Hz, 1H (major)),
5.15 (br, 1H (major)), 5.54 (br, 1H (major)), 6.88 (s, 2H (major)),
6.96 (s, 2H (minor)), 7.02-7.67 (m, 8H), 8.41 (m, 1H); 13C NMR
δ 14.1, 14.6, 22.7, 23.9, 24.1, 24.6, 28.1, 31.1, 31.5, 34.2, 38.9,
66.7, 74.6, 78.0, 119.8, 120.1, 121.5, 121.6, 123.0, 125.6, 126.0,
126.2, 126.6, 127.2, 127.4, 127.5, 127.7, 128.1, 136.2, 141.1,
142.0, 148.1, 148.2, 149.6, 153.1, 153.3, 157.1, 158.0; IR (KBr)
3398, 2620, 1582, 1456, 1414, 1060, 877, 761, 707 cm-1; EIMS
m/z 465 (M+), 358, 243, 211, 122. Anal. Calcd for C28H35NOS2:
C, 72.21; H, 7.57; N, 3.01. Found: C, 72.06; H, 7.71; N, 3.01.
5.71 (s, 1H), 6.88 (s, 2H), 7.00 (s, 1H), 6.88-8.31 (m, 14H); 13
C
NMR δ 23.9, 24.5, 31.2, 34.2, 53.4, 69.1, 81.7, 119.7, 121.4,
123.0, 126.5, 127.8, 136.0, 144.9, 146.2, 148.1, 149.9, 153.9,
157.3; IR (KBr) 3480, 2960, 1581, 1450, 1121, 876, 702 cm-1
;
EIMS m/z 524 (M+ - OH), 358, 325, 195, 167, 124, 91. Anal.
Calcd for C34H39NOS2: C, 75.37; H, 7.26; N, 2.59. Found: C,
75.16; H, 7.52; N, 2.53. HPLC (Daicel Chiralpak AD-H, hexane/
iPrOH 95/5, 0.5 mL/min) tR 9.7 (R) and 16.4 (S) min (71% ee).
2-(ter t-Bu tylth io)-1-ph en yl-2-(2-pyr idylth io)eth an ol (26).
a n ti-26: mp 75-76 °C; [R]20 -57.3 (c 0.272, CHCl3, 85% ee);
D
1H NMR δ 1.21 (s, 9H), 4.28 (d, J ) 3.0 Hz, 1H), 5.28 (d, J )
3.0 Hz, 1H), 5.73 (s, 1H), 7.20-8.50 (m, 9H); 13C NMR δ 30.8,
44.5, 56.2, 77.6, 120.1, 123.0, 127.1, 127.3, 127.5, 127.6, 136.6,
140.8, 148.9; IR (KBr) 3398, 3047, 2954, 1579, 1556, 1455,
1364, 1154, 1220, 848 cm-1; EIMS m/z 319 (M+), 243, 211, 155,
111. Anal. Calcd for C17H21NOS2: C, 63.91; H, 6.63; N, 4.38.
Found: C, 63.84; H, 6.73; N, 4.38. HPLC (Daicel Chiralpak
AD-H, hexane/iPrOH 90/10, 0.5 mL/min) tR 5.9 (1R,2S) and
2-ter t-Bu tylth io-2-(2-pyr idylth io)-1-(2,4,6-tr im eth ylph en -
yl)eth a n ol (30). a n ti-30: [R]20 -26.3 (c 0.108, CHCl3, 85%
D
1
ee); H NMR δ 1.52 (s, 9H), 2.05 (s, 3H), 2.45 (s, 6H), 3.52 (s,
1H), 5.13 (d, J ) 10.0 Hz, 1H), 5.63 (d, J ) 10.0 Hz, 1H), 6.47
(s, 2H), 6.65-8.29 (m, 4H); 13C NMR δ 20.7, 21.6, 31.4, 45.9,
54.1, 73.2, 73.2, 119.7, 122.5, 129.2, 131.2, 135.1, 136.1, 137.0,
148.2, 156.8; IR (neat) 3486, 2961, 1725, 1576, 1453, 1425,
1120, 1042, 849, 733 cm-1; EIMS m/z 361 (M+), 285, 212, 155,
111. Anal. Calcd for C20H27NOS2: C, 66.44; H, 7.53; N, 3.87.
Found: C, 66.57; H, 7.82; N, 3.84. HPLC (Daicel Chiralpak
AD-H, hexane/iPrOH 95/5, 0.7 mL/min) tR 10.4 (1S,2R) and
8.1 (1S,2R) min (85% ee). syn -26: [R]20 16.0 (c 0.332, CHCl3,
D
71% ee); 1H NMR δ 1.26 (s, 9H), 4.85 (d, J ) 6.5 Hz, 1H), 4.90-
5.00 (br, 1H), 6.30-6.40 (br, 1H), 7.20-8.55 (m, 9H); 13C NMR
δ 30.7, 45.0, 56.5, 78.0, 120.3, 123.5, 127.2, 127.5, 127.8, 136.7,
142.6, 148.8; IR (neat) 3430, 3061, 2959, 1578, 1454, 1415,
1120, 759 cm-1; EIMS m/z 319 (M+), 243, 211, 155, 111. Anal.
Calcd for C17H21NOS2: C, 63.91; H, 6.63; N, 4.38. Found: C,
63.89; H, 6.82; N, 4.26. HPLC (Daicel Chiralcel OD-H, hexane/
iPrOH 98/2, 0.5 mL/min) tR 19.2 (1S,2S) and 21.4 (1R,2R) min
(71% ee).
12.6 (1R,2S) min (85% ee). syn -30: [R]20 11.2 (c 0.84, CHCl3,
D
77% ee): 1H NMR δ 1.17 (s, 9H), 2.24 (s, 3H), 2.53 (s, 6H),
2.89 (s, 1H), 5.21 (d, J ) 10.4 Hz, 1H), 5.28 (d, J ) 10.4 Hz,
1H), 6.78 (s, 2H), 7.03-8.42 (m, 4H); 13C NMR δ 20.9, 21.5,
30.8, 45.2, 120.2, 123.1, 129.6, 134.2, 136.1, 136.5, 148.3, 158.8;
IR (neat) 3400, 2959, 1578, 145, 1415, 1120, 851, 759 cm-1
;
EIMS m/z 287 (M+ - OH, -C4H9), 285, 212, 155, 111. Anal.
Calcd for C20H27NOS2: C, 66.44; H, 7.53; N, 3.87. Found: C,
66.15; H, 7.50; N, 4.18. HPLC (Daicel Chiralpak OJ -H, hexane/
iPrOH 98/2, 0.5 mL/min) tR 25.9 (1S,2S) and 29.3 (1R,2R) min
(77% ee).
2-Isop r op ylth io-1-p h en yl-2-(2-p yr id ylth io)eth a n ol (27).
a n ti-27: [R]20D -75.8 (c 0.350, CHCl3, 85% ee); 1H NMR δ 1.18
(d, J ) 6.6 Hz, 6H), 3.05 (sep, J ) 6.6 Hz, 1H), 5.06 (d, J ) 3.2
Hz, 1H), 5.19 (d, J ) 3.2 Hz, 1H), 6.20 (s, 1H), 7.00-8.44 (m,
9H); 13C NMR δ 23.1, 23.8, 36.1, 58.4, 77.9, 120.3, 123.2, 127.2,
127.6, 127.7, 136.7, 140.7, 148.7, 158.5; IR (neat) 3411, 3061,
2-ter t-Bu tylth io-1-(2-n a p h th yl)-2-(2-p yr id ylth io)eth a -
n ol (31). a n ti-31: mp 92-93 °C; [R]20D -47.7 (c 0.166, CHCl3,
83% ee); 1H NMR δ 1.18 (s, 9H), 5.07 (d, J ) 2.8 Hz, 1H), 5.45
(d, J ) 2.8 Hz, 1H), 5.95-6.09 (br, 1H), 7.06-8.49 (m, 11H);
13C NMR δ 30.8, 44.6, 56.2, 77.7, 119.9, 122.9, 125.1, 125.3,
126.1, 126.8, 127.2, 127.9, 132.6, 132.7, 136.3, 138.0, 145.9,
148.5, 158.2; IR (KBr) 3438, 3053, 2958, 1454, 1414, 1120, 858,
802, 759 cm-1; EIMS m/z 311 (M+ - C4H9), 293, 257, 212, 155,
111. Anal. Calcd for C21H23NOS2: C, 68.26; H, 6.27; N, 3.79.
Found: C, 68.35; H, 6.26; N, 3.78. HPLC (Daicel Chiralpak
AD-H, hexane/iPrOH 90/10, 1.0 mL/min) tR 24.5 (1R,2S) and
43.0 (1S,2R) min (83% ee). syn -31: [R]20D 51.3 (c 0.306, CHCl3,
69% ee); 1H NMR δ 1.27 (s, 9H), 5.05 (d, J ) 6.4 Hz, 1H), 5.16
(d, J ) 6.4 Hz, 1H), 6.58-6.65 (br, 1H), 7.09-8.50 (m, 11H);
13C NMR δ 30.1, 45.0, 56.5, 78.2, 116.5, 120.1, 123.3, 124.7,
125.4, 125.5, 126.0, 127.2, 127.3, 127.8, 132.6, 135.4, 139.8,
148.4, 157.5; IR (neat) 3404, 3053, 2959, 145, 1415, 1121, 857,
803, 748 cm-1; EIMS m/z 311 (M+ - C4H9), 293, 257, 212, 155,
111. Anal. Calcd for C21H23NOS2: C, 68.26; H, 6.27; N, 3.79.
Found: C, 68.46; H, 6.21; N, 3.90. HPLC (Daicel Chiralcel OD-
H, hexane/iPrOH 98/2, 1.0 mL/min) tR 38.1 (1R,2R) and 48.3
(1S,2S) min (69% ee).
2959, 2924, 1721, 1579, 1453, 1415, 1121, 1054, 851, 700 cm-1
EIMS m/z 288 (M+ - OH), 243, 199, 155, 111. Anal. Calcd for
16H19NOS2: C, 62.92; H, 6.27; N, 4.59. Found: C, 62.70; H,
;
C
6.43; N, 4.64. HPLC (Daicel Chiralcel OD-H, hexane/iPrOH
97/3, 0.5 mL/min) tR 26.3 (1S,2R) and 31.8 (1R,2S) min (85%
1
ee). syn -27: [R]20 62.2 (c 0.154, CHCl3); H NMR δ 1.20 (d, J
D
) 6.4 Hz, 6H), 3.08 (sep, J ) 6.4 Hz, 1H), 4.89 (d, J ) 6.4 Hz,
1H), 4.97 (d, J ) 6.4 Hz, 1H), 6.36 (s, 1H), 7.04-8.45 (m, 9H);
13C NMR δ 22.8, 23.6, 35.9, 58.1, 76.6, 120.2, 123.0, 126.9,
127.3, 136.4, 140.4, 148.5, 158.2; IR (neat) 3391, 3061, 2959,
2923, 1578, 1453, 1415, 1121, 1050, 854, 760 cm-1; EIMS m/z
305 (M+), 286, 243, 199, 155, 111. Anal. Calcd for C16H19
-
NOS2: C, 62.92; H, 6.27; N, 4.59. Found: C, 62.71; H, 6.45;
N, 4.60.
2-Meth ylth io-1-p h en yl-2-(2-p yr id ylth io)eth a n ol (28).
a n ti-28: [R]20D -122 (c 0.340, CHCl3, 69% ee ); 1H NMR δ 2.15
(s, 3H), 4.93 (d, J ) 3.3 Hz, 1H), 5.34 (d, J ) 3.3 Hz, 1H), 6.19
(s, 1H), 7.03-8.42 (m, 9H); 13C NMR δ 15.7, 61.8, 77.5, 120.2,
123.3, 126.8, 127.5, 127.6, 136.5, 140.3, 148.5, 157.8; IR (neat)
3412, 3061, 2915, 2851, 1579, 1453, 1415, 849, 759, 456 cm-1
;
EIMS m/z 260 (M+-OH), 243, 169, 122, 90. Anal. Calcd for
14H15NOS2: C, 60.62; H, 5.45; N, 5.05. Found: C, 60.65; H,
C
2-ter t-Bu tylth io-1-(4-m eth oxyph en yl)-2-(2-pyr idylth io)-
5.47; N, 4.98. HPLC (Daicel Chiralpak AD-H, hexane/iPrOH
eth a n ol (32). a n ti-32: mp 88-89 °C; [R]20 15.5 (c 0.092,
D
90/10, 1.0 mL/min) tR 17.7 (1R,2S) and 19.7 (1S,2R) min (69%
CHCl3, 75% ee); 1H NMR δ 1.23 (s, 9H), 3.79 (s, 3H), 5.08 (br,
1H), 5.24 (d, J ) 3.0 Hz, 1H), 5.82 (s, 1H), 6.81-8.45 (m, 8H);
13C NMR δ 30.9, 45.0, 55.2, 56.5, 77.4, 112.9, 120.0, 123.2,
128.0, 134.5, 136.4, 148.4, 158.5; IR (KBr) 3350, 3046, 2954,
1582, 1514, 1456, 1416, 1252, 1120, 830, 762 cm-1; EIMS m/z
349 (M+), 331, 212, 155, 111. Anal. Calcd for C18H23NO2S2: C,
61.86; H, 6.63; N, 4.01. Found: C, 62.10; H, 6.79; N, 4.14.
HPLC (Daicel Chiralpak AD-H, hexane/iPrOH 90/10, 1.0 mL/
1
ee). syn -28: [R]20 69.0 (c 0.350, CHCl3, 57% ee); H NMR δ
D
2.20 (s, 3H), 4.73 (d, J ) 6.8 Hz, 1H), 5.00 (d, J ) 6.8 Hz, 1H),
6.59 (d, J ) 6.8 Hz, 1H), 7.26-8.42 (m, 9H); 13C NMR δ 16.1,
61.8, 77.1, 120.4, 123.9, 126.4, 127.5, 127.8, 136.7, 143.3, 148.3,
160.5; IR (neat) 3368, 3060, 2916, 2853, 1453, 1415, 853, 761
cm-1; EIMS m/z 277 (M+), 243, 169, 122, 90. Anal. Calcd for
C
14H15NOS2: C, 60.61; H, 5.45; N, 5.05. Found: C, 60.60; H,
5.66; N, 5.20. HPLC (Daicel Chiralpak AD-H, hexane/iPrOH
90/10, 1.0 mL/min) tR 22.0 (1S,2S) and 27.0 (1R,2R) min
(57% ee).
min) tR 26.3 (1R,2S) and 43.4 (1S,2R) min (75% ee). syn -32:
1
[R]20 31.3 (c 0.474, CHCl3, 55% ee); H NMR δ 1.26 (s, 9H),
D
3.89 (s, 3H), 4.95 (d, J ) 6.4 Hz, 1H), 5.05 (br, 1H), 6.09-6.21
J . Org. Chem, Vol. 69, No. 5, 2004 1587

Nakamura et al.
(br, 1H), 6.85-8.53 (m, 8H); 13C NMR δ 30.9, 44.9, 55.2, 56.5,
77.4, 112.9, 120.0, 123.2, 127.9, 134.5, 136.3, 148.4, 157.8,
158.5; IR (neat) 3435, 3046, 2958, 1578, 1511, 1455, 1415,
1247, 1120, 831, 760 cm-1; EIMS m/z 349 (M+), 273, 212, 155,
111, 56. Anal. Calcd for C18H23NO2S2: C, 61.86; H, 6.63; N,
4.01. Found: C, 61.87; H, 6.86; N, 3.77. HPLC (Daicel Chiralcel
OD-H, hexane/iPrOH 95/5, 0.5 mL/min) tR 25.6 (1R,2R) and
30.0(1S,2S) min (55% ee).
148.6, 157.7; IR (KBr) 3400, 2954, 1646, 1455, 1417, 1154,
1122, 1071, 753 cm-1; EIMS m/z 299 (M+), 242, 223, 155, 111,
56. Anal. Calcd for C15H25NOS2: C, 60.16; H, 8.41; N, 4.68.
Found: C, 60.06; H, 8.48; N, 4.52. HPLC (Daicel Chiralpak
AD-H, hexane/iPrOH 90/10, 0.5 mL/min) tR 20.7 (1R,2S) and
37.7 (1S,2R) min (88% ee). syn -36: mp 55-56 °C; [R]20D -179.7
(c 0.182, CHCl3, 70% ee); 1H NMR δ 1.05 (s, 9H), 1.36 (s, 9H),
3.74 (br, 1H), 4.97 (d, J ) 2.8 Hz, 1H), 5.60 (s, 1H), 7.01-8.44
(m, 4H); 13C NMR δ 26.8, 31.0, 36.8, 45.1, 52.3, 83.6, 119.9,
123.7, 136.2, 148.3, 156.2; IR (KBr) 3389, 2957, 1577, 1453,
1413, 1280, 1125, 1075, 755 cm-1; EIMS m/z 299(M+), 242, 223,
155, 111, 56. Anal. Calcd for C15H25NOS2: C, 60.16; H, 8.41;
N, 4.68. Found: C, 60.26; H, 8.49; N, 4.66. HPLC (Daicel
Chiralpak AD-H, hexane/iPrOH 98/2, 0.5 mL/min) tR 13.6
(1S,2S) and 15.4 (1R,2R) min (88% ee).
1-(4-Ch lor op h en yl)-2-ter t-bu tylth io-2-(2-p yr id ylth io)-
eth a n ol (33). a n ti-33: mp 115-116 °C; [R]20 -44.6 (c 0.298,
D
1
CHCl3, 88% ee); H NMR δ 1.22 (s, 9H), 4.92 (d, J ) 3.0 Hz,
1H), 5.26 (d, J ) 3.0 Hz, 1H), 6.04 (s, 1H), 7.08-8.45 (m, 8H);
13C NMR δ 30.9, 44.7, 55.8, 77.5, 120.0, 122.8, 127.3, 128.5,
133.0, 136.5, 138.9, 148.5, 158.0; IR (KBr) 3293, 2957, 1582,
1557, 1490, 1456, 1416, 1216, 1159, 1121, 813, 765 cm-1; EIMS
m/z 295 (M+ - C4H9), 277, 212, 155, 111. Anal. Calcd for
Acetyla tion of Eth a n ols 26, 30, a n d 31: 1-Acetoxy-2-
(ter t-bu tylth io)-1-p h en yl-2-(2-p yr id ylth io)eth a n e (37). To
a solution of anti-26 (132 mg, 0.413 mmol) in pyridine (1.0
mL) were added DMAP (5.1 mg, 0.04 mmol) and acetic
anhydride (0.08 mL, 0.826 mmol) at room temperature, and
the mixture was stirred for 3 h. Saturated aqueous NH4Cl was
then added to the reaction mixture, and the aqueous layer was
extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure to give the crude product, which
was purified by column chromatography (silica gel 25 g,
hexane/ethyl acetate ) 96:4) to give 37 (110 mg, 73%). The
enantiomeric excess was determined by HPLC analysis using
Chiralpak AD-H: 1H NMR δ 1.34 (s, 9H), 1.94 (s, 3H), 5.75
(d, J ) 5.6 Hz, 1H), 6.06 (d, J ) 5.6 Hz, 1H), 7.00-8.41 (m,
C
17H20ClNOS2: C, 57.69; H, 5.70; N, 3.96. Found: C, 57.78;
H, 5.82; N, 3.91. HPLC (Daicel Chiralpak AD-H, hexane/iPrOH
90/10, 1.0 mL/min) tR 13.7 (1R,2S) and 22.9 (1S,2R) min (88%
1
ee). syn -33: [R]20 30.6 (c 0.158, CHCl3, 71% ee); H NMR δ
D
1.25 (s, 9H), 4.76 (d, J ) 6.6 Hz, 1H), 4.92 (d, J ) 6.4 Hz, 1H),
6.42 (s, 1H), 6.85-8.53 (m, 8H); 13C NMR δ 30.8, 45.1, 56.2,
77.3, 120.2, 123.3, 127.5, 128.3, 132.8, 136.5, 140.9, 148.4,
157.5; IR (neat) 3450, 2959, 1721, 1579, 1454, 1119, 811, 760
cm-1; EIMS m/z 296 (M+ - C4H9), 277, 212, 155, 111, 56. Anal.
Calcd for C17H20ClNOS2: C, 57.69; H, 5.70; N, 3.96. Found:
C, 57.53; H, 5.95; N, 3.86. HPLC (Daicel Chiralcel OD-H,
hexane/iPrOH 98/2, 0.5 mL/min) tR 29.8 (1R,2R) and 43.7
(1S,2S) min (72% ee).
1-(ter t-Bu t ylt h io)-3-m et h yl-1-(2-p yr id ylt h io)b u t a n -2-
ol (34). An inseparable diastereomeric mixture of 34; 1 H NMR
δ 0.89-1.06 (m, 6H), 1.38 (s, 9H (major)), 1.39 (s, 9H (minor)),
1.77 (s, 1H), 2.04 (sep, J ) 7.4 Hz, 1H (minor)), 2.08 (sep, J )
6.8 Hz, 1H (major)), 3.46-3,56 (br, 1H (minor)), 3.63 (dd, J )
2.8, 7.8 Hz, 1H (major)), 4.65 (s, 1H (major)), 4.97 (d, J ) 5.8
Hz, 1H (minor)), 5.05 (d, J ) 2.8 Hz, 1H (major)), 6.95-7.56
(m, 3H), 8.34-8.40 (m, 1H); 13C NMR δ 17.4, 19.0, 19.8, 20.0,
31.2, 31.3, 44.2, 45.0, 53.6, 53.7, 80.7, 81.4, 119.7, 119.8, 122.7,
123.7, 136.1, 136.3, 148.4, 148.6, 155.6, 157.7; IR (neat) 3435,
2959, 1578, 1556, 1454, 1120, 1046, 759 cm-1; EIMS m/z 285
(M+), 243, 199, 155, 111, 77. Anal. Calcd for C14H23NOS2: C,
58.90; H, 8.12; N, 4.91. Found: C, 59.01; H, 8.21; N, 4.70.
HPLC (Daicel Chiralpak AD-H, hexane/iPrOH 90/10, 0.5 mL/
min) tR 16.6 (1S,2S), 18.9 (1R,2S), 30.6 (1R,2R), and 38.1
(1S,2R) min.
9H); IR (KBr) 3055, 2969, 2953, 1738, 1578, 1234, 758 cm-1
;
HPLC (Daicel Chiralpak AD-H, hexane/iPrOH 90/10, 0.5 mL/
min) tR 10.9 (1R,2S) and 15.6 (1S,2R) min (81% ee).
1-Acetoxy-2-(ter t-bu tylth io)-2-(2-p yr id ylth io)-1-(2,4,6-
tr im eth ylp h en yl)eth a n e (38): 1H NMR δ 1.47 (s, 9H), 2.05
(s, 3H), 2.08 (s, 3H), 2.47 (s, 6H), 5.71 (d, J ) 10.4 Hz, 1H),
6.34 (d, J ) 10.4 Hz, 1H), 6.64 (s, 2H), 7.16-8.30 (m, 4H);
HPLC (Daicel Chiralpak AD-H, hexane/iPrOH 98/2, 0.3 mL/
min) tR 21.2 (1R,2S) and 24.0 (1S,2R) min (85% ee).
1-Acetoxy-2-(ter t-bu tylth io)-1-(2-n ath tyl)-2-(2-pyr idylth -
io)eth a n e (39): 1H NMR δ 1.09 (s, 9H), 2.15 (s, 3H), 5.43 (br,
1H), 6.42 (br, 1H), 7.04-8.58 (m, 11H); HPLC (Daicel Chiral-
pak AD-H, hexane/iPrOH 90/10, 0.5 mL/min) tR 14.2 (1R,2S)
and 25.4 (1S,2R) min (72% ee).
Dep r otection of Dith ioa ceta ls 37-39 Su bsequ en t Re-
d u ction : (R)-1-P h en yl-1,2-eth a n ed iol (40). To a solution
of 37 (41 mg, 0.11 mmol) in aqueous acetonitrile (2.0 mL,
acetonitrile/H2O ) 9:1) was added HgCl2 (80.3 mg, 0.34 mmol)
at room temperature, and the mixture was stirred for 3 h. The
reaction mixture was filtered, and the mother liquid was
extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure to give the crude acetoxyalde-
hyde, an ethereal solution of which was then added to a
solution of LiAlH4 (21 mg, 0.56 mmol) in Et2O (1.0 mL) at 0
°C. After 3 h, saturated aqueous NH4Cl was added and the
mixture was extracted with Et2O. The combined organic
extracts were washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure to give the crude
product, which was purified by column chromatography (silica
gel 25 g, hexane/ethyl acetate ) 65:35) to give 40 (12 mg,
77%): [R]20 -57.5 (c 0.238, CHCl3, 83% ee) (lit.19 [R]20 -69
2-(ter t-Bu t ylt h io)-1-cycloh exyl-2-(2-p yr id ylt h io)et h a -
1
n ol (35). a n ti-35: [R]20 -94.5 (c 0.400, CHCl3, 81% ee); H
D
NMR δ 1.00-1.36 (m, 4H), 1.39 (s, 9H), 1.57-2.18 (m, 7H),
3.68 (dd, J ) 2.4, 7.4 Hz, 1H), 4.58 (s, 1H), 5.05 (d, J ) 2.4
Hz, 1H), 6.99-7.56 (m, 3H), 8.35-8.39 (m, 1H); 13C NMR δ
25.9, 26.1, 26.4, 28.9, 29.8, 31.2, 40.5, 44.2, 53.4, 80.1, 119.6,
122.6, 136.0, 148.5, 157.8; IR (neat) 3466, 2922, 1579, 1452,
1414, 1162, 1121, 759 cm-1; EIMS m/z 325 (M+), 307, 250, 156,
111, 82; Anal. Calcd for C14H23NOS2: C, 62.72; H, 8.36; N, 4.30.
Found: C, 62.50; H, 8.22; N, 4.28. HPLC (Daicel Chiralpak
AD-H, hexane/iPrOH 90/10, 0.5 mL/min) tR 23.6 (1R,2S) and
50.6 (1S,2R) min. syn -35: [R]20 -46.3 (c 0.160, CHCl3, 64%
D
ee); 1H NMR δ 1.01-1.38 (br, 4H), 1.37 (s, 9H), 1.60-2.18 (m,
7H), 3.54 (dd, J ) 2.8, 7.8 Hz, 1H), 4.82 (br, 1H), 5.01 (d, J )
5.4 Hz, 1H), 6.99-7.59 (m, 3H), 8.34-8.40 (m, 1H); 13C NMR
δ 25.9, 26.0, 26.48, 28.1, 30.0, 31.28, 41.5, 45.0, 53.1, 80.0,
119.8, 123.3, 136.1, 148.4, 157.3; IR (neat) 3435, 2922, 1578,
1453, 1159, 1121, 758 cm-1; EIMS m/z 325 (M+), 307, 250, 156,
111, 82. Anal. Calcd for C14H23NOS2: C, 62.72; H, 8.36; N, 4.30.
Found: C, 62.51; H, 8.36; N, 4.04. HPLC (Daicel Chiralpak
AD-H, hexane/iPrOH 95/5, 0.5 mL/min) tR 59.9 (1S,2S) and
64.9 (1R,2R) min.
D
D
1
(c 1, CHCl3)); H NMR δ 1.95 (br, 2H), 3.61 (m, 2H), 4.83 (m,
1H), 7.35 (br, 5H).
(R)-1-(2,4,6-Tr im eth ylp h en yl)-1,2-eth a n ed iol (41). [R]20
D
-43.0 (c 0.334, CHCl3, 79% ee) (lit.23 [R]20 -53.0 (c 1.01,
D
1
CHCl3)); H NMR δ 1.60-2.05 (br, 2H), 2.24 (s, 3H), 2.40 (s,
6H), 3.67 (dd, J ) 3.8, 10.8 Hz, 1H), 3.96 (t, J ) 10.8 Hz, 1H),
5.25 (dd, J ) 3.8, 10.8 Hz, 1H), 6.82 (s, 2H).
1-ter t-Bu t yl-2-(ter t-b u t ylt h io)-2-(2-p yr id ylt h io)et h a -
n ol (36). a n ti-36: mp 72-73 °C; [R]20D -238.5 (c 0.152, CHCl3,
1
88% ee); H NMR δ 1.08 (s, 9H), 1.39 (s, 9H), 3.87 (br, 1H),
(R)-1-(2-n a p h th yl)-1,2-eth a n ed iol (42). [R]20 -30.0 (c
D
5.01 (d, J ) 1.4 Hz, 1H), 5.16 (s, 1H), 6.98-8.43 (m, 4H); 13C
NMR δ 27.3, 31.5, 36.2, 44.1, 53.0, 85.0, 119.7, 123.1, 136.2,
0.035, MeOH, 68% ee) (lit.23 [R]20 -43.9 (c 1.00, MeOH)); H
1
D
NMR δ 2.03 (br, 1s), 2.60 (br, 1s), 3.71-3.90 (m, 2H), 4.99-
1588 J . Org. Chem., Vol. 69, No. 5, 2004

Enantioselective Reaction of R-Lithiated Dithioacetals
5.05 (m, 1H), 7.45-7.86 (m, 7H); HPLC (Daicel Chiralcel OD-
H, hexane/iPrOH 70/30, 0.5 mL/min) tR 13.7 (R) and 15.9 (S)
min (68% ee).
for Scientific Research (No. 11650890) from the Ministry
of Education, Science, Sports and Culture of J apan.
Su p p or tin g In for m a tion Ava ila ble: X-ray structure of
anti-26. This material is available free of charge via the
Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank Dr. Shinya Kusuda,
Ono Pharmaceutical Co., Ltd., for X-ray crystallographic
analysis. This work was supported by a Grant-in-Aid
J O035558E
J . Org. Chem, Vol. 69, No. 5, 2004 1589