New asymmetric reactions of 2-formyl- and 2-acyl-1-[(2,4,6-triisopropylphenyl)sulfinyl]naphthalenes via diastereomeric rotamers

Article abstract of DOI:10.1021/jo005581p

Nucleophilic reactions with Grignard reagents and the Mukaiyama aldol reactions of the naphthaldehydes having the (2,4,6-triisopropylphenyl)sulfinyl group produced products with high stereoselectivity. In these reactions, the stereochemistry of the major products changes depending on the Lewis acids used. Reduction of the 2-acyl-1-[(2,4,6-triisopropylphenyl)sulfinyl]naphthalenes also proceeds with high stereoselectivity but with a different stereochemistry depending on the reducing agents. We have demonstrated, by the mechanistic consideration based on the X-ray crystal structures as well as the ¹H and ¹³C NMR spectral data, that the extremely high and specific stereoselectivities of these reactions are due to the predominant rotamer around the C(naph)-S axis. Synthesis of enantiomerically pure 2-naphthylmethanol is provided as an example.

Full text of DOI:10.1021/jo005581p

8640
J . Org. Chem. 2000, 65, 8640-8650
New Asym m etr ic Rea ction s of 2-F or m yl- a n d
2-Acyl-1-[(2,4,6-tr iisop r op ylp h en yl)su lfin yl]n a p h th a len es via
Dia ster eom er ic Rota m er s
Shuichi Nakamura, Hiroki Yasuda, Yoshihiko Watanabe, and Takeshi Toru*
Department of Applied Chemistry, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, J apan
toru@ach.nitech.ac.jp
Nucleophilic reactions with Grignard reagents and the Mukaiyama aldol reactions of the
naphthaldehydes having the (2,4,6-triisopropylphenyl)sulfinyl group produced products with high
stereoselectivity. In these reactions, the stereochemistry of the major products changes depending
on the Lewis acids used. Reduction of the 2-acyl-1-[(2,4,6-triisopropylphenyl)sulfinyl]naphthalenes
also proceeds with high stereoselectivity but with a different stereochemistry depending on the
reducing agents. We have demonstrated, by the mechanistic consideration based on the X-ray crystal
structures as well as the 1H and 13C NMR spectral data, that the extremely high and specific
stereoselectivities of these reactions are due to the predominant rotamer around the Cnaph-S axis.
Synthesis of enantiomerically pure 2-naphthylmethanol is provided as an example.
In tr od u ction
to the high rotational barrier about the C-N bond, but
resolution of the optically active isomers is always needed
prior to undertaking the reaction.4c,e,g,h,6 We were inter-
ested in the asymmetric reactions of 1-sulfinylnaphtha-
lene derivatives. The barriers to rotation about the
Cnaph-S bond of sulfinylnaphthalenes have been esti-
mated to be generally lower than those around the C-N
axis, and isolation of the atropisomers have never been
reported.7 Thus, there have been no reports on the
asymmetric reactions of 2-substituted 1-sulfinylnaph-
thalenes using the rotational barrier about the Cnaph-S
bond prior to our preliminary report of this type of
reaction.8 Such rotamers around the C-S axis consist of
diastereomers. Therefore, we thought that each rotamer
would stay in a different equilibrating state depending
on the steric or electronic demands of the chiral sulfinyl
group and affect the diastereoselectivity in the nucleo-
philic additions to the carbonyl at the 2-position. Fur-
thermore, nucleophilic additions to the carbonyl of γ-ke-
tosulfoxides9 are known to proceed with rather low
stereoselectivity in contrast to the highly stereoselective
reactions of â-ketosulfoxides.10 We now report in detail
the stereoselective reactions of 2-formyl- and 2-acyl-1-
sulfinylnaphthalenes bearing the (2,4,6-triisopropylphe-
nyl)sulfinyl group with nucleophiles and reducing agents
Since the first resolution of a chiral biphenyl compound
by Christie and Kenner,1 axially chiral biaryl compounds
such as binaphthyl and biphenyl compounds have been
widely used as chiral ligands or chiral auxiliaries.2
Recently, the asymmetric reactions of nonbiaryl axially
chiral compounds have been reported, e.g., high stereo-
selectivity has been achieved in the reactions of (o-tert-
butylphenyl)maleimide,3 N-acyl-o-tert-butylanilides,4 and
N,N-diisopropylnaphthamides.5 The substrates in these
reactions enable the separation of the atropisomer due
* To whom correspondence should be addressed. Fax and tel: 81-
52-735-5217.
(1) Chistie, G. H.; Kenner, J . H. J . Chem. Soc. 1922, 121, 614.
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C.; Franzini, L.; Rafaelli, A.; Salvadori, P. Synthesis 1992, 503. (d)
Whitesell, J . K. Chem. Rev. 1989, 89, 1581. (e) Newman, M. S. Steric
Effects in Organic Chemistry; Wiley: New York, 1956.
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10.1021/jo005581p CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/14/2000

Asymmetric Reactions via Diastereomeric Rotamers
J . Org. Chem., Vol. 65, No. 25, 2000 8641
Sch em e 1a
Ta ble 1. Ster eoselective Rea ction of
1-Su lfin yl-2-n a p h th a ld eh yd es 3a -d w ith Nu cleop h iles
entry
R
R′M
additive
product yield (%) ratioa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Tol PhMgBr
Tol PhMgBr
Mes PhMgBr
Mes PhMgBr
Mes PhMgBr
Tip PhMgBr
Tip PhLi
-
7
7
8
8
8
9
9
9
9
9
9
9
9
9
9
10
11
12
13
80
81
82
34
70
96
78
49
81
-
58
83
71
76
80
94
60d
80
80
61:39
66:34
87:13
67:33
77:23
98:2
Yb(OTf)3
-
Ti(OiPr)4
Yb(OTf)3
-
-
95:5
91:9
Tip PhMgBr
Tip PhMgBr
ZnBr2
Ti(OiPr)4
76:24
-
75:25
79:21
91:9
31:69
30:70
80:20
>98:2
74:26
68:32
Tip PhMgBrb Ti(OiPr)4
Tip PhMgBr
Tip PhMgBr
Tip PhMgBr
Tip PhMgBr
Tip PhMgBr
Tip MeMgI
Ti(OiPr)2Cl2
TiCl4
Et2AlCl
Yb(OTf)3
c
Yb(OTf)3
-
-
-
-
Tip iBuMgBr
Tip AllylMgBr
tBu PhMgBr
a
b
Determined by 1H NMR. The reaction was carried out in
Et2O. c Yb(OTf)3 (2.0 equiv) was used. The (1-sulfinyl-2-naphth-
d
yl)methanol was obtained (35%).
a
(a) (1) n-BuLi, (2) ArS(O)OiPr, Et2O, -78 °C; (b) H2SO4, SiO2,
t
CH2Cl2, rt; (c) BuMgCl, THF, 0 °C; (d) (1) n-BuLi, (2) (CH2O)n,
thaldhyde dimethyl acetal11 at -78 °C in Et2O, followed
by deprotection upon treatment with silica gel containing
a small amount of sulfuric acid in CH2Cl2,12 gave the
corresponding 1-(arylsulfinyl)-2-naphthaldehydes 3a -c
in high yields. Since the 1,1-dimethylethanesulfinate did
not react with 1-lithio-2-naphthaldehyde dimethyl acetal,
(-)-menthyl (S)-naphthalenesulfinate 4 was treated with
tert-BuMgCl. The obtained sulfoxide 5 was lithiated and
then allowed to react with paraformaldehyde to give
alcohol 6, which was converted to aldehyde 3d by
oxidation of 6 with PCC (Scheme 1). Notably, we con-
firmed, by 1H NMR spectral analyses in CDCl3, that each
sulfoxide 3d or 6 exists as two rotamers, each ratio of
which was 64:36 or 73:27, respectively (vide infra).
Treatment of a THF solution of 1-sulfinyl-2-naphthal-
dehydes 3a -d with 1.5 equiv of Grignard reagents or
PhLi gave the 2-naphthylmethanols 7-13. The reaction
in the presence of a Lewis acid was carried out by stirring
a THF solution of 3a -c and the Lewis acid (1.1 equiv)
for 1 h before the addition of a solution of R′M. These
results are shown in Table 1.
THF, -78 °C f rt; (e) PCC, CH2Cl2, rt.
without prior resolution of the axially chiral or diaster-
eomeric isomer. We also describe the stereochemical
course possibly derived from the predominantly formed
rotamer around the Cnaph-S bond axis, and the trans-
formation of the product into the enantiomerically pure
2-naphthylmethanol.
Resu lts
Scheme 1 summarizes the synthetic routes for the
preparation of various racemic 1-sulfinyl-2-naphthalde-
hydes 3a -d for the study of the stereoselectivity in the
addition of nucleophiles.
Treatment of the p-toluene-, 2,4,6-trimethylbenzene-,
2,4,6-triisopropylbenzenesulfinates with 1-lithio-2-naph-
(9) For reduction of γ-ketosulfoxides: (a) Arai, Y.; Suzuki, A.;
Masuda, T.; Masaki, Y.; Shiro, M. Chem. Pharm. Bull. 1996, 44, 1756.
(b) Solladie´, G.; Hanquet, G.; Rolland, C. Tetrahedron Lett. 1997, 38,
5847. (c) Solladie´, G.; Colobert, F.; Somny, F. Tetrahedron Lett. 1999,
40, 1227. (d) Solladie´, G.; Hanquet, G.; Izzo, I.; Crumbie, R. Tetrahedron
Lett. 1999, 40, 3071. (e) Nakamura, S.; Kuroyanagi, M.; Watanabe,
Y.; Toru, T. J . Chem. Soc., Perkin Trans. 1, 2000, 3143. For the
nucleophilic addition to γ-ketosulfoxide: (f) Girodier, L. D.; Rouessac,
F. P. Tetrahedron: Asymmetry 1994, 5, 1203. (g) Arai, Y.; Masuda, T.;
Masaki, Y.; Koizumi, T. Heterocycles 1994, 38, 1751. (h) Arai, Y.;
Suzuki, A.; Masuda, T.; Masaki, Y.; Shiro, M. J . Chem. Soc., Perkin
Trans. 1 1995, 2913. (i) Arai, Y.; Masuda, T.; Masaki, Y. Synlett 1997,
1459.
(10) (a) Solladie´, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985,
26, 435. (b) Kosugi, H.; Konta, H.; Uda, H. J . Chem. Soc., Chem.
Commun. 1985, 211. (c) Solladie´-Cavallo, A.; Suffert, J .; Adib. A.;
Solladie´, G. Tetrahedron Lett. 1990, 31, 6649. (d) Carreno, M. C.;
Ruano, J . L. G.; Martin, A. M.; Pedregal, C.; Rodrigues, J . H.; Rubio,
A.; Sanchez, J .; Solladie´, G. J . Org. Chem. 1990, 55, 2120. (e) Barros,
D.; Carreno, M. C.; Ruano, J . L. G.; Maestro, M. C. Tetrahedron Lett.
1992, 33, 2733. (f) Bueno, A. B.; Carreno, M. C.; Ruano, J . L. G.; Pena,
B.; Rubio, A.; Hoyos, M. A. Tetrahedron 1994, 50, 9355.
As expected, the stereoselectivity varied, depending
upon the groups attached to the sulfinyl group. It is
apparent that 1-[(2,4,6-triisopropylphenyl)sulfinyl]-2-
naphthaldehyde 3c shows high stereoselectivity in com-
parison with the (p-tolylsulfinyl)- and [(2,4,6-trimeth-
ylphenyl)sulfinyl]naphthaldehydes 3a and 3b. Thus, the
reaction of 3c with PhMgBr and PhLi gave the 2-naph-
(11) For the preparation of the bromoacetal, see: (a) Smith, J . G.;
Dibble, P. W.; Sandborn, R. E. J . Org. Chem. 1986, 51, 3762. Lithiation
of bromoacetal, (b) Keay, B. A.; Plaumann, H. P.; Rajapaksa, D.;
Rodrigo, R. Can. J . Org. 1983, 61, 1987.
(12) Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J . M. Synthesis
1978, 63.

8642 J . Org. Chem., Vol. 65, No. 25, 2000
Nakamura et al.
Sch em e 2a
Sch em e 3a
a
(a) (1) n-BuLi, 2) (R)-diacetone D-glucosyl 2,4,6-triisopropyl-
benzenesulfinate, Et2O, -105 °C; (b) H2SO4, SiO2, CH2Cl2, rt.
thylmethanol 9 in a ratio of 98:2 and 95:5, respectively,
favoring the (RS*,S*)-isomer (entries 6 and 7). Their
stereochemistry was determined by X-ray crystallogra-
phy. The stereoselectivity was reduced when the reaction
was performed in the presence of 1.1 equiv of Lewis acids.
Notably, Yb(OTf)3 reversed the stereoselectivity favoring
the (RS*,R*)-isomer (entries 14 and 15). The stereoselec-
tivity also changed depending on the size of the Grignard
reagents. A higher diastereoselectivity was obtained as
the size of the nucleophile was bulkier (entries 16-18).
Thus, the addition product 11 was obtained with com-
plete selectivity in the reaction with iso-BuMgBr, al-
though a significant amount of the (1-sulfinyl-2-naphthyl)-
methanol was formed by the abnormal Grignard reaction.13
It should be noted that the naphthaldehyde 3d bearing
a bulky tert-butylsulfinyl group gave the product 13 with
low selectivity (entry 19).14 These results show that
higher stereoselectivity is not always obtained in the
reaction of the sulfinylnaphthaldehydes bearing a bulkier
substituent and the stereochemistry-determining step
would be strongly related to the rotational barrier around
the Cnaph-S bond as discussed in detail in the discussion
section.
a
(a)PhMgBr, THF, -78 °C; (b) n-BuLi, THF, -78 °C
Recrystallization from hexane/ethyl acetate yielded the
enantiomerically as well as diastereomerically pure ad-
duct (RS,S)-9. Cleavage of the sulfinyl moiety using
n-BuLi17 gave enantiomerically pure 2-naphthylmethanol
14. The absolute configuration of 14 was assigned to be
S by comparison of the specific rotation with the reported
value.18 This reaction provides a convenient method for
the preparation of the optically pure 2-naphthylmetha-
nols via the nucleophilic reaction of the sulfinylnaph-
thaldehyde in combination with cleavage of the sulfinyl
group.
Th e Mu k a iya m a Ald ol Rea ction of 1-Su lfin yl-2-
n a p h th a ld eh yd es. We studied the Mukaiyama aldol
reaction of sulfinylnaphthaldehydes 3a -c with the tri-
methyl- and tert-butyldimethylsilylketene acetals. The
reaction was carried out by stirring a CH2Cl2 solution of
3a -c and a Lewis acid (1.1 or 2.0 equiv) for 1 h at -78
°C and subsequent addition of the ketene acetals. These
results are shown in Table 2.
Having established a high diastereoselectivity in the
reaction of 3c, we next confirmed that this nucleophilic
reaction could be applied to the preparation of enantio-
merically pure 2-naphthylmethanol by starting with the
chiral [(2,4,6-triisopropylphenyl)sulfinyl]naphthaldehyde
(R)-3c. Scheme 2 summarizes the route for the prepara-
tion of (R)-3c from 1.
The reactions of 3a and 3b with the ketene thioacetal
in the presence of 2 equiv of BF3‚OEt2 gave products 15
and 16 with high selectivity in ratios of 79:21 and 95:5,
respectively (entries 1 and 3). On the other hand, 3c gave
(RS*,S*)-17 with complete selectivity (entry 5), whose
structure was confirmed by X-ray crystallography. The
stereochemical outcome in the presence of TiCl4 is
noteworthy. The reaction of 3a and 3b revealed good
stereoselectivity, favoring the same diastereomers as
those preferably obtained with BF3‚OEt2. The stereose-
lectivity was reversed to 30:70 in the reaction of 3c in
the presence of TiCl4, favoring the (RS*,R*)-isomer (en-
tries 6 and 7).19 We also examined the reaction of 3c with
To avoid the racemization of the sulfoxide, the reaction
was immediately quenched after the addition of the
precooled solution of (R)-diacetone D-glucosyl 2,4,6-tri-
isopropylbenzenesulfinate15 to lithiated 1 in one portion
at -105 °C. This gave a 98% yield of sulfoxide (R)-2c with
98% ee.16 Acetal (R)-2c was deprotected to quantitatively
give (R)-3c with 97% ee. The enantiomerically pure
sulfoxide (R)-3c was obtained by recrystallization from
hexane/ethyl acetate. The reaction of the chiral (R)-3c
with PhMgBr at -78 °C gave the product in a ratio of
98:2 (Scheme 3).
(13) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392.
(14) The absolute stereochemistry of 13 was determined by cleavage
of the sulfinyl group using n-BuLi.
(15) Mase, N.; Watanabe, Y.; Toru, T. J . Org. Chem. 1998, 63, 3899.
We reported an efficient method for the preparation of sulfinates:
Watanabe, Y.; Mase, N.; Tateyama, M.; T. Toru, Tetrahedron: Asym-
metry 1999, 10, 737.
(16) The reaction carried out at -78 °C or stirred for a longer time
caused racemization of the sulfoxide. The exchange reaction of lithium
for magnesium using MgBr2‚Et2O was also examined, but enantiomeric
pure product could not be obtained, see: Girodier, L.; Maignan, C.;
Rouessac, F. Tetrahedron: Asymmetry 1992, 3, 857.
(17) (a) Lockard, J . P.; Schroeck, C. W.; J ohnson, C. R. Synthesis
1973, 485. (b) Durst, T.; LeBelle, M. J .; Elzen, R. Van den.; Tin, K.-C.
Can. J . Chem. 1974, 52, 761. (c) Satoh, T.; Kaneko, Y.; Yamakawa, K.
Tetrahedron Lett. 1986, 27, 2379. (d) Furukawa, N.; Ogawa, S.;
Matsumura, K.; Fujihara, H. J . Org. Chem. 1991, 56, 6341.
(18) (a) Seebach, D.; Beck, A. K.; Roggo, S.; Wonnacott, A. Chem.
Ber. 1985, 118, 3673. (b) Soai, K.; Kawase, Y.; Oshio, A. J . Chem. Soc.,
Perkin Trans. 1 1991, 1613.
(19) Other Lewis acids such as Et2AlCl, MeAlCl2, Yb(OTf)3, MgBr2‚
OEt, and SnCl4 were also examined, but no significant results were
obtained.

Asymmetric Reactions via Diastereomeric Rotamers
J . Org. Chem., Vol. 65, No. 25, 2000 8643
Ta ble 2. Th e Mu k a iya m a Ald ol Rea ction of th e 1-Su lfin yl-2-n a p h th a ld eh yd es 3a -c
reaction
time (h)
entry
Ar
R
SiR′3
Lewis acid
product
yield (%)
ratioa
b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Tol
Tol
Mes
Mes
Tip
Tip
Tip
Tip
Tip
Tip
Tip
Tip
Tip
Tip
StBu
StBu
StBu
StBu
StBu
StBu
StBu
OEt
OEt
StBu
StBu
StBu
Ph
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
7
7
5
10
2
7
3
4
3
10
6
BF3‚OEt2
15
15
16
16
17
17
17
91
77
81
78
90
82
90
0d
79:21c
80:20c
95:5c
73:27c
>98:2
30:70
39:61
-
TiCl4
b
BF3‚OEt2
TiCl4
b
BF3‚OEt2
TiCl4
TiCl4
b
b
SitBuMe2
SitBuMe2
SitBuMe2
SitBuMe2
SitBuMe2
SiMe3
BF3‚OEt2
TiCl4
BF3‚OEt2
TiCl4
TiCl4
0d
-
b
17
17
17
18
18
62
22
42d
81
40
>98:2
10:90
12:88
>98:2
2:>98
3
4
5
b
BF3‚OEt2
TiCl4
Ph
SiMe3
a
b
d
Determined by 1H NMR. The Lewis acid (2.0 equiv) was used. c The relative stereochemistry was not determined. The reaction
mixture was warmed to room temperature.
Sch em e 4
several silyl enol ethers derived from ethyl acetate, tert-
butyl thioacetate, and acetophenone, which have often
been used in the Mukaiyama aldol reaction.20 The reac-
tion with O-tert-butyldimethylsilyl O-ethyl ketene acetal
gave no Mukaiyama aldol product in the presence of a
Lewis acid such as BF3‚OEt2 or TiCl4 (entries 8 and 9).
The reaction of the ketene thioacetal, prepared from tert-
butyl thioacetate and tert-butyldimethylsilyl chloride,
with 3c gave only (RS*,S*)-17 in the presence of BF3‚
OEt2 (entry 10) although in lower yield when compared
with the reaction using the O-trimethylsilyl ketene
thioacetal. TiCl4 again reversed the stereoselectivity,
favoring the (RS*,R*)-isomer (entries 11 and 12). The
reaction of the trimethylsilyl enol ether of acetophenone
proceeded with extremely high stereoselectivity. Thus,
each diastereomer 18 could be prepared with complete
selectivity by using either BF3‚OEt2 or TiCl4 as a Lewis
acid (entries 13 and 14). Since we have already assigned
the stereochemistry of the predominantly formed product
from the ketene thioacetal as the (RS*,S*)-isomer with
BF3‚OEt2, and hence the (RS*,R*)-isomer with TiCl4, the
stereochemistry of the product 18 was deduced as such.
Red u ction of th e 2-Acyl-1-a r ylsu lfin yln a p h th a -
len es. The pyridinium chlorochromate (PCC) oxidation
of the (1-arylsulfinyl-2-naphthyl)methanols 7-10 and 12,
which had been already prepared in the former
reaction, gave 2-acyl-1-(arylsulfinyl)naphthalenes 19a -
e. (Scheme 4).
the stereoselective reductions. The reduction of 19a with
DIBAL gave alcohol 7 in an isomer ratio of 81:19, favoring
the (RS*,S*)-isomer, whereas the reduction with LiAlH4
gave 7 in a ratio of 35:65, favoring the (RS*,R*)-isomer
(entries 1 and 2). On the other hand, the reductions of
19b with DIBAL and LiAlH4 both favor the formation of
the (RS*,R*)-isomers (entries 3 and 4). In the reduction
of 19c, a higher stereoselectivity with DIBAL was
obtained in CH2Cl2 than in THF (97:3) and the reversed
stereoselectivity was obtained with LiAlH4 (4:96)21 (en-
tries 5-7). These results show that the reaction mech-
anism of 19c may be different from that of 19a and 19b.
The reduction of 19c with other reducing agents was also
examined (Table 3, entries 8 and 9). Reaction with
NaBH4 failed (entry 10). Methyl and allyl ketones 19d
and 19e showed a stereochemical outcome similar to that
of phenyl ketone 19c, showing the dependence on the
reducing agents (entries 11-14). The relative configura-
tions of the alcohols 7-10 and 12 were determined by
comparison of the HPLC behavior with those obtained
in the previous nucleophilic reactions (Table 1).
The stereochemical outcome of the reduction including
the stereochemistry and stereoselectivity was found to
be quite different among 19a , 19b, and 19c-e, bearing
p-tolyl, 2,4,6-trimethylphenyl, and (2,4,6-triisopropylphe-
nyl)sulfinyl groups, respectively (Table 3).
Discu ssion
In the 1H NMR spectrum of the (tert-butylsulfinyl)-
naphthaldehyde 3d measured at -78 °C in THF-d8, two
Furthermore, the remarkable role of the (2,4,6-triiso-
propylphenyl)sulfinyl group was again shown through
(21) Addition of Yb(OTf)3, ZnCl2 or BF3‚OEt2 did not significantly
affect the stereoselectivity in the reduction with DIBAL, see: refs 9a-d
and 10.
(20) Gennari, C. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, pp 629-660.

8644 J . Org. Chem., Vol. 65, No. 25, 2000
Ta ble 3. Ster eoselective Red u ction of Keton es 19a -e
Nakamura et al.
entry
Ar
R
reducing agent
temp (°C)
product
yield (%)
ratioa (RS*,S*): (RS*,R*)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Tol
Tol
Mes
Mes
Tip
Tip
Tip
Tip
Tip
Tip
Tip
Tip
Tip
Tip
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
DIBAL
LiAlH4
DIBAL
LiAlH4
-78 f 0
-78
7
7
8
8
9
9
9
9
9
52
98
51
36
15
91
80
48
91
-
81:19
35:65
36:64
33:67
72:28
97: 3
4:96
6:94
79:21
-
-78 f 0
-78 f 0
-78 f 0
-78
DIBAL
DIBALb
LiAlH4
-78
L-selectride
Super-Hydride
NaBH4
-78 f 0
-78
-78f 0
-78
9
LiAlH4
10
10
12
12
72
78
64
80
26:74
90:10
20:80
80:20
DIBALb
LiAlH4
-78
-CH2-CHdCH2
-CH2-CHdCH2
-78
DIBALb
-78
a
b
Determined by 1H NMR. Reaction was carried out in CH2Cl2.
the product ratio of 68:32 (Table 1, entry 19). It can be
estimated that the rotameric forms remain long enough
to react at -78 °C (a half-life of 2470 h at -78 °C) and
indicating that the ratio of the rotamers A and B would
reflect the diastereomer ratio of the product 13 on the
basis of the rotational barrier (17.9 kcal/mol). Hence, it
can be reasonably assumed that the reaction of 3d with
a nucleophile proceeds faster than the rotation of the
rotamers and, therefore, that the reaction proceeds under
dynamic thermodynamic control. Sulfoxide 3c bearing a
sterically bulky triisopropylphenyl group may also have
a relatively high rotational barrier, although the 1H NMR
analyses of the other sulfoxides 3a -c at -95 °C in CD2-
Cl2 failed to detect the corresponding rotamers that
originated from the rotational barrier around the Cnaph-S
axis. The reactions of 3c with PhMgBr and PhLi showed
high stereoselectivity favoring the same diastereomer
(Table 1, entries 6 and 7). These results are in contrast
to those reported by Clayden and co-workers.5a They
observed the reversal in stereoselectivity in each reaction
of the 2-formyl-1-naphthamide with RMgX or RLi, which
can be ascribed to a chelated (RMgX) or nonchelated (RLi)
transition state. Furthermore, the reaction of 3c with
PhMgBr in the presence of Yb(OTf)3 predominantly
afforded a stereoisomer different from the one preferably
obtained without a Lewis acid. These results indicate that
both reactions of 3c with PhMgBr and PhLi would
proceed through a nonchelated transition state.
F igu r e 1. The barrier to rotation around the Cnaph-S bond
for 3d .
sets of signals due to the tert-butyl protons appeared at
1.27 and 1.23 ppm, the peri-H8 proton at 8.62 and 9.86
ppm, and the formyl proton at 10.8 and 11.7 ppm, which
were obviously derived from the restricted rotation about
the Cnaph-S bond. Thus, 3d exists as two conformers,
either having the sulfinyl oxygen close to the formyl
group (A-isomer) or close to the peri-H8 of the naphtha-
lene (B-isomer) as shown in Figure 1. This result is not
unusual; the barriers to rotation around the Cnaph-S bond
for several 2-substituted 1-sulfinylnaphthalenes have
been measured to be relatively high.7
The minor conformer was assigned to be rotamer B
on the basis of the downfield shift of the peri-H8 proton
due to the anisotropic effect of the sulfinyl oxygen.22 The
1
A/B ratio was 69:31 in the H NMR spectrum at -78 °C
in THF-d8. It is of interest that the A-isomer is the more
stable, because the 2-substituted, e.g., 2-fluoro, chloro,
bromo, methoxy, isopropoxycarbonyl, and methyl, 1-(alkyl-
sulfinyl)naphthalenes are known to generally prefer the
isomer having the sulfinyl oxygen close to the peri-H8
proton than the other isomer.7a,b,d The rate constant of
the rotation was found to be k ) 64 s-1 at 80 °C in DMSO-
d6 by the line shape analysis of the broadened tert-butyl
proton signal in the region of coalescence. From the rate
constant, k, the activation energy (∆Gq) of rotation was
calculated using Eyring’s equation23 to be 17.9 kcal/mol.
Hence, the A/B rotamer ratio at room temperature
turned out to be 69:31 which is essentially the same as
The configuration of product 9 was (RS*,S*), and the
origin of this stereochemistry can be directly rationalized
from the X-ray crystal structure of 3c, which showed the
sulfoxide oxygen situated away from the peri-H8 proton,
the carbonyl group almost on the plane of the naphtha-
lene ring, and the carbonyl oxygen away from the
sulfoxide (Figure 2). In this structure, one face of the
formyl group is highly hindered by the 2,4,6-triisopro-
pylphenyl group, while the other is much more exposed
to attack. Thus, the Grignard reagent or phenyllithium
predominantly approaches from the side opposite the
bulky aryl group to give (RS*,S*)-9. The stable conformer
of 3c, like that of 3d , was also different from that of
1-(alkylsulfinyl)naphthalenes having a substituent at the
(22) Lett, R.; Marquet, A. Tetrahedron 1974, 30, 3379.
(23) Eyring, H. Chem. Rev. 1935, 17, 65.

Asymmetric Reactions via Diastereomeric Rotamers
J . Org. Chem., Vol. 65, No. 25, 2000 8645
confirmed in solution. The anisotropic effect of the
sulfinyl and sulfonyl oxygens in the 1H and 13C NMR
spectra enables us to determine whether the oxygens is
close to or away from the peri-H8 proton25 (Figure 5).
Thus, it is reasonable that the peri-H8 proton of the
sulfone 20d is shifted downfield for B but not for A,
whereas the formyl carbon is shifted downfield con-
versely. For 3a , 3b, and 3c, on the other hand, no
separated signals for the peri-H8 proton and the formyl
1
carbon were observed in the H and 13C NMR spectra.
Taking into account the downfield shifts of the protons
and the carbons by converting the sulfinyl group to
sulfonyl, we can expect the most stable rotamers which
are depicted in Figure 5. The stable conformer for 3c thus
assigned by the NMR spectral analyses is in good accord
with the X-ray crystal structure (Figure 2) as well as the
most stable conformer C predicted by the MO calculation.
The structure of the stable rotamer for 3a seems to be
different from that of 3c, i.e., the rotamer bearing the
sulfinyl oxygen close to the peri-H8 proton is more stable
than the other one.26 Although the exact rotational
barrier cannot be estimated by these spectral results, the
barrier to rotation about the Cnaph-S bond is expected to
be definitely higher as the sulfinyl group is bulkier. The
poor stereoselectivity obtained in the reaction of 3a may
be due to the low barrier to rotation. On the basis of these
considerations, we have concluded that the nucleophilic
reactions of 3c would predominantly proceed through the
thermodynamically most stable rotamer as depicted in
Figures 2 and 5.27
F igu r e 2. The Chem 3D structure derived from the X-ray
crystallography of 3c and (RS*,S*)-9.
F igu r e 3. Chelated structure of 3c with Yb(OTf)3.
2-position other than the formyl group. The 2-formyl
group definitely affects the stability of the rotamer
around the Cnaph-S axis. The reason is still unclear,
although the effect of the dipole-dipole and/or stereo-
electronic interactions for this peculiar arrangement
might play a role. Furthermore, the (2,4,6-triisopropy-
lphenyl)sulfinyl group rotates around the Cnaph-S axis
and the sulfinyl oxygen is now placed close to the peri-
H8 proton in the X-ray structure of (RS*,S*)-9 (Figure 2).
The reaction of 3c in the presence of Yb(OTf)3 proceeds
through a rigid conformation fixed by chelation between
the sulfinyl and carbonyl oxygen, in which one face of
the formyl group is highly covered by 2,4,6-triisopropy-
lphenyl group and RMgBr approaches from the less
hindered side to give predominantly (RS*,R*)-9 (Figure
3). The slightly lower stereoselectivity in the reaction
with Yb(OTf)3 compared to those without Yb(OTf)3 is due
probably to the incomplete chelate formation.
The results in the Mukaiyama aldol reaction of 3c also
support the reaction pathway through the rotamer in
which the sulfinyl oxygen is directed toward the formyl
group. We examined two Lewis acids, BF3‚OEt2 (2 equiv)
and TiCl4 (1.1 equiv), which showed completely different
stereochemical behavior from one another, giving pre-
dominantly the (RS*,S*)- and (RS*,R*)-isomers, respec-
tively. Two boron trifluoride molecules independently
coordinate with the sulfinyl and carbonyl oxygens as
shown in Figure 6. A silyl enol ether approaches the
carbonyl from the side away from the 2,4,6-triisopropy-
lphenyl group. TiCl4, on the other hand, coordinates with
the sulfinyl and carbonyl oxygens to form a seven-
membered cyclic intermediate. A silyl enol ether ap-
proaches the carbonyl face from the direction avoiding
any steric interaction with the 2,4,6-triisopropylphenyl
group, giving the aldol product in a product distribution
different from that obtained in the reaction using BF3‚
OEt2. The Mukaiyama aldol reaction needs a Lewis acid
to activate the carbonyl group and thus resulted in higher
stereocontrol than the Grignard reaction with the Lewis
acids. Obviously, attack of the silyl enol ether in the
TiCl4-chelated seven-membered cyclic intermediate oc-
curs on the same carbonyl face as that in the Grignard
reaction in the presence of Yb(OTf)3 (Table 1 and Figure
3).
To obtain a more quantitative insight, we calculated
the relative energies for the conformers of 3c using the
MOPAC 93/PM3 method.24 The relative energies of the
optimized structures C, D, E, and F are depicted in
Figure 4.
Conformer C, which turned out to be the most stable,
was substantially the same rotamer as the solid structure
confirmed by X-ray crystallography, indicating that the
reaction predominantly proceeds through this conformer
to give the (RS*,S*)-isomer with high selectivity. Con-
former F was the most stable among the rotamers
presumably affording the (RS*,R*)-isomer, but its energy
was higher than that of conformer C by 1.81 kcal/mol,
which corresponds in theory to a ratio of 99.1:0.9 at -78
°C, favoring the (RS*,S*)-isomer. Conformer D is another
optimized rotamer having the sulfinyl oxygen close to the
peri-H8 proton of the naphthalene ring and is less stable
than conformer C by 1.98 kcal/mol. These data indicate
that 3c would be present to a large extent as conformer
C, which suggests why only the signal due to one rotamer
The treatment of 2-[(2,4,6-triisopropylphenyl)sulfinyl]-
benzaldehyde 21 with the silyl enol ether in the presence
1
in the H NMR spectra of 3c could be detected even at
(25) For NMR spectral analyses of 2-sulfinylnaphthalene deriva-
tives, see: refs 7a,b,d.
low temperature.
(26) Preference of this rotamer for 3a was also confirmed by the
MO calculation using the PM3 method.
(27) Although all the evidence we obtained supports our conclusion,
the kinetic pathway cannot be strictly ruled out because we are unable
to determine the barrier to rotation for 3c.
The highly stable structure derived from the MO
calculation as well as the X-ray crystallography was also
(24) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209.

8646 J . Org. Chem., Vol. 65, No. 25, 2000
Nakamura et al.
F igu r e 4. Geometry optimization of 3c by MOPAC 93/PM3.
F igu r e 6. Nonchelated and chelated intermediate in the
Mukaiyama aldol reactions of 3c with BF3‚OEt2 and TiCl4.
oxygen is directed to the carbonyl group as in the
structure of 3c, but the carbonyl face probably rotates
by the stereoelectronic effect, so that the phenyl group
is arranged in the direction opposite to the 2,4,6-triiso-
propylphenyl group (Figure 7): The dihedral angle
between the carbonyl and the naphthalene bond is 64.7°.
In this structure, one carbonyl face is highly hindered
by the 2,4,6-triisopropylphenyl group, and the other face
is open to attack. Attack from the side opposite to the
triisopropylphenyl group produces (RS*,R*)-9. Reduction
of 19c with DIBAL proceeds through a seven-membered
cyclic transition state while maintaining the conforma-
F igu r e 5. Significant 1H and 13C NMR chemical shifts for
the 1-sulfinyl- and 1-sulfonyl-2-naphthaldehydes.
of BF3‚OEt2 was found to give the product28 with much
lower stereoselectivity than that from the reaction of the
naphthaldehyde 3c (Scheme 5). The barrier to rotation
of 21 would be very low, and the product would be
kinetically formed. These results suggest that the ster-
eochemical outcome in the reactions of 3c is strongly
related to the rotational barrier about the Cnaph-S bond
derived from the significant role of the peri-H8 proton.29
The stereoselectivity in the reduction of 19c with
LiAlH4 giving (RS*,R*)-9 can also be explained from the
X-ray crystal structure of 19c, in which the sulfinyl
(29) Both reactions of 21 with PhMgBr in the presence and absence
of Yb(OTf)3 gave the same (RS*,S*)-isomer with high stereoselectivities
(>98:2). The stereochemical outcome is different from the one in the
reaction of 3c with PhMgBr, forming the (RS*,S*)-isomer through the
nonchelating intermediate and the (RS*,R)-isomer in the presence of
Yb(OTf)3. Both reactions of 21 probably proceed through a similar
chelating transition state involving the coordination of an ytterbium
or magnesium ion with the sulfinyl and carbonyl oxygens, although
freely rotating 21 would form the chelation structure different from
the ytterbium-chelating 3c.
(28) The structure of the minor product was confirmed by the X-ray
crystallography as shown in Scheme 5.

Asymmetric Reactions via Diastereomeric Rotamers
J . Org. Chem., Vol. 65, No. 25, 2000 8647
Sch em e 5
tion of the rotamer to yield (RS*,S*)-9. We assume that
the high selectivity obtained in the reduction of 19c, 19d ,
and 19e is controlled entirely by the restricted rotational
barrier around the Cnaph-S bond and the steric effect of
the bulky 2,4,6-triisopropylphenylsulfinyl group.
F igu r e 7. X-ray crystallography of 19c and the assumed
reaction direction.
Con clu sion
We have described new and excellent carbonyl-face
selective reactions of 2-formyl- and 2-acylnaphthalenes
bearing the bulky (2,4,6-triisopropylphenyl)sulfinyl group,
which can be performed without isolation of the diaster-
eomeric rotamers. We have demonstrated that high
diastereoselectivity is obtained under dynamic thermo-
dynamic control due to the restricted rotation around the
Cnaph-S bond having the bulky (2,4,6-triisopropylphenyl)-
sulfinyl group by viewing a combination of the stereo-
chemical behavior in comparison with the p-tolyl- and
mesitylsulfinylnaphthalene derivatives, and (2,4,6-tri-
isopropylphenyl)sulfinylbenzaldehyde, and the X-ray crys-
tal structures supported by the MO calculation as well
as the 1H and 13C NMR spectral data. In addition,
removal of the sulfinyl group from the products would
provide a convenient and efficient method for preparation
of the optically active 2-naphthylalkanols.
(M+, 20), 435 (74), 389 (72), 341 (100), 203 (96). Anal. Calcd
for C28H36O3S: C,74.30; H, 8.02. Found: C, 74.10; H, 8.23.
1-(2,4,6-Tr iisop r op ylp h e n yl)su lfin yl-2-n a p h t h a ld e -
h yd e (3c). To a suspension of silica gel (2.8 g) in CH2Cl2 (5.8
mL) was added 10 drops of a 15% sulfuric acid solution, and
the mixture was stirred for 5 min. Then a solution of 2c (1.27
g, 2.81 mmol) in CH2Cl2 (5.8 mL) was added. After stirring
for 1 h, a small amount of NaHCO3 was added. The mixture
was stirred for 5 min, filtered, and washed with CH2Cl2. The
filtrate was concentrated under reduced pressure to leave a
residue which was purified by column chromatography (silica
gel 50 g, hexane/ethyl acetate ) 90:10) to afford 3c (1.14 g,
100%): mp 164-165 °C (from hexane/ethyl acetate); Rf ) 0.37
(hexane/ethyl acetate ) 80:20); HPLC (COSMOSIL hexane/
ethyl acetate ) 90:10, flow rate 0.5 mL/min) tR 16.7 min,
(Daicel Chiralcel OD-H, hexane/i-PrOH ) 95:5, flow rate 0.5
1
mL/min) 16.2 (S) and 18.7 min (R); H NMR δ 0.76 (d, 6H, J
) 6.8 Hz), 1.18 (d, 3H, J ) 6.9 Hz), 1.19 (d, 3H, J ) 6.9 Hz),
1.34 (d, 6H, J ) 6.9 Hz), 2.83 (hep, 1H, J ) 6.9 Hz), 3.98 (hep,
2H, J ) 6.8 Hz), 7.01 (s, 2H), 7.29-7.38 (m, 1H), 7.46-7.55
(m, 1H), 7.77-7.88 (m, 1H), 7.95 (d, 1H, J ) 8.5 Hz), 11.3 (s,
1H); 13C NMR δ 23.5, 24.7, 28.8, 34.3, 123.4, 124.3, 125.2,
127.0, 127.9, 128.4, 130.9, 134.7, 136.8, 137.9, 150.4, 154.0,
192.4; IR (KBr) 2980, 1680, 1040 cm-1; EIMS m/z (rel intensity)
406 (M+, 15), 389 (74), 347 (100), 203 (80). Anal. Calcd for
Exp er im en ta l Section
Rep r esen ta tive P r oced u r e for th e P r ep a r a tion of th e
Su lfoxid es. 1-(2,4,6-Tr iisop r op ylp h en yl)su lfin yl-2-n a p h -
th a ld eh yd e Dim eth yl Aceta l (2c). To a solution of 1-bromo-
2-naphthaldehyde dimethyl acetal (1.15 g, 4.07 mmol) in Et2O
(10 mL) was added n-butyllithium (1.51 mol L-1, 2.70 mL, 4.07
mmol) at -78 °C, and the mixture was stirred for 30 min. A
solution of isopropyl 2,4,6-triisopropylbenzenesulfinate (1.15
g, 3.70 mmol) in Et2O (10 mL) was then added. After stirring
for 1 h, the reaction was quenched with saturated aqueous
NH4Cl and extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to leave a residue which
was purified by column chromatography (silica gel 30 g,
hexane/ethyl acetate ) 96:4) to afford 2c (1.60 g, 95%): Rf )
0.49 (hexane/ethyl acetate)80:20); HPLC (Daicel Chiralcel
OD-H, hexane/i-PrOH ) 95:5, flow rate 0.5 mL/min) tR 11.3
(S) and 16.7 min (R); 1H NMR δ 0.81 (d, 6H, J ) 6.6 Hz), 1.19
(d, 3H, J ) 6.9 Hz), 1.20 (d, 3H, J ) 6.9 Hz), 1.29 (d, 6H, J )
6.6 Hz), 2.84 (hep, 1H, J ) 6.9 Hz), 3.35 (s, 3H), 3.56 (s, 3H),
4.13 (hep, 2H, J ) 6.6 Hz), 6.97 (s, 1H), 7.03 (s, 2H), 7.20-
7.50 (m, 2H), 7.78 (d, 1H, J ) 7.2 Hz), 7.90 (s, 2H), 8.16 (d,
1H, J ) 8.5 Hz), 9.49 (d, 1H, J ) 8.9 Hz); 13C NMR δ 23.7,
24.6, 28.9, 34.2, 55.1, 55.5, 98.7, 123.3, 123.7, 125.1, 126.2,
126.3, 128.6, 129.1, 130.9, 133.4, 137.2, 138.8, 149.7, 153.0;
IR (neat) 2960, 1180, 1060 cm-1; EIMS m/z (rel intensity) 452
C
26H30O2S: C, 76.81; H, 7.44. Found: C,76.68; H, 7.57.
(R)-ter t-Bu tyl 1-Na p h th yl Su lfoxid e [(R)-5]. A solution
of tert-butylmagnesium chloride (2.50 mol L-1 solution in Et2O,
12 mL, 2.80 mmol) was slowly added to a THF (10 mL) solution
of (-)-menthyl (SS)-1-naphthylsulfinate at 0 °C, and the
mixture was stirred for 6 h. Saturated aqueous NH4Cl was
then added, and the mixture was extracted with CH2Cl2. Usual
workup gave the crude product which was purified by column
chromatography (silica gel 50 g, hexane/ethyl acetate ) 85:
15) to afford (R)-5 (420 mg, 71%): Rf ) 0.45 (hexane/ethyl
acetate ) 90:10); HPLC (Daicel Chiralpac AD, hexane/i-PrOH
) 80:20, flow rate 0.5 mL/min) tR 17.4 (S) and 25.8 min (R);
[R]23 +264 (c 0.50, toluene, 80% ee) lit.30 [R]23 +333 (c 1.1,
D
D
toluene); 1H NMR δ 1.22 (s, 9H), 7.50-7.70 (m, 3H), 7.85-
8.30 (m, 4H); 13C NMR δ 23.2, 57.9, 123.2, 124.9, 125.5, 126.2,
126.5, 128.5, 131.3, 131.5, 133.0, 136.8.
(R)-[1-(ter t-Bu tylsu lfin yl)-2-n a p h th yl]m eth a n ol [(R)-6].
To a solution of 5 (420 mg, 1.80 mmol) in THF (10 mL) was
(30) Baker, R. W.; Hockless, D. C. R.; Pocock, G. R.; Sargent, M. V.;
Skelton, B. W.; Sobolev, A. N.; Twiss, E.; White, A. H. J . Chem. Soc.,
Perkin Trans. 1 1995, 2615.

8648 J . Org. Chem., Vol. 65, No. 25, 2000
Nakamura et al.
added n-butyllithium (1.48 mol L-1, 1.34 mL, 1.99 mmol) at
-78 °C. After stirring for 10 min, a THF (5 mL) solution of
paraformaldehyde (274 mg, 9.04 mmol) was added. The
mixture was allowed to warm to room temperature and stirred
for 1 h. Usual workup gave the crude product which was
purified by column chromatography (silica gel 30 g, hexane/
ethyl acetate ) 70:30) to afford (R)-6 (145.4 mg, 31%). The
(RS*,S*)- a n d (RS*,R*)-1-[1-[(2,4,6-Tr iisop r op ylp h en yl)-
su lfin yl]-2-n a p h t h yl]et h a n ols [(RS*,S*)-10 a n d (RS*,R)-
10]. The reaction was carried as described above except using
3c (41.1 mg, 0.037 mmol) and MeMgI (2.83 mol L-1, 0.080 mL,
0.226 mmol). Usual workup gave the crude product which was
purified by column chromatography (silica gel 8 g, hexane/
ethyl acetate ) 90:10) to afford (RS*,S*)-10 (32.0 mg, 75%) and
(RS*,R*)-10 (8.0 mg, 19%). The diastereomer ratio was deter-
mined to be 80:20 by the 1H NMR analysis of the crude
product: (RS*,S*)-10: Rf ) 0.13 (hexane/ethyl acetate ) 80:
20); HPLC (COSMOSIL, hexane/ethyl acetate ) 80:20, flow
1
atropisomer ratio was determined to be 73:27 by the H NMR
analysis of the product in CDCl3 at room temperature: Rf )
0.17 (hexane/ethyl acetate ) 50:50); HPLC (Daicel Chiralpac
AD, hexane/i-PrOH ) 70:30, flow rate 0.5 mL/min) tR 16.6 (S)
1
1
and 19.5 min (R); [R]23 +164.6 (c 0.253, CHCl3, 80% ee); H
rate 0.5 mL/min) tR 32.3 min; H NMR δ 0.70 (d, 6H, J ) 6.8
D
Hz), 0.85 (d, 6H, J ) 6.0 Hz), 1.06 (d, 6H, J ) 6.8 Hz), 1.20 (d,
6H, J ) 6.8 Hz), 2.80 (hep, 1H, J ) 6.9 Hz), 3.75 (hep, 2H, J
) 6.8 Hz), 4.70 (br, 1H), 5.80-5.90 (m, 1H), 7.05 (s, 2H), 7.30-
7.70 (m, 2H), 7.70-8.00 (m, 3H), 9.00-9.10 (m, 1H); 13C NMR
δ 15.7, 23.6, 19.8, 34.4, 64.2, 122.9, 123.0, 124.6, 128.6, 131.5,
NMR δ 1.22 (s, 9H, the major isomer), 1.30 (s, 9H, the minor
isomer), 4.15-4.60 (m, 2H), 5.20-5.40 (m, 1H, the minor
isomer), 5.70-5.85 (m, 1H, the major isomer), 7.60-8.00 (m,
5H), 8.20-8.40 (m, 1H, the major isomer), 9.35-9.50 (m, 1H,
the minor isomer); 13C NMR δ 24.8, 25.0, 60.3, 60.7, 60.9, 64.4,
124.1, 125.0, 126.2, 126.4, 126.5, 126.7, 128.3, 128.5, 130.3,
132.0, 132.3, 132.9, 133.1, 143.0; IR (KBr) 3320, 2970, 1060,
cm-1; EIMS m/z (rel intensity) 262 (M+, 0.1), 188 (100), 115
(50). Anal. Calcd for C15H18O2S: C, 68.67; H, 6.92. Found: C,
68.56; H, 7.03.
132.0, 144.2, 149.8, 153.3; IR (KBr) 3350, 3000, 1060 cm-1
;
EIMS m/z (rel intensity) 422 (M+, 0.2), 345 (40), 203 (100).
Anal. Calcd for C27H34SO2: C, 76.73; H, 8.11. Found: C, 76.54;
H, 8.30. (RS*,R*)-10: Rf ) 0.24 (hexane/ethyl acetate ) 80:
20); HPLC (COSMOSIL, hexane/ethyl acetate ) 80:20, flow
1
rate 0.5 mL/min) tR 22.5 min; H NMR δ 0.43 (d, 6H, J ) 6.8
(R)-1-(ter t-Bu tylsu lfin yl)-2-n a p h th a ld eh yd e [(R)-3d ].
To a solution of PCC (179.2 mg, 0.83 mmol) in CH2Cl2 (1.5
mL) was added a solution of 6 (145.4 mg, 0.55 mmol) in CH2-
Cl2 (1.5 mL) at room temperature. After stirring for 5 h, Et2O
was added, and the supernatant decanted from the black gum.
The insoluble residue was washed thoroughly washed with
Et2O. The ethereal solution was concentrated under reduced
pressure to leave a residue which was purified by column
chromatography (silica gel 20 g, hexane/ethyl acetate ) 70:
30) to give (R)-3d (103.3 mg, 71%). The atropisomer ratio was
determined to be 69:31 by the 1H NMR analysis of the product
in THF-d8 at -78 °C: Rf ) 0.58 (hexane/ethyl acetate ) 50:
50); HPLC (COSMOSIL, hexane/ethyl acetate ) 75:25, flow
rate 0.6 mL/min) tR 15.0 min, (Daicel Chiralpac AD, hexane/
i-PrOH ) 80:20, flow rate 0.5 mL/min) tR 26.2 (S) and 35.2
Hz), 0.82 (d, 6H, J ) 6.0 Hz), 1.05 (d, 6H, J ) 6.8 Hz), 1.16 (d,
6H, J ) 6.8 Hz), 2.80 (hep, 1H, J ) 6.9 Hz), 3.75 (hep, 2H, J
) 6.8 Hz), 4.35 (br, 1H), 5.30-5.50 (m, 1H), 6.94 (s, 2H), 7.35-
7.60 (m, 2H), 7.70-7.95 (m, 3H), 8.40-8.60 (m, 1H); 13C NMR
δ 22.1, 23.2, 23.6, 24.2, 29.2, 34.2, 64.1, 123.1, 123.8, 124.5,
125.9, 126.6, 128.5, 131.4, 131.9, 133.6, 138.7, 144.1, 149.8,
153.3; IR (KBr) 3320, 2980, 1060 cm-1; EIMS m/z (rel intensity)
422 (M+, 10), 345 (55), 203 (100). Anal. Calcd for C27H34SO2:
C, 76.73; H, 8.11. Found: C, 76.79; H, 8.02.
(RS*,S*)-3-Meth yl-1-[1-[(2,4,6-tr iisop r op ylp h en yl)su lfi-
n yl]-2-n a p h th yl]-1-bu ta n ol [(RS*,S*)-11]. The reaction was
carried as described above except using 3c (46.3 mg, 0.114
i
mmol) and BuMgBr (1.0 mol L-1, 0.17 mL, 0.17 mmol). Usual
workup gave the crude product which was purified by column
chromatography (silica gel 10 g, hexane/ethyl acetate ) 92:8)
to afford (RS*,S*)-11 (31.7 mg, 60%) and 1-[1-[(2,4,6-triisopro-
pylphenyl)sulfinyl]-2-naphthyl]methanol (16.3 mg, 35%). The
diastereomer ratio was determined to be >98:2 by the 1H NMR
analysis of the crude product. (RS*,S*)-11: Rf ) 0.41 (hexane/
ethyl acetate ) 80/20): 1H NMR δ 0.77 (d, 6H, J ) 6.7 Hz),
0.93 (d, 3H, J ) 6.7 Hz), 0.97 (d, 3H, J ) 6.7 Hz), 1.15-1.25
(m, 12H), 1.45-1.60 (m, 1H), 1.70-1.90 (m, 1H, J ) 6.7 Hz),
1.90-2.10 (m, 1H), 2.84 (hep, 1H, J ) 6.7 Hz), 3.75 (br, 1H),
3.91 (hep, 2H, J ) 6.7 Hz), 5.90-6.00 (m, 1H), 7.10 (s, 2H),
7.15-7.30 (m, 1H), 7.30-7.45 (m, 1H), 7.70-8.00 (m, 4H);13C
NMR δ 22.5, 23.4, 23.6, 23.8, 24.2, 25.2, 29.1, 34.2, 45.9, 68.0,
123.3, 123.7, 125.9, 128.3, 129.5, 130.9, 132.9, 138.2, 144.5,
149.6, 153.1; IR (KBr) 3420, 2980, 1060 cm-1; EIMS m/z (rel
intensity) 464 (M+, 0.3), 447 (80), 243 (92), 203 (100). Anal.
Calcd for C30H40SO2: C, 77.54; H, 8.68. Found: C, 77.41; H,
8.81.
min (R); [R]26 +155.7 (c 0.184, CHCl3, 80% ee); 1H NMR δ
D
1.23 (s, 9H), 7.50-7.70 (m, 2H) 7.80-8.10 (m, 3H), 8.35-8.45
(m, 1H, the major isomer), 9.65-9.72 (m, 1H, the minor
isomer), 10.8 (s, 1H, the major isomer), 11.6 (s, 1H, the minor
isomer); 13C NMR δ 24.1, 24.9, 60.3, 61.1, 122.7, 123.9, 125.5,
127.4, 127.7, 127.8, 128.0, 128.3, 128.5, 128.6, 128.8, 129.2,
131.6, 132.5, 134.7, 136.8, 138.8, 139.0, 188.5, 191.8; IR (neat)
2980, 1680, 1050 cm-1; EIMS m/z (rel intensity) 260 (M+, 0.3),
204 (90), 187 (100), 158 (32), 115 (34). Anal. Calcd for
C
15H16O2S: C, 69.20; H, 6.19. Found: C, 69.28; H, 6.11; ∆Gq
C-S
) 17.9 kcal/mol (DMSO-d6).
Rea ction of th e 1-Su lfin yl-2-n a p h th a ld eh yd es w ith
Nu cleop h iles. (RS*,S*)-a n d (RS*,R*)-1-P h en yl-1-[1-[(2,4,6-
t r iis o p r o p y lp h e n y l)s u lfin y l]-2-n a p h t h y l]m e t h a n o ls
[(RS*,S*)-9 a n d (RS*,R*)-9]. To a solution of 3c (15.0 mg,
0.037 mmol) in THF (0.4 mL) was added PhMgBr (0.965
mol L-1, 0.045 mL, 0.043 mmol) at -78 °C, and the mixture
was stirred for 15 min. Usual workup gave the crude product
which was purified by column chromatography (silica gel
10 g, hexane/CH2Cl2/Et2O ) 50:48:2) to afford a mixture
of (RS*,S*)-9 and (RS*,R*)-9 (17.0 mg, 96%). The
diastereomer ratio was determined to be 98:2 by 1H NMR
(RS*,S*)- a n d (RS*,R*)-1-[1-[(2,4,6-Tr iisop r op ylp h en yl)-
su lfin yl]-2-n a p h t h yl]-3-b u t en e-1-ols [(RS*,S*)-12 a n d
(RS*,R)-12]. The reaction was carried as described above
except using 3c (60.0 mg, 0.148 mmol) and CH2dCHCH2MgBr
(0.125 mol L-1 solution in THF, 1.77 mL, 0.221 mmol). Usual
workup gave the crude product that was purified by column
chromatography (silica gel 10 g, hexane/CH2Cl2/Et2O ) 50:
48:2) to afford a mixture of (RS*,S*)-12 and (RS*,R*)-12 (53
mg, 80%). The diastereomer ratio was determined to be 76:24
by the 1H NMR analysis of the crude product: Rf ) 0.24
(hexane/ethyl acetate ) 80:20); HPLC (COSMOSIL, hexane/
ethyl acetate ) 90:10, flow rate 0.5 mL/min) tR 38.1 and 42.8
analysis and HPLC analysis of the crude product: Rf
)
0.41 (CH2Cl2/Et2O ) 95:5); HPLC (COSMOSIL, hexane/ethyl
acetate ) 90:10, flow rate 0.5 mL/min) tR 24.7 min, (Daicel
Chiralcel OD-H, hexane/i-PrOH
) 90:10, flow rate 1.0
mL/min) tR 9.0 (RS,R) and 37.7 min (RS,S); 1H NMR δ
0.78 (d, 6H, J ) 6.3 Hz), 1.18 (d, 6H, J ) 6.6 Hz), 1.22
(d, 6H, J ) 6.3 Hz), 2.85 (hep, 1H, J ) 6.6 Hz), 3.70-3.90
(m, 2H), 4.00 (hep, 2H, J ) 6.3 Hz), 7.03 (s, 2H), 7.10-7.50
(m, 8H), 7.70-7.85 (m, 2H), 8.17 (d, 1H, J ) 8.7 Hz);
13C NMR δ 25.1, 25.2, 25.7, 30.8, 35.8, 70.5, 124.9, 125.4,
127.7, 127.9, 128.3, 129.3, 129.5, 130.1, 132.5, 132.8, 135.0,
140.1, 144.0, 144.8, 151.3, 154.9; IR (KBr) 3320, 2980, 1040
cm-1; EIMS m/z (rel intensity) 484 (M+, 0.1), 389 (54),
347 (96), 203 (100). Anal. Calcd for C32H36 O2S: C, 79.30;
H, 7.49. Found: C, 79.50; H, 7.45.
1
min; H NMR δ 0.54 (d, 6H, J ) 6.8 Hz, the major isomer),
0.85 (d, 6H, J ) 6.8 Hz, the minor isomer), 1.10-1.40 (m, 12H),
2.15-2.40 (m, 1H), 2.40-3.00 (m, 2H), 3.70-4.20 (m, 2H),
4.80-5.20 (m, 2H), 5.40-5.90 (m, 2H), 6.98 (s, 2H, the major
isomer), 7.05 (s, 2H, the minor isomer), 7.20-8.00 (m, 5H),
8.60 (d, 1H, J ) 8.0 Hz, the minor isomer), 9.00 (d, 1H, J )
8.0 Hz, the major isomer); 13C NMR δ 23.4, 23.7, 23.8, 24.3,
28.8, 29.3, 34.2, 34.3, 41.4, 41.9, 67.3, 70.3, 117.5, 117.6, 123.2,
123.5, 123.9, 125.1, 126.0, 126.1, 126.4, 126.7, 128.5, 131.1,

Asymmetric Reactions via Diastereomeric Rotamers
J . Org. Chem., Vol. 65, No. 25, 2000 8649
131.4, 133.4, 134.5, 134.7, 142.8, 149.6; IR (KBr) 3350, 2980,
1060 cm-1; EIMS m/z (rel intensity) 448 (M+, 0.1), 430 (66),
347 (100), 227 (32), 203 (30). Anal. Calcd for C29H36O2S: C,
77.64; H, 8.09. Found: C, 77.81; H, 7.99.
mg, 0.057 mmol) in CH2Cl2 (0.5 mL) was added BF3‚OEt2 (1.34
mol L-1 solution in CH2Cl2, 0.084 mL, 0.113 mmol) at -78 °C
and the mixture was stirred for 1 h. A solution of S-tert-butyl
O-trimethylsilylketene acetal (28.0 mg, 0.137 mmol) in CH2-
Cl2 (0.5 mL) was then added. After stirring for 2 h, HCl (1
mol L-1) was added, and the mixture was stirred for 15 min.
Usual workup gave the crude product which was purified by
column chromatography (silica gel 10 g, hexane/CH2Cl2/Et2O
) 50:48:2) to afford (RS*,S*)-17 (27.5 mg, 90%). The diastere-
omer ratio was determined to be >98:2 by the 1H NMR
analysis of the crude product: mp 184-185 °C; Rf ) 0.43 (CH2-
Cl2/Et2O ) 95:5); 1H NMR δ 0.73 (d, 6H, J ) 6.7 Hz), 1.22 (d,
6H, J ) 7.0 Hz), 1.30 (d, 6H, J ) 6.7 Hz), 1.45 (s, 9H), 2.25
(dd, 1H, J ) 2.6, 16.1 Hz), 2.84 (dd, 1H, J ) 9.4, 16.1 Hz),
2.85 (hep, 1H, J ) 7.0 Hz), 4.03 (hep, 2H, J ) 6.7 Hz), 4.17 (d,
1H, J ) 3.9 Hz), 6.11 (ddd, 1H, J ) 2.6, 3.9, 9.4 Hz), 7.03 (s,
2H), 7.25-7.50 (m, 3H), 7.65-7.95 (m, 2H), 8.68 (d, 1H, J )
8.9 Hz); 13C NMR δ 23.5, 23.9, 24.6, 29.4, 29.8, 34.3, 48.6, 50.7,
66.0, 123.4, 123.8, 125.0, 126.2, 126.4, 128.5, 130.8, 131.1,
133.3, 140.7, 149.9, 200.0; IR (KBr) 3320, 2980, 1670, 1160,
1070 cm-1; EIMS m/z (rel intensity) 538 (M+, 12), 431 (20),
389 (40), 347 (60), 203 (100). Anal. Calcd for C32H42O3S2: C,
71.33; H, 7.86. Found: C, 71.23; H, 7.96.
(RS,S)- a n d (RS,R)-1-[1-(ter t-Bu tylsu lfin yl)-2-n a p h th yl]-
1-p h en ylm eth a n ols [(RS,S)-13 a n d (RS,R)-13]. The reaction
was carried as described above except using (R)-3d (103.3 mg,
0.397 mmol) and PhMgBr (1.0 mol L-1, 0.4 mL, 0.40 mmol).
Usual workup gave the crude product that was purified by
column chromatography (silica gel 10 g, hexane/ethyl acetate
) 90:10) to afford the mixture of (RS,S)-13 and (RS,R)-13 (107.4
mg, 80%). The diastereomer ratio was determined to be 68:32
by the HPLC analysis of the crude product. The diastereomeric
atropisomer ratio a:b:c:d was determined to be 52:16:32:0 by
the 1H NMR analysis of the crude product: Rf ) 0.34 (hexane/
ethyl acetate ) 50:50); HPLC (COSMOSIL, hexane/ethyl
acetate ) 75:25, 0.6 mL/min) tR 24.9 and 28.0 min;1H NMR δ
1.32 (s, 9H, a), 1.36 (s, 9H, b), 1.49 (s, 9H, c), 3.20 (br, 1H, a),
3.60 (br, 1H, b), 5.00 (br, 1H, c), 6.70 (s, 1H, a), 6.80 (s, 1H, c),
7.00-8.00 (m, 10H), 8.30-8.50 (m, 1H, a+c)), 9.50-9.70 (m,
1H, b), two singlet 1.32 and 1.36 ppm appeared at 1.34 ppm
as a singlet at 60 °C; IR (KBr) 3300, 2980, 1080 cm-1; EIMS
m/z (rel intensity) 338 (M+, 0.1), 266 (70), 247 (100). Anal.
Calcd for C21H22O2S: C, 74.52; H, 6.55. Found: C, 74.42; H,
6.65.
P r ep a r a tion of th e Ch ir a l Su lfoxid es. (R)-[1-(2,4,6-
Tr iisop r op ylp h en yl)su lfin yl]-2-n a p h th a ld eh yd e Dim e-
th yl Aceta l [(R)-2c]. The reaction was carried out as de-
scribed in the preparation of racemic-3c except using (-)-1,1-
diacetone-D-glucosyl 2,4,6-triisopropylbenzenesulfinate (1.14
g, 2.24 mmol), 1-bromo-2-naphthaldehyde dimethyl acetal
(599.8 mg, 2.13 mmol) and n-butyllithium (1.51 mol L-1, 1.48
mL, 2.24 mmol) at -105 °C. Usual workup gave the crude
product which was purified by column chromatography (silica
gel 50 g, hexane/ethyl acetate ) 96:4) to afford (R)-2c (950.5
mg, 98%). See the HPLC data of 2c.
ter t-Bu tyl (RS*,R*)- a n d (RS*,S*)-3-Hyd r oxy-3-[1-[(2,4,6-
t r i i s o p r o p y lp h e n y l)s u lfi n y l]-2-n a p h t h y l]t h i o p r o -
p a n oa tes [(RS*,R*)-17 a n d (RS*,S*)-17]. To a solution of 3c
(48.3 mg, 0.119 mmol) in CH2Cl2 (1.0 mL) was added TiCl4
(0.015 mL, 0.137 mmol) at -78 °C and the mixture was stirred
for 1 h. A solution of S-tert-butyl O-tert-butyldimethylsi-
lylketene acetal (35.2 mg, 0.143 mmol) in CH2Cl2 (0.5 mL) was
then added. After stirring for 7 h, HCl (1 mol L-1) was added,
and the mixture was stirred for 15 min. Usual workup gave
the crude product which was purified by column chromatog-
raphy (silica gel 10 g, hexane/CH2Cl2/Et2O ) 50:48:2) to afford
a mixture of (RS*,R*)-17 and (RS*,S*)-17 (27.1 mg, 42%). The
1
diastereomer ratio was determined to be 88:12 by the H NMR
(R)-1-(2,4,6-Tr iisop r op ylp h en yl)su lfin yl-2-n a p h th a ld e-
h yd e [(R)-3c]. The reaction was carried as described in the
preparation of racemic-3c except using 6 drops of 15% sulfuric
acid solution, silica gel (1.50 g), and (R)-2c (631.9 mg, 1.40
mmol). Usual workup gave the crude product which was
purified by column chromatography (silica gel 20 g, hexane/
ethyl acetate ) 96:4) to afford (R)-3c (565 mg, 100%). The
enantiomer ratio was determined to be >98:2 by the HPLC
analysis using Chiralcel OD-H; see the data of 3c: [R]20D -20.0
(c 0.724, CHCl3).
analysis of the crude product. (RS*,R*)-17: Rf ) 0.43 (CH2Cl2/
1
Et2O ) 95:5); H NMR δ 0.81 (d, 6H, J ) 6.7 Hz), 1.10-1.40
(m, 12H), 1.42 (s, 9H), 2.75-2.95 (m, 1H), 3.08 (dd, 1H, J )
5.4, 15.2 Hz), 3.20 (dd, 1H, J ) 8.0, 15.2 Hz), 3.90-4.00 (m,
2H), 4.68 (d, 1H, J ) 6.7 Hz), 5.85-6.00 (m, 1H), 7.05 (s, 2H),
7.20-7.50 (m, 2H), 7.60-7.90 (m, 3H), 8.20 (d, 1H, J ) 8.6
Hz); 13C NMR δ 14.1, 22.7, 23.7, 24.3, 29.1, 29.7, 52.3, 69.8,
123.5, 123.7, 126.2, 126.4, 126.9, 128.6, 129.0, 131.3, 137.8,
141.4, 149.8, 153.2, 198.7; IR (KBr) 3360, 2980, 1680, 1040
cm-1; EIMS m/z (rel intensity) 538 (M+, 20), 431 (15), 389 (70),
203 (100). Anal. Calcd for C32H42O3S2: C, 71.33; H, 7.86.
Found: C, 71.35; H, 7.81.
Rea ction of (R)-3c w ith P h MgBr . (RS,S)-1-P h en yl-1-[1-
[(2,4,6-t r iisop r op ylp h en yl)su lfin yl]-2-n a p h t h yl]m et h a -
n ol [(RS,S)-9]. The reaction was carried as described in the
preparation of racemic-9 except using (R)-3c (33.5 mg, 0.082
mmol) and PhMgBr (0.72 mol L-1, 0.172 mL, 0.124 mmol).
Usual workup gave the crude product which was purified by
column chromatography (silica gel 10 g, hexane/CH2Cl2/Et2O
) 50:48:2) to afford a mixture of (RS,S)-9 and (RS,R)-9 (38.3
mg, 96%). The diastereomer ratio was determined to be 98:2
by the 1H NMR analysis of the crude product. Recrystallization
from hexanes-ethyl acetate afforded (RS,S)-9 with 98% ee; see
(RS*,S*)-3-Hyd r oxy-1-p h en yl-3-[1-[(2,4,6-t r iisop r op yl-
p h en yl)su lfin yl]-2-n a p h th yl]-1-p r op a n on e [(RS*,S*)-18].
The reaction was carried as described above except using 3c
(37.3 mg, 0.092 mmol), BF3‚OEt2 (1.34 mol L-1 solution in CH2-
Cl2, 0.15 mL, 0.201 mmol), and the O-trimethylsilyl enol ether
of acetophenone (26.5 mg, 0.138 mmol). Usual workup gave
the crude product which was purified by column chromatog-
raphy (silica gel 10 g, hexane/ethyl acetate ) 90:10) to afford
(RS*,R*)-18 (39.2 mg, 81%). The diastereomer ratio was
the HPLC data of 9: [R]20 -96.9 (c 0.98, CHCl3).
determined to be >98:2 by the H NMR analysis of the crude
1
D
P r ep a r a t ion of (S)-1-(2-n a p h t h yl)-1-p h en ylm et h a n ol
[(S)-14]. To a solution of (RS,S)-9 (28.0 mg, 0.058 mmol) in
THF (0.2 mL) was added n-BuLi (0.19 mL, 1.51 mol L-1 in
hexane, 0.289 mmol) at -78 °C, and the mixture was stirred
for 10 min. Usual workup gave the crude product which was
purified by column chromatography (silica gel 7 g, hexane/
CH2Cl2/Et2O ) 50:47.5:2.5) to afforded (S)-14 (8.3 mg, 61%):
HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH ) 93:7, flow
product: mp 168-169 °C; Rf ) 0.20 (hexane/ethyl acetate )
1
80:20); H NMR δ 0.76 (d, 6H, J ) 6.8 Hz), 0.92 (d, 3H, J )
6.9 Hz), 0.99 (d, 3H, J ) 6.9 Hz), 1.28 (d, 6H, J ) 6.8 Hz),
2.50 (dd, 1H, J ) 3.0, 17.9 Hz), 2.55 (hep, 1H, J ) 6.8 Hz),
3.16 (dd, 1H, J ) 9.6, 17.9 Hz), 4.14 (hep, 2H, J ) 6.9 Hz),
4.22 (d, 1H, J ) 3.0 Hz), 6.18 (ddd, 1H, J ) 3.0, 3.0, 9.6 Hz),
6.93 (s, 2H), 7.30-7.60 (m, 5H), 7.70-8.00 (m, 5H), 9.08 (d,
1H, J ) 9.3 Hz); 13C NMR δ 23.2, 23.4, 24.6, 29.5, 33.9, 45.6,
64.9, 123.1, 123.8, 124.6, 126.2, 127.8, 127.9, 128.0, 128.6,
131.3, 133.5, 135.0, 136.4, 139.0, 140.7, 150.0, 153.3, 199.5;
IR (KBr) 3400, 2980, 1600, 1070 cm-1; EIMS m/z (rel intensity)
526 (M+, 1), 390 (33), 347 (100), 203 (64), 105 (98). Anal. Calcd
for C34H38O3S: C, 77.53; H, 7.27. Found: C, 77.42; H, 7.38.
(RS*,R*)-3-Hyd r oxy-1-p h en yl-3-[1-[(2,4,6-tr iisop r op yl-
p h en yl)su lfin yl]-2-n a p h th yl]-1-p r op a n on e [(RS*,R*)-18].
The reaction was carried as described above except using 3c
(32.3 mg, 0.079 mmol), TiCl4 (1.41 mol L-1 solution in CH2-
rate 1.0 mL/min) tR 36.6 (S) and 44.8 min(R); [R]19 -7.3 (c
D
0.83, benzene) lit.18 [R]20 +7.4 (c 0.77, benzene) for the (R)-
D
1
isomer: Rf ) 0.61 (CH2Cl2/Et2O ) 95:5); H NMR δ 2.45 (br,
1H, -OH), 6.05 (s, 1H, -CH-), 7.20-7.60 (m,8H, Ar), 7.80-
8.00 (m, 4H, Ar); IR (KBr) 3600, 3040 cm-1
.
Rep r esen ta tive P r oced u r e for th e Mu k a iya m a Ald ol
Rea ction of th e Su lfoxid es. ter t-Bu tyl (RS*,S*)-3-Hy-
d r oxy-3-[1-[(2,4,6-tr iisop r op ylp h en yl)su lfin yl]-2-n a p h th -
yl]th iop r op a n oa te [(RS*,S*)-17]. To a solution of 3c (23.0

8650 J . Org. Chem., Vol. 65, No. 25, 2000
Nakamura et al.
Cl2, 0.06 mL, 0.085 mmol), and O-trimethylsilyl enol ether of
acetophenone (24.0 mg, 0.125 mmol). Usual workup gave the
crude product which was purified by column chromatography
(silica gel 10 g, hexane/ethyl acetate ) 92:8) to afford (RS*,S*)-
18 (16.7 mg, 40%) and 3c (17.8 mg, 55%). The diastereomer
was extracted with CH2Cl2. Usual workup gave the crude
product which was purified by column chromatography (silica
gel 3 g, hexane/CH2Cl2/Et2O ) 50:48:2) to afford a mixture of
(RS*,S*)-9 and (RS*,R*)-9 (14.4 mg, 91%). The diastereomer
ratio was determined to be 97:3 by the 1H NMR analysis of
the crude product.
1
ratio was determined to be >98:2 by the H NMR analysis of
the crude product: Rf ) 0.20 (hexane/ethyl acetate)80:20); 1H
NMR δ 0.86 (d, 6H, J ) 6.8 Hz), 1.16 (d, 6H, J ) 6.8 Hz), 1.18
(d, 6H, J ) 6.8 Hz), 2.80 (hep, 1H, J ) 6.8 Hz), 3.40-3.75 (m,
2H), 4.05 (hep, 2H, J ) 6.8 Hz), 4.65 (d, 1H, J ) 5.5 Hz), 6.08-
6.20 (m, 1H), 7.03 (s, 2H), 7.25-7.60 (m, 5H), 7.70-8.10 (m,
5H), 8.38 (d, 1H, J ) 8.5 Hz); 13C NMR δ 23.6, 23.9, 24.2, 28.9,
34.2, 47.1, 68.6, 123.4, 123.9, 126.2, 126.3, 126.5, 128.3, 128.6,
130.1, 131.6, 133.4, 136.8, 137.3, 142.0, 149.7, 153.0, 199.4;
IR (neat) 3380, 2960, 1680, 1040 cm-1; EIMS m/z (rel intensity)
526 (M+, 1), 390 (40), 347 (100), 203 (64), 105 (80). Anal. Calcd
for C34H38O3S: C, 77.53; H, 7.27. Found: C, 77.51; H, 7.30.
Rep r esen ta tive P r oced u r e for th e P r ep a r a tion of th e
2-Acyl-1-su lfin yln a p h th a len es. 1-[(2,4,6-Tr iisop r op ylp h e-
n yl)su lfin yl]-2-ben zon a p h th on e (19c). To a solution of PCC
(11.0 mg, 0.051 mmol) in CH2Cl2 (0.1 mL) was added 9 (16.5
mg, 0.034 mmol) at room temperature. After stirring for 3 h,
Et2O was added and the supernatant decanted from the black
gum. The insoluble residue was washed thoroughly washed
with Et2O. The ethereal solution was concentrated under
reduced pressure to leave a residue which was purified by
column chromatography (silica gel 10 g, hexane/CH2Cl2/Et2O
) 50:48:2) to afford 19c (13.3 mg, 81%): mp 92-93 °C (from
hexane/ethyl acetate); Rf ) 0.50 (CH2Cl2/Et2O ) 95:5); 1H NMR
δ 0.66 (d, 6H, J ) 6.6 Hz), 1.09 (d, 6H, J ) 6.9 Hz), 1.22 (d,
6H, J ) 6.6 Hz), 2.73 (hep, 1H, J ) 6.9 Hz), 3.96 (hep, 2H, J
) 6.6 Hz), 6.91 (s, 2H), 7.18-7.50 (m, 6H), 7.60-7.75 (m, 3H),
7.80-7.90 (m, 2H); 13C NMR δ 23.5, 23.6, 28.6, 34.2, 123.2,
123.8, 125.9, 126.9, 128.3, 126.9, 128.3, 128.7, 128.8, 128.9,
130.4, 132.3, 133.5, 136.3, 138.3, 138.4, 140.8, 150.8, 153.7,
196.3; IR (KBr) 3420, 3030, 1670, 1660, 1050 cm-1; EIMS m/z
(rel intensity) 482 (M+, 70), 377 (80), 263 (64), 234 (100), 149
(50), 105 (80). Anal. Calcd for C32H34O2S: C, 79.63; H, 7.10.
Found: C, 79.59; H, 7.14.
Red u ction of 19c w ith LiAlH4. (RS*,R*)-1-P h en yl-1-[1-
[(2,4,6-t r iisop r op ylp h en yl)su lfin yl]-2-n a p h t h yl]m et h a -
n ol [(RS*,R*)-9]. To a solution of LiAlH4 (1.6 mg, 0.042 mmol)
in THF (0.2 mL) was added a solution of 19c (13.3 mg, 0.028
mmol) in THF (0.2 mL) at -78 °C, and the mixture was stirred
for 40 min. Usual workup gave the crude product which was
purified by column chromatography (silica gel 2 g, hexane/
CH2Cl2/Et2O ) 50:48:2) to afford a mixture of (RS*,R*)-9 and
(RS*,S*)-9 (10.6 mg, 80%). The diastereomer ratio was deter-
mined to be 96:4 by the 1H NMR analysis of the crude product.
Recrystallization from hexanes-ethyl acetate afforded
(RS*,R*)-9 with >98% de: Rf ) 0.42 (CH2Cl2/Et2O ) 95:5);
HPLC (COSMOSIL, hexane/ethyl acetate ) 90:10, flow rate
0.5 mL/min) tR 20.7 min, (Daicel Chiralcel OD-H, hexane/i-
PrOH ) 90:10, 1.0 mL/min) tR 15.8 (RS,R) and 37.7 min (RS,S);
1H NMR δ 0.87 (d, 6H, J ) 6.8 Hz), 1.08 (d, 6H, J ) 6.8 Hz),
1.22 (d, 3H, J ) 6.9 Hz), 2.97 (hep, 1H, J ) 6.9 Hz), 3.93 (d
1H, J ) 5.4 Hz), 4.12 (hep, 2H, J ) 6.8 Hz), 6.81 (d 1H, J )
5.4 Hz), 7.08 (s, 2H), 7.15-7.55 (m, 8H), 7.75-7.85 (m, 2H),
8.50-8.60 (m, 1H); 13C NMR δ 23.7, 23.8, 24.3, 28.8, 34.2, 71.2,
123.5, 123.6, 126.2, 126.4, 126.9, 127.9, 128.0, 128.2, 128.7,
131.5, 133.2, 142.5, 142.5, 142.9, 149.7, 152.9; IR (KBr) 3400,
2960, 1660, 1100 cm-1; EIMS m/z (rel intensity) 484 (M+, 0.1),
389 (60), 347 (90), 203 (100). Anal. Calcd for C32H36O2S: C,
79.30; H, 7.49. Found: C, 79.10; H, 7.30.
Ack n ow led gm en t. We thank Dr. Shinya Kusuda,
Ono Pharmaceutical Co., Ltd., for the X-ray crystal-
lographic analyses. This work was supported by a
Grant-in-Aid for Scientific Research (no. 11650890) from
the Ministry of Education, Science, Sports and Culture
of J apan and the Sasakawa Scientific Research Grant
from The J apan Science Society.
Rep r esen ta tive P r oced u r e for th e Red u ction of th e
2-Acyl-1-su lfin yln a p h t h a len es. R ed u ct ion of 19c w it h
DIBAL. (RS*,S*)- a n d (RS*,R*)-1-P h en yl-1-[1-[(2,4,6-tr i-
isopr opylph en yl)su lfin yl]-2-n aph th yl]m eth an ol [(RS*,S*)-
9 a n d (RS*,R*)-9]. To a solution of 19c (15.7 mg, 0.033 mmol)
in CH2Cl2 (0.35 mL) was added DIBAL (0.95 mol L-1 solution
in hexane, 0.070 mL, 0.067 mmol) at -78 °C, and the mixture
was stirred for 1 h. MeOH was then added and the mixture
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic char-
acterization of the products 2a ,b, 3a ,b, 7, 8, 15, 16, 19a ,b,d ,e,
20-22 and X-ray crystallographic data of 3c, 9, 17, 19c, and
22. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O005581P