Lewis acid-catalyzed asymmetric diels-alder reactions using chiral sulfoxide ligands: chiral 2-(arylsulfinylmethyl)-1,3-oxazoline derivatives.

Article abstract of DOI:10.1248/cpb.50.372

New chiral sulfoxide-1,3-oxazoline ligands have been developed as chiral ligands for Lewis acid-catalyzed asymmetric Diels-Alder reactions. The use of chiral sulfinyl 1,3-oxazoline ligands in copper(II)-catalyzed asymmetric Diels-Alder reactions provided an endo cycloadduct as a major product with moderate enantioselectivity. A rationale is proposed for the mechanism of the asymmetric induction.

Full text of DOI:10.1248/cpb.50.372

372
Chem. Pharm. Bull. 50(3) 372—379 (2002)
Vol. 50, No. 3
Lewis Acid-Catalyzed Asymmetric Diels–Alder Reactions Using Chiral
Sulfoxide Ligands: Chiral 2-(Arylsulfinylmethyl)-1,3-oxazoline Derivatives
Kazuhiro WATANABE, Takashi HIRASAWA, and Kunio HIROI*
Tohoku Pharmaceutical University, 4–4–1 Komatsushima, Aoba-ku, Sendai, Miyagi 981–8558, Japan.
Received October 29, 2001; accepted November 22, 2001
New chiral sulfoxide-1,3-oxazoline ligands have been developed as chiral ligands for Lewis acid-catalyzed
asymmetric Diels–Alder reactions. The use of chiral sulfinyl 1,3-oxazoline ligands in copper(II)-catalyzed asym-
metric Diels–Alder reactions provided an endo cycloadduct as a major product with moderate enantioselectivity.
A rationale is proposed for the mechanism of the asymmetric induction.
Key words chiral sulfoxide; chiral 1,3-oxazoline; chiral ligand; asymmetric Diels–Alder reaction; Lewis acid; copper catalyst
A catalytic asymmetric carbon–carbon bond-forming reac- methyl iodide was carried out in a similar way as described
tion has received much attention for the creation of complex above, giving (4S,5R,Ss)-12 through (4S,5R,Rs)-11. The
organic molecules with stereochemical efficiency. A number same procedures as described above were applied to the syn-
of methodologies have been proposed for asymmetric thesis of another chiral 2-(arylsulfinylmethyl)-1,3-oxazoline
Diels–Alder reactions by introducing chiral auxiliaries into ligand (4S,5R,Ss)-17 from chiral b-amino alcohol (1S,2R)-
substrates for the stereoselective formation of six-mem- 13.
bered carbo- and heterocycles.1) Currently, however, catalytic
The use of chiral sulfoxides obtained above as chiral
asymmetric Diels–Alder reactions are receiving attention due ligands was studied in the Lewis acid-catalyzed asymmetric
to their efficiency, and chiral ligands of various kinds have Diels–Alder reactions of N-acryloyl-1,3-oxazolidinone (18)
been developed.2)
with cyclopentadiene (19).9) Initially, the effects of Lewis
The use of chiral sulfinyl functionality as chiral auxiliaries acids in the asymmetric Diels–Alder reaction were studied
in organic synthesis has been investigated, and numerous using (Rs,S)-5d as a ligand and MgBr2·OEt2, MgI2,
asymmetric syntheses have been achieved with this method- Mg(OTf)2, Zn(OTf)2, Cu(OTf)2, Cu(AbF6)2, Cu(ClO4)2, or
ology. However, few precedents for the use of chiral sulfox- FeI3 as a Lewis acid.10)
ides as chiral ligands have been reported.3) We have devel-
The reactions of 18 with 19 (5.0 eq) were carried out in
oped chiral sulfoxide ligands of various types, and applied dichloromethane at Ϫ20—78 °C in the presence of a Lewis
them to palladium-catalyzed asymmetric allylic alkylations.4) acid such as MgBr2·OEt2, Mg(OTf)2, Zn(OTf)2, Cu(OTf)2 or
Chiral sulfoxide functionality has two possibilities for the FeI3 to give an endo adduct 20a as a main product along with
formation of chelates by coordination of sulfinyl oxygen or an exo adduct 20b as a minor product. The ratios of 20a
sulfur atoms to metals, depending on the metals employed. (endo adduct) to 20b (exo adduct) and the enantiomeric ex-
As we have already reported, a chiral sulfoxide provides a cess of the major product 20a obtained were determined by
chelate coordinated by the sulfur atom with a palladium cata- the HPLC analysis with Chiralcel OD eluted with 10% iso-
lyst.5)
We describe here the use of chiral sulfoxides as chiral lig-
PrOH in hexane.11)
Surprisingly, in this case with chiral 2-(arylsulfinyl-
ands in Lewis acid-catalyzed asymmetric Diels–Alder reac- methyl)-1,3-oxazolines12) as ligand, substantially different ef-
tions.
fects on enantioselectivity depending on the Lewis acids
Chiral sulfoxide ligands were prepared by the following used were observed, compared with the case with 2-[2-(aryl-
procedure starting from readily available a-amino acids. sulfinyl)pheny]-1,3-oxazolines,12) when the use of MgI2 as a
1,3-Oxazolines were readily obtainable by the reaction of Lewis acid was apparently the most effective in achieving the
ethyl acetimidate hydrochloride6) with b-amino alcohols highest enantioselectivity. In the present case, however, MgI2
derived from commercially available a-amino acids in was not as useful for increasing the enantioselectivity. The
dichloromethane (CH2Cl2) at room temperature.7) Sulfinyla- use of other Lewis acids such as Mg(OTf)2, Zn(OTf)2, and
tion of 1,3-oxazolines 3a—f6) with (Ss)-4 was carried out in FeI3 in the above reaction provided much lower enantioselec-
tetrahydrofuran (THF) at Ϫ78 °C using lithium diisopropyl- tivity.
amide (LDA) as the base to give (Rs)-5a—f. Methylation of
The results of the MgBr2·OEt2-catalyzed asymmetric
(Rs)-5a—f with methyl iodide (LDA, THF, at Ϫ78 °C— Diels–Alder reactions of 18 with 19 using 5a—f, 7a—f, 10,
room temperature) gave (Rs)-6a—f, which were further 12, 15, and 17 as chiral ligands are summarized in Table 1.
methylated by the reaction of methyl iodide using potassium
hexamethyldisilazide (KHMDS) as the base at Ϫ78 °C— substituted-1,3-oxazolines were not useful as chiral ligands
room temperature, affording (Ss)-7a—f.8)
in the MgBr2·OEt2-catalyzed Diels–Alder reactions of 18
As shown in Table 1, chiral 2-(p-toluenesulfinylmethyl)-4-
Similar procedures were applied to chiral b-amino alco- with 19, giving very poor enantioselectivity. Interestingly,
hols (1R,2S)-8 and (1S,2R)-13. 1,3-Oxazoline (4S,5R)-9 was however, the chiral 4,5-disubstituted-1,3-oxazolines 10 and
obtained by the reaction of (1R,2S)-8 with 2 in CH2Cl2 at 15 resulted in a slight increase in the enantioselectivity of
room temperature. Sulfinylation of (4S,5R)-9 with (Ss)-4 (2S)-20a with a high ratio of endo-20a to exo-20b. Against
gave (4S,5R,Rs)-10. Methylation of (4S,5R,Rs)-10 with expectations, the use of cupric salts such as cupric trifrate,
To whom correspondence should be addressed. e-mail: khiroi@tohoku-pharm.ac.jp
© 2002 Pharmaceutical Society of Japan

March 2002
373
Chart 1
Chart 2
hexafluoroantimonate, and perchlorate as Lewis acids in the tioned above.
above Diels–Alder reaction provided the rather high enan- The copper(II)-catalyzed asymmetric Diels–Alder reac-
tioselectivity of 20a with the use of the types of ligands men- tions of 18 with 19 were studied using the chiral sulfoxide

374
Vol. 50, No. 3
ligands 2-(p-toluenesulfinylmethyl)-1,3-oxazolines 5a—f,
10, and 15. The results are summarized in Table 2.
The copper(II) complexes CuX2 (XϭOTf, ClO4, SbF6)
were prepared by reacting the chiral ligands 5a—f, 10, and
15 with CuCl2 in CH2Cl2 at room temperature for 4 h in the
presence of silver(I) salts such as silver triflate, perchlorate,
and hexafluoroantimonate.
Chart 3
Table 1. Studies on the MgBr2·OEt2-Catalyzed Asymmetric Diels–Alder Reactions of 18 with 19 Using Chiral Ligands 5a—f, 7a—f, 12, and 17a)
endo/exo
Entry
Ligand (mol%)
Time (h)
Yield (%)
ee (%) of (S)-20a
20a/20b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
5a (10)
5b (10)
5c (10)
5d 10)
5e (10)
5f (10)
24
24
24
24
24
24
24
24
20
18
24
24
24
24
24
24
24
24
81
79
88
82
82
81
83
94
92
93
91
90
88
82
86
84
92
93
90/10
89/11
88/12
83/17
87/13
89/11
91/ 9
89/11
90/10
91/ 9
91/ 9
93/ 7
93/ 7
92/ 8
91/ 9
92/ 8
90/10
93/ 7
Ͻ1
8
13
8
6
7
15
32
27
29
Ͻ1
3
5
3
3
5
7
5
10
15
15
15
(10)
(10)
(20)
(30)
7a (10)
7b (10)
7c (10)
7d (10)
7e (10)
7f (10)
12
17
(10)
(10)
a) The reactions of 18 with 19 (5.0 eq) were carried out at Ϫ78 °C in CH2Cl2 in the presence of MgBr2·OEt2 and chiral ligands 5a—f, 7a—f, 12, and 17.
Table 2. Studies on the Cu(II)-Catalyzed Asymmetric Diels–Alder Reactions of 18 with 19 Using Chiral Ligands 5a—f, 10, and 15a)
endo/exo
Entry
Couterion
Ligand (mol%)
Solvent
Time (h)
Yield (%)
ee (%) of 20a
20a/20b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
OTf
5a
5a
5a
5b
5b
5b
5c
5c
5c
5c
5c
5c
5c
5c
5d
5d
5d
5e
5e
5e
5f
(10)
(10)
(10)
(10)
(10)
(10)
(5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
12
12
10
24
24
6
16
10
9
89
88
91
90
87
96
85
90
99
99
63
80
93
89
61
69
88
86
90
85
89
87
93
86
83
87
80
75
93
92/ 8
91/ 9
94/ 6
87/13
86/14
94/ 6
94/ 6
96/ 4
95/ 5
96/ 4
91/ 9
95/ 5
95/ 5
97/ 3
81/19
83/17
91/ 9
89/11
88/12
94/ 6
93/ 7
91/ 9
92/ 8
93/ 7
93/ 7
93/ 7
84/16
82/18
88/12
2
3
1
6
8
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
ClO4
SbF6
OTf
ClO4
SbF6
OTf
OTf
OTf
OTf
OTf
10
50
59
48
57
21
57
23
34
48
21
7
39
34
66
13
11
9
(10)
(15)
(20)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
8
36
24
10
8
OTf
ClO4
SbF6
OTf
ClO4
SbF6
OTf
ClO4
SbF6
OTf
ClO4
SbF6
OTf
ClO4
SbF6
OTf
ClO4
SbF6
24
24
10
22
22
10
24
24
10
24
24
10
24
24
8
5f
5f
10
10
10
15
15
15
29
25
16
23
18
16
a) The reactions of 18 with 19 (5.0 eq) were carried out at Ϫ78 °C in the presence of copper complexes CuX2 (XϭOTf, ClO4, and SbF6), which were prepared by reacting
ligands 5, 10, and 15 with CuCl2 at room temperature in CH2Cl2 for 4 h.

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Table 3. Studies on the Cu(II)-Catalyzed Asymmetric Diels–Alder Reactions of 18 with 19 Using Chiral Ligands 7a—f, 12, and 17a)
endo/exo
20a/20b
Entry
Couterion
Ligand
Time (h)
Yield (%)
ee (%) of (R)-20a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
OTf
7a
7a
7a
7b
7b
7b
7c
7c
7c
7d
7d
7d
7e
7e
7e
7f
24
24
12
24
24
12
19
19
6
24
24
24
24
24
24
24
24
18
24
24
20
24
24
18
70
67
69
68
63
72
60
52
77
65
60
62
63
61
65
71
72
72
71
68
68
62
60
65
91/ 9
90/10
92/ 8
90/10
88/12
89/11
91/ 9
87/13
89/11
88/12
89/11
86/14
88/12
86/14
89/11
88/12
88/12
89/11
87/13
89/11
90/10
86/14
87/13
87/13
5
2
3
ClO4
SbF6
OTf
ClO4
SbF6
OTf
ClO4
SbF6
OTf
ClO4
SbF6
OTf
ClO4
SbF6
OTf
ClO4
SbF6
OTf
ClO4
SbF6
OTf
ClO4
SbF6
20
13
17
50
28
46
36
24
49
28
21
32
18
16
25
26
18
14
40
31
33
7f
7f
12
12
12
17
17
17
a) The reactions of 18 with 19 (5.0 eq) were carried out in CH2Cl2 at Ϫ78 °C in the presence of copper complexes CuX2 (XϭOTf, ClO4, and SbF6), which were prepared by
reacting ligands 7, 12, and 17 (0.1 eq) with CuCl2 at room temperature in CH2Cl2 for 4 h.
The solvent effects in the copper(II)-catalyzed asymmetric (Ss,S)-7c with cupric triflate provided (2R)-20a with rather
Diels–Alder reactions are shown in Table 2. Among the sol- high enantioslectivity (50%). Similarly, cupric triflate was
vent examined, the rather high enantioselectivity (59—58%) useful achieving rather high enantioselectivity in the case of
of (S)-20a was provided with the use of CH2Cl2 or THF as (4S,5R,Ss)-17. However, with (Ss,S)-7e as a ligand, cupric
solvent, as listed in entries 8, 11, and 12 of Table 2, using hexafluoroantimonate was more effective, as shown in Table
cupric triflate (10 mol%) as a catalyst.
2. The highest enantioselectivity (66%) of (2R)-20a was ob-
The chirality of the sulfoxide in 5 was not so effective for tained with (Rs,S)-5e as a chiral ligand using hexafluoroanti-
the asymmetric Diels–Alder reactions with copper(II) cata- monate as a counterion.
lysts, since the loss of the chiralities on the 1,3-oxazolines
provided lower enantioselectivity of (S)-20a (entries 1—3, reactions is proposed for the rationalization of the stereo-
21—23 in Table 2). chemical results obtained. Based on the rather high level of
The following mechanism of these catalytic asymmetric
The steric bulk of the substituents on the 1,3-oxazolines the asymmetric induction with these chiral ligands, the for-
were effective in achieving high enantioselectivity. The chiral mation of a six-membered square planar copper chelate coor-
ligand (Rs,S)-5b including iso-propyl was not useful for the dinated by the nitrogen atom of the 1,3-oxazoline and the
asymmetric induction, while the use of the ligands (Rs,S)- sulfinyl oxygen atom should be predicted as an intermediate.
5c—e with tert-butyl, phenyl, and benzyl groups provided In the conformational equilibrium of the copper chelate of
higher enantioselectivity of (2S)- and (2R)-20a, respectively, the 1,3-oxazoline ligands with bulky substituents such as iso-
except for the case of the copper(II) catalyst derived from propyl and tert-butyl groups on the rings, conformer 21b
ligand 5d with hexafluoroantimonate (entry 17), presumably would be preferred to conformer 21a because of the exis-
due to the steric interference between the phenyl substituent tence of the rather severe A1,3) strain between the bulky
and the bulky counterion. Surprisingly, however, the absolute groups and X (the counterion or the reaction substrate) in
configuration of the resulting endo adduct 20a was depen- 21a. Therefore cyclopentadiene attacks the dienophile part in
dent on the ligands and the counterions employed. Introduc- the substrate preferentially from the sterically less crowded
tion of a phenyl or benzyl group as the chiral center at the C3 side (Re face in 21b-II), giving (S)-20a as a main product. A
position on the 1,3-oxazoline rings provided (2R)-20a, which similar explanation is applicable to the case with 10, since
was inversed in the absolute configuration to that obtained the intermediate derived from 10 has rather severe steric in-
above with (Rs,S)-5c.
terference by the phenyl group at the 4 position on the 1,3-
The anchored effects by dimethyl substituents were stud- oxazolines, due to the conformational rigidity induced by the
ied with cupric catalysts using 2-[1-methyl-1-(p-toluene- adjacent phenyl group at the 5 position.
sulfinyl)ethyl]-1,3-oxazoline ligands (Ss)-7a—f, 12, and 17.
On the other hand, in the case of the chiral ligands with
The results obtained are summarized in Table 3. Similar ef- phenyl or benzyl groups, conformer 22a would be favorable
fects of counterions and substituents on the 1,3-oxazolines to 22b because of the existence of the less crowded steric
were observed as those by 5a—f, 10, and 15. The use of space arised due to the less bulky groups or the p–p stacking

376
Vol. 50, No. 3
Chart 4
formed with Merck silica gel 60 (230—400 mesh). Thin-layer or thick-layer
plates (preparative TLC) were made of Merck silica gel 60PF-254 activated
by drying at 140 °C for 3.5 h.
interaction between the phenyl or benzyl group and the car-
bon–carbon double bond in 22a-II. Therefore cyclopentadi-
ene attacks the reaction site from the Si-face in 22a-I or in
22a-II, affording (R)-20a as a main product.
2-Methyl-2-oxazoline (3a) To a stirred solution of ethyl acetimidate hy-
drochloride6) (2) (376.5 mg, 3 mmol) in dichloromethane (15 ml) at 0 °C was
In the case of chiral ligands 7a—f, 12, and 17 anchored by added a solution of ethanolamine (183 mg, 3 mmol) in dichloromethane
(10 ml). The resulting solution was slowly allowed to warm to room temper-
ature and stirred overnight. The reaction mixture was poured into water
(10 ml) and extracted with dichloromethane (3ϫ10 ml). The combined or-
ganic layers were dried over anhydrous Na2SO4, and the solvent was re-
dimethyl groups, the sterically more stable isomer 23 is pref-
erentially formed due to the conformational fixation of the
six-membered chelate with an equatorial tolyl group. The at-
tack of cyclopentadiene occurs in the same way as mentioned
above in 22a to give (R)-20a as a main product.
moved by distillation at atmospheric pressure. Distillation gave 2-methyl-2-
oxazoline (3a) (181.1 mg, 71%) as a colorless liquid, bp 109—110 °C.
film
max
3a: IR n
cmϪ1: 1674 (O–CϭN). 1H-NMR (CDCl3) d: 1.96 (3H, s,
In conclusion, we have prepared chiral sulfinyl 1,3-oxazo-
line derivatives and applied them as chiral ligands to catalytic
asymmetric Diels–Alder reactions, in which moderate asym-
metric induction was observed. The degree of the asymmet-
ric induction and the absolute configuration of the product
were dependent on the steric bulk of the substituents at the
chiral centers on the 1,3-oxazolines. A novel mechanism of
asymmetric induction with these new chiral sulfoxide ligands
is proposed for the rationalization of the steric results ob-
tained.
CH3), 3.76—3.84 (2H, m, O–CH2 or N–CH), 4.19—4.26 (2H, m, O–CH2 or
N–CH). 13C-NMR (CDCl3) d: 18.6, 52.4, 56.6, 164.2. MS m/z: 85 (Mϩ), 74,
60, 55, 43 (BP). Exact mass determination: 85.0550 (Calcd for C4H7NO:
85.0527).
The cyclization of 1b—f with ethyl acetimidate hydrochloride (2) was
carried out using the same procedure as described above to give (S)-iso-
propyl-(3b), (S)-tert-butyl-(3c), (S)-phenyl-(3d), (S)-benzyl-(3e), 4,4-
diphenyl-(3f), (4S,5R)-4,5-diphenyl-2-methyl-2-oxazole (9), and (3aS,8aR)-
3a,8a-dihydro-8H-indeno[1,2-d]oxazole (14), respectively.
film
max
(S)-3b: 70% yield. Colorless oil. [a]D Ϫ87.3° (cϭ2.51, CHCl3). IR n
cmϪ1: 1678 (O–CϭN). NMR (CDCl3) d: 0.85—0.89 (6H, d, Jϭ7.2 Hz,
CH(CH)2), 2.09 (3H, d, Jϭ1.3 Hz, CH3), 3.81—3.82 (1H, m, O–CH2 or
N–CH), 3.99—4.05 (1H, t, Jϭ8.4 Hz, O–CH2 or N–CH), 4.13—4.18 (1H,
Experimental
Infrared (IR) spectra were obtained in the indicated state with a JASCO dd, Jϭ8.4, 10.1 Hz, O–CH2 or N–CH). 13C-NMR (CDCl3) d: 17.4, 17.8,
DR-81 Fourier-transform infrared spectrometer. Nuclear magnetic resonance 18.9, 27.9, 58.5, 69.3. MS m/z: 127 (Mϩ), 101 (BP), 90. Exact mass deter-
(NMR) spectra were determined in the indicated solvents with a JEOL mination: 127.2234 (Calcd for C7H13NO: 127.2230).
GSX-400 (1H-NMR, 400 MHz; 13C-NMR, 100 MHz), EX-270 (1H-NMR,
270 MHz; 13C-NMR, 67.5 MHz), or JNM PMX-60SI (60 MHz) high-resolu-
(S)-3c7): 75% yield.
(S)-3d: 68% yield. Colorless oil. [a]D Ϫ98.2° (cϭ1.66, CHCl3). IR n
film
max
tion NMR spectrometer; chemical shifts are given in parts per million with cmϪ1: 1672 (O–CϭN), 1605, 1493, 756 (aromatic). NMR (CDCl3) d: 2.09
tetramethylsilane as an internal standard. Mass spectra (MS) were recorded (3H, d, Jϭ1.5 Hz, CH3), 4.05—4.11 (1H, t, Jϭ8.3 Hz, O–CH2 or N–CH),
on a JEOL JMS-DX 303/JMA-DA 5000 system. Optical rotations were 4.55—4.63 (1H, dd, Jϭ8.3, 10.1 Hz, O–CH2 or N–CH), 5.12—5.19 (1H,
measured with a JASCO DIP-370 polarimeter. High-performance liquid ddd, Jϭ1.5, 8.3, 10.1 Hz, O–CH2 or N–CH), 7.21—7.52 (5H, m, CHC6H5).
chromatographic (HPLC) data were obtained with a Tosoh UV-8010, CCPM 13C-NMR (CDCl3) d: 13.8, 69.7, 74.5, 126.4, 126.6, 127.4, 128.2, 128.6,
(column, Daicel chiralpack OD). Flash column chromatography was per- 142.3, 165.7. MS m/z: 161 (Mϩ), 130 (BP), 119, 104, 90. Exact mass deter-

March 2002
377
CH3C6H4). 13C-NMR (CDCl3) d: 18.2, 18.8, 21.4, 30.9, 32.6, 55.9, 70.9,
72.6, 77.2, 124.3, 129.9, 140.1, 142.2, 158.7. MS m/z: 265 (Mϩ), 249, 217,
206, 174, 149, 139 (BP). Exact mass determination: 265.1098 (Calcd for
C14H19NO2S: 265.1136).
mination: 161.0825 (Calcd for C10H11NO: 161.0841).
film
max
(S)-3e: 65% yield. Colorless oil. [a]D Ϫ47.9° (cϭ5.60, CHCl3). IR n
cmϪ1: 1671 (O–CϭN), 1603, 1496, 750 (aromatic). NMR (CDCl3) d: 1.96
(3H, d, Jϭ1.3 Hz, CH3), 2.60—2.68 (1H, dd, Jϭ8.5, 13.9 Hz, CH2–C6H5),
3.04–3.11 (1H, dd, Jϭ8.5, 13.9 Hz, CH2–C6H5), 3.89—3.95 (1H, dd, Jϭ7.4,
8.5 Hz, O–CH2), 4.12—4.19 (1H, t, Jϭ8.5 Hz, O–CH2), 4.29—4.41 (1H, m,
N–CH), 7.12—7.32 (5H, m, CH2C6H5). 13C-NMR (CDCl3) d: 13.8, 30.8,
41.7, 68.8, 71.7, 128.4, 129.0, 129.1, 129.2, 137.9, 164.9. MS m/z: 175
(Mϩ), 84, 56 (BP). Exact mass determination: 175.1007 (Calcd for
(Rs,S)-5c: 56% yield. Colorless oil. [a]D ϩ137.6° (cϭ1.97, CHCl3). IR
max
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n
cmϪ1: 1668 (O–CϭN), 1541 (aromatic), 1057, 812 (S–O). NMR
(CDCl3) d: 0.85 (9H, s, C(CH3)3), 2.42 (3H, s, C6H4CH3), 3.62—3.68 (1H,
d, Jϭ13.5 Hz, S–CH2), 3.80—3.85 (1H, d, Jϭ13.5 Hz, S–CH2), 3.82—3.90
(1H, m, N–CH), 4.00—4.06 (1H, t, Jϭ8.5 Hz, O–CH2), 4.20—4.24 (1H, t,
Jϭ8.5 Hz, O–CH2), 7.26—7.65 (4H, m, CH3C6H4). 13C-NMR (CDCl3) d:
21.4, 25.7, 33.5, 56.1, 69.3, 76.2, 77.2, 124.3, 129.9, 140.3, 142.2. MS m/z:
279 (Mϩ), 231, 174, 139 (BP). Exact mass determination: 279.1290 (Calcd
C11H13NO: 175.0997).
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max
3f: 63% yield. Colorless column (CHCl3–hexane), mp 77 °C. IR n
cmϪ1
: 1671 (O–CϭN), 1599 (aromatic). NMR (CDCl3) d: 2.11 (3H, s,
CH3), 4.76 (2H, s, O–CH2), 7.18—7.62 (10H, m, CC6H5). 13C-NMR
(CDCl3) d: 14.1, 79.2, 79.3, 126.4, 126.9, 127.2, 127.8, 128.4, 128.6, 146.1,
163.9. MS m/z: 237 (Mϩ), 207, 194, 178, 165 (BP). Exact mass determina-
tion: 237.1150 (Calcd for C16H15NO: 237.1154). Anal. Calcd for C16H15NO:
C, 80.98; H, 6.37; N, 5.90. Found: C, 80.90; H, 6.39; N, 5.83.
for C15H21NO2S: 279.1293).
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max
(Rs,S)-5d: 53% yield. Colorless oil. [a]D ϩ50.4° (cϭ1.40, CHCl3). IR n
cmϪ1: 1659 (O–CϭN), 1541 (aromatic), 1053, 812 (S–O). NMR (CDCl3) d:
2.43 (3H, s, C6H4CH3), 3.74—3.80 (1H, dd, Jϭ1.3, 12.2 Hz, S–CH2), 3.90—
3.96 (1H, d, Jϭ12.9 Hz, S–CH2), 4.05—4.11 (1H, t, Jϭ8.5 Hz, O–CH2),
4.61—4.67 (1H, dd, Jϭ1.8, 8.5 Hz, O–CH2), 5.15—5.22 (1H, m, N–CH),
7.10—7.65 (9H, m, CH3C6H4, C6H5). 13C-NMR (CDCl3) d: 21.5, 55.7, 63.5,
69.9, 75.2, 77.2, 77.8, 98.1, 124.3, 126.6, 127.7, 128.7, 130.1, 139.9, 141.2,
142.3, 160.1. MS m/z: 299 (Mϩ), 283, 251, 209, 139 (BP). Exact mass deter-
mination: 299.0994 (Calcd for C17H17NO2S: 299.0980).
(4S,5R)-9: 93% yield. Colorless column (CHCl3–hexane), mp 204—
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205 °C. [a]D Ϫ123.2° (cϭ1.01, CHCl3). IR n
cmϪ1: 1671 (O–CϭN),
1599 (aromatic). NMR (CDCl3) d: 2.27 (3H, d, Jϭ1.5 Hz, CH3), 5.49—5.54
(1H, m, N–CH or O–CH), 5.81—5.85 (1H, m, N–CH or O–CH), 6.86—7.31
(10H, m, C6H4). 13C-NMR (CDCl3) d: 23.5, 85.3, 126.3, 126.5, 127.3,
127.5, 127.6, 127.7, 127.8, 128.0, 128.1, 136.6, 136.9, 137.8, 139.7, 166.0.
MS m/z: 237 (Mϩ), 194, 180, 130 (BP). Exact mass determination: 237.1357
(Calcd for C16H15NO: 237.1355). Anal. Calcd. for C16H15NO: C, 80.98; H,
6.37; N, 5.90. Found: C, 80.88; H, 6.31; N, 5.98.
(Rs,S)-5e: 53% yield. Colorless oil. [a]D ϩ41.3° (cϭ1.56, CHCl3). IR
max
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n
cmϪ1: 1660 (O–CϭN), 1597, 1495 (aromatic), 1053, 812 (S–O). NMR
(CDCl3) d: 2.43 (3H, s, C6H4CH3), 2.49—2.60 (1H, m, C6H5–CH2–CH),
3.74—3.80 (1H, dd, Jϭ1.3, 12.2 Hz, S–CH2), 3.90—3.96 (1H, d,
Jϭ12.2 Hz, S–CH2), 4.05—4.11 (1H, t, Jϭ8.5 Hz, O–CH2), 4.61—4.67 (1H,
dd, Jϭ1.8, 8.5 Hz, O–CH2), 5.15—5.22 (1H, m, N–CH), 7.10—7.65 (9H, m,
CH3C6H4, C6H5). 13C-NMR (CDCl3) d: 20.9, 37.5, 57.9, 61.4, 65.7, 123.4,
123.6, 125.8, 128.4, 128.6, 128.7, 128.8, 130.3, 130.5, 138.8, 140.1, 143.1,
164.2. MS m/z: 313 (Mϩ), 297, 265, 222, 206, 174, 139, 117, 91 (BP). Exact
(4S,5R)-14: 90% yield. Colorless column (CHCl3-hexane), mp 67—68 °C.
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[a]D Ϫ327.2° (cϭ1.91, CHCl3). IR n cmϪ1: 1659 (O–CϭN), 1480, 1224,
max
1199 (aromatic). NMR (CDCl3) d: 1.94 (3H, d, Jϭ1.2 Hz, CH3), 3.19—3.26
(1H, dd, Jϭ1.6, 17.8 Hz, CH2–C6H4), 3.38—3.47 (1H, dd, Jϭ6.8, 17.8 Hz,
CH2–C6H4), 5.26—5.33 (1H, m, O–CH), 5.48—5.51 (1H, dd, Jϭ1.2, 8.1 Hz,
N–CH), 7.21—7.48 (4H, m, C6H4). 13C-NMR (CDCl3) d: 14.0, 39.8, 76.6,
82.9, 125.2, 125.3, 127.4, 128.4, 139.7, 142.1, 165.0. MS m/z: 173 (Mϩ),
144, 132, 115, 104 (BP). Exact mass determination: 173.0824 (Calcd for
C11H11NO: 173.0841). Anal. Calcd for C11H11NO: C, 76.27; H, 6.40; N,
8.09. Found: C, 76.15; H, 6.36; N, 8.18.
mass determination: 313.1102 (Calcd for C18H19NO2S: 313.1136).
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max
(Rs)-5f: 52% yield. Colorless oil. [a]D ϩ10.9° (cϭ1.10, CHCl3). IR n
cmϪ1: 1663 (O–CϭN), 1597 (aromatic), 1055, 810 (S–O). NMR (CDCl3) d:
2.38 (3H, s, C6H4CH3), 3.77—3.82 (1H, d, Jϭ13.4 Hz, S–CH2), 3.99—4.04
(1H, d, Jϭ13.4 Hz, S–CH2), 4.73 (2H, s, O–CH2), 7.13—7.73 (14H, m,
CH3C6H4, C6H5, C6H5). 13C-NMR (CDCl3) d: 21.5, 44.5, 69.0, 77.2, 125.5,
126.4, 126.5, 126.6, 127.2, 127.3, 127.5, 127.7, 128.3, 128.4, 128.5, 128.6,
129.8, 129.9, 139.6, 141.9, 142.3, 144.1, 145.2, 145.3, 158.2. MS m/z:
375 (Mϩ), 359, 320, 227, 182, 165, 139 (BP). Exact mass determination:
375.1279 (Calcd for C23H21NO2S: 375.1293).
(Rs)-2-(p-Toluenesulfinylmethyl)-1,3-oxazoline (5a)
A 50-ml two-
necked flask equipped with a septum inlet and magnetic stirring bar was
flushed with argon and maintained under a positive pressure of argon. A
1.5 M hexane solution of n-butyllithium (1.47 ml, 2.2 mmol) was added at
Ϫ78 °C to a solution of diisopropylamine (0.31 ml, 2.2 mmol) in THF (7 ml).
The mixture was stirred at Ϫ78 °C for 30 min. Then a solution of 3a (85 ml,
1 mmol) in THF (3 ml) was added to the above solution. The reaction mix-
ture was stirred at Ϫ78 °C for 1 h. A solution of (Ϫ)-menthyl (S)-p-toluene-
sulfinate (4) (323.4 mg, 1.1 mmol) in THF (10 ml) was added to the above
solution, and the reaction mixture was stirred at Ϫ78 °C for 12 h. The reac-
tion solution was diluted with CHCl3 and the solution was washed with satu-
rated aqueous NH4Cl and saturated aqueous NaCl, dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude product was subjected to
preparative TLC (AcOEt : hexaneϭ1 : 1) to give (Rs)-5a (138.3 mg, 62%
yield).
(4S,5R,Rs)-10: 61% yield. Colorless column (CHCl3–hexane), mp 124 °C.
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max
[a]D ϩ40.9° (cϭ1.1, CHCl3). IR n
cmϪ1: 1669 (O–CϭN), 1541 (aro-
matic), 1053, 812 (S–O). NMR (CDCl3) d: 2.45 (3H, s, C6H4CH3), 3.87—
3.93 (1H, d, Jϭ12.5 Hz, S–CH2), 4.07—4.13 (1H, d, Jϭ12.5 Hz, S–CH2),
5.54—5.58 (1H, d, Jϭ10.6 Hz, O–CH or N–CH), 5.86—5.90 (1H, d,
Jϭ10.6 Hz, O–CH or N–CH), 6.90—7.73 (14H, m, CH3C6H4, N–CH–C6H5,
O–CH–C6H5). 13C-NMR (CDCl3) d: 21.5, 56.3, 74.4, 77.2, 86.0, 124.5,
126.4, 127.0, 127.5, 127.6, 127.7, 127.8, 130.2, 135.7, 136.8, 140.3, 142.5,
160.3. MS m/z: 375 (Mϩ), 359, 236, 194, 180, 130 (BP). Exact mass deter-
mination: 375.1314 (Calcd for C23H21NO2S: 375.1293). Anal. Calcd for
C23H21NO2S: C, 73.57; H, 5.64; N, 3.73. Found: C, 73.45; H, 5.55; N, 3.83.
(1R,2S,Rs)-15: 81% yield. Colorless column (CHCl3–hexane), mp 85—
87 °C. [a]D Ϫ249.0° (cϭ1.1, CHCl3). IR nfimlamx cmϪ1: 1657 (O–CϭN), 1601
(aromatic), 1051, 810 (S–O). NMR (CDCl3) d: 2.35 (3H, s, C6H4CH3),
2.96—3.03 (1H, dd, Jϭ7.1, 18.2 Hz, O–CH–CH2–C6H4), 3.30—3.39 (1H,
dd, Jϭ7.1, 18.2 Hz, O–CH–CH2–C6H4), 3.57—3.61 (1H, d, Jϭ12.5 Hz,
S–CH2), 3.82—3.87 (1H, d, Jϭ12.5 Hz, S–CH2), 5.22—5.30 (1H, m,
O–CH), 5.50—5.53 (1H, d, Jϭ8.1 Hz, N–CH), 7.07—7.51 (8H, m,
CH3C6H4, C6H4). 13C-NMR (CDCl3) d: 21.4, 30.9, 39.5, 55.3, 76.8, 77.2,
83.7, 124.2, 125.2, 125.4, 127.5, 128.6, 129.7, 139.3, 139.5, 141.3, 141.9,
159.1. MS m/z: 311(Mϩ), 262, 220, 172, 139 (BP). Exact mass determina-
tion: 311.1004 (Calcd for C18H17NO2S: 311.0980). Anal. Calcd for
C18H17NO2S: C, 60.22; H, 7.16; N, 5.85. Found: C, 60.18; H, 7.21; N, 5.91.
(Rs)-2-[1-(p-Toluenesulfinyl)ethyl]-1,3-oxazoline (6a) A 50-ml two-
necked flask equipped with a septum inlet and magnetic stirring bar was
flushed with argon and maintained under a positive pressure of argon. A
1.5 M hexane solution of n-butyllithium (1.47 ml, 2.2 mmol) was added at
Ϫ78 °C to a solution of diisopropylamine (0.31 ml, 2.2 mmol) in THF
(10 ml). The mixture was stirred at Ϫ78 °C for 30 min. Then a solution of
(Rs)-2-(p-toluenesulfinylmethyl)-1,3-oxazoline (5a) (223 mg, 1 mmol) in
THF (5 ml) was added to the above solution. The reaction mixture was
stirred at Ϫ78 °C for 1 h. A solution of iodomethane (312.2 mg, 2.2 mmol)
in THF (5 ml) was added to the above solution, and the reaction mixture was
(Rs)-5a: Colorless column (CHCl3–hexane), mp 105—107 °C. [a]D
film
ϩ97.5° (cϭ1.5, CHCl3). IR n cmϪ1: 1665 (O–CϭN), 1525, (aromatic),
max
1047 (S–O). NMR (CDCl3) d: 2.42 (3H, s, C6H4CH3), 3.62—3.64 (1H, d,
Jϭ1.2 Hz, S–CH2), 3.80—3.88 (3H, m, S–CH2, O–CH2), 4.18—4.31 (2H,
m, N–CH2), 7.29—7.60 (4H, m, CH3C6H4). 13C-NMR (CDCl3) d: 20.9,
52.8, 57.3, 57.6, 123.2, 123.5, 130.1, 130.5, 140.1, 143.1, 163.6. MS m/z:
223 (Mϩ), 207, 175, 139 (BP), 123, 111, 105, 91. Exact mass determination:
223.0702 (Calcd for C11H13NO2S: 223.0667). Anal. Calcd for C11H13NO2S:
C, 59.17; H, 5.87; N, 6.27. Found: C, 59.22; H, 5.81; N, 6.20.
The sulfinylation of 3b—f, 9, and 14 with (Ss)-4 was carried out using the
same procedure as described above to give (Rs,S)-4-iso-propyl-2-(p-toluene-
sulfinylmethyl)-(5b), (Rs,S)-4-tert-butyl-2-(p-toluenesulfinylmethyl)-(5c),
(Rs,S)-4-phenyl-2-(p-toluenesulfinylmethyl)-(5d), (Rs,S)-4-benzyl-2-(p-
toluenesulfinylmethyl)-(5e), (Rs)-4,4-diphenyl-2-(p-toluenesulfinylmethyl)-
(5f), (4S,5R,Rs)-4,5-diphenyl-2-(p-toluenesulfinylmethyl)-1,3-oxazoline (10),
and (3aS,8aR)-3a,8a-dihydro-2-(p-toluenesulfinylmethyl)-8H-indeno[1,2-
d]1,3-oxazole (15), respectively.
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(Rs,S)-5b: 58% yield. Colorless oil. [a]D ϩ56.8° (cϭ1.1, CHCl3). IR n
cmϪ1: 1663 (O–CϭN), 1595, 1468 (aromatic), 1053, 812 (S–O). NMR
(CDCl3) d: 0.83—0.85 (3H, d, Jϭ6.8 Hz, CH3), 0.91—0.93 (3H, d,
Jϭ6.8 Hz, CH3), 2.42 (3H, s, CH3C6H4), 3.62—3.67 (1H, d, Jϭ12.4 Hz,
S–CH2), 3.79—3.85 (1H, d, Jϭ12.4 Hz, S–CH2), 3.82—3.96 (2H, m, N–CH
or O–CH2), 4.20—4.31 (1H, m, N–CH or O–CH2), 7.14—7.65 (4H, m,

378
Vol. 50, No. 3
(3H, m, S–CH–CH3), 2.44 (3H, s, C6H4–CH3), 3.72—3.80, 4.03—4.11 (1H,
m, S–CH–CH3), 5.50—5.56 (1H, m, N–CH or O–CH), 5.81—5.89 (1H, m,
N–CH or O–CH), 6.83—7.67 (14H, m, CH3C6H4, C6H4). 13C-NMR (CDCl3)
d: 7.6, 20.7, 61.4, 70.8, 75.2, 123.4, 123.6, 125.7, 127.4, 127.5, 127.6,
127.7, 127.9, 128.3, 128.5, 128.6, 128.8, 130.2, 130.4, 140.1, 140.2, 140.9,
143.2, 164.8. S m/z: 389 (Mϩ), 341, 196, 165, 143 (BP), 116, 89. Exact mass
determination: 389.1424 (Calcd for C24H23NO2S: 389.1450). Anal. Calcd for
C24H23NO2S: C, 74.01; H, 5.95; N, 3.60. Found: C, 74.16; H, 5.93; N, 3.55.
stirred at Ϫ78 °C for 12 h. The reaction solution was dilluted with CHCl3
and the solution was washed with saturated aqueous NH4Cl and saturated
aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo.
The crude product was subjected to preparative TLC (AcOEt : hexaneϭ1 : 1)
to give 6a (97.2 mg, 41% yield) and 7a (57.7 mg, 23% yield).
(Rs)-6a: 68% yield (7b: 23% yield). Colorless oil. [a]D ϩ22.4° (cϭ1.38,
CHCl3). IR nfimlamx cmϪ1: 1664 (O–CϭN), 1526 (aromatic), 1047, 752 (S–O).
NMR (CDCl3) d: 1.31—1.55 (3H, m, S–CH–CH3), 2.41 (3H, s, C6H4–CH3),
3.48—3.55 (1H, m, S–CH), 3.75—3.96 (2H, m, N–CH2 or O–CH2), 4.18—
4.26 (2H, m, N–CH2 or O–CH2), 7.27—7.55 (4H, m, C6H4–CH3). 13C-NMR
(CDCl3) d: 7.8, 20.8, 53.2, 57.4, 60.7, 123.3, 123.5, 130.4, 130.5, 140.1,
143.1, 164.6. MS m/z: 237 (Mϩ), 210, 188, 151, 140 (BP). Exact mass deter-
mination: 237.1287 (Calcd for C12H15NO2S: 237.1293).
The methylation of 5b—f, 10, and 15 with iodomethane was carried
out using the same procedure as described above to give (Rs,S)-2-[1-
(p-toluenesulfinyl)ethyl]-4-iso-propyl-(6b), (Rs,S)-4-tert-butyl-2-[1-(p-tolu-
enesulfinyl)ethyl]-(6c), (Rs,S)-2-[1-(p-toluenesulfinyl)ethyl]-4-phenyl-(6d),
(Rs,S)-4-benzyl-2-[1-(p-toluenesulfinyl)ethyl)-(6e), (Rs)-4,4-diphenyl-2-[1-
(p-toluenesulfinyl)ethyl]-(6f), (4S,5R,Rs)-2-[1-(p-toluenesulfinyl)ethyl]-4,5-
diphenyl-1,3-oxazoline (11), and (3aS,8aR,Rs)-3a,8a-dihydro-2-[1-(p-tolu-
enesulfinyl)ethyl]-8H-indeno[1,2-d]1,3-oxazole (16), respectively.
(Rs,S)-16: 96% yield. Colorless column (CHCl3–hexane), mp 105—
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max
107 °C. [a]D Ϫ184.1° (cϭ1.13, CHCl3). IR n
cmϪ1: 1649 (O–CϭN),
1597 (aromatic), 1051, 812 (S–O). NMR (CDCl3) d: 1.32—1.36 (3H, d,
Jϭ7.1 Hz, CHCH3), 1.60—1.63, 2.33—2.34 (3H, d, Jϭ7.2 Hz, CH3–C6H4),
2.75—2.81, 3.09—3.16 (2H, d, Jϭ18.0 Hz, O–CH–CH2–C6H4), 3.25—3.52
(1H, m, CH3–CH), 5.17—5.29 (1H, m, O–CH), 5.47—5.53 (1H, t,
Jϭ8.1 Hz, N–CH), 6.98—7.56 (8H, m, CH3C6H4, C6H4). 13C-NMR (CDCl3)
d: 8.4, 12.6, 21.5, 39.5, 39.6, 57.3, 60.2, 76.5, 76.8, 83.1, 83.5, 124.9, 125.2,
125.5, 125.6, 127.5, 128.6, 129.4, 129.5. MS m/z: 325(Mϩ), 309, 277, 186,
115 (BP). Exact mass determination: 325.1154 (Calcd for C19H19NO2S:
325.1137). Anal. Calcd for C19H19NO2S: C, 70.13; H, 5.89; N, 4.30. Found:
C, 70.06; H, 5.94; N, 4.24.
(Rs)-2-[1-Methyl-1-(p-toluenesulfinyl)ethyl]-1,3-oxazoline (7a) A 25-
ml two-necked flask equipped with a septum inlet and magnetic stirring bar
was flushed with argon and maintained under a positive pressure of argon. A
0.5 M toluene solution of potassium hexamethyldisilazide (KHMDS) (1.5 ml,
0.75 mmol) was added at Ϫ78 °C to a solution of 6a (118.5 mg, 0.5 mmol) in
THF (8 ml). A solution of iodomethane (0.07 ml, 1.1 mmol) in THF (3 ml)
was added to the above solution, and the reation mixture was stirred at room
temperature for 24 h. The reaction solution was dilluted with CHCl3 and the
solution was washed with saturated aqueous NH4Cl and saturated aqueous
NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude
product was subjected to preparative TLC (AcOEt : hexaneϭ1 : 1) to give
(Rs)-7a (92.9 mg, 74% yield).
(Rs,S)-6b: 68% yield (7b: 23% yield). Colorless oil. [a]D ϩ12.3°
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max
(cϭ1.87, CHCl3). IR n
cmϪ1: 1660 (O–CϭN), 1456 (aromatic), 1053,
812 (S–O). NMR (CDCl3) d: 0.81—0.94 (6H, m, CH(CH3)2), 1.33—1.52
(3H, m, S–CH–CH3), 2.41 (3H, s, C6H4–CH3), 3.48—3.55 (1H, m, S–CH),
3.75—3.96 (2H, m, N–CH, O–CH2), 4.18—4.26 (1H, m, N–CH, O–CH2),
7.27—7.55 (4H, m, C6H4–CH3). 13C-NMR (CDCl3) d: 7.8, 17.4, 17.7, 20.8,
27.9, 59.3, 61.0, 70.1, 123.4, 123.5, 130.4, 130.6, 140.5, 143.3, 164.1. MS
m/z: 279 (Mϩ), 263, 231, 210, 188, 151, 140 (BP). Exact mass determina-
tion: 279.1287 (Calcd for C15H21NO2S: 279.1293).
(Rs,S)-6c: 54% yield (7c: 22% yield). Colorless oil. [a]D ϩ26.5°
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max
(cϭ1.62, CHCl3). IR n
cmϪ1: 1665 (O–CϭN), 1480 (aromatic), 1053,
(Rs)-7a: 71% yield. Colorless column (CHCl3–hexane), mp 76 °C. [a]D
Ϫ35.9° (cϭ1.48, CHCl3). IR nfimlamx cmϪ1: 1671 (O–CϭN), 1589 (aromatic),
1051, 812 (S–O). NMR (CDCl3) d: 0.80—0.83 (3H, d, Jϭ6.8 Hz,
CH(CH3)2), 0.89—0.92 (3H, d, Jϭ6.8 Hz, CH(CH3)2), 1.30 (3H, s, CCH3),
1.59 (3H, s, CCH3), 1.63—1.76 (1H, m, CH(CH3)2), 2.40 (3H, s,
C6H5–CH3), 3.75—3.84 (2H, m, N–CH2), 3.92—3.99 (1H, t, Jϭ8.5 Hz,
O–CH2), 4.17—4.20 (1H, t, Jϭ8.5 Hz, O–CH2), 7.25—7.49 (4H, m,
C6H4–CH3). 13C-NMR (CDCl3) d: 20.8, 14.8, 14.9, 53.5, 57.7, 65.3, 123.1,
123.8, 130.1, 130.5, 140.1, 143.3, 164.5. MS m/z: 294 (Mϩ), 251, 181, 154,
140, 110, 91, 69, 41 (BP). Exact mass determination: 251.1475 (Calcd for
C13H17NO2S: 251.1450). Anal. Calcd for C13H17NO2S: C, 62.12; H, 6.82; N,
5.57. Found: C, 62.01; H, 6.88; N, 5.48.
The methylation of 6b—f, 11, and 16 with iodomethane was carried
out using the same procedure as described above to give (Rs,S)-2-[1-
methyl-1-(p-toluenesulfinyl)ethyl]-4-iso-propyl-(7b), (Rs,S)-4-tert-butyl-2-
[1-methyl-1-(p-toluenesulfinyl)ethyl]-(7c), (Rs,S)-2-[1-methyl-1-(p-toluene-
sulfinyl)ethyl]-4-phenyl-(7d), (Rs,S)-4-benzyl-2-[1-methyl-1-(p-toluene-
sulfinyl)ethyl]-(7e), (Rs)-4,4-diphenyl-2-[1-methyl-1-(p-toluenesulfinyl)-
ethyl]-(7f), (4S,5R,Rs)-2-[1-methyl-1-(p-toluenesulfinyl)ethyl]-4,5-diphenyl-
1,3-oxazoline (12), and (3aS,8aR,Rs)-3a,8a-dihydro-2-[1-methyl-1-(p-tolue-
nesulfinyl)ethyl]-8H-indeno[1,2-d]1,3-oxazole (17), respectively.
812 (S–O). NMR (CDCl3) d: 0.85 (9H, s, C(CH3)3), 1.30—1.33, 1.47—1.50
(3H, dd, S–CH–CH3), 2.41 (3H, s, C6H4–CH3), 3.49—3.57 (1H, m, S–CH),
3.75—3.87 (1H, m, N–CH or O–CH2), 4.00—4.09 (1H, m, N–CH or
O–CH2), 4.13—4.21 (1H, m, N–CH or O–CH2), 7.27—7.65 (4H, m,
C6H4–CH3). 13C-NMR (CDCl3) d: 7.8, 20.9, 24.5, 24.8, 24.9, 31.0, 56.6,
61.3, 78.1, 123.3, 123.9, 130.1, 130.7, 140.1, 143.1, 164.2. MS m/z: 293
(Mϩ), 277, 245, 220, 188, 168, 154 (BP). Exact mass determination:
293.1474 (Calcd for C16H23NO2S: 293.1450).
(Rs,S)-6d: 71% yield (7d: 14% yield). Colorless oil. [a]D Ϫ21.2°
film
max
(cϭ1.23, CHCl3). IR n
cmϪ1: 1657 (O–CϭN), 1493 (aromatic), 1051,
812 (S–O). NMR (CDCl3) d: 1.43—1.45, 1.56—1.59 (3H, m, S–CH–CH3),
3.42 (3H, s, C6H4–CH3), 3.59—3.69 (1H, m, CH3–CH), 3.87—3.95 (1H, m,
CH3–CH), 4.02—4.13 (1H, m, O–CH2 or N–CH), 4.58—4.66 (1H, m,
O–CH2 or N–CH), 5.11—5.18 (1H, m, O–CH2 or N–CH), 7.10—7.56 (9H,
m, CH3C6H4, C6H5). 13C-NMR (CDCl3) d: 10.2, 21.5, 58.3, 69.5, 74.9, 77.2,
124.8, 125.2, 126.6, 127.6, 128.7, 129.8, 138.8, 141.3, 142.0, 142.2, 163.9.
MS m/z: 313 (Mϩ), 297, 265 (BP), 209, 174, 158, 139, 120. Exact mass de-
termination: 313.1115 (Calcd for C18H19NO2S: 313.1136).
(Rs,S)-6e: 62% yield (7e: 20% yield). Colorless oil. [a]D ϩ10.5°
film
max
(cϭ3.89, CHCl3). IR n
cmϪ1: 1657 (O–CϭN), 1493, 1452 (aromatic),
1051, 812 (S–O). NMR (CDCl3) d: 1.35—1.51 (3H, m, CHCH3), 2.42 (3H,
s, C6H4–CH3), 2.49—2.60 (1H, m, C6H5–CH2–CH), 2.94—3.09 (1H, m,
C6H5–CH2–CH), 3.44—3.54 (1H, m, CH–CH3), 3.82—3.95 (1H, m, O–
CH2), 4.10—4.18 (1H, m, O–CH), 4.27—4.40 (1H, m, N–CH), 7.12—7.54
(8H, m, CH3C6H4, C6H4). 13C-NMR (CDCl3) d: 7.5, 20.4, 37.4, 61.0, 61.7,
65.6, 123.2, 123.6, 125.7, 128.1, 128.3, 128.5, 128.8, 130.2, 130.5, 138.8,
140.1, 143.2, 164.2. MS m/z: 327 (Mϩ), 279, 210, 188, 139, 91 (BP). Exact
mass determination: 327.1267 (Calcd for C19H21NO2S: 327.1293).
(Rs,S)-7b: 73% yield. Colorless oil. [a]D Ϫ50.3° (cϭ1.77, CHCl3). IR
max
film
n
cmϪ1: 1658 (O–CϭN), 1589 (aromatic), 1051, 812 (S–O). NMR
(CDCl3) d: 0.80—0.83 (3H, d, Jϭ6.8 Hz, CH(CH3)2), 0.89—0.92 (3H, d,
Jϭ6.8 Hz, CH(CH3)2), 1.30 (3H, s, CCH3), 1.59 (3H, s, CCH3), 1.63—1.76
(1H, m, CH(CH3)2), 2.40 (3H, s, C6H5–CH3), 3.75—3.84 (1H, m, N–CH),
3.92—3.99 (1H, t, Jϭ8.5 Hz, O–CH2), 4.17—4.20 (1H, t, Jϭ8.5 Hz,
O–CH2), 7.25—7.49 (4H, m, C6H4–CH3). 13C-NMR (CDCl3) d: 14.5, 14.9,
17.3, 17.6, 20.9, 27.7, 59.6, 65.4, 70.5, 123.2, 123.6, 130.5, 130.7, 140.5,
143.3, 164.8. S m/z: 294 (Mϩ), 225, 181, 154, 140, 110, 91, 69, 41 (BP).
Exact mass determination: 293.1475 (Calcd for C16H23NO2S: 293.1450).
(Rs,S)-6f: 51% yield (7f: 31% yield). Colorless column (CHCl3–hexane),
mp 92—94 °C. [a]D ϩ4.4° (cϭ2.25, CHCl3). IR nfimlamx cmϪ1: 1653 (O–Cϭ
N), 1541, 1491 (aromatic), 1053, 812 (S–O). NMR (CDCl3) d: 1.42—1.67
(3H, m, S–CH–CH3), 2.33—2.42 (3H, m, C6H4–CH3), 3.64—4.02 (1H, m,
S–CH), 4.64—4.80 (2H, m, O–CH2), 7.07—7.84 (14H, m, CH3C6H4, C6H4).
13C-NMR (CDCl3) d: 7.8, 20.9, 61.5, 72.0, 75.8, 123.2, 123.6, 126.0, 126.5,
128.1, 128.3, 128.5, 128.6, 129.0, 129.2, 129.4, 129.5, 130.1, 130.4, 140.2,
143.0, 143.2, 143.3, 164.2. MS m/z: 389 (Mϩ), 373, 341, 320, 304, 180, 165,
139 (BP). Exact mass determination: 389.1402 (Calcd for C24H23NO2S:
389.1450). Anal. Calcd. for C24H23NO2S: C, 74.01; H, 5.95; N, 3.60. Found:
C, 73.90; H, 5.87; N, 3.65.
(Rs,S)-7c: 86% yield. Colorless oil. [a]D Ϫ41.5° (cϭ1.52, CHCl3). IR
max
film
n
cmϪ1: 1661 (O–CϭN), 1478 (aromatic), 1051, 812 (S–O). NMR
(CDCl3) d: 0.84 (9H, s, C(CH3)3), 1.29 (3H, s, S–C(CH3)2), 1.58 (3H, s,
S–C(CH3)2), 2.40 (3H, s, C6H4–CH3), 3.71—3.77 (1H, dd, Jϭ2.5, 7.6 Hz,
N–CH), 4.06—4.19 (2H, m, O–CH2), 7.25—7.56 (4H, m, C6H4–CH3). 13C-
NMR (CDCl3) d: 14.3, 14.8, 20.7, 24.5, 24.6, 24.9, 31.1, 57.3, 65.7, 78.6,
123.2, 123.6, 130.1, 130.5, 140.3, 143.1, 164.2. MS m/z: 307 (Mϩ), 168,
153, 140, 112, 92, 69, 57 (BP). Exact mass determination: 307.1682 (Calcd
for C17H25NO2S: 307.1606).
(Rs,S)-11: 53% yield (12: 27% yield). Colorless column (CHCl3–hexane),
mp 85—87 °C. [a]D Ϫ14.3° (cϭ3.90, CHCl3). IR nfimlamx cmϪ1: 1663 (O–Cϭ
N), 1541, 1495 (aromatic), 1051, 812 (S–O). NMR (CDCl3) d: 1.47—1.69
(Rs,S)-7d: 75% yield. Colorless oil. [a]D Ϫ69.2° (cϭ2.66, CHCl3). IR
max
film
n
cmϪ1: 1653 (O–CϭN), 1599, 1493 (aromatic), 1051, 812 (S–O). NMR

March 2002
379
(CDCl3) d: 1.41 (3H, s, S–C(CH3)2), 1.66 (3H, s, S–C(CH3)2), 2.41 (3H, s,
C6H4–CH3), 4.04—4.10 (1H, t, Jϭ8.6 Hz, N–CH or O–CH2), 4.59—4.66
(1H, t, Jϭ8.6 Hz, N–CH or O–CH2), 5.06—5.13 (1H, m, N–CH or O–CH2),
7.10–7.49 (9H, m, C6H4–CH3, C6H5). 13C-NMR (CDCl3) d: 17.4, 20.7, 21.5,
60.9, 69.5, 75.0, 124.3, 125.7, 126.6, 126.7, 127.7, 128.7, 129.3, 129.6,
130.1, 136.8, 141.5, 142.2, 167.4. MS m/z: 327 (Mϩ), 279, 214, 188, 172,
157, 140, 117, 91 (BP). Exact mass determination: 327.1338 (Calcd for
C19H21NO2S: 327.1293).
After the reaction time described, the reaction was quenched with saturated
aqueous NaCl solution. The mixture was extracted with CHCl3 (3ϫ10 ml)
and the combined organic layer was dried over anhydrous Na2SO4. Evapora-
tion of the solvent under reduced pressure afforded a crude product that was
purified by column chromatography over silca gel (35% acetone in hexane
as eluent) to provide a cycloadduct, (2S)-endo-20a. The results obtained are
listed in Tables 1—3.
The standard analysis of 20 was performed by HPLC analysis on a Daicel
OD column with 10% 2-propanol in hexane as the eluent [1 ml/min; average
retention times: 19.9 and 20.7 min for exo-20b enantiomers, 21.9 min for
(2S)-endo-20a and 24.6 min for (2R)-endo-20a]. The endo and exo ratio was
determined by 1H-NMR analysis.11)
(Rs,S)-7e: 70% yield. Colorless oil. [a]D Ϫ45.3° (cϭ1.17, CHCl3). IR
max
film
n
cmϪ1: 1653 (O–CϭN), 1493, 1454 (aromatic), 1051, 812 (S–O). NMR
(CDCl3) d: 1.33 (3H, s, CCH3), 1.54 (3H, s, CCH3), 2.40 (3H, s,
C6H4–CH3), 2.51–2.59 (1H, dd, Jϭ4.6, 8.6 Hz, C6H5–CH2), 2.99—3.06 (1H,
dd, Jϭ4.6, 8.6 Hz, C6H5–CH2), 3.91—3.97 (1H, dd, Jϭ0.8, 7.6 Hz, O–CH2),
4.10—4.17 (1H, dd, Jϭ0.8, 8.6 Hz, O–CH2), 4.23—4.34 (1H, m, N–CH),
7.13—7.42 (9H, m, CH3C6H4, C6H5). 13C-NMR (CDCl3) d: 14.7, 14.9, 20.9,
37.6, 62.1, 65.6, 65.9, 123.2, 123.5, 125.8, 128.2, 128.4, 128.7, 128.8, 130.2,
130.5, 138.9, 140.5, 143.1, 164.1. MS m/z: 341 (Mϩ), 202, 140, 110, 91
(BP). Exact mass determination: 341.1441 (Calcd for C20H23NO2S:
341.1450).
References
1) Seyden-Penne J., “Chiral Auxiliaries and Ligands in Asymmetric Syn-
thesis,” John Wiley & Sons, New York, 1995, pp. 536—592.
2) Johnson J. S., Evans D. A., Acc. Chem. Res., 33, 325—335 (2000);
Jorgensen K. A., Angew Chem. Int. Ed., 39, 3558—3588 (2000); Si-
monse K. B., Svenstrup N., Roberson M., Jorgensen K. A., Chem. Eur.
J., 6, 123—128 (2000); Yao S., Saaby S., Hazell R. G., Jorgensen K.
A., ibid., 6, 2435—2448 (2000); Crosignani S., Desimoni G., Faita G.,
Filippone S., Mortoni A., Righetti P., Zema M., Tetrahedron Lett., 40,
7007—7010, (1999); Evans D. A., Barnes D. M., Johnson J. S., Lectka
T., Matt P. V., Miller S. J., Murry J. A., Norcross R. D., Shaughnessy
E. A., Campos K. R., J. Am. Chem. Soc., 121, 7582—7594 (1999);
Lipkowitz K. B., Schefzick S., ibid., 123, 6710—6711 (2001).
3) Khiar N., Fernandez I., Alcudia F., Tetrahedron Lett., 34, 123—126
(1993); Ordonez M., Guerrero-de la Rosa V., Labastida V., Llera J. M.,
Tetrahedron Asymm., 7, 2675—2686 (1996); Quite recently, chiral
bis(sulfinyl)imidamidine ligands were reported; Owens T. D., Hollan-
der F. J., Oliver A. G., Ellman J. A., J. Am. Chem. Soc., 123, 1539—
1540 (2001); Bolm C., Simic O., ibid., 123, 3830—3831 (2001).
4) Hiroi K., Suzuki Y., Heterocycles, 46, 77—81 (1997); Hiroi K., Suzuki
Y., Abe I., Hasegawa Y., Suzuki K., Tetrahedron Asymm., 9, 3797—
3817 (1998); Suzuki Y., Abe I., Hiroi K., Heterocycles, 50, 89—94
(1999); Hiroi K., Suzuki Y., Abe I., Chem. Lett., 1999, 149—150;
Hiroi K., Suzuki Y., Tetrahedron Lett., 39, 6499—6502 (1998); Hiroi
K., Suzuki Y., Kawagishi R., ibid., 40, 715—718 (1999); Hiroi K.,
Suzuki Y., Abe I., Kawagishi R., Tetrahedron, 56, 4701—4710 (2000).
5) Hiroi K., Umemura M., Tomikawa Y., Kaneko M., Kato F., Chem.
Pharm. Bull., 45, 759—764 (1997); Hiroi K., Umemura M., Tetrahe-
dron Lett., 33, 3343—3346 (1992); Idem, Tetrahedron, 49, 1831—
1840 (1993).
(Rs,S)-7f: 72% yield. Colorless column (CHCl3–hexane), mp 74—77 °C.
[a]D Ϫ40.2° (cϭ1.64, CHCl3). IR nfimlamx cmϪ1: 1653 (O–CϭN), 1491, 1447
(aromatic), 1051, 812 (S–O). NMR (CDCl3) d: 1.41 (3H, s, CCH3), 1.71
(3H, s, CCH3), 2.29 (3H, s, C6H4–CH3), 4.73 (2H, d, Jϭ8.6 Hz, O–CH2),
6.87—7.80 (14H, m, CH3C6H4, C6H5). 13C-NMR (CDCl3) d: 14.7, 14.9,
20.7, 65.8, 72.4, 76.1, 123.6, 123.7, 126.0, 126.3, 128.2, 128.4, 128.6, 128.9,
129.2, 129.3, 129.5, 129.8, 130.4, 130.6, 140.3, 143.3, 143.5, 143.8, 164.2.
MS m/z: 403 (Mϩ), 334 (BP), 264, 233, 211, 196, 139. Exact mass determi-
nation: 403.1620 (Calcd for C25H25NO2S: 403.1606). Anal. Calcd for
C25H25NO2S: C, 74.41; H, 6.25; N, 3.47. Found: C, 74.34; H, 6.31; N, 3.38.
(Rs,S)-12: 72% yield. Colorless column (CHCl3–hexane), mp 93—94 °C.
[a]D Ϫ70.6° (cϭ2.65, CHCl3). IR nfimlamx cmϪ1: 1655 (O–CϭN), 1541, 1491
(aromatic), 1049, 812 (S–O). NMR (CDCl3) d: 1.47 (3H, s, CCH3), 1.77
(3H, s, CCH3), 2.43 (3H, s, C6H4–CH3), 5.44—5.48 (1H, d, Jϭ10.6 Hz,
N–CH or O–CH), 5.85—5.89 (1H, d, Jϭ10.6 Hz, N–CH or O–CH), 6.83—
7.64 (14H, m, CH3C6H4, C6H4). 13C-NMR (CDCl3) d: 14.4, 14.9, 20.9, 71.1,
75.8, 65.8, 123.2, 123.6, 125.7, 127.3, 127.4, 127.5, 127.8, 127.9, 128.3,
128.4, 128.6, 128.7, 130.6, 130.8, 140.1, 140.2, 140.9, 143.2, 164.1. MS
m/z: 339 (Mϩ), 196, 165, 143 (BP). Exact mass determination: 339.2354
(Calcd for C20H21NO2S: 339.2341). Anal. Calcd for C20H21NO2S: C, 70.77;
H, 6.24; N, 4.13. Found: C, 70.69; H, 6.31; N, 4.08.
(Rs,S)-17: 72% yield. Colorless column (CHCl3–hexane), mp 96 °C. [a]D
film
Ϫ196.0° (cϭ1.26, CHCl3). IR n cmϪ1: 1639 (O–CϭN), 1597 (aromatic),
max
1049, 814 (S–O). NMR (CDCl3) d: 1.27 (3H, s, CCH3), 1.61 (3H, s, CCH3),
2.34 (3H, s, C6H4–CH3), 3.00—3.06 (1H, d, Jϭ18.1 Hz, O–CH–CH2–C6H4),
3.33—3.42 (1H, dd, Jϭ7.2,18.1 Hz, O–CH–CH2–C6H4), 5.22—5.30 (1H, m,
O–CH), 5.50—5.53 (1H, d, Jϭ8.1 Hz, N–CH), 6.97—7.59 (8H, m,
CH3C6H4, C6H4). 13C-NMR (CDCl3) d: 15.7, 21.4, 22.6, 39.7, 60.3, 76.7,
77.2, 83.2, 125.2, 125.5, 125.7, 127.5, 128.6, 129.1, 136.7, 139.7, 141.4,
141.7, 166.6. MS m/z: 339 (Mϩ), 262, 214, 199 (BP), 170, 140. Exact mass
determination: 339.1258 (Calcd for C20H21NO2S: 339.1293). Anal. Calcd for
C20H21NO2S: C, 70.77; H, 6.24; N, 4.13. Found: C, 70.68; H, 6.31; N, 4.06.
The Copper(II)-Catalyzed Asymmetric Diels–Alder Reactions of 18
with 19 Genaral Procedure: Anhydrous CuCl2 (5.4 mg, 0.04 mmol) is re-
acted with chiral 2-(arylsulfinylmethyl)-1,3-oxazoline (5, 7, 10, 12, 15, or
17) (0.04 mmol) in dichloromethane (1 ml) at room temperature for 4 h
under an argon atomosphere. Another 25-ml two-necked flask equipped with
a septum inlet and a magnetic stirring bar and containing AgX2 (XϭOTf,
ClO4, and SbF6) (0.08 mmol) was flushed with argon, and maintained under
a positive pressure of argon. The above solution was added and the mixture
was stirred for 4 h at room temperature. The resulting mixture was cooled to
Ϫ78 °C with a dry ice–CH3OH bath, and a solution of N-acyl-1,3-oxazoli-
dine-2-one (18) (56.4 mg, 0.4 mmol) in CH2Cl2 (2 ml) and freshly distilled
cyclopentadiene (19) (132 mg, 2 mmol) were sequentially added dropwise.
The reaction mixture was stirred under the conditions listed in Tables 1—3.
6) “Organic Syntheses,” Collective Vol. I, John Wiley & Sons, Inc., New
York, 1941, pp. 5—7.
7) Meyers A. I., Shipman M., J. Org. Chem., 56, 7098—7102 (1991).
8) Khiar N., Fernandez I., Alcudia F., Tetrahedron Lett., 34, 123—126
(1993).
9) Narasaka K., Inoue M., Okada N., Chem. Lett., 7, 1109—1112 (1986).
10) Brunel J. M., Campo B. D., Buono G., Tetrahedron Lett., 39, 9663—
9666 (1998); Crosignani S., Desimoni G., Faita G., Righetti P. P.,
Tetrahedron, 54, 15721—15730 (1998); Ghosh A. K., Cho H., Cap-
piello J., Tetrahedron Asymm., 9, 3687—3691 (1998); Desimoni G.,
Faita G., Righetti P. P., Tetrahedron Lett., 37, 3027—3030 (1996);
Crosignani S., Desimoni G., Faita G., Filippone S., Mortoni A.,
Righetti P. P., Zema M., ibid., 40, 7007—7010 (1999); Peer M., de
Jong J. C., Kiefer M., Langer T., Rieck H., Schell H., Sennhenn P.,
Sprinz J., Steinhagen H., Wiese B., Helmchen G., Tetrahedron, 52,
7547—7583 (1996); Pyne S. G., Hayipour A. R., Prabakaran K.,
Tetrahedron Lett., 35, 645—648 (1994).
11) Nishida A., Yamanaka M., Nakagawa M., Tetrahedron Lett., 40,
1555—1558 (1999).
12) Hiroi K., Watanabe K., Abe I., Koseki M., Tetrahedron Lett., 42,
7617—7619 (2001).