New chiral sulfoxide ligands in catalytic asymmetric Diels-Alder reactions: Double acceleration by the chiralities of the sulfoxides and oxazolines

Article abstract of DOI:10.1016/S0040-4039(01)01646-X

New chiral sulfoxide ligands which are useful for catalytic asymmetric Diels-Alder reactions have been developed. The new ligands involve a chiral sulfinyl function and a 1,3-oxazoline ring with an asymmetric carbon center, in which the chiral sulfinyl group has been revealed to play a crucial role in achieving high enantioselectivity in asymmetric Diels-Alder reactions. Among the Lewis acid catalysts employed, magnesium iodide provided the highest chemical and stereochemical efficiency in the cycloaddition reactions. A mechanistic pathway for the asymmetric synthesis is proposed on the basis of the stereochemical outcomes obtained.

Full text of DOI:10.1016/S0040-4039(01)01646-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7617–7619
New chiral sulfoxide ligands in catalytic asymmetric Diels–Alder
reactions: double acceleration by the chiralities of the sulfoxides
and oxazolines
Kunio Hiroi,* Kazuhiro Watanabe, Ikuko Abe and Michiko Koseki
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan
Received 13 July 2001; revised 21 August 2001; accepted 31 August 2001
Abstract—New chiral sulfoxide ligands which are useful for catalytic asymmetric Diels–Alder reactions have been developed. The
new ligands involve a chiral sulfinyl function and a 1,3-oxazoline ring with an asymmetric carbon center, in which the chiral
sulfinyl group has been revealed to play a crucial role in achieving high enantioselectivity in asymmetric Diels–Alder reactions.
Among the Lewis acid catalysts employed, magnesium iodide provided the highest chemical and stereochemical efficiency in the
cycloaddition reactions. A mechanistic pathway for the asymmetric synthesis is proposed on the basis of the stereochemical
outcomes obtained. © 2001 Elsevier Science Ltd. All rights reserved.
Catalytic asymmetric cycloaddition reactions have
recently attracted much attention for stereoselective
and efficient preparation of optically active carbocyclic
and heterocyclic compounds, especially with multi-
functionalized groups.1 A number of asymmetric syn-
thetic methods with chiral ligands have been developed
so far,2 and are being applied to the total synthesis of
natural products and biologically active compounds
with high efficiency.3
We wish to communicate herein a novel catalytic asym-
metric Diels–Alder reaction with new chiral sulfoxide
ligands. Hitherto we have developed a number of chiral
sulfoxide ligands and demonstrated the usefulness of
the ligands in transition metal-catalyzed asymmetric
reactions, indicating the mode of the coordination of
the chiral sulfinyl function to the transition metals and
the mechanistic pathways for the asymmetric synthe-
ses.4 Few chiral sulfoxide ligands have previously been
O
O
Ph
Ph
O
R1
1= H
= Ph
= Bn
= t -Bu
= t -Bu
2 = OMe
= OMe
= OMe
= OMe
= H
R
(RS)-2a
(S,RS)-2b
R
R
N
O
N
O
N
O
c
d
e
S
S
S
p-Tol
R2
MeO
(RS)-3
=
= OMe
(R,RS)-2f
R= Ph
= t -Bu
(S,RS)-1a
OMe
b
Ph
O
O
O
S
Ph
N
O
N
N
O
SO2
S
MeO
(S)-4
MeO
(4S,5R,RS)-6
MeO
(4S,5R,RS)-5
Figure 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01646-X

7618
K. Hiroi et al. / Tetrahedron Letters 42 (2001) 7617–7619
reported in asymmetric cycloaddition reactions.5,6 We
describe in this report a doubly accelerated asymmetric
Diels–Alder reaction with the chirality on oxazolines
and that of sulfoxides, providing the highest (>90% e.e.)
enantioselectivity over those from the previous chiral
sulfoxide ligands.
be the most effective for giving (2S)-9a (81% e.e.; on
the use of (S,Rs)-2d in CH2Cl2 at −78°C for 24 h). Use
of other Lewis acids (Cu(OTf)2, CuI2, FeI3, MgCl2,
MgBr2, MgBr2·OEt2, and Mg(OTf)2) under the same
reaction conditions provided (2S)-9a with 1, 1, 41, 6, 8,
45, and 1% e.e., respectively (Scheme 1).
New chiral oxazoline-sulfoxide ligands (Rs)-1a,b, 2a–f,
3, 5, and 6 were prepared in the usual way by lithiation
of 2-(2-bromophenyl)-1,3-oxazolines7 (derived from the
corresponding amino alcohols and 2-bromobenzoyl
chloride) with n-butyllithium followed by the sulfinyla-
tion with (−)-menthyl (Ss)-p-toluene-, 1-naphthalene-,
or 2-methoxy-1-naphthalenesulfinate.8 The oxazoline-
sulfone ligand (S)-4 was obtainable from (S,Rs)-2d by
oxidation with m-chloroperbenzoic acid (Fig. 1).
The reactions were carried out under the following two
reaction conditions for confirming the complete forma-
tion of the Lewis acid complex with the ligands used:
reacted with a ligand in CH2Cl2 at room temperature
for 30 min (method A) or in THF at 40°C for 1.5 h
(method B) prior to the addition of the substrates. The
latter reaction condition was preferred, since it pro-
vided the Diels–Alder adduct 9 with higher enantiose-
lectivity, as shown in Table 1 (entries 4 and 5).
The Diels–Alder reactions of 7 with cyclopentadiene (8)
using chiral oxazoline-sulfoxide ligands obtained above
were studied under catalysis with Lewis acids. Marked
effects of the Lewis acid catalysts on the asymmetric
induction in the reaction of 7 with 8 were observed;
among the Lewis acids examined, MgI2 was revealed to
The 2-methoxy-1-naphthyl sulfoxides (S,Rs)-2a–d and
(R,Rs)-2f provided higher enantioselectivity than the
other aryl sulfoxides, p-tolyl sulfoxides (S,Rs)-1a,b and
1-naphthyl sulfoxide (S,Rs)-2e. The effects of sub-
stituents on the oxazoline rings were studied using
bulky substituents such as phenyl, benzyl, t-butyl or
10 mol%
MgI2
O
O
O
O
H
+
+
N
O
O
N
O
1-6
H
N
O
O
(2R)-9b
7
8
(2S)-9a
Scheme 1.
Table 1. Studies on the MgI2-catalyzed asymmetric Diels–Alder reactions of 7 with 8 using chiral ligands 1–6a
Entry
Ligand (mol%)
Methodb
Solvent
Temp. (°C)
Time (h)
Yield of 9 (%)
endo (9a)/exo
(9b)c
e.e. (%) of the
endo product 9ad
1
2
3
4
5
6
7
8
1a (10)
1b (10)
2a (10)
2b (10)
2b (10)
2c (10)
2d (10)
2d (10)
2d (10)
2d (10)
2d (5)
2d (10)
2d (20)
2d (30)
2e (10)
2f (10)
2f (10)
3 (10)
B
B
B
A
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH3CN
Toluene
EtNO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−20
−78
−78
−78
−78
−78
24
24
24
24
24
24
24
48
24
24
36
24
12
12
24
12
24
24
36
36
24
82
86
82
45
83
99
30
10
47
43
28
90
88
89
81
98
90
96
62
90
52
93/7
94/6
94/6
93/7
94/6
93/7
88/12
88/12
98/2
95/5
\99/1
97/3
97/3
98/2
93/7
90/10
94/6
84/16
92/8
94/6
96/4
30 (2S)
46 (2S)
17 (2S)
24 (2S)
50 (2S)
21 (2S)
3 (2R)
15 (2S)
21 (2S)
54 (2S)
70 (2S)
81 (2S)
75 (2S)
71 (2S)
36 (2S)
71 (2S)
92 (2S)
36 (2S)
6 (2S)
9
10
11
12
13
14
15
16
17
18
19
20
21
4 (10)
5 (10)
6 (10)
42 (2S)
37 (2S)
a The reactions of 7 with 8 (5.0 equiv.) were carried out in the presence of Lewis acid catalysts and chiral ligands 1–6.
b The Lewis acid catalyst was reacted with a ligand in CH2Cl2 at room temperature for 30 min (method A) or reacted in THF at 40°C for 1.5
h (method B) prior to the addition of the substrates 7 and 8.
c Determined by 1H NMR at 270 MHz.
d Enantiomeric excess of the endo adduct 9a was determined by HPLC analysis using a chiral column (Daicel, Chiralcel OD).

K. Hiroi et al. / Tetrahedron Letters 42 (2001) 7617–7619
7619
OMe
S
2-methoxyisopropyl groups (2b–f) in the magnesium
OMe
S
iodide-catalyzed asymmetric reaction of 7 with 8, and
the results obtained are listed in Table 1. Table 1
indicates that the chiral oxazoline ligand ((R,Rs)-2f)
bearing a 2-methoxyisopropyl substituent provided
(2S)-9a with the highest enantioselectivity (92%). This
high asymmetric induction was clearly concluded to
arise from the double acceleration with the two chiral
centers, that on the oxazoline and of the sulfoxide,
respectively, since the loss of chirality on the oxazoline
((Rs)-2a and 3) or of the sulfoxide ((S)-4) provided
much lower enantioselectivity, as shown in Table 1.
O
N
O
O
N
O
Mg
Mg
O
O
Re -face
O
O
Re -face
O
N
OMe
N
O
MeO
10a
10b
Figure 2.
Solvent effects were studied using THF, MeCN, tolu-
ene, nitroethane, or dichloromethane in the magnesium
iodide-catalyzed Diels–Alder reaction of 7 with 8. As
listed in Table 1 (entries 7–10 and 12), use of CH2Cl2 as
the solvent provided (2S)-9a with the highest enantiose-
lectivity (81%) in the above reaction with MgI2 (0.1
equiv.). Effects of the amount of catalyst (MgI2) were
examined changing the amount with a range of 0.05 to
0.3 equivalents in CH2Cl2: use of 0.1 equivalent of MgI2
and a chiral ligand 2d was the most efficient (81%) for
the asymmetric cycloaddition reaction.
Thus, chiral sulfoxide functionality was revealed to play
a crucial role as a chiral ligand in catalytic asymmetric
synthesis, stereocontrolled by the coordination of sulfur
or oxygen atoms in the chiral sulfoxides depending on
metal catalysts used.
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condition for the asymmetric Diels–Alder reactions is
as follows: the reaction of 7 with 8 (5.0 equiv.) was
carried out at −78°C for 24 h in CH2Cl2 in the presence
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9
of the chiral magnesium catalyst (prepared from MgI2
(0.1 equiv.) and (R,Rs)-2f (0.1 equiv.) in THF at 40°C
for 1.5 h prior to the cycloaddition reaction), providing
(2S)-9 in 90% yield (the ratio of the endo (2S)-9a
(92%e.e.) to the exo (2S)-9b isomer, 95:5).
A possible mechanistic pathway for the above catalytic
asymmetric synthesis is rationalized as follows. Inter-
mediary tetrahedral magnesium complexes 10a,b coor-
dinated by the nitrogen atom of the oxazoline ring, the
sulfinyl oxygen, and the two carbonyl oxygens of the
substrate would be formed. The attack of 8 from the Re
face side opposite the bulky 2-methoxyisopropyl group
in 10a or from the Re face side opposite the 2-methoxy-
1-naphthyl group in 10b gives (2S)-9a. The substantial
effect of the 2-methoxy group in 2a–d, f would be
ascribed presumably to the fixation of the conformation
of the naphthyl group by the dipole–dipole repulsion
between the sulfinyl and the methoxy groups.
This paper reports one of the few precedents of chiral
sulfoxide ligands in asymmetric cycloaddition reactions,
and the first example of the catalytic asymmetric Diels–
Alder reaction with novel chiral sulfoxide-oxazoline
ligands, via seven-membered chelates of sulfoxide-mag-
nesium complexes (normally six-membered chelates
were formed in previous oxazoline ligands) indicating
particularly the potential advantage of the chirality of
the sulfoxide functionality for achieving high enantiose-
lectivity, because of the synthetically ready availability
of the chiral sulfoxide ligands and the chemical stability
of the intermediary magnesium complex (Fig. 2).
6. Quite recently, chiral bis(sulfinyl)imidoamidine ligands
were reported; Owens, T. D.; Hollander, F. J.; Oliver, A.
G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 1539–1540.
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Schell, H.; Sennhenn, P.; Sprinz, J.; Steinhagen, H.; Wiese,
B.; Helmchen, G. Tetrahedron 1996, 52, 7547–7583.
8. Pyne, S. G.; Hayipour, A. R.; Prabakaran, K. Tetrahedron
Lett. 1994, 35, 645–648.
9. The activated magnesium iodide was obtained by heating
magnesium (0.11 equiv.) and iodine (0.11 equiv.) in anhy-
drous THF at 40°C for 2 h.