Enantioselective radical cyclization of α,β-unsaturated sulfonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2004.04.024

Enantioselective intramolecular radical cyclization of benzimidazolyl iodoalkenyl and iodoalkadienyl sulfones using chiral Lewis acids gave products with good enantioselectivity. Newly formed chiral centers could be induced effectively by enantioselective coordination to one of the sulfonyl oxygens.

Full text of DOI:10.1016/j.tetlet.2004.04.024

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4213–4216
Enantioselective radical cyclization of a,b-unsaturated
sulfonyl compounds
Hideki Sugimoto, Makoto Kobayashi, Shuichi Nakamura and Takeshi Toru*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan
Received 11 March 2004;revised 5 April 2004;accepted 8 April 2004
Abstract—Enantioselective intramolecular radical cyclization of benzimidazolyl iodoalkenyl and iodoalkadienyl sulfones using
chiral Lewis acids gave products with good enantioselectivity. Newly formed chiral centers could be induced effectively by enan-
tioselective coordination to one of the sulfonyl oxygens.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
L*
O O M L*
R1
O O
S
Free radical-mediated asymmetric reactions have been
extensively studied.1 There are a number of reports of
the diastereoselective radical intramolecular cyclization
using chiral auxiliaries, for example, ())-8-phenylmen-
thyl ester,2 Oppolzer’s sultam,3 a sulfinyl group,4 and
others.5 However, there are only a few reports of the
highly enantioselective intramolecular radical cycliza-
tion involving enantioselective radical addition to a
double bond. High enantioselectivity has been reported
in the reaction of vinyl radical cyclization using a chiral
aluminum Lewis acid derived from Me3Al and
BINOLs.6 Recently, we have reported allylation and
hydrogen atom transfer reactions of a-sulfonyl radicals
in the presence of chiral Lewis acids, which proceed with
high enantioselectivity.7 These reactions showed selec-
tive coordination of a chiral Lewis acid to one of the
prochiral oxygens in the sulfonyl group, which could be
a powerful strategy for the asymmetric synthesis8 (Fig.
1). We now report an enantioselective radical cyclization
of a,b-unsaturated sulfonyl compounds by selective
coordination of a chiral Lewis acid to an enantiotrophic
sulfonyl oxygen.
N
S
R1
ML2
*
N
N
N
R2
R2
Figure 1. Asymmetric induction by the prochiral sulfonyl group.
The results are shown in Table 1. A Lewis acid
(1.1 equiv) was stirred with a chiral ligand (1.2 equiv) in
CH2Cl2 (0.01 mol/L) for 1 h at room temperature and
then the x-iodoalkenyl sulfone 1a was added. After
being stirred for 1 h at room temperature, the mixture
was cooled to )78 °C. A hydrogen atom donor
(2.0 equiv) and triethylborane (2.0 equiv) were added
successively and the reaction mixture was stirred for an
appropriate time. The reaction of N-benzylbenzimidaz-
olyl sulfone 1a using tributyltin hydride in the presence
of MgBr2-bis(oxazoline)-Ph 3 or Mg(ClO4)2-bis(oxazo-
line)-Ph 3 afforded the cyclized product 2a in high yield
but with no enantioselectivity (entries 1 and 2). On the
other hand, the reaction using a combination of 3 and
Zn(OTf)2 gave 2a with good enantioselectivity (entry 3).
The reaction using triphenyltin hydride also gave good
enantioselectivity (entry 4). The reaction using
tris(trimethylsilyl)silane gave 2a with 70% ee,9 but a
longer reaction time was required for completion of the
reaction in comparison with that using tributyltin and
triphenyltin hydride (entry 5 vs entries 3 and 4).
Bis(oxazoline)-Ph 3 gave better enantioselectivity than
other bis(oxazoline)s 4, 5, and 610 (entries 6–8). The
substituents on the nitrogen of the benzimidazolyl group
We first examined the radical 5-exo cyclization of
benzimidazolyl x-iodoalkenyl sulfones 1a–d (Scheme 1).
Keywords: Radical;Cyclization;Sulfone;Chiral Lewis acid.
* Corresponding author. Tel./fax: +81-52-735-5217;e-mail: toru@
nitech.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.024

4214
H. Sugimoto et al. / Tetrahedron Letters 45 (2004) 4213–4216
1) Lewis acid
ligand
I
O O
S
O O
S
2) hydrogen atom donor
Et3B
O
O
N
N
2a-d
N
N
N
CH2Cl2, -78 °C
R1
R1
1a-d
1a : R1 = C6H5CH2
O
O
O
O
1b : R1 = 3,5-Me2C6H3CH2
1c : R1 = 2,4,6-Me3C6H2CH2
1d : R1 = Me
N
N
N
R2
R2
3 : R2 = Ph
4 : R2 = iPr
5 : R2 = t-Bu
6
Scheme 1.
Table 1. Radical cyclization of benzimidazolyl x-iodoalkenyl sulfones 1a–d
Entry
Vinyl sulfone
R1
Lewis acid
Ligand
Hydrogen
atom donor
Time (min)
Product
Yield (%) Ee (%)a
1
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
C6H5CH2
C6H5CH2
MgBr2
3
3
3
3
3
4
5
6
3
3
3
Bu3SnH
Bu3SnH
Bu3SnH
Ph3SnH
(TMS)3SiH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
10
1
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
97
99
99
94
93
90
90
79
100
96
92
0
0
2
Mg(ClO4)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
3
C6H5CH2
C6H5CH2
1
64
55
70
1
4
1
5
C6H5CH2
C6H5CH2
4.5 h
1
6
7
C6H5CH2
C6H5CH2
1
2
8
10
3
2
9
3,5-Me2C6H3CH2
2,4,6-Me3C6H2CH2
Me
67
45
6
10
11
3
1
a Determined by HPLC analysis using CHIRALPAKâ AD.
were examined. The reaction of 1b having the N-(3,5-
dimethylphenyl)methyl group showed good enantio-
selectivity (entry 9), whereas N-(2,4,6-trimethylphenyl)-
methyl- and N-methylbenzimidazolyl sulfones 1c and 1d
lowered the enantioselectivity (entries 10 and 11).
tiomer of 2a was determined to be R by comparison of
the value of optical rotation with that of (R)-2a derived
from the chiral alcohol 13.14
Figure 2 shows a steric requirement in the transition
state for the formation of (R)-2a from 1a. In this plau-
sible transition state, the pro-R oxygen of the sulfonyl
group and the nitrogen atom of the benzimidazolyl
group in 1a are coordinated with tetrahedral zinc15 and
the complex is well arranged to avoid the severe steric
repulsion between the alkenyl and the phenyl groups on
the bis(oxazoline) ring. As a result, this transition state
turned out to be similar to those assumed in our previ-
ous reports for the allylation and hydrogen atom
transfer to a-sulfonyl radicals, in which the pro-R sul-
fonyl oxygen is coordinated with tetrahedral zinc. In the
present cyclization, the carbon radical attacks the Si-
face of the double bond to afford (R)-2a.
We next examined the radical cyclization of iodoalkenyl
and iodoalkadienyl sulfones 7–9 having the N-benzyl-
benzimidazolyl group (Table 2). The 6-exo-trig cycliza-
tion of 7 with tributyltin hydride or tris(tri-methyl-
silyl)silane afforded the product 10 in high yield with
good enantioselectivity (entries 1 and 2). The 5-exo-trig
cyclization of vinyl radicals derived from sulfones 8 and
9 gave 11 and 12 in high yield with good enantio-
selectivity using tributyltin hydride as well as tris(tri-
methylsilyl)silane (entries 3–6).
The absolute configuration of the major product 2a
was determined by comparison with (R)-2a separately
prepared from (S)-3-tetrahydrofuranmethanol 1311
(Scheme 2). Treatment of 13 with TsCl, Et3N, and
Et3NÆHCl gave the tosylate 14,12 which was converted to
the (R)-sulfide on treatment with 1-benzylbenzimidole-
2-thiol in the presence of DBU.13 Oxidation of the sul-
fide 15 with m-CPBA afforded the sulfone (R)-2a with
98% ee. The absolute configuration of the major enan-
2. Conclusion
In conclusion, we have demonstrated that selective
coordination of a chiral Lewis acid to one of the enan-
tiotrophic sulfonyl oxygens is an efficient method for the

H. Sugimoto et al. / Tetrahedron Letters 45 (2004) 4213–4216
Table 2. Radical cyclization of iodoalkenyl and iodoalkadienyl sulfones 7–9
4215
Entry Vinyl sulfone
Hydrogen
atom donor
Time
Product
Yield (%)
Ee (%)a
I
O O
S
O O
S
1
Bu3SnH
(TMS)3SiH
0.5 h
5 h
97
62
62
59
O
O
N
N
2
N
N
Bn
Bn
7
10
O O
S
I
O O
S
N
N
3
4
Bu3SnH
(TMS)3SiH
5 min
2.5 h
67
66
60
66
N
Bn
11
N
Bn
8
I
O O
S
O O
S
N
N
5
6
Bu3SnH
(TMS)3SiH
3 min
3.5 h
93
96
60
50
N
N
Bn
Bn
12
9
a Determined by the HPLC analysis using Chiralcel OJ-H and CHIRALPAKâ AD.
References and notes
N
HS
TsCl, Et3N
Et3N H Cl
OTs
N
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