Enantioselective conjugate radical addition to α'-phenylsulfonyl enones

Article abstract of DOI:10.1016/j.tetlet.2010.07.014

Enantioselective conjugate addition reactions of alkyl radicals to α'-phenylsulfonyl enones are described. A bis-oxazoline-zinc triflate complex proved to be an effective catalyst leading to high enantioselectivities and chemical yields.

Full text of DOI:10.1016/j.tetlet.2010.07.014

Tetrahedron Letters 51 (2010) 4947–4949
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective conjugate radical addition to a0-phenylsulfonyl enones
Jin Young Lee a, Sundae Kim b, Sunggak Kim a,b,
*
a Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea
b Divison of Chemistry & Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Enantioselective conjugate addition reactions of alkyl radicals to a0-phenylsulfonyl enones are described.
A bis-oxazoline-zinc triflate complex proved to be an effective catalyst leading to high enantioselectivi-
ties and chemical yields.
Article history:
Received 26 April 2010
Revised 16 June 2010
Accepted 2 July 2010
Available online 23 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Enantioselective conjugate radical addition reactions have been
studied to take advantage of the unique features of radical chemis-
try, in which detachable achiral auxiliaries play an important role
in determining the enantioselectivity.1,2 We have been interested
in developing bidentate achiral templates derived from enones
and the previously reported enantioselective conjugate radical
addition reactions of a0-hydroxy enones3 and a0-phosphoric enon-
es using chiral Lewis acids.4,5 In particular, the a0-phosphoric en-
5. The use of 20–30 mol % of the chiral Lewis acid gave the same
enantioselectivity for the conjugate addition as compared to the
reaction with a stoichiometric amount. Reducing the amount of
catalyst to 10 mol % gave almost the same enantioselectivity (80%
ee vs 79% ee). The yields were still good. Further lowering of the
catalyst loading to 5 mol % resulted in a significant decrease in
enantioselectivity (33% ee) as well as in the chemical yield (65%).
To improve the enantioselectivity in the conjugate addition, the
effect of structural variation of the a0-phenylsulfonyl enone 8 was
studied. As shown in Table 3, structural modification of the sulfo-
nyl groups did not influence the enantioselectivity significantly. t-
Butylsulfonyl and p-toluenesulfonyl groups gave almost the same
enantiomeric excess (entries 3 and 4). Furthermore, when the
phenylsulfonyl group was changed to bulkier 4-biphenylsulfonyl
one template showed
a high chemical reactivity and good
enantioselectivity with the chiral Lewis acid derived from chiral
bis-oxazoline (Box) derivative and zinc(II) triflate.4 In the course
of our studies on enantioselective radical reactions, we investi-
gated the possibility of using an a0-phenylsulfonyl enone template
in conjugate radical addition, as the phenylsulfonyl group can be
removed under mild conditions6 or utilized for further transforma-
tions.7 The a0-phenylsulfonyl group has been utilized previously as
a highly efficient 1,5-chelating template in the catalytic enantiose-
lective Diels–Alder8 and Mukaiyama–Michael reactions.9
The effect of various Lewis acids along with Box ligands was
examined (Table 1). The chiral Lewis acid, derived from Zn(OTf)2
and bis-phenyl Box ligand 5, gave the highest enantiomeric excess
(entry 10). Ligands 1 and 4 were totally ineffective (entries 6 and
9). Cu(OTf)2 was also ineffective (entries 4 and 5) but magnesium
salts with ligand 5 gave poor to moderate enantioselectivities (en-
tries 2 and 3). As compared with the previous results obtained with
a0-phosphoric enones,4 a similar trend was observed in terms of
the Lewis acid and the ligand. The effect of the solvent was briefly
examined as shown in Table 2 and diethyl ether gave the best re-
sult (entry 4). The reaction was faster in toluene and gave a high
chemical yield, but the enantioselectivity decreased to a small ex-
tent (entry 3). Furthermore, the reaction was slow in dichloro-
methane and THF and the enantioselectivity was moderate
(entries 1 and 2). In addition, we briefly examined the catalytic effi-
ciency of the chiral Lewis acid derived from zinc triflate and ligand
Table 1
Effect of Lewis acids and ligands on the conjugate radical additiona
chiral Lewis acid
n-Bu3SnH, Et3B/O2
O
O
PhO2S
i-PrI
PhO2S
Ph
CH2Cl2, -78 oC, 24 h
Ph
6
7
Entry
Lewis acid
Ligand
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
None
MgBr2
None
51 (44)
59 (27)
66 (23)
51 (33)
57 (18)
65 (27)
68 (12)
66 (13)
63 (27)
75 (10)
—
39
52
0
4
0
13
6
0
(4R,5S)-5
(4R,5S)-5
(R)-2
(4R,5S)-5
(S)-1
(R)-2
(S)-3
(S)-4
(4R,5S)-5
Mg(ClO4)2
Cu(OTf)2
Cu(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
10
71
a
Typical reaction conditions: 1.0 equiv of substrate, 0.3 equiv of chiral Lewis
acid, 10.0 equiv of alkyl iodide, 3.0 equiv of Bu3SnH, and 2.0 equiv of Et3B were
employed.
b
Isolated yield; yield of recovered 6 in parentheses.
ees were determined using chiral HPLC.
* Corresponding author. Tel.: +65 6592 7765; fax: +65 6791 1961.
E-mail address: sgkim@ntu.edu.sg (S. Kim).
c
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.014

4948
J. Y. Lee et al. / Tetrahedron Letters 51 (2010) 4947–4949
Table 2
Table 4
Effect of solventa
Addition of alkyl radicals to a0-phenylsulfonyl enonea
5
20 mol% Zn(OTf)2, 5
n-Bu3SnH, Et3B/O2
Zn(OTf)2,
n-Bu3SnH, Et3B/O2
O
O
O
O
R'
PhO2S
PhO2S
PhO2S
PhO2S
R'
I
i-PrI
R
Ph
R
Ph
solvent, -78 o
C
Et2O, -78 oC, 12 h
7
6
10
11
Entry
Solvent
Time (h)
Yieldb (%)
eec (%)
Entry
R
R0
Yieldb (%)
72
ee (%)
1
2
3
4
CH2Cl2
THF
Toluene
Et2O
24
24
6
75 (10)
61 (27)
96
71
66
72
80
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Me
Me
Me
Me
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
Et
90
74
78
77
86
95
78
91
77
73
c-Hexyl
t-Bu
Et
89
94
83
94
91
88
92
91
85
12
92
i-Pr
a
Chiral Lewis acid 5 (30 mol %) used.
Isolated yield; yield of recovered 6 in parentheses.
ees were determined using chiral HPLC.
c-Hexyl
t-Bu
Et
i-Pr
t-Bu
b
c
10
and mesitylsulfonyl groups, the enantioselectivities dropped to
58% ee and 42% ee, respectively (entries 7 and 8). Although the t-
butylsulfonyl group was slightly better than the phenylsulfonyl
group in terms of the enantioselectivity, a0-phenylsulfonyl enone
6 was utilized to determine the scope of the present method due
to the synthetic utility of the phenylsulfonyl group relative to the
t-butylsulfonyl group.10
a
Typical reaction conditions: 1.0 equiv of substrate, 0.2 equiv of chiral Lewis
acid, 10.0 equiv of alkyl iodide, 3.0 equiv of n-Bu3SnH, and 2.0 equiv of Et3B were
used.
b
Isolated yield.
O
O
5% Na(Hg)
PhO2S
O
O
Ph
Ph
MeOH, -20 oC, 2 h
O
O
O
O
N
N
N
N
N
N
7
80% ee
12
[a]D20 = -30.4 (c 0.76 in CHCl )
t-Bu
t-Bu
Ph
Ph
3
2
1
=
3
reference -38.9 (c = 0.97 in CHCl3, 24 oC)
for S, 98% ee
O
O
O
O
Ph
Ph
N
N
N
N
Scheme 1. Absolute configuration.
Ph
Ph
4
5
To determine the scope and limitations of the present method,
the reaction was carried out with several structurally different a0
Si face
Ph
R'
-
phenylsulfonyl enones using the chiral Lewis acid (20 mol %) de-
rived from Zn(OTf)2 and ligand 5 in diethyl ether at ꢀ78 °C for
12 h. As shown in Table 4, conjugate addition reactions of 10 with
several alkyl iodides proceeded cleanly, yielding the addition prod-
ucts 11 in high yields. The enantioselectivities of the products ran-
ged from 73% to 95% ee, the highest being achieved when 10
(R = Me) was reacted with cyclohexyl iodide (entry 6). The size of
the alkyl radical did not have a large impact on the level of enanti-
oselectivity in the conjugate addition. Although the enantioselec-
O
N
O
Zn
N
O
O
S
O
Ph
Ph
Ph
Figure 1. Tetrahedral model for the catalyst-substrate complex.
tivities were not always very high, this method accommodates
primary, secondary, and tertiary alkyl radicals.
Table 3
The absolute stereochemistry was determined by converting 7
into known compound 12.11 Treatment of 7 with sodium amalgam
in MeOH at ꢀ20 °C for 2 h afforded 12 in 75% yield (Scheme 1).12
On the basis of the previously reported optical rotation, the stereo-
chemistry was assigned as S.11 Figure 1 shows a tentative model
which accommodates the observed facial selectivity, where Zn2+
occupies the center of the tetrahedral transition state.13 Two coor-
dination sites are occupied by two nitrogen atoms of the Box
ligand, and the remaining two sites accommodate the oxygen
atoms of the a0-phenylsulfonyl enone template. Due to the pres-
ence of a phenyl group at the 4-position in the ligand, the alkyl rad-
ical would approach from the Si face of the double bond.
Furthermore, it is assumed that the s-cis-conformation of a0-phen-
Modification of the a0-phenylsulfonyl enonea
5
Zn(OTf)2,
n-Bu3SnH, Et3B/O2
O
O
RO2S
RO2S
i-PrI
Ph
Ph
Et2O, -78 oC, 12 h
8
9
Entry
R
Yieldb (%)
ee (%)
1
2
3
4
5
6
7
8
9
Ph
CH3
t-Bu
p-Tolyl
4-Chlorophenyl
4-t-Butylphenyl
4-Biphenyl
Mesityl
92
71
87
80
61
85
84
60
72
58
42
69
88
58 (33)
91
87
76
84
ylsulfonyl enones could result from
p–p stabilization of the transi-
tion state.14
Naphthyl
a
In summary, the a0-phenylsulfonyl enone template has been
introduced to achieve an enantioselective conjugate radical addi-
tion process. Several alkyl radicals worked well, yielding the conju-
gate addition products in high yields and good enantioselectivities.
Typical reaction conditions: 1.0 equiv of substrate, 0.2 equiv of chiral Lewis
acid, 10.0 equiv of alkyl iodide, 3.0 equiv of Bu3SnH, and 2.0 equiv of Et3B were
used.
b
Isolated yield; recovered starting material in parentheses.

J. Y. Lee et al. / Tetrahedron Letters 51 (2010) 4947–4949
4949
Barroso, S.; Blay, G.; Al-Midfa, L.; Munoz, M. C.; Pedro, J. R. J. Org. Chem. 2008, 7,
6389.
Acknowledgments
9. Yang, H.; Kim, S. Synlett 2008, 555.
We thank the Korea Research Foundation (R01-2007-000-
21315-0) and the Nanyang Technological University for financial
support.
10. Typical procedure: Box ligand
5 (11 mg, 0.02 mmol) and Zn(OTf)2 (7 mg,
0.02 mmol) were dissolved in Et2O (1.0 mL) under N2. After being stirred at
room temperature for 45 min, an Et2O solution (2 mL) of a0-phenylsulfonyl
enone 6 (28 mg, 0.10 mmol) was added via cannula. The mixture was stirred
for 30 min, the reaction mixture was cooled down to ꢀ78 °C and then isopropyl
iodide (100
lL, 1.0 mmol), tributyltin hydride (83 lL, 0.30 mmol), and
References and notes
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