The first organocatalyst-mediated enantioselective substitution of racemic iodoalkanes under radical conditions

Article abstract of DOI:10.1016/j.tetasy.2008.10.031

We have demonstrated for the first time an organocatalyst-mediated enantioselective substitution of racemic iodoalkanes at either a tertiary or a secondary stereogenic center leading to the corresponding optically active products with a tertiary or a quat

Full text of DOI:10.1016/j.tetasy.2008.10.031

Tetrahedron: Asymmetry 19 (2008) 2479–2483
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The first organocatalyst-mediated enantioselective substitution
of racemic iodoalkanes under radical conditions
b
b
b
b
Masatoshi Murakata a,b, , Toshiaki Jono , Tetsuya Shoji , Akiko Moriya , Yoko Shirai
*
a Synthetic Technology Research Dept., Drug Engineering Div., Chugai Pharmceutical Co, Ltd, Kita-Ku, Tokyo 115-8543, Japan
b Faculty of Pharmaceutical Sciences, Science University of Tokyo, Shinjuku-Ku, Tokyo 162, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have demonstrated for the first time an organocatalyst-mediated enantioselective substitution of
racemic iodoalkanes at either a tertiary or a secondary stereogenic center leading to the corresponding
optically active products with a tertiary or a quaternary allylated stereogenic center under radical
conditions.
Received 30 September 2008
Accepted 27 October 2008
Available online 29 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
racemic 3-iodo-3,4-dihydrocoumarins 1 with allyltributylstann-
ane.5 The enantioselectivity in this reaction is ascribed to coordina-
Asymmetric induction in radical reactions has been a focus in
synthetic organic chemistry over the last few decades.1 There have
been reports of a number of stereoselective radical reactions, some
of which have led to the establishment of optically active prod-
ucts.2 However, there were no reports concerning asymmetric
induction in organocatalyst-mediated radical reactions, until we
reported the enantioselective allylation of some racemic precur-
sors under radical conditions in the presence of an organocatalyst.3
In principle, radical reactions proceed under neutral conditions
without the requirement of any metallic catalysts serving as a
Lewis acid or a Lewis base, which were previously used in enantio-
selective radical reactions. We, therefore, explored a radical meth-
od allowing introduction of tertiary and quaternary stereogenic
centers in an enantioselective manner by using a chiral organocat-
alyst in place of a metallic catalyst, in order to extend radical meth-
ods of enantiocontrolled synthesis.4 In this paper, we report our
finding that the expected enantioselective reaction took place
when a racemic iodoalkane was allylated under radical conditions
in the presence of a chiral organocatalyst having a Bronsted acidic
nature to give rise to the optically active products carrying either a
tertiary or a quaternary stereogenic center. Herein, we also report
this first example of an organocatalyst-mediated enantioselective
radical allylation in detail.
tion between the carbonyl oxygen of the radical intermediates
generated from the racemic 1 and the chiral Lewis acid, which
endows chirality to the prochiral radical center (Fig. 1a). If we
use a catalyst which is presumed to be capable of allowing
hydrogen bonding at the appropriate center(s), a similar effect to
that brought about by Lewis acid coordination may be expected
(Fig. 1b).6 Thus, we sought a chiral organic molecule capable of
hydrogen bonding under the radical allylation conditions of the
prochiral radical intermediates, using the racemic 3-iodo-3,4-dihy-
drocoumarin derivatives 1a–d as substrates (Scheme 1, Fig. 2).
a: coordination to Lewis acid
I
X
X
O
O
O
O
Me Al
1
*
b
: hydrogen bonding
X
X
H
H
*
O
O
H
H
O
O
2. Results and discussion
*
Figure 1. Radicals complexed with chiral compounds.
We have already established a chiral Lewis acid-mediated enan-
tioselective allylation via a prochiral radical center generated from
We chose five C2-symmetric chiral molecules 3a–e carrying
two active hydrogens as the organic catalysts so as to form the
hydrogen bonding required for chiral induction.7 Thus, in each
reaction, a 1.2 M excess of catalyst was present, together with
1.0 M equiv of dihydrocoumarin substrates 1a–d, allyltributyltin,
* Corresponding author at present address: Synthetic Technology Research Dept.,
Drug Engineering Div., Chugai Pharmceutical Co, Ltd, Kita-Ku, Tokyo 115-8543,
Japan. Fax: +81 3 3968 8340.
E-mail address: murakatamst@chugai-pharm.co.jp (M. Murakata).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.031

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M. Murakata et al. / Tetrahedron: Asymmetry 19 (2008) 2479–2483
Table 1
Enantioselective allylations of iododihydrocoumarins 1 to generate 2 under radical
I
conditions in the presence of oraganocatalysts 3a
R
O
organocatalyst 3
R
O
Entry
Substrate 1
Organocatalyst 3
Solvent
Product 2
ee
(%)
Confign
yieldb (%)
allyltributylstannane
Et3B
solvent
O
O
1
2
3
4
5
1a
1a
1a
1c
1a
1a
1a
1b
1c
1a
1a
1d
3a
3b
3c
3c
3d
3e
3e
3e
3e
3e
3e
3e
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
CH2Cl2
71
72
72
75
68
75
71
77
68
69
50
63
0
4
—
1
2
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
a: R = CH2OMe
b: R = CH2OEt
c: R = CH2OBn
15
10
1
30
29
16
11
11
6
6
d:
R =H
7c
8
Scheme 1. Enantioselective allylations of 1 under radical conditions in the presence
of organocatalysts 3.
9
10
11d
12
20
a
SiPh3
1.2 equiv of catalysts were used (3:1 = 1.2:1). All reactions were carried out by
using 1.0 equiv each of allyltributyltin and Et3B for a substrate at ꢀ78 °C, unless
otherwise noted.
OH
OH
OH
OH
b
Isolated yield.
c
The reaction was carried out by using 3.0 equiv of allyltributyltin.
d
Reaction was carried out at ꢀ50 °C.
SiPh3
Ph
3b
3a
Encouraged by these findings, and to improve the chiral induc-
tion ratio we further examined the reaction of 1a using other
organocatalysts 3d and e. Among these, the best result was ob-
tained when the reaction was carried out in the presence of a
1.2 M equiv of the bistrifluorosulfonamide-substituted binapthyl
3e (entry 6) though the enantioselectivity of 2a attained (at best
30% ee) was still less than satisfactory. It is noteworthy that the
use of an excess of allyltributyltin (3 equiv) did not affect either
chemical yield or enantioselectivity (entry 7), which seemed to
support a hydrogen bonding mechanism (Fig. 1b); in the absence
of such a mechanism, a reduced enantiomeric excess would be
expected.11
Ph
CF3CH2SO2HN
Ph
Ph
NHSO2CH2CF3
CF3SO2HN
NHSO2CF3
3c
3d
NHSO2CF3
NHSO2CF3
3e
The same catalyst also brought about chiral induction when
both the ethyl analogue 1b and the benzyl analogue 1c were trea-
ted under the same conditions to give the corresponding optically
active products 2b and 2c, although both were obtained with lower
enantioselectivity than 1a (entries 8 and 9). On the other hand,
organocatalyst 3d, a one-carbon homologue of 3c, was found to
bring about chiral induction under the same conditions. However,
it could not compete with the corresponding nor-analogue 3c,
either in chemical yield or in enantiomeric excess (entries 5). These
findings indicate that the homologation prevented the formation of
the favorable hydrogen bonding (Fig. 1b) by increasing steric con-
gestion of both the substrates and the catalyst and by diminishing
the amide acidity of the catalysts.
Owing to the insolubility of the organocatalyst 3e, the reaction
could not be fully examined in toluene, although tighter hydrogen
bonding leading to better enantiomeric induction would be ex-
pected in this solvent (Fig. 1b) (entries 10 and 11).
The present method was also found to be promising for the
enantiocontrolled construction of a tertiary stereogenic center.
Thus, the secondary iodide 1d treated under the same conditions
as for 1a in the presence of the organocatalyst 3e afforded product
2d with a tertiary stereogenic center in 63% yield with chiral induc-
tion of 20% ee (entry 12).
Figure 2. Structures of organocatalysts 3.
and the radical initiator triethylborane.8 The results are summa-
rized in Table 1.
The reaction was first examined using two BINOL derivatives
3a,b as organocatalysts. The reaction of the substrate iodide 1a
with (R)-triphenylsilyl BINOL 3a, [the Al(III) complex of which gen-
erates 2a with high enantioselectivity5a] exhibited no enantiose-
lective induction in CH2Cl2 at ꢀ78 °C, although the expected
transformation proceeded to give the racemic quaternary allyla-
tion product 2a in satisfactory yield (entry 1). However, when
(R)-BINOL 3b was used under the same conditions, the expected
chiral induction took place to give optically active 2a in 72% yield,
which was found to be a 4% ee (entry 2). The reaction in the pres-
ence of sulfonamides 3c–e was examined next.9 When bis-trifluo-
romethylsulfonamide 3c was present in the reaction of 1a in
CH2Cl2 at ꢀ78 °C, the chiral induction ratio was increased to give
product 2a in 72% yield with 15% ee (entry 3). Under the same con-
ditions, benzyl ether 1c afforded the expected product 2c in 75%
yield with 10% ee (entry 4). The enantiomeric induction ratios
observed with these two reactions were too low to be of practical
use. However, these should be noted as the first instances
involving not only organocatalyst-mediated asymmetric induction,
but also the generation of a prochiral radical stereogenic center
directly from a racemic halogeno-carbon stereogenic center.10
Although some organocatalyst-mediated enantioselective radical
reactions have been reported since our findings, no chiral
induction reaction at the racemic stereogenic center via a prochiral
radical intermediate has been reported to date.
It is known that borane species derived from triethylborane
during the reaction act as Lewis acids.12 Thus, chiral borane species
could have been generated under the present radical conditions by
the reaction with chiral organocatalysts 3 present in the reaction
medium. We therefore examined the organocatalyst-mediated
reaction using AIBN as the radical initiator under photolysis condi-
tions in place of using the boron radical initiator, to alleviate the
possibility of the generation of a boron complex serving as a Lewis

M. Murakata et al. / Tetrahedron: Asymmetry 19 (2008) 2479–2483
2481
acid. Thus, both 1a and 1c were reacted with allyltributylstannane
in the presence of AIBN and the organocatalyst 3 under irradiation
using a mercury lamp in CH2Cl2 at ꢀ78 °C. The expected reaction
occurred to give the allylated products, 2a with 23% ee from 1a
with 3e, and 2c with 8% ee from 1c with 3c, respectively. Since
the enantioselectivities observed were comparable to those
observed by using triethylborane (entries 4 and 6), it can be
concluded that the boron radical initiator does not participate in
the enantiocontrol (Scheme 2).
tion of 2d to determine the absolute configuration of the latter as
(S) (Scheme 3).
3. Conclusion
In conclusion, we have demonstrated an enantioselective allyla-
tion reaction which formed quaternary and tertiary stereogenic
centers through generation of prochiral radical centers starting
from a corresponding racemic iodo-alkane precursor in the pres-
ence of an optically active organocatalyst having Bronsted acidic
nature. Although the enantioselectivity attained is still too low to
be of practical use, the demonstration of the present reaction
which allows the enantioselective modification of a tertiary and a
quaternary prochiral radical center is noteworthy and promising
for its future use in radical chemistry.
I
R
O
organocatalyst 3
R
O
allyltributylstannane
AIBN, mercury lamp
CH2Cl2 –78 ºC
O
O
1
2
4. Experimental
4.1. General
a: R = CH2OMe
c: R = CH2OBn
Scheme 2. Photochemical enantioselective organocatalyst-mediated allylations of
1 using 3.
All melting points were measured on a Yanagimoto (hot plate)
melting point apparatus, and are uncorrected. IR spectra were
obtained with a Horiba FT-210 spectrophotometer or a JASCO FT/
IR-410 spectrophotometer. 1H NMR (270 MHz, 400 MHz or
500 MHz) and 13C NMR (67.5 MHz, 100 MHz or 125 MHz) spectra
were recorded with a JEOL EX 270 spectrometer, a JEOL JNM-
LA400 spectrometer or a JEOL JNM-LA500 spectrometer in CDCl3
solution using tetramethylsilane as an internal standard, unless
otherwise noted. Mass spectra were measured on a JEOL JMS-
SX102A spectrometer. Specific rotation was measured on a JASCO
P-1030 digital polarimeter. The enantiomeric excess (ee) of 2 and
9 was determined by HPLC analysis using chiral columns (DAICEL).
Column chromatography was performed on silica gel. Thin-layer
chromatography was carried out on precoated (0.2 mm) Merck
Silica Gel F-254 plates. Photochemical reactions were performed
by using micro photochemical reaction assembly (Sigma–Aldrich).
The absolute configuration of the optically active product with a
tertiary stereogenic center 2d was determined by correlation with
(S)-propyldihydrocoumarin 9, which was prepared from (R)-2-
benzyl-3-hydroxypropyl acetate 413 as follows: compound (R)-4
was first converted into tosyloxypropyl acetate 5 whose tosyloxy
group was next replaced by an ethyl group using a cuprate reagent,
to give 2-benzylpentanol 6 after deacetylation. Jones oxidation of 6
gave carboxylic acid 7, which after transformation into the acid
chloride was subjected to a Friedel–Crafts reaction to readily yield
indanone 8, though some racemization occurred. Baeyer–Villiger
oxidation of 8 with m-CPBA proceeded regioselectively to afford
(S)-3-propyl-3,4-dihydrocoumarin 9 whose enantiomeric purity
was determined to be 61% ee by HPLC analysis. This compound
was compared with product 9 generated by catalytic hydrogena-
TsCl
DMAP
TsO
Bn
HO
Bn
Et3N
AcO
AcO
CH2Cl2
rt, 98%
5
(R)-4
Et
Et
Bn
CrO3–H2SO4
Et2CuLi
Et2O
– 40 ºC, 76%
Bn
HO
acetone
0 ºC, 56%
HO
O
6
7
i) (COCl)2, DMF (cat.)
CH2Cl2, 0 ºC
Pr
ii) AlCl3, CH2Cl2
0 ºC, 83%
O
8
Pr
O
Pd-C / H2
m-CPBA
EtOH
rt, 97%
CH2Cl2
reflux, 65%
O
O
O
9
(S)-
2d
(S)-
Scheme 3. Determination of the absolute configuration of 2d.

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M. Murakata et al. / Tetrahedron: Asymmetry 19 (2008) 2479–2483
4.2. Preparation of 3-iodo-3,4-dihydrocoumarins 1a–d and
organocatalysts 3a–e
2848, 1770, 1643, 1615, 1589, 1147 cmꢀ1. MS m/z 188 (M+); HRMS
calcd for C12H12O2 188.0836 (M+), found 188.0827 (M+).
3-Iodo-3,4-dihydrocoumarins 1a–c and organocatalysts 3a, c–e
were prepared according to the method described in the
literature.5,8
(R)-BINOL 3b was obtained from commercial sources and used
without further purification.
4.3.2. Enantioselective allylations by photochemical reactions
(without triethylborane)
Compound (S)-2a. A solution of ( )-3-iodo-3-methoxymethyldi-
hydrocoumarin 1a (31.8 mg, 0.1 mmol) and organocatalyst (R)-3e
(65.8 mg, 0.12 mmol) in CH2Cl2 (4 mL) was cooled to ꢀ78 °C, and
the mixture was stirred for 30 min at ꢀ78 °C. Allyltributyltin
4.2.1. 3-Iodo-3,4-dihydrocoumarin 1d
(31 lL, 0.1 mmol) and AIBN (7 mg, 0.04 mmol) were added succes-
Under an argon atmosphere, a solution of 3,4-dihydrocoumarin
(3 g, 20.3 mmol) in THF (30 mL) was added to a preformed solution
of LDA (22.3 mmol) in THF (50 mL) at ꢀ78 °C, and the mixture was
stirred for 30 min. This solution was added to a solution of I2 (7.7 g,
30.3 mmol) in THF (30 mL) at ꢀ78 °C, and the mixture was stirred
at the same temperature for 30 min. After the addition of 10% HCl,
the resulting solution was extracted with Et2O (100 mL ꢁ 2). The
organic layer was washed with water, 5% aqueous Na2S2O3, aque-
ous NaHCO3, and brine successively, and dried over MgSO4. Con-
centration followed by purification through silica gel column
chromatography (benzene) gave 1d (4.2 g, 76%). Colorless crystals:
mp 165–166 °C. 1H NMR (270 MHz) d 3.11 (1H, dd, J = 17.5, 2.7 Hz),
3.49 (1H, dd, J = 17.5, 4.4 Hz), 4.95 (1H, dd, J = 4.4, 2.7 Hz), 7.10–
7.20 (3H, m), 7.32–7.40 (1H, m). 13C NMR (67.5 MHz) d 12.6,
34.9, 116.8, 120.3, 125.0, 128.6, 129.0, 151.5, 165.0. IR (KBr)
3066, 2950, 1751, 1728, 1616, 1171 cmꢀ1. MS m/z 274 (M+); HRMS
calcd for C9H7IO2 273.9491 (M+), found 273.9499 (M+).
sively at ꢀ78 °C. The resulting solution was irradiated (5.5 W, mer-
cury lamp) at ꢀ78 °C for 2 h. Additional AIBN (7 mg, 0.04 mmol)
was added, and then the solution was irradiated (5.5 W, mercury
lamp) at ꢀ78 °C for 60 min. The solvent was removed under re-
duced pressure. Concentration followed by purification through
column chromatography (benzene) gave (S)-2a as colorless oil
[10.6 mg, 46%, 23% ee [HPLC: Chiralcel OD, hexane–2-propa-
nol = 50:1, flow rate 0.5 mL/min, Rt 17 min for (R)-isomer and
19 min for (S)-isomer)].
Compound (R)-2c. The reaction was carried out by the same
method described for (S)-2a using
a-iodo-a-benzyloxymethyldi-
hydrocoumarin 1c (39.7 mg, 0.1 mmol) and organocatalyst (S,S)-
3c (52.8 mg, 0.11 mmol) in CH2Cl2 (4 mL). The crude product was
purified by column chromatography (benzene) and gave (R)-2c as
a colorless oil [10.3 mg, 41%, 8% ee [HPLC: Chiralcel OJ, hexane–
2-propanol = 9:1, flow rate 1.0 mL/min, Rt 16 min for (S)-isomer
and 23 min for (R)-isomer)].
4.3. Enantioselective allylations
4.4. Determination of the absolute configuration of 2d
The ees and configurations of 2a–c were determined directly by
HPLC using a chiral column. Spectroscopic data were identical with
those for the products described in the literature.5a The ee of 2d
was determined directly by HPLC using Chiralcel OD. The configu-
ration was determined by chemical correlation with (S)-3-propyl-
3,4-dihydrocoumarin 9. See Scheme 3 for the determination of
the absolute configuration of 2d.
The absolute configuration of 2d was determined by chemical
correlation with (S)-3-propyldihydrocoumarin
9 as shown in
Scheme 3. Authentic (S)-9 was synthesized from (R)-2-benzyl-3-
hydroxypropyl acetate 4 {enantiomeric excess: 97%; [a]D = +28 (c
1.32, CHCl3)} prepared according to the literatures.13
4.4.1. (S)-2-Benzyl-3-toluenesulfonyloxypropyl acetate 5
Colorless solid. [
D = +4.8 (c 1.13, CHCl3). 1H NMR (270 MHz) d
a
]
4.3.1. Enantioselective allylations with triethylborane: typical
procedure
1.96 (3H, s), 2.22–2.32 (1H, m), 2.46 (3H, s), 2.64 (2H, dd, J = 7.6,
2.3 Hz), 3.89–5.30 (4H, m), 7.04–7.07 (2H, m), 7.19–7.28 (3H, m),
7.34 (2H, d, J = 8.3 Hz), 7.77 (2H, d, J = 8.3 Hz). 13C NMR
(67.5 MHz) d 20.7, 21.6, 33.9, 39.5, 63.0, 68.9, 126.6, 128.0, 128.6,
128.95, 129.86, 132.7, 138.0, 144.9, 177.6. IR (KBr) 3089, 3060,
3032, 2972, 2960, 2929, 2901, 2867, 1733, 1654, 1561,
A solution of ( )-3-iodo-3-methoxymethyldihydrocoumarin 1a
(31.8 mg, 0.1 mmol) and organocatalyst (R)-3e (65.8 mg,
0.12 mmol) in CH2Cl2 (2 mL) was cooled to ꢀ78 °C, and the mixture
was stirred for 30 min at ꢀ78 °C. Allyltributyltin (31
lL, 0.1 mmol)
and a solution of triethylborane in hexane (1 M: 0.1 mL, 0.1 mmol)
were added successively at ꢀ78 °C, and the mixture was allowed to
stand for 1 h at the same temperature. After the addition of AcOH
(0.1 mL) at ꢀ78 °C, the mixture was stirred for 1 h. H2O was added,
and the mixture was extracted with CH2Cl2 (20 mL ꢁ 2). The or-
ganic layer was washed with saturated aqueous NaHCO3 and brine
successively, and dried over MgSO4. After filtration, the solvent
was removed under reduced pressure. The residue was taken up
in MeCN. The mixture was washed with hexane. Concentration fol-
lowed by purification through column chromatography (benzene)
gave (S)-2a as colorless oil [17.4 mg, 75%, 30% ee (HPLC: Chiralcel
OD, hexane–2-propanol = 50:1, flow rate 0.5 mL/min, Rt 16 min
for (R)-isomer and 18 min for (S)-isomer)].
1544 cmꢀ1 MS m/z 363 (M+); HRMS calcd for C19H23O5S
.
363.1266 (M+), found 363.1259 (M+).
4.4.2. (S)-2-Benzylpentanol 6
Colorless oil: bp 145–155 °C/2 mm Hg (bulb-to-bulb distilla-
tion). [
a
]
D = ꢀ9.9 (c 1.09, MeOH). 1H NMR (270 MHz) d 0.90 (3H,
t, J = 6.9 Hz), 1.25–1.46 (4H, m), 1.74–1.88 (1H, m), 2.63 (2H, d,
J = 7.3 Hz), 3.52 (2H, d, J = 5.0 Hz), 7.17–7.21 (3H, m), 7.27–7.31
(2H, m). 13C NMR (67.5 MHz) d 14.3, 20.1, 33.1, 37.7, 42.4, 64.9,
125.8, 128.3, 129.2, 140.9. IR (NaCl) 3349, 3085, 3062, 3025,
2958, 2927, 2869, 1603 cmꢀ1. MS m/z 178 (M+); HRMS calcd for
C12H18O 178.1357 (M+), found 178.1362 (M+).
(S)-2d. Colorless oil: bp 130–150 °C/1.5 mmHg (bulb-to-bulb
4.4.3. (S)-2-Benzylpentanoic acid 7
distillation). ½a D23
ꢂ
¼ þ11:4 (c 1.47, CHCl3); 20% ee (HPLC: Chiralcel
Colorless oil. [a]
D = +19.5 (c 2.21, c-hexane). 1H NMR (270 MHz)
OD, hexane–2-propanol = 50:1, flow rate 0.5 mL/min, Rt 20 min
for (R)-isomer and 22 min for (S)-isomer)]. 1H NMR (270 MHz) d
2.30–2.41 (1H, m), 2.66–2.87 (3H, m), 2.93–3.07 (1H, m), 5.10–
5.17 (2H, m), 5.77–5.92 (1H, m), 7.02–7.28 (4H, m). 13C NMR
(67.5 MHz) d 28.6, 33.9, 38.7, 116.6, 118.2, 122.5, 124.3, 128.1,
128.2, 134.3, 151.6, 170.4. IR (NaCl) 3078, 3014, 2980, 2920,
d 0.90 (3H, t, J = 7.1 Hz), 1.28–1.71 (4H, m), 2.62–2.70 (1H, m), 2.75
(1H, dd, J = 13.2, 6.9 Hz), 2.97 (1H, dd, J = 13.2, 7.6 Hz), 7.16–7.31
(5H, m). 13C NMR (67.5 MHz) d 13.9, 20.4, 33.9, 38.1, 47.2, 126.4,
128.4, 128.9, 139.2, 182.1. IR (NaCl) 3366, 3028, 2960, 2926,
2871, 1705, 1603 cmꢀ1
.
MS m/z 192 (M+); HRMS calcd for
C12H16O2 192.1149 (M+), found 192.1140 (M+).

M. Murakata et al. / Tetrahedron: Asymmetry 19 (2008) 2479–2483
2483
Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH:
Weinheim, 1995; (d) Haslam, E. Shikimic Acid Metabolism and Metabolites; John
Wiley & Sons: New York, 1993.
4.4.4. (S)-2-Propylindanone 8
Colorless oil: bp 140–150 °C/4 mm Hg (bulb-to-bulb distilla-
tion). [a]
D = +32.5 (c 0.71, benzene). 1H NMR (270 MHz) d 0.96
2. Recent reviews including enantioselective radical reactions, see: (a) Renaud, P.;
Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562–2579; (b) Sibi, M. P.; Porter, N.
A. Acc. Chem. Res. 1999, 32, 163–171; (c) Radicals in Organic Synthesis; Renaud,
P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001.
3. Preliminary results of the present paper were presented at the 122th Annual
Meetings of the Pharmaceutical Society of Japan, Chiba, Japan, 2002, see,
Proceedings of these meetings, 2002, p 99. All reactions described in this article
were carried out in the Science University of Tokyo.
4. Diastereocontrol under radical conditions using an organocatalyst has been
reported, see: (a) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259–3261; For
recent examples of enantioselective reaction in the presence of organocatalysts
under radical conditions, see: (b) Aechtner, T.; Dressel, M.; Bach, T. Angew.
Chem., Int. Ed. 2004, 43, 5849–5851; Bauer, A.; Westkaemper, F.; Grimme, S.;
Bach, T. Nature 2005, 436, 1139–1140; Dressel, M.; Aechtner, T.; Bach, T.
Synthesis 2006, 2206–2214; Cho, D. H.; Jang, D. O. Chem. Commun. 2006, 5045–
5047; Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124–4125; Beeson,
T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007,
316, 582–585.
5. (a) Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O. J. Am. Chem. Soc. 1997, 119,
11713–11714; (b) Murakata, M.; Jono, T.; Hoshino, O. Tetrahedron: Asymmetry
1998, 9, 2087–2092.
6. For a pertinent review of chiral hydrogen-bond donors, see: Taylor, M. S.;
Jacobsen, E. L. Angew. Chem., Int. Ed. 2006, 45, 1520–1543.
7. Although it was found that the chiral molecules were required in more than a
stoichiometric amount to induce the enantioselectivity effectively, we use the
term ‘catalyst’ or ‘organocatalyst’ for each of these compounds as an external
substance that leads a substrate to a particular product without changing
itself.
(3H, t, J = 7.1 Hz), 1.39–1.54 (3H, m), 1.83–2.01 (1H, m), 2.61–
2.72 (1H, m), 2.81 (1H, dd, J = 17.2, 3.8 Hz), 3.31 (1H, dd, J = 17.2,
7.9 Hz), 7.33–7.76 (4H, m). 13C NMR (67.5 MHz) d 14.1, 20.7,
32.9, 33.6, 47.3, 123.9, 126.5, 127.3, 134.6, 136.9, 153.8, 209.1. IR
(NaCl) 3072, 2961, 2928, 2870, 1712, 1609, 1589 cmꢀ1. MS m/z
174 (M+); HRMS calcd for C12H14
174.1047 (M+).
O
174.1045 (M+), found
4.4.5. (S)-3-Propyldihydrocoumarin 9
Colorless oil: bp 140–150 °C/3 mm Hg (bulb-to-bulb distilla-
tion). [
D = ꢀ12.4 (c 1.25, CHCl3); 61% ee (HPLC: Chiralcel OD, hex-
a]
ane–2-propanol = 50:1, flow rate 0.5 mL/min, Rt 18 min for (R)-
isomer and 20 min for (S)-isomer)]. 1H NMR (270 MHz) d 0.95
(3H, t, J = 7.1 Hz), 1.41–1.62 (3H, m), 1.84–1.96 (1H, m), 2.64–
2.84 (2H, m), 3.03 (1H, dd, J = 15.1, 5.3 Hz), 7.00–7.11 (2H, m),
7.16–7.26 (2H, m). 13C NMR (125 MHz) d 13.8, 20.0, 29.2, 31.8,
38.9, 116.5, 122.6, 124.2, 128.1, 128.2, 151.6, 171.0. IR (NaCl)
3043, 2960, 2930, 2871, 1769, 1724, 1615, 1589 cmꢀ1. MS m/z
190 (M+); HRMS calcd for C12H14O2 190.0992 (M+), found
190.0980 (M+).
8. Organocatalysts 3a, c–e were prepared according to the method described in
the literature. For 3a, see: (a) Maruoka, K.; Itoh, T.; Araki, Y.; Shirasaka, T.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 1988, 61, 2975–2976; For 3c, see: (b) Corey,
E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc. 1989, 111, 5493–
5495; (c) Corey, E. J.; Sarshar, S. J. Am. Chem. Soc. 1992, 114, 7938–7939. and
references cited therein; For 3d, see: Ref. 5b. For 3e, see: (d) Shi, M.; Sui, W.-S.
Chirality 2000, 12, 574–580 (R)-BINOL 3b was obtained from commercial
sources and was used without further purification.
9. These chiral sulfonamides gave moderate enantiomeric excess in the
enantioselective allylations catalyzed by an aluminum reagent, see: Ref. 5b.
10. After this observation, some organocatalyst-mediated enantioselective radical
syntheses have appeared, but they did not intervene in a prochiral radical
4.4.6. Conversion of (S)-3-allyldihydrocoumarin 2d into (S)-3-
propyldihydrocoumarin 9
A solution of (S)-2d (obtained by enatioselective allylation; 20%
ee; 9.4 mg, 0.05 mmol) in EtOH (3 mL) was hydrogenated over 10%
Pd–C (10 mg) under H2 (1 atm) at room temperature for 3 h. After
filtration, the solvent was removed under reduced pressure to give
(S)-9 as a colorless oil [9.2 mg, 97%, 20% ee (HPLC: Chiralcel OD,
hexane–2-propanol = 50:1, flow rate 0.5 mL/min, Rt 18 min for
(R)-isomer and 20 min for (S)-isomer)]. Spectroscopic data were
identical with those for the product (S)-9 obtained from (R)-2-
benzyl-3-hydroxypropyl acetate 4.
stereogenic center directly generated from
a racemic halogeno-carbon
stereogenic center, see: Ref. 4b.
11. The enantioselectivity would decrease under excess tin reagent conditions
when chiral tin reagents, formed by coordination of (R)-3e, are responsible for
enantioselection, because achiral tin exists much more in stoichiometric
conditions. However, the enantioselectivity in entry 7 strongly indicates that
chiral tin reagents did not produce and/or influence the asymmetric induction
in this system.
12. Recent example of radical reactions in which triethylborane displays Lewis
acidity, see: Devin, P.; Fensterbank, L.; Malacria, M. Tetrahedron Lett. 1999, 40,
5511–5514 and references cited therein.
Acknowledgment
M.M. thanks Dr. Kunio Ogasawara, Professor Emeritus, Tohoku
University, for helpful disscussion for preparing the manuscript.
References
13. (R)-2-Benzyl-3-hydroxypropyl acetate
4 was prepared by use of lipase-
mediated transesterification according to the literatures Tsuji, K.; Terao, Y.;
Achiwa, K. Tetrahedron Lett. 1989, 30, 6189–6192; lipase-mediated hydrolysis:
Mori, K.; Chiba, N. Liebigs Ann. Chem. 1989, 957–962.
1. For reviews of asymmetric radical reactions: (a) Porter, N. A.; Giese, B.; Curran,
D. P. Acc. Chem. Res. 1991, 24, 296–304; (b) Smadja, W. Synlett 1994, 1–26; (c)