Substituent effect on the diastereoselectivity in the chelation-controlled radical reactions of γ-(p-substituted-benzyloxy)-α-methylene esters with alkyl iodides

Article abstract of DOI:10.1016/j.tet.2004.05.020

A pronounced substituent effect on the diastereoselectivity in the chelation controlled radical reactions of ethyl γ-(p-substituted- benzyloxy)-α-methylenecarboxylates with alkyl iodides was observed. The syn-selectivity increased in the order of electron-donating ability NO ₂31H NMR spectroscopy and the competition experiments between p-isopropylbenzyloxy and p-trifluoromethylbenzyloxy esters showed that the electron-donating p-isopropyl group stabilized the seven-membered chelate ring to give high syn-selectivity.

Full text of DOI:10.1016/j.tet.2004.05.020

Tetrahedron 60 (2004) 5683–5693
Substituent effect on the diastereoselectivity in the
chelation-controlled radical reactions of
g-(p-substituted-benzyloxy)-a-methylene esters with alkyl iodides
*
Tomoko Yajima, Kyoko Okada and Hajime Nagano
Department of Chemistry, Faculty of Science, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
Received 23 April 2004; revised 12 May 2004; accepted 13 May 2004
Abstract—A pronounced substituent effect on the diastereoselectivity in the chelation controlled radical reactions of ethyl g-(p-substituted-
benzyloxy)-a-methylenecarboxylates with alkyl iodides was observed. The syn-selectivity increased in the order of electron-donating ability
NO2,CN,CF3,F,H,i-Pr, Me, OMe of the p-substituent, and the plot of the log(syn/anti) versus Hammett sigma constants gave a linear
correlation. The complexation experiments of the substrates with Lewis acid using 1H NMR spectroscopy and the competition experiments
between p-isopropylbenzyloxy and p-trifluoromethylbenzyloxy esters showed that the electron-donating p-isopropyl group stabilized the
seven-membered chelate ring to give high syn-selectivity.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
sponding g-hydroxy, g-methoxy, g-methoxymethoxy and
g-methoxyethoxy esters (R2¼H, Me, MOM, MEM). Based
on the conformational analysis of the radical intermediates
obtained by combining CONFLEX and PM3 calculations,5
we have revealed that the high syn-selectivity is referred to
the H-atom transfer to the outside face of radical center in
the sharply folded seven-membered chelate inter-
mediates.4c,d,6,7 In order to realize much higher diastereo-
selectivity in the radical reactions of g-benzyloxy esters, we
investigated the effect of p-substituent on the g-benzyloxy
group.
During the past decade the stereochemical control of acyclic
radical reactions has received considerable attention and
significant levels of diastereoselectivity in reactions involv-
ing stereogenic center adjacent to the radical center (1,2-
asymmetric induction) have been achieved.1 The use of
mono- or bidentate Lewis acids expanded the scope of the
stereoselective reactions.2 However, to our knowledge, little
is known about radical mediated 1,3-asymmetric induction.3
We have recently reported the chelation-controlled 1,3-
asymmetric induction in the radical mediated additions to
a-methylene-g-oxycarboxylic acid esters (Scheme 1).4 The
radical reactions of g-benzyloxy esters (R2¼Bn) with alkyl
iodides performed in the presence of MgBr2·OEt2 showed
higher syn-selectivities compared to those of the corre-
We report herein the substituent effect on the diastereo-
selectivity in the chelation controlled alkyl radical addition
to g-(p-substituted-benzyloxy)-a-methylenecarboxylic acid
esters 3–12. This work also includes experimental evidence
for the origin of the substituent effect.
Scheme 1. Radical reactions of ethyl a-methylene-g-oxycarboxylates with alkyl iodides.
Keywords: Radical reaction; 1,3-Asymmetric induction; Substituent effect; Seven-membered chelation.
*
Corresponding author. Tel.: þ81-3-5978-5348; fax: þ81-3-5978-5715; e-mail address: nagano@cc.ocha.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.020

5684
T. Yajima et al. / Tetrahedron 60 (2004) 5683–5693
Scheme 2.
2. Results and discussion
The results of the radical reactions of g-(p-substituted-
benzyloxy)-a-methylene esters 3–12, which were prepared
by the benzylation of alcohols 14a and 24b with p-substituted
benzyl bromides (Scheme 2), are shown in Table 1. All the
reactions gave good yields except for the reaction of
p-nitrobenzyloxy ester 3 (entry 1) and the diastereo-
selectivities were strongly affected by the benzyloxy
substituents. In the reactions with isopropyl iodide, the
syn-selectivity increased in the order of electron-donating
ability NO2,CN,CF3,F,H,i-Pr, Me, OMe of the
p-substituent (entries 1–8). The plot of the log(syn/anti)
versus Hammett sigma constants8,9 gave a linear correlation
(r 2¼0.94) with a negative slope r¼21.06 (Fig. 1). A
similar tendency was observed in the reactions with ethyl
iodide (entries 9–15) and the Hammett plot also showed a
Figure 1. Plot of log(syn/anti) values versus Hammett sigma constants for
the ethyl and isopropyl radical additions to 3–10.
linear correlation (r 2¼0.92, r¼21.00). Furthermore, in the
reactions with methyl and tert-butyl radicals, the introduc-
tion of an electron-donating methyl group at the p-position
enhanced syn-selectivities, however the increment of
selectivity in the tert-butyl radical additions was smaller
than those in the reaction with methyl, ethyl and isopropyl
radicals (entries 16–19). The reactions of aliphatic substrate
12 with isopropyl and tert-butyl iodides showed that
p-methyl substituent enhanced the syn-selectivities (entries
20–23). The lower syn-selectivity in the addition of methyl
radical (entries 16 and 17) compared to the diastereo-
selectivities of the corresponding reactions with isopropyl
and ethyl radicals (entries 5, 7, 12 and 14) has been
explained by the conformational analysis of the seven-
membered chelate intermediate, in which the ethoxy group
of ester moiety with E-geometry shields the outside face of
radical center.4d,10 In the addition of tert-butyl radical
(entries 18, 19, 22 and 23), however, the neopentyl group
shields the outside face of radical center and consequently
lowers the syn-selectivity.4d,10
Table 1. Radical reactions of 3–12 with alkyl iodides R2I in the presence of
MgBr2·OEt2
a
Entry Substrate R1
X
R2
Product Yield (%) syn/antib
1
2
3
3
4
5
6
7
8
9
10
4
5
6
7
8
9
10
7
9
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
i-Pr
NO2 i-Pr 13
36
84
85
87
86
94
86
67
63
97
85
82
94
77
63
71
71
85
77
75
71
67
78
1.6:1
2.0:1
6.0:1
13:1
CN
CF3
F
H
i-Pr
Me
i-Pr 14
i-Pr 15
i-Pr 16
i-Pr 17
i-Pr 18
i-Pr 19
4
5c
6
15:1
.20:1
.20:1
.20:1
1.4:1
2.7:1
3.9:1
6.8:1
12:1
7
8
9
OMe i-Pr 20
CN
CF3
F
H
i-Pr
Me
OMe Et
H
Me
H
Me
H
Et
Et
Et
Et
Et
Et
21
22
23
24
25
26
27
28
29
10
11
12
13
14
15
16
17
18
19
20
21
22
23
12:1
13:1
Me
Me
3.0:1
5.0:1
3.6:1
4.0:1
11:1
.20:1
3.7:1
5.0:1
t-Bu 30
t-Bu 31
i-Pr 32
i-Pr 33
t-Bu 34
t-Bu 35
9
The reactions would proceed through complexed radical
intermediates A and B and non-complexed radical inter-
mediate C being in equilibrium (Scheme 3). The seven-
membered chelate intermediate A gives syn-product
predominantly,4d while the intermediate B formed by
monodentate coordination to the carbonyl oxygen atom
11
12
11
12
i-Pr Me
i-Pr
i-Pr Me
H
Reaction conditions: R2I (3 equiv.), n-Bu3SnH (2 equiv.), Et3B (1 equiv.),
MgBr2·OEt2 (3 equiv.), CH2Cl2, 0 8C.
For entries 5 and 18, see Ref. 4d; for entries 20 and 22, see Ref. 4e.
a
and non-chelation intermediate
C
give syn/anti
b
mixtures without stereoselectivity. The electron-donating
substituents, i-Pr, Me and OMe, stabilize the seven-
membered chelate ring and give a large population of
chelate intermediate A. The p-substituents remote from the
chelate ring would not affect the ring structure of
intermediate A.
The stereochemistries of the products 13–16, 18–29 and 31 were
determined by comparing their chemical shift values with those of 17 and
30.4d The stereochemistries of the products 33 and 35 were determined by
comparing their chemical shift values with those of 32 and 34.4e
c
Without Lewis acid, 35% yield and diastereomer ratio syn/anti¼1:1.2.
Use of BF3·OEt2 (1 equiv.) instead of MgBr2·OEt2 gave 82% yield and
diastereomer ratio syn/anti¼1.2:1.

T. Yajima et al. / Tetrahedron 60 (2004) 5683–5693
5685
Figure 2. Plot of log(syn/anti) versus Dd values [dH(substrateþMgBr2·
OEt2)2dH(substrate)] of benzyl proton for the ethyl and isopropyl radical
additions to 5–10.
of 5 (0.5 equiv.) and 8 (0.5 equiv.) with isopropyl iodide
(0.5 equiv.), n-Bu3SnH (1 equiv.) and Et3B (1 equiv.) were
carried out in the presence of Lewis acid, MgBr2·OEt2
(3 equiv.) or BF3·OEt2 (1 equiv.), and in the absence of
Lewis acid. The unreacted substrates 5 and 8 were recovered
and their ratios were obtained by integrating 1H NMR
signals. The substrates 5 and 8 showed equal reactivity in
the absence of Lewis acid. The complexation with Lewis
acids would lower the LUMO energy of the substrates and
enhance the rate of the nucleophilic alkyl radical addition
reactions.12 Monodentate Lewis acid, BF3·OEt2, coordinat-
ing to the carbonyl oxygen of the substrates 5 and 8,
enhanced the reactivity of both the substrates equally, but
did not affect their diastereoselectivities (see, footnote c in
Table 1). In the presence of MgBr2·OEt2, however, substrate
8 reacted faster than 5. The higher reactivity and higher syn-
selectivity as well (Table 1, entries 3 and 6) of 8 represent
the more efficient chelation of the p-isopropylbenzyloxy
group with MgBr2·OEt2 compared to p-trifluoromethyl-
benzyloxy group.
Scheme 3. Reaction pathways.
In order to gain insight into the chelate ring stability, we
carried out complexation experiments of substrates 5–10
with MgBr2·OEt2 using 1H NMR spectroscopy.11 The
complexation of the substrate with 3 equiv. of MgBr2·OEt2
in CDCl3 was achieved by sonication at room temperature
for 1 h.4d The Dd values [dH(substrateþMgBr2·OEt2)2
dH(substrate)] of 5–10 are shown in Table 2. The chemical
shift increments Dd by adding the Lewis acid and in
particular, the large difference of chemical shift increments
between the diastereotopic b-methylene protons suggest the
formation of bidentate complex. Figure 2 shows a plot of
log(syn/anti) values in the ethyl and isopropyl radical
additions to 5–10 versus Dd values of one of the benzyl
protons affording larger one. The increase of Dd values with
increasing the electron-donating ability CF3,F,H,i-Pr,
Me, OMe of the p-substituent suggests that the population of
the chelate intermediates increases in the order.
Finally, we compared the substituent effects with those of
the chelation-controlled radical reactions of b-benzyloxy-a-
methylene esters 36 and 37 derived from the corresponding
Baylis–Hillman adducts (Scheme 5).1,13 The isopropyl
radical addition to b-benzyloxy-a-methylene ester 36 and
p-methylbenzyloxy ester 3714 in the presence of MgBr2·
OEt2 performed at 278 8C gave 38 and 39 in good yields
with syn-selectivities. Similarly to the reaction of 7 and 9
(Table 1, entries 5 and 7), the syn-selectivity of 37 was also
higher than that of 36. However, the reactions of 36 and 37
at 0 8C gave no substituent effect.
Furthermore, we investigated the competition reactions of
the substrates 5 and 8 bearing an electron-withdrawing
trifluoromethyl group and an electron-donating isopropyl
group, respectively (Scheme 4). The competition reactions
1
Table 2. H NMR spectral data of 5–10 complexed with MgBr2·OEt2
Entry
Substrate
(X)
Dd values (ppm)
Bn
b-H
g-H
Olefin
1
2
3
4
5
6
5 (CF3)
6 (F)
0.09
0.01
0.05
0.01
0.01
0.09
0.06
0.20
0.01
0.15
0.02
0.01
0.00
0.22
0.25
0.03
0.18
0.15
3. Conclusion
In summary, we have shown the substituent effect on
chelation-controlled 1,3-asymmetric induction in the reac-
tions of g-(p-substituted-benzyloxy)-a-methylene esters
with alkyl iodides. The syn-selectivity increased in the
order of electron-donating ability NO2,CN,CF3,F,H,
i-Pr, Me, OMe of the p-substituent, and the plot of
log(syn/anti) versus Hammett sigma constants gave a linear
correlation. The electron-donating substituents i-Pr, Me and
OMe, stabilize the seven-membered chelate rings and yield
syn-products predominantly.
7 (H)
0.50
0.01
0.33
0.03
0.26
0.21
8 (i-Pr)
9 (Me)
10 (OMe)
0.56
0.02
0.34
0.05
0.22
0.19
0.62
0.02
0.38
0.09
0.25
0.21
0.62
0.03
0.34
0.07
0.21
0.16
Dd values: [dH(substrateþMgBr2·OEt2)2dH(substrate)].

5686
T. Yajima et al. / Tetrahedron 60 (2004) 5683–5693
Scheme 4. Competitive radical reactions of 5 and 8 with isopropyl iodide.
Scheme 5. Radical reactions of 36 and 37 with isopropyl iodide in the presence of MgBr2·OEt2.
1
4. Experimental
penoate 3. H NMR (270 MHz) d 8.16 (2H, d, J¼8.9 Hz,
p-NO2C6H2H2), 7.43 (2H, d, J¼8.9 Hz, p-NO2C6H2H2),
7.32 (5H, m, Ph), 6.20 (1H, d, J¼1.4 Hz, vCHH), 5.54 (1H,
d, J¼1.4 Hz, vCHH), 4.58 (1H, dd, J¼8.1, 5.1 Hz, CH),
4.53 (1H, d, J¼13.5 Hz, CHHPh), 4.37 (1H, d, J¼13.5 Hz,
CHHPh), 4.16 (2H, q, J¼7.0 Hz, CO2CH2CH3), 2.87 (1H,
ddd, J¼14.0, 8.4, 1.1 Hz, CHCHH), 2.71 (1H, ddd, J¼14.0,
5.4, 1.1 Hz, CHCHH), 1.28 (3H, t, J¼7.0 Hz, CO2CH2-
CH3); 13C NMR (67.5 MHz) d 166.8, 147.0, 146.1, 141.0,
136.8, 128.5, 127.9, 127.6, 127.5, 126.6, 123.4, 80.7, 69.3,
60.7, 41.2, 14.3; IR (neat) 2978, 2881, 2348, 1718, 1521,
1346, 1194, 1149, 1077, 855, 739, 702 cm21; MS m/z 310
(Mþ2OEt, 1%), 242 (67), 173 (15), 167 (21), 136 (100),
129 (19), 105 (30), 91 (49); HRMS calcd for C18H16NO4
[Mþ2OEt] 310.1080, found 310.1101.
4.1. General
1H NMR spectra were recorded on a JEOL GSX-270
(270 MHz) or GSX-400 (400 MHz) spectrometer with
CDCl3 as the solvent and tetramethylsilane as an
internal standard. 13C NMR spectra were recorded on the
instruments operating at 67.9 or 100.5 MHz with CDCl3 as
the solvent and internal standard (d 77.0). IR spectra
were taken on a SHIMADZU FTIR-8700 spectrometer.
Mass spectra (EIþ) were obtained on a JEOL JMS-700
mass spectrometer. Precoated Merck Kieselgel 60 F254 and
Kanto silica gel 60 (spherical neutral) were used for thin
layer chromatography and flash chromatography,
respectively.
4.2.2. Ethyl 2-[2-(p-cyanobenzyloxy)-2-phenylethyl]pro-
1
4.2. Preparation of the substrates 3–6, 8–10, 12, 36 and
37
penoate 4. H NMR (400 MHz) d 7.60 (2H, d, J¼8.1 Hz,
p-NCC6H2H2), 7.37 (2H, d, J¼8.1 Hz, p-NCC6H2H2), 7.30
(5H, m, Ph), 6.19 (1H, d, J¼1.6 Hz, vCHH), 5.53 (1H, d,
J¼1.6 Hz, vCHH), 4.55 (1H, dd, J¼8.4, 5.1 Hz, CH), 4.48
(1H, d, J¼13.0 Hz, p-NCC6H4CHH), 4.32 (1H, d,
J¼13.0 Hz, p-NCC6H4CHH), 4.16 (2H, q, J¼7.0 Hz, CO2-
CH2CH3), 2.85 (1H, dd, J¼14.0, 8.4 Hz, CHCHH), 2.69
(1H, dd, J¼14.0, 5.1 Hz, CHCHH), 1.27 (3H, t, J¼7.0 Hz,
CO2CH2CH3); 13C NMR (100 MHz) d 166.8, 144.0, 141.0,
133.3, 132.3, 131.9, 129.6, 128.4, 128.1, 127.5, 126.6,
111.0, 80.6, 69.5, 60.7, 41.1, 14.3; IR (neat) 2911, 2870,
2229, 1704, 1601, 1448, 1270, 1071, 1027, 950, 821,
703 cm21; MS m/z 290 (Mþ2OEt, 4%), 223 (49), 219 (21),
173 (48), 129 (35), 116 (100), 105 (85), 91 (25); HRMS
calcd for C19H16NO2 [Mþ2OEt] 290.1181, found
290.1176.
Substrates 3–6 and 8–10 were prepared from 1 and
p-nitrobenzyl bromide, p-cyanobenzyl bromide, p-trifluoro-
methylbenzyl bromide, p-fluorobenzyl bromide, p-iso-
propylbenzyl bromide, p-methylbenzyl bromide and
p-methoxybenzyl bromide, respectively, following the
procedures reported previously.4c Substrate 12 was prepared
from 2 and p-methylbenzyl bromide following the pro-
cedures reported previously.4d Treatment of ethyl
2-(hydroxyphenylmethyl)propenoate with benzyl trichloro-
acetimidate and p-methylbenzyl trichloroacetimidate gave
36 and 37, respectively.14
4.2.1. Ethyl 2-[2-(p-nitrobenzyloxy)-2-phenylethyl]pro-

T. Yajima et al. / Tetrahedron 60 (2004) 5683–5693
5687
4.2.3. Ethyl 2-[2-(p-trifluoromethylbenzyloxy)-2-phenyl-
1
ethyl]propenoate 5. H NMR (270 MHz) d 7.55 (2H, d,
(3H, t, J¼7.3 Hz, CO2CH2CH3); 13C NMR (100 MHz) d
166.9, 141.8, 137.0, 135.3, 128.8, 128.3, 127.7, 127.5,
127.4, 126.7, 126.2, 79.5, 70.3, 60.6, 41.1, 21.2, 14.2; IR
(neat) 2986, 2926, 1718, 1634, 1456, 1307, 1191, 1148,
1074, 941, 803, 757, 702 cm21; MS m/z 219 (Mþ2CH2C6H4-
Me-p, 5%), 209 (67), 149 (84), 129 (17), 117 (13), 105 (100),
91 (54); HRMS calcd for C13H15O2 [Mþ2OCH2C6H4Me-p]
203.1072, found 203.1071.
J¼8.1 Hz, p-CF3C6H2H2), 7.35 (2H, d, J¼8.1 Hz,
p-CF3C6H2H2), 7.33 (5H, m, Ph), 6.18 (1H, d, J¼1.6 Hz,
vCHH), 5.53 (1H, d, J¼1.6 Hz, vCHH), 4.55 (1H, dd,
J¼8.0, 5.2 Hz, CH), 4.50 (1H, d, J¼11.3 Hz, p-CF3C6H4-
CHH), 4.31 (1H, d, J¼11.3 Hz, p-CF3C6H4CHH), 4.14 (2H,
q, J¼7.0 Hz, CO2CH2CH3), 2.83 (1H, dd, J¼13.2, 8.0 Hz,
CHCHH), 2.69 (1H, dd, J¼13.2, 5.2 Hz, CHCHH), 1.25
(3H, t, J¼7.0 Hz, CO2CH2CH3); 13C NMR (100 MHz) d
166.9, 142.5, 141.3, 136.9, 129.5 (q, JC–F¼32 Hz), 128.4,
127.8, 127.5, 127.4, 126.6, 125.1 (q, JC–F¼3.6 Hz), 124.1
(q, JC–F¼270 Hz), 80.2, 69.6, 60.7, 41.2, 14.2; IR (neat)
2992, 2926, 1717, 1623, 1456, 1419, 1326, 1067, 1018, 823,
760, 702 cm21; MS m/z 219 (Mþ2CH2C6H4CF3-p, 5%),
203 (7), 173 (13), 159 (10), 129 (13), 109 (25), 105 (29), 91
(19); HRMS calcd for C13H15O2 [Mþ2CH2C6H4CF3-p]
219.1021, found 219.0993.
4.2.7. Ethyl 2-[2-(p-methoxybenzyloxy)-2-phenylethyl]-
1
propenoate 10. H NMR (270 MHz) d 7.26–7.36 (5H, m,
Ph), 7.18 (2H, d, J¼12.8 Hz, p-MeOC6H2H2), 6.84 (2H, d,
J¼12.8 Hz, p-MeOC6H2H2), 6.15 (1H, d, J¼1.6 Hz,
vCHH), 5.49 (1H, d, J¼1.6 Hz, vCHH), 4.53 (1H, dd,
J¼8.4, 4.9 Hz, CH), 4.39 (1H, d, J¼11.6 Hz, p-MeOC6H4-
CHH), 4.18 (1H, d, J¼11.6 Hz, p-MeOC6H4CHH), 4.13
(2H, q, J¼7.3 Hz, CO2CH2CH3), 3.79 (3H, s, p-MeO), 2.80
(1H, dd, J¼14.0, 8.4 Hz, CHCHH), 2.64 (1H, dd, J¼14.0,
4.9 Hz, CHCHH), 1.25 (3H, t, J¼7.3 Hz CO2CH2CH3); 13
C
4.2.4. Ethyl 2-[2-(p-fluorobenzyloxy)-2-phenylethyl]pro-
1
penoate 6. H NMR (400 MHz) d 7.23–7.30 (9H, m, Ph,
NMR (100 MHz) d 166.9, 159.0, 141.8, 137.0, 129.3, 129.2,
128.3, 127.5, 127.3, 126.7, 113.6, 79.4, 71.5, 60.6, 55.3,
41.1, 14.3; IR (neat) 2836, 1714, 1612, 1513, 1302, 1248,
1135, 820, 758, 702 cm21; MS m/z 340 (Mþ, 2%), 258 (22),
219 (2), 203 (3), 137 (35), 121 (100); HRMS calcd for
C21H24O4 [Mþ] 340.1674, found 340.1677.
C6H4), 6.17 (1H, d, J¼1.6 Hz, vCHH), 5.50 (1H, d,
J¼1.6 Hz, vCHH), 4.53 (1H, dd, J¼8.0, 5.2 Hz, CH), 4.41
(1H, d, J¼11.3 Hz, p-FC6H4CHH), 4.21 (1H, d, J¼11.3 Hz,
p-FC6H4CHH), 4.14 (2H, q, J¼7.0 Hz, CO2CH2CH3), 2.81
(1H, dd, J¼14.0, 8.0 Hz, CHCHH), 2.66 (1H, dd, J¼14.0,
5.2 Hz, CHCHH), 1.26 (3H, t, J¼7.0 Hz, CO2CH2CH3); 13
C
4.2.8. Ethyl 2-[2-(p-methylbenzyloxy)-3-methylbutyl]-
1
propenoate 12. H NMR (270 MHz) d 7.10–7.24 (4H, m,
NMR (100 MHz) d 166.9, 162.1 (d, JC–F¼239 Hz), 141.5,
137.0, 134.1 (d, JC–F¼2.8 Hz), 129.2, 128.4, 127.7, 127.4,
126.7, 115.0 (d, JC–F¼21 Hz), 79.8, 69.8, 60.6, 41.2, 14.2;
IR (neat) 2978, 1718, 1628, 1603, 1509, 1307, 1223, 1193,
C6H4), 6.19 (1H, d, J¼1.6 Hz, vCHH), 5.63 (1H, d,
J¼1.6 Hz, vCHH), 4.43 (2H, s, p-MeC6H4CH2), 4.18 (2H,
q, J¼7.0 Hz, CO2CH2CH3), 3.38 (1H, dd, J¼8.4, 4.1 Hz,
i-PrCH), 2.56 (1H, dd, J¼10.5, 4.1 Hz, CHCHH), 2.41 (1H,
dd, J¼13.4, 8.4 Hz, CHCHH), 2.32 (3H, s, p-Me), 1.89 (1H,
m, CH(CH3)2), 1.29 (3H, t, J¼7.0 Hz, CO2CH2CH3), 0.95
(3H, d, J¼6.8 Hz, CHCH3), 0.94 (3H, d, J¼6.8 Hz,
CHCH3); 13C NMR (67.5 MHz) d 167.2, 138.1, 136.8,
135.8, 128.8, 127.7, 126.9, 82.3, 72.0, 60.6, 34.0, 31.0, 21.2,
18.3, 17.9, 14.3; IR (neat) 2874, 1716, 1610, 1270, 1181,
1021, 808, 755 cm21; MS m/z 290 (Mþ, 13%), 217 (15),
185 (3), 169 (3), 144 (18), 121 (18), 105 (100); HRMS calcd
for C18H26O3 [Mþ] 290.1882, found 290.1843.
1148, 1074, 948, 824, 759 cm21
;
MS m/z 219
(Mþ2CH2C6H4F-p, 12%), 215 (97), 173 (25), 129 (26),
110 (55), 109 (100), 105 (32), 91 (40); HRMS calcd for
C13H15O3 [Mþ2CH2C6H4F-p] 219.1021, found 219.0992.
4.2.5. Ethyl 2-[2-(p-isopropylbenzyloxy)-2-phenylethyl]-
1
propenoate 8. H NMR (270 MHz) d 7.18–7.35 (9H, m,
Ph, C6H4), 6.18 (1H, d, J¼1.6 Hz, vCHH), 5.51 (1H, d,
J¼1.6 Hz, vCHH), 4.55 (1H, dd, J¼8.4, 5.4 Hz, CHPh),
4.55 (1H, d, J¼11.6 Hz, p-i-PrC6H4CHH), 4.22 (1H, d,
J¼11.6 Hz, p-i-PrC6H4CHH), 4.13 (2H, q, J¼7.3 Hz,
CO2CH2CH3), 2.89 (1H, sep, J¼7.0 Hz, CH(CH3)2), 2.81
(1H, dd, J¼14.3, 8.4 Hz, CHCHH), 2.66 (1H, dd, J¼14.3,
5.4 Hz, CHCHH), 1.24 (6H, d, J¼7.0 Hz, CH(CH3)2), 1.24
(3H, t, J¼7.3 Hz, CO2CH2CH3); 13C NMR (100 MHz) d
166.9, 148.0, 144.0, 141.8, 137.0, 128.3, 127.7, 127.5,
127.4, 126.7, 126.2, 79.7, 70.4, 60.6, 41.2, 33.9, 24.1, 14.3;
IR (neat) 2956, 2869, 1716, 1634, 1456, 1305, 1146, 1019,
817, 760, 701 cm21; MS m/z 219 (Mþ2CH2C6H4i-Pr-p,
8%), 204 (73), 173 (31), 158 (24), 149 (42), 134 (85), 133
(100), 129 (41), 118 (49), 105 (66), 91 (63); HRMS calcd for
C13H15O3 [Mþ2CH2C6H4i-Pr-p] 219.1021, found
219.0993.
4.2.9. Ethyl 2-benzyloxyphenylmethyl propenoate 36. 1H
NMR (400 MHz) d 7.21–7.40 (10H, m, 2£Ph), 6.35 (1H, s,
CH), 6.01 (1H, s, vCHH), 5.34 (1H, s, vCHH), 4.48 (2H,
s, CH2Ph), 4.15 (2H, dq, J¼7.3, 11.2 Hz, CO2CHHCH3),
4.12 (2H, dq, J¼7.3, 11.2 Hz, CO2CHHCH3), 1.22 (3H, t,
J¼7.3 Hz, CO2CH2CH3); 13C NMR (100 MHz) d 165.7,
141.4, 139.5, 138.1, 128.4, 128.2, 127.8, 127.7, 127.6,
127.5, 124.9, 78.6, 70.8, 60.7, 14.1; MS m/z 205 (Mþ2Bn,
22%), 203 (7), 190 (41), 178 (16), 159 (17); HRMS calcd for
C12H13O3 [Mþ2Bn] 205.0865, found 205.0873.
4.2.10. Ethyl 2-(p-methylbenzyloxy)phenylmethyl pro-
penoate 37. 1H NMR (400 MHz) d 7.29–7.39 (5H, m, Ph),
7.21 (2H, d, J¼7.3 Hz, C6H2H2), 7.13 (2H, d, J¼7.3 Hz,
C6H2H2), 6.35 (1H, s, CH), 6.00 (1H, s, vCHH), 5.33 (1H,
s, vCHH), 4.44 (2H, s, CH2Ph), 4.13 (2H, dq, J¼7.3,
12.2 Hz, CO2CHHCH3), 4.10 (2H, dq, J¼7.3, 12.2 Hz,
CO2CHHCH3), 2.34, (3H, s, p-Me), 1.22 (3H, t, J¼7.3 Hz,
CO2CH2CH3); 13C NMR (100 MHz) d 165.7, 141.4, 139.6,
137.1, 135.0, 128.9, 128.2, 127.7, 127.6, 127.5, 124.8, 78.4,
70.6, 60.7, 21.2, 14.1; MS m/z 205 Mþ2CH2C6H4Me-p,
4.2.6. Ethyl 2-[2-(p-methylbenzyloxy)-2-phenylethyl]-
1
propenoate 9. H NMR (270 MHz) d 7.09–7.35 (9H, m,
Ph, C6H4), 6.17 (1H, d, J¼1.4 Hz, vCHH), 5.51 (1H, d,
J¼1.4 Hz, vCHH), 4.54 (1H, dd, J¼8.2, 5.1 Hz, CH), 4.42
(1H, d, J¼11.6 Hz, p-MeC6H4CHH), 4.20 (1H, d,
J¼11.6 Hz, p-MeC6H4CHH), 4.13 (2H, q, J¼7.3 Hz, CO2-
CH2CH3), 2.80 (1H, dd, J¼14.2, 8.2 Hz, CHCHH), 2.65
(1H, dd, J¼14.2, 5.1 Hz, CHCHH), 2.33 (3H, s, p-Me), 1.23

5688
T. Yajima et al. / Tetrahedron 60 (2004) 5683–5693
5%), 190 (68), 144 (19), 121 (32), 116 (33); HRMS calcd for
C12H13O3 [Mþ2CH2C6H4Me-p] 205.0865, found 205.0873.
CHCHHCH), 1.55 (2H, m, i-PrCH2), 1.26 (1H, m,
CH(CH3)2), 1.18 (3H, t, J¼7.2 Hz, CO2CH2CH3), 0.85
(3H, d, J¼6.4 Hz, CHCH3), 0.80 (3H, d, J¼6.4 Hz,
CHCH3); 13C NMR (100 MHz) d 176.1, 143.9, 141.1,
132.0, 128.6, 128.4, 128.0, 127.7, 126.4, 111.0, 80.8, 69.4,
60.1, 42.5, 41.2, 41.1, 25.0, 22.9, 22.1, 14.4.
4.3. Radical reactions
General procedure of the radical reactions. To a solution of
a-methylene ester (0.15 mmol) in dry CH2Cl2 (1.5 cm3)
was added MgBr2·OEt2 (0.45 mmol, 3 equiv.), and the
mixture was stirred at room temperature for 10 min. To the
suspension cooled to 0 8C were added alkyl iodide
(0.45 mmol, 3 equiv.), n-Bu3SnH (0.30 mmol, 2 equiv.)
and Et3B (1.06 mol dm23 in hexane; 0.15 mmol, 1 equiv.).
The mixture was stirred at 0 8C for 3 h. KF and water were
added and the reaction mixture was stirred at room
temperature for 3 h. After filtration, the solvent was
evaporated in vacuo. The residue was purified by flash
chromatography on silica gel to give the product as an oily
inseparable diastereomeric mixture.
4.3.3. Ethyl 4-methyl-2-[2-phenylethyl-2-(p-trifluoro-
methylbenzyloxy)]pentanoate 15 (syn and anti). IR
(neat) 2958, 2871, 2331, 1733, 1455, 1326, 1165, 1125,
1066, 1018, 823, 702 cm21; MS m/z 393 (Mþ2Et, 17%),
377 (3), 265 (61), 247 (11), 217 (97), 159 (100), 109 (12),
105 (34); HRMS calcd for C22H24O3F3 [Mþ2Et] 393.1678,
1
found 393.1700. syn: H NMR (400 MHz) d 7.59 (2H, d,
J¼8.1 Hz, p-CF3C6H2H2), 7.43 (2H, d, J¼8.1 Hz,
p-CF3C6H2H2), 7.30 (5H, m, Ph), 4.46 (1H, d, J¼11.3 Hz,
p-CF3C6H4CHH), 4.31 (1H, dd, J¼9.6, 3.6 Hz, PhCH), 4.29
(1H, d, J¼11.3 Hz, p-CF3C6H4CHH), 4.07 (2H, m, CO2-
CH2CH3), 2.84 (1H, m, CHCO2Et), 1.97 (1H, ddd, J¼14.0,
9.6, 4.0 Hz, CHCHHCH), 1.90 (1H, ddd, J¼14.0, 9.2,
3.6 Hz, CHCHHCH), 1.55 (2H, m, i-PrCH2), 1.25 (1H, m,
CH(CH3)2), 1.22 (3H, t, J¼7.0 Hz, CO2CH2CH3), 0.90 (3H,
4.3.1. Ethyl 4-methyl-2-[2-(p-nitrobenzyloxy)-2-phenyl-
ethyl]pentanoate 13 (syn and anti). IR (neat) 2870, 1726,
1606, 1522, 1453, 1364, 1097, 1015, 844, 739, 702 cm21
;
MS m/z 354 (Mþ2OEt, 3%), 263 (16), 242 (83), 217 (71),
203 (17), 136 (100), 105 (40), 91(15); HRMS calcd for
C21H24NO3 [Mþ2OEt] 354.1706, found 354.1720. syn: 1H
NMR (270 MHz) d 8.16 (2H, d, J¼8.9 Hz, p-NO2C6H2H2),
7.43 (2H, d, J¼8.9 Hz, p-NO2C6H2H2), 7.32 (5H, m, Ph),
4.44 (1H, d, J¼13.5 Hz, p-NO2C6H4CHH), 4.34 (2H, m,
PhCH, p-NO2C6H4CHH), 4.03 (2H, m, CO2CH2CH3), 2.83
(1H, m, CHCO2Et), 1.96 (2H, m, CHCH2CH), 1.58 (3H, m,
CH(CH3)2, i-PrCH2), 1.23 (3H, t, J¼7.2 Hz, CO2CH2CH3),
0.90 (3H, d, J¼6.4 Hz, CHCH3), 0.88 (3H, d, J¼6.4 Hz,
CHCH3). anti: 1H NMR (270 MHz) d 8.16 (2H, d, J¼
8.9 Hz, p-NO2C6H2H2), 7.43 (2H, d, J¼8.9 Hz,
p-NO2C6H2H2), 7.32 (5H, m, Ph), 4.44 (1H, d, J¼
13.5 Hz, p-NO2C6H4CHH), 4.34 (2H, m, p-NO2C6H4CHH,
PhCH), 4.03 (2H, m, CO2CH2CH3), 2.47 (1H, m, CHCO2-
Et), 2.32 (1H, m, CHCHHCH), 1.74 (1H, m, CHCHHCH),
1.58 (3H, m, CH(CH3)2, i-PrCH2), 1.19 (3H, t, J¼7.2 Hz,
CO2CH2CH3), 0.85 (3H, d, J¼6.4 Hz, CHCH3), 0.80 (3H, d,
J¼6.4 Hz, CHCH3).
d, J¼6.4 Hz, CHCH3), 0.87 (3H, d, J¼6.4 Hz, CHCH3); 13
C
NMR (100 MHz) d 176.1, 142.4, 141.7, 129.6 (q,
JC–F¼32 Hz), 129.4, 128.5, 127.6, 126.4, 125.1 (q,
JC–F¼3.6 Hz), 124.1 (q, JC–F¼270 Hz), 80.3, 70.0, 60.1,
42.2, 41.0, 40.4, 26.1, 22.9, 22.3, 14.4. anti: 1H NMR
(400 MHz) d 7.59 (2H, d, J¼8.1 Hz, p-CF3C6H2H2), 7.43
(2H, d, J¼8.1 Hz, p-CF3C6H2H2), 7.30 (5H, m, Ph), 4.46
(1H, d, J¼11.3 Hz, p-CF3C6H4CHH), 4.33 (1H, dd, J¼9.6,
3.6 Hz, PhCH), 4.29 (1H, d, J¼11.3 Hz, p-CF3C6H4CHH),
4.07 (2H, m, CO2CH2CH3), 2.47 (1H, m, CHCO2Et), 2.27
(1H, ddd, J¼14.0, 9.6, 9.6 Hz, CHCHHCH), 1.72 (1H, ddd,
J¼14.0, 3.6, 3.6 Hz, CHCHHCH), 1.55 (2H, m, i-PrCH2),
1.25 (1H, m, CH(CH3)2), 1.17 (3H, t, J¼7.0 Hz, CO2CH2-
CH3), 0.85 (3H, d, J¼6.4 Hz, CHCH3), 0.80 (3H, d,
J¼6.4 Hz, CHCH3).
4.3.4. Ethyl 2-[2-(p-fluorobenzyloxy)-2-phenylethyl]-4-
methylpentanoate 16 (syn and anti). IR (neat) 2870,
2359, 1734, 1509, 1224, 1016, 824, 702 cm21; MS m/z 327
(Mþ2OEt, 3%), 263 (20), 247 (4), 219 (96), 144 (68), 125
(62), 109 (100), 101 (50); HRMS calcd for C21H24O2F
[Mþ2OEt] 327.1760, found 327.1754. syn: 1H NMR
(400 MHz) d 7.26–7.38 (7H, m, Ph, p-FC6H2H2), 6.99
(2H, m, p-FC6H2H2), 4.37 (1H, d, J¼11.2 Hz, p-FC6H4-
CHH), 4.28 (1H, dd, J¼9.4, 4.0 Hz, PhCH), 4.19 (1H, d,
J¼11.2 Hz, p-FC6H4CHH), 4.06 (2H, m, CO2CH2CH3),
2.83 (1H, m, CHCO2Et), 1.91 (2H, m, CHCH2CH), 1.54
(2H, m, i-PrCH2), 1.24 (1H, m, CH(CH3)2), 1.23 (3H, t,
J¼7.2 Hz, CO2CH2CH3), 0.89 (3H, d, J¼6.4 Hz, CHCH3),
0.86 (3H, d, J¼6.4 Hz, CHCH3); 13C NMR (100 MHz) d
176.2, 162.1 (d, JC–F¼243 Hz), 142.0, 134.0, 129.7 (d,
JC–F¼8.2 Hz), 128.4, 127.8, 126.4, 115.0 (d, JC–F¼21 Hz),
79.6, 69.5, 59.7, 42.3, 41.6, 40.4, 26.0, 22.9, 22.2, 14.4. anti:
1H NMR (400 MHz) d 7.26–7.38 (7H, m, Ph, p-FC6H2H2),
6.99 (2H, m, p-FC6H2H2), 4.37 (1H, d, J¼11.2 Hz, p-FC6-
H4CHH), 4.28 (1H, dd, J¼9.4, 4.0 Hz, PhCH), 4.19 (1H, d,
J¼11.2 Hz, p-FC6H4CHH), 4.06 (2H, m, CO2CH2CH3),
2.46 (1H, m, CHCO2Et), 2.24 (1H, m, CHCHHCH), 1.70
(1H, m, CHCHHCH), 1.54 (2H, m, i-PrCH2), 1.24 (1H, m,
CH(CH3)2), 1.19 (3H, t, J¼7.2 Hz, CO2CH2CH3), 0.85 (3H,
d, J¼6.4 Hz, CHCH3), 0.79 (3H, d, J¼6.4 Hz, CHCH3).
4.3.2. Ethyl 2-[2-(p-cyanobenzyloxy)-2-phenylethyl]-4-
methylpentanoate 14 (syn and anti). IR (neat) 2966,
2870, 2228, 1729, 1456, 1269, 1176, 1021, 821, 703 cm21
;
MS m/z 334 (Mþ2OEt, 3%), 263 (14), 247 (16), 222 (31),
217 (48), 116 (91), 105 (48), 91 (11); HRMS calcd for
C22H24NO2 [Mþ2OEt] 334.1807, found 334.1768. syn: 1H
NMR (400 MHz) d 7.28–7.69 (9H, m, Ph, C6H4), 4.44 (1H,
d, J¼12.8 Hz, p-NCC6H4CHH), 4.34 (1H, m, PhCH), 4.30
(1H, d, J¼12.4 Hz, p-NCC6H4CHH), 4.07 (2H, m, CO2-
CH2CH3), 2.82 (1H, m, CHCO2Et), 1.95 (2H, m, CHCH2-
CH), 1.55 (2H, m, i-PrCH2), 1.26 (1H, m, CH(CH3)2), 1.23
(3H, t, J¼7.2 Hz, CO2CH2CH3), 0.90 (3H, d, J¼6.4 Hz,
CHCH3), 0.87 (3H, d, J¼6.4 Hz, CHCH3); 13C NMR
(100 MHz) d 176.1, 143.9, 141.5, 132.0, 128.5, 128.4,
128.2, 127.8, 126.6, 111.0, 80.4, 69.8, 60.1, 42.2, 41.7, 40.4,
20.1, 22.9, 22.3, 14.3. anti: 1H NMR (400 MHz) d
7.28–7.69 (9H, m, Ph, C6H4), 4.44 (1H, d, J¼12.8 Hz,
p-NCC6H4CHH), 4.34 (1H, m, PhCH), 4.30 (1H, d,
J¼12.4 Hz, p-NCC6H4CHH), 4.00 (2H, m, CO2CH2CH3),
2.46 (1H, m, CHCO2Et), 2.28 (1H, ddd, J¼13.6, 8.4, 8.4 Hz,
CHCHHCH), 1.73 (1H, ddd, J¼14.0, 4.8, 4.8 Hz,

T. Yajima et al. / Tetrahedron 60 (2004) 5683–5693
5689
4.3.5. Ethyl 2-[2-(p-isopropylbenzyloxy)-2-phenylethyl]-
4-methylpentanoate 18 (syn and anti). IR (neat) 2868,
2362, 1733, 1456, 1177, 1019, 818, 701 cm21; MS m/z 280
(Mþ2CO2Et-i-Pr, 4%), 247 (12), 217 (32), 149 (24), 133
(100), 101 (37); HRMS calcd for C20H24O [Mþ2CO2Et-i-
4.35 (1H, d, J¼11.2 Hz, p-MeOC6H4CHH), 4.28 (1H, dd,
J¼9.2, 4.0 Hz, PhCH), 4.16 (1H, d, J¼11.2 Hz, p-MeOC6H4-
CHH), 4.07 (2H, m, CO2CH2CH3), 3.77 (3H, s, OMe), 2.48
(1H, m, CHCO2Et), 2.22 (1H, m, CHCHHCH), 1.65 (1H, m,
CHCHHCH), 1.54 (2H, m, i-PrCH2), 1.28 (1H, m,
CH(CH3)2), 1.19 (3H, t, J¼7.2 Hz, CO2CH2CH3), 0.84 (3H,
d, J¼6.4 Hz, CHCH3), 0.79 (3H, d, J¼6.4 Hz, CHCH3).
1
Pr] 280.1827, found 280.1828. syn: H NMR (400 MHz) d
7.17–7.36 (9H, m, Ph, C6H4), 4.37 (1H, d, J¼11.2 Hz, p-i-
PrC6H4CHH), 4.29 (1H, dd, J¼9.2, 4.4 Hz, PhCH), 4.22
(1H, d, J¼11.2 Hz, p-i-PrC6H4CHH), 4.07 (2H, m, CO2-
CH2CH3), 2.90 (1H, sep, J¼6.8 Hz, CH(CH3)2), 2.86 (1H,
m, CHCO2Et), 1.90 (2H, m, CHCH2CH), 1.55 (3H, m,
i-PrCH2, CH(CH3)2), 1.24 (6H, d, J¼6.8 Hz, CH(CH3)2),
1.23 (3H, t, J¼7.6 Hz, CO2CH2CH3), 0.89 (3H, d,
J¼6.4 Hz, CHCH3), 0.86 (3H, d, J¼6.4 Hz, CHCH3); 13C
NMR (100 MHz) d 176.3, 148.1, 142.3, 135.6, 128.4, 127.9,
127.5, 126.4, 126.3, 79.5, 70.7, 60.0, 42.3, 41.8, 40.4, 26.1,
4.3.8. Ethyl 2-[2-(p-cyanobenzyloxy)-2-phenylethyl]-
pentanoate 21 (syn and anti). IR (neat) 2931, 2873,
2228, 1729, 1454, 1269, 1176, 1070, 820, 702 cm21; MS
m/z 320 (Mþ2OEt, 4%), 249 (25), 233 (5), 222 (46), 203
(99), 116 (100); HRMS calcd for C21H22NO2 [Mþ2OEt]
320.1650, found 320.1602. syn: 1H NMR (400 MHz) d
7.30–7.64 (9H, m, Ph, C6H4), 4.44 (1H, d, J¼12.4 Hz,
p-NCC6H4CHH), 4.32 (1H, dd, J¼9.6, 4.0 Hz, PhCH), 4.29
(1H, d, J¼12.4 Hz, p-NCC6H4CHH), 4.08 (2H, m, CO2-
CH2CH3), 2.76 (1H, m, CHCO2Et), 2.01 (1H, ddd, J¼14.0,
9.6, 3.2 Hz, CHCHHCH), 1.92 (1H, ddd, J¼14.0, 9.6,
4.0 Hz, CHCHHCH), 1.60 (1H, m, CHHEt), 1.42 (1H, m,
CHHEt), 1.32 (2H, m, CH2CH2CH3), 1.23 (3H, t, J¼7.2 Hz,
CO2CH2CH3), 0.89 (3H, t, J¼7.2 Hz, CH2CH2CH3); 13C
NMR (100 MHz) d 175.8, 143.9, 141.5, 132.0, 128.5, 127.8,
127.7, 126.3, 118.8, 111.1, 80.3, 69.8, 60.1, 42.0, 41.1, 35.2,
1
24.1, 23.0, 22.2, 14.4, 14.1. anti: H NMR (400 MHz) d
7.17–7.36 (9H, m, Ph, C6H4), 4.37 (1H, d, J¼11.2 Hz, p-i-
PrC6H4CHH), 4.29 (1H, dd, J¼9.2, 4.4 Hz, PhCH), 4.22
(1H, d, J¼11.2 Hz, p-i-PrC6H4CHH), 4.07 (2H, m, CO2-
CH2CH3), 2.90 (1H, sep, J¼6.8 Hz, CH(CH3)2), 2.51 (1H,
m, CHCO2Et), 2.22 (1H, m, CHCHHCH), 1.55 (4H, m,
i-PrCH2, CHCHHCH, CH(CH3)2), 1.24 (6H, d, J¼6.8 Hz,
CH(CH3)2), 1.18 (3H, t, J¼7.6 Hz, CO2CH2CH3), 0.84 (3H,
d, J¼6.4 Hz, CHCH3), 0.78 (3H, d, J¼6.4 Hz, CHCH3).
1
20.5, 14.4, 14.0. anti: H NMR (400 MHz) d 7.30–7.64
(9H, m, Ph, C6H4), 4.41 (1H, d, J¼12.8 Hz, p-NCC6H4-
CHH), 4.32 (1H, dd, J¼8.8, 5.2 Hz, PhCH), 4.29 (1H, d,
J¼12.8 Hz, p-NCC6H4CHH), 4.07 (2H, m, CO2CH2CH3),
2.38 (1H, m, CHCO2Et), 2.32 (1H, ddd, J¼13.6, 8.8, 8.8 Hz,
CHCHHCH), 1.75 (1H, ddd, J¼13.6, 5.2, 5.2 Hz,
CHCHHCH), 1.54 (1H, m, CHHEt), 1.40 (1H, m,
CHHEt), 1.27 (2H, m, CH2CH2CH3), 1.19 (3H, t, J¼
7.2 Hz, CO2CH2CH3), 0.85 (3H, t, J¼7.2 Hz, CH2CH2-
CH3); 13C NMR (100 MHz) d 175.9, 144.0, 141.3, 132.0,
128.6, 127.8, 127.7, 126.6, 118.8, 111.1, 80.8, 69.4, 60.1,
42.8, 40.7, 35.0, 20.4, 14.3, 14.0.
4.3.6. Ethyl 4-methyl-2-[2-(p-methylbenzyloxy)-2-
1
phenylethyl]pentanoate 19 (syn). H NMR (270 MHz) d
7.13–7.37 (9H, m, Ph, C6H4), 4.37 (1H, d, J¼11.3 Hz,
p-MeC6H4CHH), 4.28 (1H, dd, J¼9.3, 4.1 Hz, PhCH), 4.17
(1H, d, J¼11.3 Hz, p-MeC6H4CHH), 4.06 (2H, m, CO2-
CH2CH3), 2.84 (1H, m, CHCO2Et), 2.34 (3H, s, p-Me), 1.86
(2H, m, CHCH2CH), 1.58 (2H, m, i-PrCH2), 1.37 (1H, m,
CH(CH3)2), 1.23 (3H, t, J¼7.3 Hz, CO2CH2CH3), 0.89 (3H,
d, J¼6.8 Hz, CHCH3), 0.86 (3H, d, J¼6.8 Hz, CHCH3); 13
C
NMR (67.5 MHz) d 176.4, 142.4, 137.3, 135.3, 128.9,
128.4, 128.0, 127.5, 126.5, 79.4, 70.6, 60.0, 42.3, 41.7, 40.3,
26.0, 22.9, 22.2, 21.2, 14.3; IR (neat) 2868, 1730, 1517,
1453, 1367, 1178, 1022, 801, 756, 702 cm21; MS m/z 368
(Mþ, 2%), 247 (17), 225 (22), 217 (39), 209 (37), 144 (85),
133 (17), 121 (11), 105 (100); HRMS calcd for C16H23O2
[Mþ2OCH2C6H4Me-p] 247.1699, found 247.1697.
4.3.9. Ethyl 2-[2-(p-trifluoromethylbenzyloxy)-2-phenyl-
ethyl]pentanoate 22 (syn and anti). IR (neat) 2873, 1729,
1326, 1165, 1126, 1066, 1019, 823, 702 cm21; MS m/z 363
(Mþ2OEt, 5%), 265 (40), 249 (30), 233 (22), 203 (88), 159
(100), 105 (38); HRMS calcd for C21H22O2F3 [Mþ2OEt]
363.1572, found 363.1536. syn: 1H NMR (400 MHz) d 7.59
(2H, d, J¼8.0 Hz, p-CF3C6H2H2), 7.43 (2H, d, J¼8.0 Hz,
p-CF3C6H2H2), 7.25–7.35 (5H, m, Ph), 4.45 (1H, d,
J¼12.0 Hz, p-CF3C6H4CHH), 4.32 (1H, dd, J¼9.6,
4.0 Hz, PhCH), 4.28 (1H, d, J¼12.0 Hz, p-CF3C6H4CHH),
4.07 (2H, m, CO2CH2CH3), 2.77 (1H, m, CHCO2Et), 2.00
(1H, ddd, J¼14.0, 9.6, 4.0 Hz, CHCHHCH), 1.91 (1H, dd,
J¼14.0, 9.6, 4.0 Hz, CHCHHCH), 1.59 (1H, m, CHHEt),
1.43 (1H, m, CHHEt), 1.32 (2H, m, CH2CH2CH3), 1.22
(3H, t, J¼7.2 Hz, CO2CH2CH3), 0.89 (3H, t, J¼7.2 Hz,
CH2CH2CH3); 13C NMR (100 MHz) d 175.9, 142.4, 141.8,
129.6 (q, JC–F¼32 Hz), 128.5, 127.7, 127.5, 126.4, 125.1
(q, JC–F¼3.6 Hz), 124.1 (q, JC–F¼270 Hz), 80.0, 70.0,
60.1, 42.0, 41.2, 35.3, 20.5, 14.4, 14.0. anti: 1H NMR
(400 MHz) d 7.59 (2H, d, J¼8.0 Hz, p-CF3C6H2H2), 7.42
(2H, d, J¼8.0 Hz, p-CF3C6H2H2), 7.25–7.35 (5H, m, Ph),
4.43 (1H, d, J¼12.0 Hz, p-CF3C6H4CHH), 4.32 (1H, dd,
J¼8.0, 4.8 Hz, PhCH), 4.28 (1H, d, J¼12.0 Hz, p-CF3C6-
H4CHH), 4.07 (2H, m, CO2CH2CH3), 2.39 (1H, m,
CHCO2Et), 2.30 (1H, ddd, J¼14.0, 8.0, 8.0 Hz,
CHCHHCH), 1.74 (1H, ddd, J¼14.0, 4.8, 4.8 Hz,
4.3.7. Ethyl 2-[2-(p-methoxybenzyloxy)-2-phenylethyl]-
4-methylpentanoate 20 (syn and anti). IR (neat) 2953,
2173, 1730, 1507, 1278, 1174, 1037 cm21; MS m/z 247
(Mþ2OCH2C6H4OMe-p, 7%), 222 (56), 217 (87), 144 (11),
116 (100), 105 (43), 101 (18); HRMS calcd for C16H23O2
[Mþ2OCH2C6H4OMe-p] 247.1698, found 247.1718. syn:
1H NMR (400 MHz) d 7.33 (5H, m, Ph), 7.23 (2H, d,
J¼12.8 Hz, p-MeOC6H2H2), 6.86 (2H, d, J¼12.8 Hz,
p-MeOC6H2H2), 4.35 (1H, d, J¼11.2 Hz, p-MeOC6H4-
CHH), 4.28 (1H, dd, J¼9.2, 4.0 Hz, PhCH), 4.16 (1H, d,
J¼11.2 Hz, p-MeOC6H4CHH), 4.07 (2H, m, CO2CH2CH3),
3.80 (3H, s, OMe), 2.84 (1H, m, CHCO2Et), 1.89 (2H, m,
CHCH2CH), 1.54 (2H, m, i-PrCH2), 1.28 (1H, m,
CH(CH3)2), 1.24 (3H, t, J¼7.2 Hz, CO2CH2CH3), 0.89
(3H, d, J¼6.4 Hz, CHCH3), 0.86 (3H, d, J¼6.4 Hz,
CHCH3); 13C NMR (100 MHz) d 176.2, 159.0, 142.3,
130.4, 129.4, 128.4, 127.5, 126.4, 113.0, 79.3, 70.5, 60.0,
55.3, 42.3, 41.8, 40.4, 26.1, 23.0, 22.2, 14.4. anti: 1H NMR
(400 MHz) d 7.33 (5H, m, Ph), 7.23 (2H, d, J¼12.8 Hz,
p-MeOC6H2H2), 6.86 (2H, d, J¼12.8 Hz, p-MeOC6H2H2),

5690
T. Yajima et al. / Tetrahedron 60 (2004) 5683–5693
CHCHHCH), 1.59 (1H, m, CHHEt), 1.43 (1H, m, CHHEt),
1.32 (2H, m, CH2CH2CH3), 1.18 (3H, t, J¼7.2 Hz,
CO2CH2CH3), 0.84 (3H, t, J¼7.2 Hz, CH2CH2CH3); 13C
NMR (100 MHz) d 175.9, 142.5, 141.4, 129.6 (q,
JC–F¼32 Hz), 128.5, 127.7, 127.5, 126.7, 125.9 (q,
JC–F¼3.6 Hz), 124.1 (q, JC–F¼270 Hz), 80.4, 69.5, 60.1,
42.8, 40.7, 34.9, 20.4, 14.3, 14.0.
2330, 1730, 1456, 1176, 1067, 818, 701 cm21; MS m/z 382
(Mþ, 2%), 249 (9), 233 (50), 203 (41), 159 (21), 149 (28),
133 (100); HRMS calcd for C25H34O3 [Mþ] 382.2508,
found 382.2517. syn: 1H NMR (400 MHz) d 7.17–7.35 (9H,
m, Ph, C6H4), 4.37 (1H, d, J¼11.2 Hz, p-i-PrC6H4CHH),
4.31 (1H, dd, J¼10.4, 3.2 Hz, PhCH), 4.19 (1H, d,
J¼11.2 Hz, p-i-PrC6H4CHH), 4.08 (2H, m, CO2CH2CH3),
2.90 (1H, sep, J¼6.8 Hz, CH(CH3)2), 2.80 (1H, m,
CHCO2Et), 1.97 (1H, ddd, J¼14.0, 10.4, 3.6 Hz,
CHCHHCH), 1.88 (1H, ddd, J¼14.0, 9.6, 3.2 Hz,
CHCHHCH), 1.59 (1H, m, CHHEt), 1.43 (1H, m,
CHHEt), 1.29 (2H, m, CH2CH2CH3), 1.24 (6H, d, J¼
6.8 Hz, CH(CH3)2), 1.23 (3H, t, J¼7.2 Hz, CO2CH2CH3),
0.88 (3H, t, J¼7.2 Hz, CH2CH2CH3); 13C NMR (100 MHz)
d 176.1, 142.4, 135.6, 128.4, 128.0, 127.9, 127.5, 126.4,
126.3, 79.5, 70.7, 60.0, 42.0, 41.4, 35.4, 33.9, 24.1, 20.5,
4.3.10. Ethyl 2-[2-(p-fluorobenzyloxy)-2-phenylethyl]-
pentanoate 23 (syn and anti). IR (neat) 2956, 2873,
1729, 1511, 1455, 1223, 1157, 824, 759, 702 cm21; MS m/z
249 (Mþ2CH2C6H4F-p, 15%), 233 (2), 203 (69), 130 (50),
109 (100), 105 (32); HRMS calcd for C15H21O3
[Mþ2CH2C6H4F-p] 249.1490, found 249.1526. syn: 1H
NMR (400 MHz) d 7.26–7.38 (7H, m, Ph, p-FC6H2H2),
7.01 (2H, m, p-FC6H2H2), 4.37 (1H, d, J¼11.2 Hz, p-FC6H4-
CHH), 4.29 (1H, dd, J¼10.0, 3.6 Hz, PhCH), 4.18 (1H, d,
J¼11.2 Hz, p-FC6H4CHH), 4.08 (2H, m, CO2CH2CH3),
2.75 (1H, m, CHCO2Et), 1.92 (2H, m, CHCH2CH), 1.58
(1H, m, CHHEt), 1.42 (1H, m, CHHEt), 1.30 (2H, m,
CH2CH2CH3), 1.24 (3H, t, J¼7.2 Hz, CO2CH2CH3), 0.88
(3H, t, J¼7.2 Hz, CH2CH2CH3); 13C NMR (100 MHz) d
175.9, 162.1 (d, JC–F¼243 Hz), 142.1, 134.0, 129.6 (d,
JC–F¼7.3 Hz), 128.4, 127.6, 126.4, 115.0 (d, JC–F¼21 Hz),
79.6, 70.1, 60.1, 42.0, 41.2, 35.3, 20.5, 14.4, 14.1. anti: 1H
NMR (400 MHz) d 7.26–7.38 (7H, m, Ph, p-FC6H2H2),
7.01 (2H, m, p-FC6H2H2), 4.35 (1H, d, J¼11.2 Hz, p-FC6H4-
CHH), 4.29 (1H, dd, J¼10.0, 3.6 Hz, PhCH), 4.18 (1H, d,
J¼11.2 Hz, p-FC6H4CHH), 4.04 (2H, m, CO2CH2CH3),
2.38 (1H, m, CHCO2Et), 2.25 (1H, ddd, J¼13.6, 8.8, 8.8 Hz,
CHCHHCH), 1.71 (1H, ddd, J¼14.0, 5.2, 5.2 Hz,
CHCHHCH), 1.55 (1H, m, CHHEt), 1.37 (1H, m,
CHHEt), 1.24 (2H, m, CH2CH2CH3), 1.19 (3H, t, J¼
7.2 Hz, CO2CH2CH3), 0.83 (3H, t, J¼7.2 Hz, CH2CH2-
1
14.4, 14.1. anti: H NMR (400 MHz) d 7.17–7.35 (9H, m,
Ph, C6H4), 4.37 (1H, d, J¼11.2 Hz, p-i-PrC6H4CHH), 4.31
(1H, dd, J¼10.0, 3.2 Hz, PhCH), 4.19 (1H, d, J¼11.2 Hz,
p-i-PrC6H4CHH), 4.08 (2H, m, CO2CH2CH3), 2.90 (1H,
sep, J¼6.8 Hz, CH(CH3)2), 2.41 (1H, m, CHCO2Et), 2.24
(1H, m, CHCHHCH), 1.70 (1H, m, CHCHHCH), 1.59 (1H,
m, CHHEt), 1.43 (1H, m, CHHEt), 1.29 (2H, m, CH2CH2-
CH3), 1.24 (6H, d, J¼6.8 Hz, CH(CH3)2), 1.18 (3H, t,
J¼7.2 Hz, CO2CH2CH3), 0.83 (3H, t, J¼7.2 Hz, CH2CH2-
CH3).
4.3.13. Ethyl 2-[2-(p-methylbenzyloxy)-2-phenylethyl]-
pentanoate 26 (syn and anti). IR (neat) 2930, 2872,
1729, 1454, 1379, 1176, 1067, 1022, 758, 702 cm21; MS
m/z 354 (Mþ, 6%), 307 (12), 249 (5), 233 (23), 209 (87), 130
(61), 105 (93); HRMS calcd for C23H30O3 [Mþ] 354.2195,
found 354.2181. syn: 1H NMR (400 MHz) d 7.12–7.35 (9H,
m, Ph, C6H4), 4.37 (1H, d, J¼11.2 Hz, p-MeC6H4CHH),
4.29 (1H, dd, J¼9.6, 3.6 Hz, PhCH), 4.17 (1H, d,
J¼11.2 Hz, p-MeC6H4CHH), 4.07 (2H, m, CO2CH2CH3),
2.78 (1H, m, CHCO2Et), 2.34 (3H, s, p-Me), 1.97 (1H, ddd,
J¼13.6, 10.2, 3.6 Hz, CHCHHCH), 1.86 (1H, ddd, J¼13.6,
9.6, 3.6 Hz, CHCHHCH), 1.57 (1H, m, CHHEt), 1.42 (1H,
m, CHHEt), 1.28 (2H, m, CH2CH2CH3), 1.23 (3H, t,
J¼7.2 Hz, CO2CH2CH3), 0.87 (3H, t, J¼7.2 Hz, CH2CH2-
CH3); 13C NMR (100 MHz) d 176.0, 142.3, 137.0, 135.2,
128.8, 128.3, 127.9, 127.4, 126.4, 79.4, 70.6, 60.0, 42.0,
41.3, 35.3, 21.2, 20.4, 14.4, 14.0. anti: 1H NMR (400 MHz)
d 7.12–7.35 (9H, m, Ph, C6H4), 4.47 (1H, dd, J¼9.6,
3.6 Hz, PhCH), 4.37 (1H, d, J¼11.2 Hz, p-MeC6H4CHH),
4.16 (1H, d, J¼11.2 Hz, p-MeC6H4CHH), 4.07 (2H, m,
CO2CH2CH3), 2.43 (1H, m, CHCO2Et), 2.31 (3H, s, p-Me),
2.22 (1H, m, CHCHHCH), 1.70 (1H, m, CHCHHCH), 1.57
(1H, m, CHHEt), 1.42 (1H, m, CHHEt), 1.28 (2H, m,
CH2CH2CH3), 1.19 (3H, t, J¼7.2 Hz, CO2CH2CH3), 0.83
(3H, t, J¼7.2 Hz, CH2CH2CH3); 13C NMR (100 MHz) d
176.0, 141.9, 136.9, 135.1, 128.8, 128.5, 127.8, 127.6,
126.8, 79.2, 70.1, 60.4, 42.5, 40.8, 34.5, 21.1, 20.4, 14.3,
14.0.
CH3); 13C NMR (100 MHz) d 175.9, 162.1 (d, JC–F
243 Hz), 141.6, 134.1, 129.4 (d, JC–F¼7.3 Hz), 128.4,
127.8, 126.7, 115.0 (d, JC–F¼21 Hz), 79.8, 69.6, 60.1, 42.7,
40.7, 34.7, 20.4, 14.3, 14.0.
¼
4.3.11. Ethyl 2-(2-benzyloxy-2-phenylethyl)pentanoate
24 (syn and anti). IR (neat) 2928, 2871, 1722, 1494,
1454, 1229, 1150, 1078, 736, 700 cm21; MS m/z 249
(Mþ2Bn, 7%), 233 (19), 203 (23), 200 (12), 197 (40), 181
(37), 176 (17), 129 (12), 117 (33), 105 (82), 91 (100);
HRMS calcd for C15H21O3 [Mþ2Bn] 249.1490, found
249.1507. syn:1H NMR (400 MHz) d 7.18–7.35 (10H, m,
2£Ph), 4.42 (1H, d, J¼11.0 Hz, CHHPh), 4.31 (1H, dd,
J¼9.6, 4.3 Hz, BnOCH), 4.22 (1H, d, J¼11.0 Hz, CHHPh),
4.07 (2H, m, CO2CH2CH3), 2.79 (1H, m, CHCO2Et), 1.94
(2H, m, CHCH2CH), 1.40 (4H, m, CH2Et, CH2CH3), 1.23
(3H, t, J¼7.2 Hz, CO2CH2CH3), 0.88 (3H, t, J¼7.2 Hz,
CH2CH3); 13C NMR (100 MHz) d 176.0, 142.2, 138.3,
128.4, 128.2, 127.8, 127.5, 127.4, 126.4, 79.6, 70.8, 60.0,
42.0, 41.3, 35.3, 20.5, 14.4, 14.1. anti: 1H NMR (400 MHz)
d 7.18–7.35 (10H, m, 2£Ph), 4.42 (1H, d, J¼11.0 Hz,
CHHPh), 4.31 (1H, dd, J¼9.6, 4.3 Hz, BnOCH), 4.20 (1H,
d, J¼11.0 Hz, CHHPh), 4.07 (2H, m, CO2CH2CH3), 2.41
(1H, m, CHCO2Et), 2.27 (1H, m, CHCHHCH), 1.40 (5H, m,
CH2Et, CHCHHCH, CH2CH3), 1.19 (3H, t, J¼7.2 Hz,
CO2CH2CH3), 0.83 (3H, t, J¼7.2 Hz, CH2CH3).
4.3.14. Ethyl 2-[2-(p-methoxybenzyloxy)-2-phenylethyl]-
pentanoate 27 (syn and anti). IR (neat) 2933, 2782, 1729,
1612, 1514, 1455, 1302, 1279, 1174, 1035, 822, 758,
702 cm21; MS m/z 370 (Mþ, 3%), 234 (5), 203 (12), 137
(45), 121 (100); HRMS calcd for C23H30O4 [Mþ] 370.2144,
found 370.2133. syn: 1H NMR (400 MHz) d 7.20–7.34 (7H,
m, Ph, p-MeOCH2H2), 6.86 (2H, m, p-MeOCH2H2), 4.35
4.3.12. Ethyl 2-[2-(p-isopropylbenzyloxy)-2-phenyl-
ethyl]pentanoate 25 (syn and anti). IR (neat) 2958, 2872,

T. Yajima et al. / Tetrahedron 60 (2004) 5683–5693
5691
(1H, d, J¼11.2 Hz, p-MeOC6H4CHH), 4.29 (1H, dd, J¼9.2,
3.2 Hz, PhCH), 4.15 (1H, d, J¼11.2 Hz, p-MeOC6H4CHH),
4.07 (2H, m, CO2CH2CH3), 3.81 (3H, s, OMe), 2.77 (1H, m,
CHCO2Et), 1.96 (1H, ddd, J¼14.0, 9.2, 3.6 Hz,
CHCHHCH), 1.85 (1H, ddd, J¼14.0, 9.6, 3.2 Hz,
CHCHHCH), 1.57 (1H, m, CHHEt), 1.42 (1H, m,
CHHEt), 1.30 (2H, m, CH2CH2CH3), 1.24 (3H, t, J¼
7.2 Hz, CO2CH2CH3), 0.87 (3H, t, J¼7.2 Hz, CH2CH2-
CH3); 13C NMR (67.5 MHz) d 176.0, 142.4, 130.6, 130.4,
129.4, 128.4, 127.4, 126.4, 113.6, 79.3, 70.5, 60.0, 55.3,
42.1, 41.4, 35.4, 20.5, 14.4, 14.0. anti: 1H NMR (400 MHz)
d 7.20–7.34 (7H, m, Ph, p-MeOCH2H2), 6.86 (2H, m,
p-MeOCH2H2), 4.29 (1H, d, J¼11.2 Hz, p-MeOC6H4-
CHH), 4.22 (1H, dd, J¼9.6, 3.6 Hz, PhCH), 4.13 (1H, d,
J¼11.2 Hz, p-MeOC6H4CHH), 4.07 (2H, m, CO2CH2CH3),
3.80 (3H, s, OMe), 2.39 (1H, m, CHCO2Et), 2.23 (1H, ddd,
J¼14.4, 9.6, 3.6 Hz, CHCHHCH), 1.69 (1H, ddd, J¼13.6,
9.6, 3.6 Hz, CHCHHCH), 1.57 (2H, m, CH2Et), 1.26 (2H,
m, CH2CH2CH3), 1.20 (3H, t, J¼7.2 Hz, CO2CH2CH3),
0.83 (3H, t, J¼7.2 Hz, CH2CH2CH3); 13C NMR (67.5 MHz)
d 176.0, 141.9, 130.4, 129.3, 127.6, 127.6, 126.8, 126.4,
113.7, 79.1, 70.0, 60.0, 57.8, 42.6, 40.8, 34.6, 20.4, 14.3,
14.0.
128.9, 128.4, 127.9, 127.5, 126.4, 79.4, 70.6, 60.0, 43.6,
1
41.3, 26.3, 21.2, 14.4, 11.6. anti: H NMR (400 MHz) d
7.12–7.38 (9H, m, Ph, C6H4), 4.47 (1H, dd, J¼9.6, 3.6 Hz,
PhCH), 4.38 (1H, d, J¼11.2 Hz, p-MeC6H4CHH), 4.16 (1H,
d, J¼11.2 Hz, p-MeC6H4CHH), 4.08 (2H, m, CO2CH2-
CH3), 2.48 (1H, m, CHCO2Et), 2.33 (3H, s, p-Me), 2.18
(1H, m, CHCHHCH), 1.71 (1H, m, CHCHHCH), 1.58 (2H,
m, CHCH2CH3), 1.20 (3H, t, J¼7.2 Hz, CO2CH2CH3), 0.84
(3H, t, J¼7.2 Hz, CHCH2CH3); 13C NMR (100 MHz) d
176.0, 142.3, 137.0, 134.4, 128.8, 128.5, 127.9, 127.8,
126.7, 79.3, 71.7, 61.7, 42.0, 41.3, 25.5, 20.4, 14.0, 11.5.
4.3.17. Ethyl 4,4-dimethyl-2-[2-(p-methylbenzyloxy)-2-
phenylethyl]pentanoate 31 (syn and anti). IR (neat)
2954, 2867, 1733, 1317, 1454, 1366, 1154, 1064, 1028,
802, 756, 701 cm21; MS m/z 277 (Mþ2CH2C6H4Me-p,
3%), 262 (14), 261 (9), 231 (35), 209 (7), 158 (84), 121 (15),
117 (11), 105 (100), 101 (62), 91 (21); HRMS calcd for
C17H25O3
[Mþ2CH2C6H4Me-p]
277.1803,
found
1
277.1788. syn: H NMR (400 MHz) d 7.10–7.37 (9H, m,
Ph, C6H4), 4.35 (1H, d, J¼11.0 Hz, p-MeC6H4CHH), 4.24
(1H, dd, J¼9.6, 3.6 Hz, PhCH), 4.21 (1H, d, J¼11.0 Hz,
p-MeC6H4CHH), 4.07 (2H, m, CO2CH2CH3), 2.85 (1H, m,
CHCO2Et), 2.34 (3H, s, p-Me), 1.91 (2H, m, CHCH2CH),
1.76 (2H, dd, J¼14.4, 9.2 Hz, t-BuCH2), 1.24 (3H, t,
J¼7.2 Hz, CO2CH2CH3), 0.87 (9H, s, t-Bu); 13C NMR
(100 MHz) d 177.1, 142.2, 137.0, 135.3, 128.9, 128.4,
127.9, 127.5, 126.4, 79.6, 70.8, 60.1, 47.0, 44.2, 39.0, 31.0,
4.3.15. Ethyl 4-benzyloxy-2-ethyl-4-phenylbutanoate 28
(syn and anti). IR (neat) 2955, 2873, 1729, 1455, 1177,
1028, 735, 700 cm21; MS m/z 281 (Mþ2OEt, 1%), 270
(18), 220 (15), 197 (22), 181 (100), 179 (62), 165 (31), 130
(12), 116 (27), 105 (30), 91 (96); HRMS calcd for C19H21O2
[Mþ2OEt] 281.1542, found 281.1523. syn: 1H NMR
(400 MHz) d 7.18–7.35 (10H, m, 2£Ph), 4.42 (1H, d,
J¼11.0 Hz, CHHPh), 4.32 (1H, dd, J¼9.6, 3.5 Hz, PhCH),
4.22 (1H, d, J¼11.0 Hz, CHHPh), 4.07 (2H, m, CO2CH2-
CH3), 2.71 (1H, m, CHCO2Et), 1.93 (2H, m, CHCH2CH),
1.57 (2H, m, CH2CH3), 1.23 (3H, t, J¼7.2 Hz, CO2CH2-
CH3), 0.89 (3H, t, J¼7.2 Hz, CH2CH3); 13C NMR
(100 MHz) d 175.8, 142.2, 138.3, 128.4, 128.2, 127.8,
127.5, 127.4, 126.4, 79.6, 70.8, 60.0, 43.6, 40.9, 26.3, 14.4,
11.6. anti: 1H NMR (400 MHz) d 7.18–7.35 (10H, m,
2£Ph), 4.42 (1H, d, J¼11.0 Hz, CHHPh), 4.31 (1H, dd,
J¼9.6, 3.5 Hz, PhCH), 4.21 (1H, d, J¼11.0 Hz, CHHPh),
4.07 (2H, m, CO2CH2CH3), 2.46 (1H, m, CHCO2Et), 2.29
(1H, m, CHCHHCH), 1.57 (3H, m, CHCHHCH, CH2CH3),
1.19 (3H, t, J¼7.2 Hz, CO2CH2CH3), 0.84 (3H, t, J¼7.2 Hz,
CH2CH3); 13C NMR (100 MHz) d 176.0, 141.8, 139.3,
128.3, 128.1, 127.7, 127.5, 127.3, 126.8, 79.6, 70.3, 59.1,
43.7, 41.3, 25.5, 14.3, 11.5.
1
29.5, 21.2, 14.3. anti: H NMR (400 MHz) d 7.10–7.37
(9H, m, Ph, C6H4), 4.30 (1H, dd, J¼9.6, 3.6 Hz, PhCH),
4.35 (1H, d, J¼11.0 Hz, p-MeC6H4CHH), 4.19 (1H, d,
J¼11.0 Hz, p-MeC6H4CHH), 4.07 (2H, m, CO2CH2CH3),
2.52 (1H, m, CHCO2Et), 2.33 (3H, s, p-Me), 2.20 (1H, m,
CHCHHCH), 1.71 (1H, m, CHCHHCH), 1.65 (2H, dd,
J¼14.4, 9.2 Hz, t-BuCH2), 1.19 (3H, t, J¼7.2 Hz, CO2-
CH2CH3), 0.82 (9H, s, t-Bu); 13C NMR (100 MHz) d 177.0,
141.9, 136.9, 135.2, 128.8, 128.6, 127.9, 127.6, 126.7, 79.2,
70.2, 60.1, 46.1, 43.4, 39.3, 30.9, 29.4, 20.5, 14.1.
4.3.18. Ethyl 2-isobutyl-5-methyl-4-(p-methylbenzyl-
oxy)hexanoate 33 (syn and anti). IR (neat) 2871, 1731,
1471, 1174, 1088, 797 cm21; MS m/z 334 (Mþ, 5%), 291
(10), 264 (94), 234 (33), 213 (24), 209 (28), 121 (7), 105
(100); HRMS calcd for C21H34O3 [Mþ] 334.2508, found
334.2528. syn: 1H NMR (400 MHz) d 7.26 (2H, d,
J¼7.8 Hz, p-MeC6H4CH2H2), 7.15 (2H, d, J¼7.8 Hz,
p-MeC6H4CH2H2), 4.49 (1H, d, J¼10.4 Hz, p-MeC6H4-
CHH), 4.40 (1H, d, J¼10.4 Hz, p-MeC6H4CHH), 4.10 (2H,
m, CO2CH2CH3), 3.10 (1H, m, i-PrCH), 2.67 (1H, m,
CHCO2Et), 2.33 (3H, s, p-Me), 1.95 (1H, m, CH(CH3)2),
1.76 (1H, ddd, J¼14.0, 11.2, 2.4 Hz, CHCHHCH), 1.54
(4H, m, CHCHHCH, CH(CH3)2, i-PrCH2), 1.23 (3H, t,
4.3.16. Ethyl 2-ethyl-4-(p-methylbenzyloxy)-4-phenyl-
butanoate 29 (syn and anti). IR (neat) 2874, 3356, 1728,
1683, 1455, 1179, 1093, 807, 757, 702 cm21; MS m/z 235
(Mþ2CH2C6H4Me-p, 4%), 219 (4), 189 (33), 130 (10), 121
(13), 116 (51), 105 (100), 91 (18); HRMS calcd for
J¼7.2 Hz, CO2CH2CH3), 0.90 (12H, m, 2£CH(CH3)2); 13
C
C14H19O3
[Mþ2CH2C6H4Me-p]
235.1334,
found
NMR (100 MHz) d 176.7, 136.9, 135.8, 128.8, 127.8, 82.3,
72.1, 59.9, 42.8, 40.3, 33.9, 30.5, 26.2, 23.1, 21.9, 18.6,
17.2, 14.4. anti: 1H NMR (400 MHz) d 7.26 (2H, d,
J¼7.8 Hz, p-MeC6H4CH2H2), 7.15 (2H, d, J¼7.8 Hz,
p-MeC6H4CH2H2), 4.49 (1H, d, J¼10.4 Hz, p-MeC6H4-
CHH), 4.40 (1H, d, J¼10.4 Hz, p-MeC6H4CHH), 4.10 (2H,
m, CO2CH2CH3), 3.20 (1H, m, i-PrCH), 2.54 (1H, m,
CHCO2Et), 2.33 (3H, s, p-Me), 1.95 (1H, m, CH(CH3)2),
1.76 (1H, ddd, J¼14.0, 11.2, 2.4 Hz, CHCHHCH), 1.54
(4H, m, CHCHHCH, CH(CH3)2, i-PrCH2), 1.23 (3H, t,
1
235.1286. syn: H NMR (400 MHz) d 7.12–7.38 (9H, m,
Ph, C6H4), 4.38 (1H, d, J¼11.2 Hz, p-MeC6H4CHH), 4.31
(1H, dd, J¼9.6, 3.6 Hz, PhCH), 4.17 (1H, d, J¼11.2 Hz,
p-MeC6H4CHH), 4.08 (2H, m, CO2CH2CH3), 2.71 (1H, m,
CHCO2Et), 2.33 (3H, s, p-Me), 1.97 (1H, ddd, J¼13.6, 10.0,
3.6 Hz, CHCHHCH), 1.86 (1H, ddd, J¼13.6, 9.6, 3.6 Hz,
CHCHHCH), 1.58 (2H, m, CHCH2CH3), 1.24 (3H, t,
J¼7.2 Hz, CO2CH2CH3), 0.88 (3H, t, J¼7.2 Hz, CHCH2-
CH3); 13C NMR (100 MHz) d 175.9, 142.3, 137.1, 135.2,

5692
T. Yajima et al. / Tetrahedron 60 (2004) 5683–5693
J¼7.2 Hz, CO2CH2CH3), 0.90 (12H, m, 2£CH(CH3)2); 13
C
PhCHH), 4.19 (1H, d, J¼10.4 Hz, PhCHH), 4.21 (2H, q,
J¼6.8 Hz, CO2CH2CH3), 2.87 (1H, m, CHCO2Et), 1.50
(2H, m, CHCH2CH), 1,37 (1H, m, CH(CH3)2), 1.26 (3H, t,
J¼6.8 Hz, CO2CH2CH3), 0.75 (3H, d, J¼6.2 Hz, CHCH3),
0.73 (3H, d, J¼6.2 Hz, CHCH3); 13C NMR (100 MHz) d
174.8, 139.2, 138.0, 128.4, 128.2, 128.0, 127.8, 127.6,
127.3, 83.6, 70.5, 60.4, 51.6, 38.0, 26.1, 23.6, 21.1, 14.4.
NMR (100 MHz) d 175.3, 137.1, 135.2, 129.0, 127.7, 81.5,
71.7, 59.9, 42.7, 40.8, 33.4, 29.9, 26.2, 23.3, 21.9, 18.0,
16.7, 14.1.
4.3.19. Ethyl 5-methyl-4-(p-methylbenzyloxy)-2-(2,2-
dimethypropyl)hexanoate 35 (syn and anti). IR (neat)
2871, 1731, 1470, 1173, 1078, 796 cm21; MS m/z 227
(Mþ2CH2C6H4Me-p, 8%), 203 (5), 158 (88), 121 (20), 105
(100), 101 (63); HRMS calcd for C14H27O2 [Mþ2CH2C6-
H4Me-p] 277.2011 found 277.2052. syn: 1H NMR
(400 MHz) d 7.27 (2H, d, J¼8.3 Hz, p-MeOC6H4CH2H2),
7.14 (2H, d, J¼8.3 Hz, p-MeOC6H4CH2H2), 4.48 (1H, d,
J¼10.4 Hz, p-MeC6H4CHH), 4.43 (1H, d, J¼10.4 Hz,
p-MeC6H4CHH), 4.09 (2H, m, CO2CH2CH3), 3.07 (1H,
m, i-PrCH), 2.74 (1H, m, CHCO2Et), 2.34 (3H, s, p-Me),
1.95 (1H, m, CH(CH3)2), 1.78 (2H, m, CHCH2CH), 1.50
(2H, m, t-BuCH2), 1.24 (3H, t, J¼7.2 Hz, CO2CH2CH3),
0.88 (6H, d, J¼6.8 Hz, CH(CH3)2), 0.87 (9H, s, t-Bu); 13C
NMR (100 MHz) d 177.5, 136.9, 135.9, 128.9, 127.9, 82.3,
72.1, 60.0, 47.5, 38.8, 36.4, 31.0, 29.5, 21.2, 18.6, 17.2,
4.3.21. Ethyl 4-methyl-2-[(p-methylbenzyloxy)phenyl-
methyl]pentanoate 39 (syn and anti). The radical reaction
of 37 was carried out according to the procedure as
described above. MS m/z 249 (Mþ2CH2C6H4Me-p, 2%),
234 (62), 190 (35), 178 (36), 160 (44), 121 (30); HRMS
calcd for C15H21O3 [Mþ2CH2C6H4Me-p] 249.1491, found
249.1503. syn:1H NMR (400 MHz) d 7.06–7.40 (9H, m, Ph,
C6H4), 4.37 (1H, d, J¼8.8 Hz, PhCH), 4.32 (1H, d,
J¼11.8 Hz, PhCHH), 4.14 (1H, d, J¼11.8 Hz, PhCHH),
3.80 (2H, q, J¼6.8 Hz, CO2CH2CH3), 2.84 (1H, m,
CHCO2Et), 2.34 (3H, s, p-Me), 1.74 (2H, m, CHCH2CH),
1,49 (1H, m, CH(CH3)2), 0.93 (3H, t, J¼6.8 Hz, CO2CH2-
CH3), 0.75 (3H, d, J¼6.8 Hz, CHCH3), 0.73 (3H, d,
J¼6.2 Hz, CHCH3); 13C NMR (100 MHz) d 174.8, 139.7,
137.1, 135.0, 128.9, 128.1, 127.8, 127.7, 127.5, 82.3, 70.3,
59.9, 52.4, 38.4, 26.6, 23.7, 21.6, 21.2, 13.9. anti:1H NMR
(400 MHz) d 7.06–7.40 (9H, m, Ph, C6H4), 4.42 (1H, d,
J¼11.8 Hz, PhCHH), 4.39 (1H, d, J¼8.8 Hz, PhCH), 4.19
(1H, d, J¼11.8 Hz, PhCHH), 4.14 (2H, m, CO2CH2CH3),
2.85 (1H, m, CHCO2Et), 2.32 (3H, s, p-Me), 1.49 (2H, m,
CHCH2CH), 1,35 (1H, m, CH(CH3)2), 1.26 (3H, t,
J¼6.8 Hz, CO2CH2CH3), 0.89 (3H, d, J¼6.8 Hz,
CHCH3), 0.87 (3H, d, J¼6.2 Hz, CHCH3); 13C NMR
(100 MHz) d 174.8, 139.6, 139.3, 135.0, 128.9, 128.1,
127.8, 127.7, 127.5, 83.3, 70.2, 60.3, 51.5, 38.0, 26.1, 23.6,
21.6, 21.2, 14.4.
1
14.3. anti: H NMR (400 MHz) d 7.27 (2H, d, J¼8.3 Hz,
p-MeOC6H4CH2H2), 7.23 (2H, d, J¼8.3 Hz, p-MeOC6H4-
CH2H2), 4.48 (1H, d, J¼10.4 Hz, p-MeC6H4CHH), 4.43
(1H, d, J¼10.4 Hz, p-MeC6H4CHH), 4.01 (2H, m, CO2-
CH2CH3), 3.18 (1H, m, i-PrCH), 2.52 (1H, m, CHCO2Et),
2.35 (3H, s, p-Me), 1.95 (1H, m, CH(CH3)2), 1.78 (2H, m,
CHCH2CH), 1.50 (2H, m, t-BuCH2), 1.20 (3H, t, J¼7.2 Hz,
CO2CH2CH3), 0.88 (6H, d, J¼6.8 Hz, CH(CH3)2), 0.83
(9H, s, t-Bu); 13C NMR (100 MHz) d 177.5, 137.0, 135.2,
128.8, 127.8, 81.5, 71.0, 60.1, 46.3, 39.1, 35.3, 30.5, 29.5,
21.4, 18.0, 17.5, 14.1.
4.3.20. Ethyl 4-methyl-2-(benzyloxyphenylmethyl)-
pentanoate 38 (syn and anti). To a solution of a-methylene
ester 36 (0.15 mmol) in dry CH2Cl2 (1.5 cm3) was added
MgBr2·OEt2 (0.75 mmol, 5 equiv.), and the mixture was
stirred at room temperature for 10 min. To the suspension
cooled to 278 8C were added isopropyl iodide (0.45 mmol,
3 equiv.), n-Bu3SnH (0.30 mmol, 2 equiv.) and Et3B
(1.06 mol dm23 in hexane; 0.03 mmol, 0.2 equiv.). The
mixture was stirred at 278 8C for 6 h. KF and water were
added and the reaction mixture was stirred at room
temperature for 3 h. After filtration, the solvent was
evaporated in vacuo. The residue was purified by flash
chromatography on silica gel to give the product as an oily
inseparable diastereomeric mixture. The stereochemistry
was determined by comparing their chemical shift values
with those of methyl 2-methyl-3-benzyloxy-3-phenyl-
propanoate.12 MS m/z 249 (Mþ2Bn, 5%), 234 (24), 197
(82), 178 (19), 160 (24), 105 (26); HRMS calcd for
C15H21O3 [Mþ2Bn] 249.1491, found 249.1503. syn:1H
NMR (400 MHz) d 7.18–7.40 (10H, m, 2£Ph), 4.44 (1H, d,
J¼10.4 Hz, PhCHH), 4.39 (1H, d, J¼8.8 Hz, BnOCH), 4.23
(1H, d, J¼10.4 Hz, PhCHH), 3.82 (2H, q, J¼6.8 Hz,
CO2CH2CH3), 2.84 (1H, m, CHCO2Et), 1.75 (2H, m,
CHCH2CH), 1,50 (1H, m, CH(CH3)2), 0.99 (3H, d,
J¼6.2 Hz, CHCH3), 0.90 (3H, t, J¼6.8 Hz, CO2CH2CH3),
0.87 (3H, d, J¼6.2 Hz, CHCH3); 13C NMR (100 MHz) d
173.4, 139.6, 138.1, 128.2, 128.1, 127.9, 127.7, 127.6,
127.5, 82.5, 70.5, 59.9, 52.4, 38.4, 26.6, 23.7, 21.6, 13.9.
References and notes
1. For reviews and books, see: (a) Smadja, W. Synlett 1994,
1–26. (b) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem.
Res. 1991, 24, 296–304. (c) RajanBabu, T. V. Acc. Chem. Res.
1991, 24, 139–145. (d) Renaud, P.; Sibi, M. P. Radicals in
Organic Synthesis; VCH: Weinheim, 2001; Vols. 1–2.
(e) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH: Weinheim, 1996.
2. For reviews, see: (a) Sibi, M. P.; Porter, N. A. Acc. Chem. Res.
1999, 32, 163–171. (b) Renaud, P.; Gerster, M. Angew. Chem.
´
Int. Ed. 1998, 37, 2562–2579. (c) Guindon, Y.; Guerin, B.;
Rancourt, J.; Chabot, C.; Makintosh, N.; Ogilvie, W. W. Pure.
Appl. Chem. 1996, 68, 89–96. For recent examples, see:
(d) Iserloh, U.; Curran, D. P.; Kanemasa, S. Tetrahedron:
Asymmetry 1999, 10, 2417–2428. (e) Watanabe, Y.; Mase, N.;
Furue, R.; Toru, T. Tetrahedron Lett. 2001, 42, 2981–2984.
(f) Halland, N.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans.
1 2001, 1290–1295.
3. For a review on 1,3-asymmetric induction, see: (a) Mengel, A.;
Reiser, O. Chem. Rev. 1999, 99, 1191–1223. For radical
mediated 1,3-asymmetric inductions via eight-membered
chelate rings, see: (b) Hayen, A.; Koch, R.; Metzger, J. O.
J. Am. Chem. Soc. 2000, 122, 12458–12468.
1
anti: H NMR (400 MHz) d 7.18–7.40 (10H, m, 2£Ph),
4. (a) Nagano, H.; Toi, S.; Yajima, T. Synlett 1999, 53–54.
(b) Nagano, H.; Hirasawa, T.; Yajima, T. Synlett 2000,
4.42 (1H, d, J¼9.0 Hz, BnOCH), 4.35 (1H, d, J¼10.4 Hz,

T. Yajima et al. / Tetrahedron 60 (2004) 5683–5693
5693
1073–1075. (c) Nagano, H.; Matsuda, M.; Yajima, T. J. Chem.
Soc., Perkin Trans. 1 2001, 174–182. (d) Nagano, H.; Toi, S.;
Hirasawa, T.; Matsuda, M.; Hirasawa, S.; Yajima, T. J. Chem.
Soc., Perkin Trans. 1 2002, 2525–2538. (e) Nagano, H.;
Ohkouchi, H.; Yajima, T. Tetrahedron 2003, 59, 3649–3663.
5. (a) Goto, H.; Osawa, E. J. Am. Chem. Soc. 1989, 111,
8950–8953. (b) Goto, H.; Osawa, E. J. Chem. Soc., Perkin
Trans. 2 1993, 187–198.
Chem. 1994, 59, 7723–7731. (d) Chini, M.; Crotti, P.;
Minutolo, F.; Dezi, E.; Lombardozzi, A.; Pizzabiocca, A.;
Renzi, G. Tetrahedron 1993, 49, 5845–5858. (e) Kunieda, N.;
Nokami, J.; Kinoshita, M. Bull. Chem. Soc. Jpn 1992, 65,
526–529. (f) Kunieda, N.; Nakanishi, T.; Kinoshita, M. Bull.
Chem. Soc. Jpn 1989, 62, 2229–2234. (g) Chini, M.; Crotti, P.;
Ferretti, M.; Macchia, F. Tetrahedron 1988, 44, 2001–2014.
10. The radical reaction of 7 with i-PrI using n-Bu3SnD showed
the D-atom abstraction of the radical a to the ester carbonyl
group. An alternative reaction mechanism involving the
intramolecular 1,5-hydrogen atom transfer from the benzylic
position was thus excluded. For the 1,5-hydrogen transfer from
benzylic position, see: (a) Kunishima, M.; Hioki, K.; Kono,
K.; Kato, A.; Tani, S. J. Org. Chem. 1997, 62, 7542–7543.
(b) Benati, L.; Capella, L.; Montevecchi, P. C.; Spagnolo, P.
J. Org. Chem. 1994, 59, 2818–2823. (c) Rochigneux, I.;
Fontanel, M.-L.; Malanda, J.-C.; Doutheau, A. Tetrahedron
Lett. 1991, 32, 2017–2020.
6. For the reaction via seven-membered chelation with Lewis
acid, see:(a) Yang, M. G.; Modi, D. P.; Wexler, R. R.; Olson,
R. E. Tetrahedron Lett. 2004, 45, 111–112. (b) Krafft, M. E.;
Dasse, O. A.; Jarrett, S.; Fievre, A. J. Org. Chem. 1995, 60,
5093–5101. (c) Angert, H.; Kunz, T.; Reissig, H.-U.
Tetrahedron 1992, 48, 5681–5690.
7. For the conformation of seven-membered cyclic radicals, see;
(a) Sibi, M. P.; Asano, Y.; Sausker, J. B. Angew. Chem. Int.,
Ed. 2001, 40, 1293–1296. For examples of five and six-
membered cyclic radicals, see: (b) Giese, B. Angew. Chem.
Int. Ed. Engl. 1989, 28, 969–980. (c) Damm, W.; Giese, B.;
Hartung, J.; Hasskerl, T.; Houk, K. N.; Hu¨ter, O.; Zipse, H.
J. Am. Chem. Soc. 1992, 114, 4067–4079. (d) Cai, Y.;
Roberts, B. P. J. Chem. Soc., Perkin Trans. 1 1998, 467–476.
8. Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96–99.
9. For the correlations of diastereoselectivities versus Hammett
sigma constants, see: (a) Galardon, E.; Le Maux, P.;
Simonneaux, G. Tetrahedron 2000, 56, 615–621. (b) Morgan,
A. J.; Masse, C. E.; Panek, J. S. Org. Lett. 1999, 1, 1949–1952.
(c) Gugelchuk, M. M.; Chan, P. C.-M.; Sprules, T. J. J. Org.
11. NMR studies on complexation of b-benzyloxy aldehyde with
MgBr2·OEt2, see: (a) Keck, G. E.; Castellino, S. J. Am. Chem.
Soc. 1986, 108, 3847–3849. (b) Keck, G. E.; Castellino, S.;
Wiley, M. R. J. Org. Chem. 1986, 51, 5480–5482.
12. Brown, D. J. J. Appl. Chem. (London) 1952, 2, 202–203.
13. Guindon, Y.; Rancourt, J. J. Org. Chem. 1998, 63,
6554–6565.
14. (a) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999,
2311–2312. (b) Wessel, H.-P.; Iversen, T.; Bundle, D. R.
J. Chem. Soc., Perkin Trans. 1 1985, 2247–2249.