Stereoselectivity in the formation and radical reduction of cyclic bromoacetals, key intermediates for the synthesis of δ-hydroxy- and ε-hydroxy-α-methylcarboxylic acid esters

Article abstract of DOI:10.1016/S0040-4039(03)01738-6

We report the stereoselectivity in the formation and radical reduction of six- and seven-membered cyclic bromoacetals. The oxidative ring cleavage of the resulting acetals gave the corresponding acyclic δ-hydroxy- and ε-hydroxy-α-methylcarboxylic acid esters.

Full text of DOI:10.1016/S0040-4039(03)01738-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6867–6870
Stereoselectivity in the formation and radical reduction of cyclic
bromoacetals, key intermediates for the synthesis of d-hydroxy-
and o-hydroxy-a-methylcarboxylic acid esters
Hajime Nagano,* Ayako Mikami and Tomoko Yajima
Department of Chemistry, Faculty of Science, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
Received 4 June 2003; revised 10 July 2003; accepted 11 July 2003
Abstract—We report the stereoselectivity in the formation and radical reduction of six- and seven-membered cyclic bromoacetals.
The oxidative ring cleavage of the resulting acetals gave the corresponding acyclic d-hydroxy- and o-hydroxy-a-methylcarboxylic
acid esters.
© 2003 Elsevier Ltd. All rights reserved.
During the past decade the stereochemical control of
acyclic radical reactions has received considerable
attention and significant levels of diastereoselectivity in
the reactions involving stereogenic centers adjacent to
the radical center (1,2-asymmetric induction) or chiral
auxiliaries have been achieved when they adopt pre-
ferred conformations.1 The use of Lewis acids offers the
possibility to regulate conformations and improves the
stereoselectivity in acyclic radical reactions.2 We have
recently reported the chelation-controlled 1,3-asymmet-
ric induction in the radical-mediated additions to a-
methylene-g-oxycarboxylic acid esters.3 To extend the
stereocontrol in acyclic radical reactions, we have
attempted the 1,4-asymmetric induction in the radical
reactions of a-methylene-d-oxycarboxylic acid esters in
the presence of Lewis acid, but the reactions showed no
diastereoselectivity. The poor chemical shift increment
values Dl=[lH(substrate+MgBr2·OEt2)−lH(substrate)]
in the complexation experiments with MgBr2·OEt2 in
3d
CDCl3 indicated that the substrates did not form an
eight-membered chelate ring.4 To overcome the limita-
tion of the chelation-mediated stereocontrol in acyclic
radical reactions, we examined the indirect asymmetric
induction through a series of reactions involving (a)
bromoacetalization of acyclic olefinic alcohols
3
(Scheme 1), (b) radical reduction of the resulting cyclic
bromoacetals 4 and 5 (Scheme 2), and (c) subsequent
ring cleavage yielding acyclic hydroxy esters 10 and 11
(Scheme 3). Kiyooka and co-workers have recently
reported the highly diastereoselective radical reduction
Scheme 1. Preparation of olefinic alcohols 3 and their bromoacetalization to 4 and 5.
Keywords: radical reaction; cyclic bromoacetal; remote asymmetric induction; d-hydroxy-a-methylcarboxylic acid ester; o-hydroxy-a-methylcar-
boxylic acid ester.
* Corresponding author. Fax: +81(3)5978-5715; e-mail: nagano@cc.ocha.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01738-6

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H. Nagano et al. / Tetrahedron Letters 44 (2003) 6867–6870
The bromoacetals 4 and 5 were prepared from lactones
1 (Scheme 1 and Table 1). d-Phenyl-d-lactone 1d8 was
prepared from diethyl glutarate in 19% overall yield [(i)
PhLi, Et2O, −70°C to rt; (ii) NaBH4, EtOH, 0°C;
p-TsOH, PhH, rt]. Bulky substituents n-C7H15, Ph or
n-C6H13 were chosen to decrease volatility.
The bromoacetalization of 3a (E:Z=4:1) with N-bro-
mosuccinimide (NBS) in CH2Cl2 at 0°C gave a mixture
of two diastereomers 4a and 5a in high yield with a
diastereomer ratio of 5.1:1 (Table 1, entry 1).9,10 Among
the four possible diastereomers, 4a and 5a were
obtained
preferentially.
The
diastereoselectivity
increased as the temperature was lowered (entry 2). The
bromoacetalization of 3b (E:Z=7:1) at 0°C also gave a
mixture of 4b and 5b in a diastereomer ratio of 10.1:1
(entry 3). The reaction performed at −70°C showed a
higher selectivity (13.0:1) (entry 4). Treatment of the
homologous substrates 3c and 3d with NBS in CH2Cl2
under reflux gave the seven-membered cyclic bromoac-
etals 4c/5c and 4d/5d, respectively, but the yields were
lower because of the difficulty of ring closure (entries 5
and 6).11 The yields decreased as the temperature was
lowered. Moreover, the diastereoselectivity was not
ameliorated even at low temperature. The reaction was
furthermore attempted under high dilution condition
using a syringe pump, but the yield was not improved.12
The bromoacetals 4 and 5 were, fortunately, separated
by silica gel column chromatography (hexane–benzene
10:1).
Scheme 2. Radical reduction of bromoacetals 4 and 5.
The relative configurations between C-2 and C-6 of
bromoacetals 4a,b, 5a and 5b were established based on
their NOE experiments. The trans relationship between
the substituents Br and OMe was assigned based on the
chemical shift values of 3-Me (lC=22.0 for the axial
Me of more polar 4a,b; lC=30.3 and 30.4 for the
equatorial Me of less polar 5a,b, respectively).13 The
configurations at C-2 and C-7 of bromoacetals 4c,d and
5c,d were also established based on their NOE experi-
ments, but the stereochemistry at C-3 was tentatively
assigned from the polarity of the bromoacetals; the
more polar products were assigned to 4 and the less
polar products were assigned to 5.
Scheme 3. Ring cleavage of 6–8 yielding acyclic hydroxy
esters 10 and 11.
of a-bromo-a-methyl-d-lactones yielding 2,4-syn dialkyl
g-lactone, which would be converted to a variety of
acyclic derivatives.5 In our case the diastereoselectivity
of the radical reduction would be controlled by the
methoxy group attached to the newly created stereo-
genic center in the cyclic bromoacetals.6,7
The reduction of the major bromoacetal 4a with n-
Bu3SnH (2 equiv.) and Et3B (1 equiv.) in CH2Cl2 at 0°C
gave acetals 6a and 7a in a ratio of 2.1:1 (Scheme 2.,
Table 2, entry 1). Bulky reducing reagent Ph3SnH gave
Table 1. Bromoacetalization of 3a–d with N-bromosuccinimide in CH2Cl2
Entry
Substrate (E:Z)
3a (4:1)
Temp. (°C)
Product
4a, 5a
4b, 5b
Yield (%)
Diastereomer ratio (4:5)
1
2
3
4
5
6
0
−70
0
−70
Reflux
Reflux
93
98
88
95
50
32
5.1:1
6.8:1
10.1:1
13.0:1
1.2:1
3b (7:1)
3c (6:1)
3d (7:1)
4c, 5c
4d, 5d
1.3:1

H. Nagano et al. / Tetrahedron Letters 44 (2003) 6867–6870
6869
Table 2. Radical reduction of bromoacetals 4 and 5 with tin hydride and Et3B
Entry
Bromoacetal
Tin reagent
Temp. (°C)
Product
Yield (%)
d.r. (6/7 or 8/9)
1
2
3
4
5
6
7
8
4a
n-Bu3SnH
Ph3SnH
Ph3SnH
n-Bu3SnH
n-Bu3SnH
Ph3SnH
n-Bu3SnH
n-Bu3SnH
Ph3SnH
n-Bu3SnH
n-Bu3SnH
n-Bu3SnH
Ph3SnH
n-Bu3SnH
Ph3SnH
0
0
0
6a,7a
91
97
92
98
90
90
90
90
90
90
77a
90
80
89
89
2.1:1
4.3:1
6.0:1
1:4.2
1:11
1:2.5
1:2.5
1:6.3
1:1.8
4b
4c
6b,7b
6c,7c
0
−70
−70
0
−70
−70
0
4d
6d,7d
9
10
11
12
13
14
15
5a
5b
5c
8a
8b
8c,9c
0
−70
−70
−70
−70
16:1
5.7:1
12:1
5d
8d,9d
3.2:1
a Substrate 5b was recovered in 20% yield.
a higher diastereoselectivity 4.3:1 (entry 2). The reac-
tion temperature did not affect the diastereoselectivity.
Bromoacetal 4b was reduced with Ph3SnH to give 6b
and 7b in 92% yield and with a diastereomer ratio of
6.0:1 (entry 4). The diastereomeric mixtures of the
reduction products were separated by silica gel column
chromatography (hexane–benzene 10:1). The reduction
of the minor bromoacetals 5a and 5b with n-Bu3SnH
gave exclusively 8a and 8b, respectively. The iodoacetal-
ization of 3a and 3b with N-iodosuccinimide and the
subsequent reduction of the resulting iodoacetals pro-
ceeded in similar yields and diastereomer ratios. How-
ever, the separation of the diastereomeric products was
not attained because of the too small differences of
polarity among them.
energy minimization.10 The configurations of the phenyl
substituted acetals 6–9 were assigned by comparing
their 1H NMR spectral data with those of 6c, 7c, 8c and
9c.
The origin of the high diastereoselectivity for the reac-
tions of acetals 4c,d, 5c and 5d can be rationalized on
the basis of the structural analysis of the low energy
conformers of the radical intermediates. The exhaustive
searches of low-energy conformers of the flexible seven-
membered radical intermediates A and B were per-
formed with CONFLEX program,10 followed by
semi-empirical molecular orbital calculations (PM3) of
the resulting low energy conformers.3d,e The low energy
conformers including the global energy minimum con-
former A-1 show that the hydrogen atom transfer pro-
ceeds preferentially from the less hindered upper face to
give 7d, whereas the hydrogen atom transfer to the
global energy minimum conformer B-1 proceeds prefer-
entially from the lower face to give 8d (Fig. 1).
The configurations at C-2 of the acetals 6, 7 and 8 were
assigned based on the NOE difference spectra. The
equatorial methoxy group attached to the carbon atom
neighboring to radical center increase the amount of
axial attack of the tin reagent to give preferentially 6a
and 6b.5 The axial methoxy group in the bromoacetals
5a and 5b shield the lower face of the radical center to
give exclusively 8a and 8b, respectively.5,14
Finally, the acetal rings of 6a–6c, 7a, 7c, and 8c were
cleaved by treating with ozone in ethyl acetate at −75°C
In contrast to the reduction of the bromoacetals 4a and
4b, the diastereoselectivity in the reduction of the
homologous bromoacetals 4c and 4d with n-Bu3SnH
remarkably depended on the reaction temperature
(entries 4, 5, 7 and 8). Higher diastereoselectivities were
attained at lower temperature. In the reaction of 4c, 4d,
5c and 5d, Ph3SnH was inferior to n-Bu3SnH in
diastereoselectivity (entries 5 versus 6; 8 versus 9; 12
versus 13; 14 versus 15). The diastereomeric mixtures 8
and 9 were separated by silica gel column chromatogra-
phy (hexane–benzene 10:1).
The configurations of methyl group at C-2 of the
acetals 6c, 7c, 8c and 9c were assigned based on the
NOE difference spectra and the conformational analy-
sis of the flexible seven-membered rings performed with
CONFLEX program using the MM2 force field for
Figure 1. Global energy minimum conformers of the radical
intermediates A and B generated from bromoacetals 4d and
5d, respectively.

6870
H. Nagano et al. / Tetrahedron Letters 44 (2003) 6867–6870
to give 10a–10c, 11a and 11c, respectively, following the
procedures reported by Delongchamps and co-
workers15 (Scheme 3). The reaction of acetal 8a having
an axial methoxy group did not proceed as predicted
from the literature.
J.; Hasskerl, T.; Houk, K. N.; Hu¨ter, O.; Zipse, H. J.
Am. Chem. Soc. 1992, 114, 4067–4079.
7. Recently radical haloacetal cyclizations (Ueno–Stork
reaction) controlled by the acetal center have been
reported: (a) Villar, F.; Kolly-Kovac, T.; Equey, O.
Renaud, P. Chem. Eur. J. 2003, 9, 1566–1577; (b)
Corminboeuf, O.; Renaud, P.; Schiesser, C. H. Chem.
Eur. J. 2003, 9, 1578–1584.
8. (a) Downham, R.; Edwards, P. J.; Entwistle, D. A.;
Hughes, A. B.; Kim, K. S.; Ley, S. V. Tetrahedron:
Asymmetry 1995, 6, 2403–2440; (b) Bosci, A.; Chiappe,
C.; De Rubertis, A.; Ruasse, M. F. J. Org. Chem. 2000,
65, 8470–8477.
In summary, we reported the stereoselectivity in the
formation and radical reduction of cyclic bromoacetals
4 and 5. The oxidative ring cleavage of the resulting
acetals 6–8 gave the acyclic d- and o-hydroxy-a-methyl-
carboxylic acid esters 10 and 11. The overall yields of
10a–10c from 3a–3c were 48, 37 and 14%, respectively.
9. The analysis of low energy conformers of the intermedi-
ate bromonium ions in the bromoacetalization of enol
ether (E)-3b calculated by the use of CONFLEX (Ref.
10) and subsequent PM3 programs shows that the lowest
energy conformer yielding the minor bromoacetal 5b is
2.5 kcal mol−1 higher in energy than the global minimum
energy conformer of the bromonium ion yielding the
major bromoacetal 4b. The calculations for the minor
(Z)-3b suggest the preferential formation of 4b.
10. (a) Goto, H.; Osawa, E. J. Am. Chem. Soc. 1989, 111,
8950–8951; (b) Goto, H.; Osawa, E. J. Chem. Soc.,
Perkin Trans. 2 1993, 187–198.
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