Diastereoselective radical debromination approach toward divergent syntheses of syn- and anti-propionate units, coupled with enantioselective and/or diastereoselective Lewis acid-promoted aldol reactions

Article abstract of DOI:10.1016/j.tetasy.2003.06.005

A practical methodology directed to the enantioselective synthesis of polypropionate backbones, available for the synthesis of polyketide natural products, has been developed by iterative enantio- and diastereoselective Lewis acid-promoted aldol reactions, followed by diastereoselective radical debromination reactions. A chiral oxazaborolidinone-promoted aldol reaction of a racemic aldehyde, derived from 2-methyl-1,3-propanediol, with a silylketene acetal from ethyl 2-bromopropionate, resulted in highly enantioselective formation of the corresponding bromo aldol adduct, followed by radical debromination with Bu₃SnH in the presence of Et₃B to divergently give syn- and anti-propionate aldols, which are versatile stereotriads. Furthermore, elongation of the propionate units has also been achieved: the BF₃·OEt₂-promoted aldol reaction of chiral syn- and anti-α-methyl-β-protected-oxy aldehydes with the silyl nucleophile proceeded with essentially complete syn-selectivity while the TiCl₄-promoted aldol reaction resulted in fairly good anti-selectivity. The resulting bromo aldol adducts were divergently debrominated by the radical reduction to give a complete set of stereotetrads.

Full text of DOI:10.1016/j.tetasy.2003.06.005

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2897–2910
Diastereoselective radical debromination approach toward
divergent syntheses of syn- and anti-propionate units, coupled
with enantioselective and/or diastereoselective Lewis
acid-promoted aldol reactions
Syun-ichi Kiyookaa,b
aDepartment of Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
bInstitute for Fundamental Research of Organic Chemistry, Kyushu University, Higashi-ku, Fukuoka 812-8581, Japan
Received 22 March 2003; accepted 13 June 2003
Abstract—A practical methodology directed to the enantioselective synthesis of polypropionate backbones, available for the
synthesis of polyketide natural products, has been developed by iterative enantio- and diastereoselective Lewis acid-promoted
aldol reactions, followed by diastereoselective radical debromination reactions. A chiral oxazaborolidinone-promoted aldol
reaction of a racemic aldehyde, derived from 2-methyl-1,3-propanediol, with a silylketene acetal from ethyl 2-bromopropionate,
resulted in highly enantioselective formation of the corresponding bromo aldol adduct, followed by radical debromination with
Bu3SnH in the presence of Et3B to divergently give syn- and anti-propionate aldols, which are versatile stereotriads. Furthermore,
elongation of the propionate units has also been achieved: the BF3·OEt2-promoted aldol reaction of chiral syn- and anti-a-methyl-
b-protected-oxy aldehydes with the silyl nucleophile proceeded with essentially complete syn-selectivity while the TiCl4-promoted
aldol reaction resulted in fairly good anti-selectivity. The resulting bromo aldol adducts were divergently debrominated by the
radical reduction to give a complete set of stereotetrads.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
obtained from the enantioselective aldol reaction at the
first step, are divergently transferred to each corre-
sponding syn- or anti-propionate by using distinctive,
highly diastereoselective radical debrominations in the
second step. The other part of the strategy appears in
the diastereoselective aldol reactions of aldehydes,
involving stereogenic centers, with the same nucleophile
2, where the bulkiness of 2, might work again effec-
tively for the diastereoselectivity, followed by the same
radical debromination procedures. We herein report
versatile synthetic studies of propionate stereotriads
and stereotetrads aiming at a general methodology,
available for the asymmetric synthesis of polyketide
natural products, which is based on Lewis acid-pro-
moted aldol reactions coupled with radical reductions.
Although a number of successful examples have been
reported in the area of the enantioselective synthesis of
syn- and anti-propionate aldol adducts, divergent syn-
thesis of these compounds has not been realized to
date.1 After continuous studies on chiral oxazaborolidi-
none 1 promoted asymmetric aldol reactions,2 we found
however that the enantioselective aldol reaction with a
silylketene acetal 2 derived from ethyl 2-bromopropi-
onate, followed by diastereoselective debromination
reactions, can resolve this problem to give divergently
enantiopure syn- and anti-propionate aldol adducts.3
The approach is available as part of the overall strategy
for constructing both single propionate and iterative
polypropionate units, as shown in Scheme 1. The
bromo substituent in 2 has dual roles: the first is to
provide a suitable steric bulkiness of the silyl nucleo-
phile leading to very high enantioselectivity in the
aldol condensation process and the second is to serve as
a group which can be readily eliminated from the
resulting intermediates in a subsequent radical reduc-
tion process.4 Essentially enantiopure aldol adducts,
2. Results and discussion
2.1. Enantioselective synthesis of stereotriads available
for construction of a variety of skeletons of polyketide
natural products
Our strategy, developed in a divergent enantioselective
E-mail: kiyo@cc.kochi-u.ac.jp
synthesis of syn- and anti-propionate alodol adducts,3
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.06.005

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S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
Scheme 1. Enantioselective or diastereoselective approach to propionate units.
was applied to the racemic aldehyde 5, derived from a
cheap achiral diol 3,5 which was chosen as a simple
and suitable starting material because of it having a
minimum propionate functionality for elongation. Pro-
vided the so-called ‘catalyst control’, where a newly
created center is formed depending only on the chiral-
ity of the used catalysts (promoters) without any influ-
ence of the existing chiral centers of the aldehyde, is
possible in this system of aldehyde 5 with silyl nucleo-
phile 2 in the presence of chiral oxazaborolidinones,
(S)-1 and (R)-1, as observed in a previous report of
the oxazaborolidi2none-promoted asymmetric aldol
reaction with racemic aldehydes,2h we can expect to
obtain a pair of highly enantioselective aldol adducts,
essential for the enantioselective synthesis of propi-
onate skeletons. A strategy to the quite effective enan-
tioselective synthesis of versatile stereotriads has been
tioselectivity is achieved through an effective kinetic
resolution where chiral pairs of enantiopure aldol
adducts are in practice obtainable from a racemic
starting material. An additional interesting selectivity
leads to an excellent 2,3-syn relationship in the aldol
adducts,2u although the stereochemistry at C-2 is not
so important in this strategy involving the following
radical debromination procedure. In the case of chiral
oxazaborolidinone-promoted asymmetric aldol reac-
tions of 5, the predominance of the catalyst (pro-
moter) control over the substrate control should be
explained for the facial selection, as depicted in Figure
1.
In supplying effectively protected substrates to allow
higher diastereoselectivity in the following radical
debromination, bromo aldol adducts, 6 and 7, were
converted with methylal/P2O5 to the corresponding
MOM-protected compounds, 8 and 9, respectively, in
good yields. After research by Guindon et al.4 and our
improved work,3 diastereoselective reductive reactions
via radicals a to the carboxyl ester function have
become a promising method to obtain syn- and anti-
propionates. The a-bromo ester is suitable as a precur-
sor for the radical reduction with Bu3SnH in the
presence of a catalytic amount of Et3B.7 In radical
debromination of a-bromo-b-protected-oxy-a-methyl
esters with Bu3SnH/Et3B, syn-selectivity is generally
observed while anti-selectivity is predominantly
preliminarily reported using
a
TBS-protected
homologous aldehyde with respect to the enantioselec-
tive synthesis of (+)-discodermolide.6
After mono-protection of 3 with TBDPSCl/NaH,
Swern oxidation gave aldehyde 5 in good yield. In the
presence of a stoichiometric amount of chiral borane
(S)-1, which was prepared in situ by stirring L-TsVal
and BH3·THF in CH2Cl2 at 0°C, the aldol reaction of
5 with 2 was carried out at −78°C for 3 h. The
reaction proceeded smoothly to give a mixture of aldol
adducts in 85% yield along with a small amount of
isomers at C-2 and C-3 (ꢀ4% yield), as shown in
Scheme 2. The major mixture was constituted of an
almost 1:1 ratio of (+)-2,3-syn-3,4-syn-6 and (−)-2,3-
syn-3,4-anti-7 which were determined to be 92% ee
and 91% ee, respectively, by chiral HPLC analysis
using Daicel Chiralcel OD-H. The same reaction with
(R)-1 also resulted in the production of the enan-
tiomers (−)-6 and (+)-7 with nearly the same level of
enantioselectivity. The stereocenter at C-3, installed
during the reaction, is primarily controlled by the pro-
moters (S)-1 and (R)-1, respectively. The high enan-
achieved in the presence of
a large excess of
MgBr2·OEt2, where the diastereoselectivity is explained
by the dipole–dipole control for the former and the
chelation control for the latter. Even b-hydroxy esters
could accept the chelation control with MgBr2·OEt2.3
The effects of b-hydroxy protection on the diastereose-
lectivity have been observed, to a considerable extent,
but it is necessary to take into account the selection of
an appropriate protecting group available for the prac-
tical procedure. If MOM-protection effectively affects

S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
2899
Scheme 2.
diastereoisomers at C-2 by flash-column chromatogra-
phy, the debrominated major compounds, 10–13, were
selectively deprotected on treatment with 1 equiv of
TiCl4 in CH2Cl2 at rt, so as to derive the final stereotri-
ads, 14–17, without decomposition of the TBDPS pro-
tection. The methoxymethyl moiety might be expected
to play a role for enhanced steric assistance in both
dipole and chelation modes, depicted in Figure 2. Thus,
the enantioselective synthesis of all stereotriads of ethyl
5-(tert-butyldiphenylsiloxy)-2,4-dimethyl-3-hydroxypent-
anoate is necessarily achieved by using a sequence of
the enantioselective aldol reaction and the following
diastereoselective radical reduction reaction.
Figure 1.
both controls in the radical debromination by expecting
enhanced dipole–dipole and chelation interactions, the
MOM group should be chosen for their ease of protec-
tion and deprotection procedures.
2.2. Diastereoselective synthesis of chiral stereotetrads
available for construction of the polypropionate frame-
work of polyketide natural products8
As shown in Scheme 3, debromination of 8 and 9 under
dipole conditions (Bu3SnH/Et3B in toluene at −78°C)
results in fairly good 2,3-anti selection of 15:1 for 10
and 12:1 for 12, respectively, in good yields. Debromi-
nation of 8 and 9 under chelation conditions (Bu3SnH/
Et3B in the presence of MgBr2·OEt2 in CH2Cl2 at
−78°C) led to good 2,3-syn selection of 8:1 for 11 and
5:1 for 13, respectively. After easy separation of the
More straightforward approaches to the diastereoselec-
tive construction of polypropionates, possessing units
with alternative hydroxyl and methyl groups, towards
the versatile synthesis of biologically active polyketide
natural products would be expected in a sequential
procedure of a chiral oxazaborolidinone-promoted

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S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
Scheme 3.
Figure 2. More effective assistance with methoxymethyl moiety.
enantioselective aldol reaction with silylketene acetal 2
and a radical debromination reaction, as mentioned
above. However, the enantioselective aldol reaction did
not work sufficiently well on the enantioselective
diastereoselection in the iterative construction of the
bulky propionate system, having alternative protected-
We selected ethyl (2S,3S)- and (2R,3S)-3-hydroxy-2-
methyl-3-phenylpropionate, 20 and 21, as the first pro-
pionate units in order to test the efficiency of our
iterative aldol reaction strategy. The propionates, 20
and 21, were prepared by our sequential method of
chiral oxazaborolidinone-promoted aldol reaction, fol-
lowed by debromination, as shown in Scheme 4. The
enantioselective aldol reaction of benzaldehyde with
silyl nucleophile 2 gave syn-selectively with a mixture of
bromo aldol adducts composed of 18 (66%) and 19
(10%) with 90% ee.3 The mixture was directly converted
to the desired propionate aldols, 20 (30%) and 21 (49%)
with 90% ee under non-selective conditions without
protection of the hydroxy group (Bu3SnH/Et3B, in
toluene at −78°C). Both highly enantiopure aldehydes
syn-24 and anti-25, were obtained by successive reac-
tions of methylation (MeI/Ag2O) and DIBAL
reduction.
oxy and methyl groups.9 We then planned
a
diastereoselective approach using the classical
Mukaiyama aldol reaction as an alternative to the
enantioselective aldol reaction. Excellent syn-
diastereoselection (Felkin–Anh control) has been recog-
nized in the BF3·OEt2-mediated aldol reaction of
a-methyl-b-siloxy aldehydes with a silylketene acetal
from ethyl propionate.9,10 A complementary access is,
however, needed to clarify the iterative syn- and anti-
stereoselection necessary for the diastereoselective
polypropionate construction because such systematic
studies have been restricted to the case of aldehydes
bearing only an a- or a b-stereocenter.11 Typical biden-
tate Lewis acids, e.g. TiCl4 and SnCl4, were known to
undergo chelation-controlled addition reactions in the
case of the above aldehydes.12 However, such Lewis
acids were reported to exhibit little to no chelating
capability in the aldol reaction of a-methyl-b-benzyloxy
aldehydes bearing a b-substituent with enol silanes.13
With respect to the process of introducing the stereo-
genic center at C-3, the Mukaiyama aldol reaction of
the silylketene acetal
BF3·OEt2 and TiCl4. As expected above, the BF3·OEt2
(1 equiv.)-mediated addition reaction of to
diastereomeric aldehydes, syn-24 and anti-25, resulted
2 was examined by using
2

S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
2901
Scheme 4.
in excellent 3,4-syn-selection to give Felkin–Anh con-
trolled products, 26 (single at C-2) and 27 (2:1 at C-2),
respectively, as shown in Scheme 5. Thus, the complete
syn-selection was confirmed to be reproducible at least
in this reaction system, although a relatively different
contribution of the resident b-stereocenter has been
reported for the Felkin–Anh controlled diastereoselec-
tivity in the non-chelate-controlled addition reaction of
similar aldehydes with enol silanes.10 On the other
hand, in spite of the predicted drawbacks of the lower
chelation ability13 of TiCl4 to the aldehyde type in
question, the TiCl4 (1.7 equiv.)-mediated addition reac-
tion of aldehydes, syn-24 and anti-25, with 2 was also
found to lead to fairly good 3,4-anti selection to give
the desired chelate-controlled adducts, 28 (a mixture at
C-2) and 29 (a mixture at C-2), respectively. The selec-
tivity at C-2 in achiral Lewis acid-promoted reactions
was not observed except in the case of 26 in contract to
that in chiral oxazaborolidinone-promoted aldol reac-
tions. The stereochemical outcomes in the above reac-
tions are rationally predicted, as follows: The
syn-adducts might be formed via the Felkin–Anh con-
trolled addition modes where the major factor responsi-
ble for the high syn-selection is attributable to the
potential differences in the steric bulkiness between the
methyl group and the residual group, involving the
methoxy substituent, at the C-2 of the aldehydes, as
shown in Figure 3. In spite of the indefinite prediction
of TiCl4 chelation control on a-methyl-b-protected-oxy
aldehydes as described above,13 the TiCl4-mediated
reaction of the syn-aldehyde 24 with 2 resulted in fairly
good anti selection (10:1). The reaction conditions are
noteworthy in that trapped TMS syn-selective adducts,
obtained through a catalytic reaction mode, were found
when the amount of TiCl4 used was not sufficient.
When we used SnCl4 under similar reaction conditions,
very high syn-selection (30:1) was found, which implied
a loss of the chelating ability of the Lewis acid. In the
case of the anti-aldehyde 25, if the chelation with TiCl4
was possible, the anti-selectivity would be considerably
diminished, because of the desired approach of the silyl
nucleophile under the chelation control would be pre-
vented by the b-methoxy substituent, oppositely
directed relative to the a-methyl in the chelated con-
former. Unexpectedly, the TiCl4-mediated reaction led
to remarkably good anti-selection (9:1). These results
suggest that the chelation controls are surely possible in
the TiCl4-mediated reaction of both syn- and anti-alde-
hydes, 24 and 25, as shown in Figure 3.
For the purpose of introducing a stereogenic center at
C-2 in elongating the polypropionate chains, an appro-
priate choice of a b-hydroxy protecting group of aldol
adducts was required while bearing in mind the stereo-
chemical demands for the following debromination pro-
cedures directed to syn- and anti-selections. Surveying a
number of protecting groups suitable for the following
diastereoselective debromination reactions, we again

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S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
position. In the debromination processes, the MOM
protection group allowed extremely high diastereoselec-
tion for both routes to the 2,3-syn-isomer via chelation
control and the 2,3-anti-isomer via dipole control, as
shown in Scheme 6. The MOM protection bearing two
oxygens prevented the participation of the methoxy
group at C-5 under the conditions of chelation control,
while the two oxygens enhanced the transient dipole
moment under the conditions of dipole control. The
stereocenter at C-2 of the bromides did not contribute
to the stereochemical outcome in the radical debromi-
nation process because the diastereoselection is
achieved at the sp2 carbon center of the radical species,
generated by Et3B. The 2,3-syn-selection can be
attributed to the effective chelation of MgBr2 to the
ethoxycarbonyl and the MOM moiety while the 2,3-
anti-selection was enhanced by the induced dipole–
dipole repulsion between the ethoxycarbonyl and the
MOM moiety, as indicated in Figure 2. After deprotec-
tion of the MOM group, followed by simple column
chromatography, the expected eight stereotetrads of
ethyl 3-hydroxy-2,4-dimethyl-5-methoxy-5-phenylpen-
tanoate, 42–49, were obtained essentially enantiopure
and in good yield.
3. Conclusion
The sequence in Scheme 1 of the highly enantioselective
and/or diastereoselective aldol reactions (process A)
and the following highly diastereoselective radical
debromination reaction (process B) has opened up a
very versatile and iterative approach towards the diver-
gent construction of polypropionate chains with accept-
able selectivity in good overall yields. This
straightforward strategy can tailor the desired configu-
ration in question during the synthesis of a class of
polyketide natural products. In the sequential process
A, iterative aldol reactions as reliable discrete ways to
the reverse diastereoselection can be simply achieved by
the selection of classical Lewis acids, BF3·OEt2 and
TiCl4. In process B, the MOM protection group effec-
tively affects both debromination reaction modes so as
to more predominantly allow an alternative
diastereoselection.
Scheme 5. Reagents and conditions: *1 BF3·OEt2 (1 equiv.),
CH2Cl2, −78°C, 1 h, 2 (1.5 equiv.); *2 TiCl4 (2 equiv.),
CH2Cl2, −78°C, 1 h, 2 (1.5 equiv.).
4. Experimental
4.1. General
Infrared spectra (IR) were determined with a JASCO
FT/IR-5300 Fourier-transform infrared spectrometer.
1H NMR spectra were determined at 400 MHz with a
JEOL JNM-LA 400 spectrometer. Chemical shifts are
expressed in ppm downfield from internal tetra-
methylsilane. 13C NMR spectra were measured at 100
MHz with a JEOL JNM-LA 400 spectrometer. High
performance liquid chromatography (HPLC) was done
with a JASCO Model PU-980 liquid chromatograph,
using DAICEL chiral columns. Optical rotations were
determined with a JASCO DIP-370 digital polarimeter.
Merck silica-gel 60 (230–400 mesh) was used for flash-
column chromatography.
Figure 3.
selected a methoxymethyl (MOM) protection group,
available for highly diastereoselective debrominations
to the desired eight stereotetrads. The major aldol
adducts, 26–29, were treated with dimethoxymethane
and P2O5 to give the corresponding MOM-protected
esters, 30–33, which consisted of isomers at the C-2

S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
2903
Scheme 6. Reaction conditions: The bromides, 27, 28, and 29 except 26, were converted to the corresponding MOM-derivatives,
30–33, without separation of isomers at C-2. The debromination procedures were done under the following conditions:
*1 MgBr2·OEt2 (7 equiv.), Bu3SnH (5 equiv.), Et3B (1 equiv.), CH2Cl2, −78°C, 15 h. *2 Bu3SnH (4 equiv.), Et3B (1 equiv.), toluene,
−78°C, 2 h. The major products were isolated after deprotection of the MOM group through the acidic work-up procedure.
4.2. 2-Bromo-1-ethoxy-2-methyl-1-(trimethylsiloxy)-
ethene 2
4.3. (2RS)-3-(tert-Butyldiphenylsiloxy)-2-methyl-
propanol 4
To a stirred solution of LDA (58 mmol) in THF (35
mL) (prepared in situ) at −78°C was added dropwise
ethyl 2-bromopropionate (9.1 g, 50 mmol) over 5 min.
After 15 min of stirring at the same temperature,
TMSCl (9.0 g, 83 mmol) was added over 10 min. The
reaction mixture was allowed to warm to ambient
temperature after which THF was removed with a
rotary evaporator and residue mixed with dry hexane
and filtered. After removal of the solvent, the residue
was distilled under a reduced pressure to give 2 (9.0 g,
71%, bp 73–74°C/0.1 mmHg), which contained ethyl
2-bromo-2-(trimethylsilyl)propionate (10–20%); IR
To a suspension of NaH (4.4 g, 100 mmol) in dry THF
(150 mL) was slowly added 2-methyl-1,3-propanediol (9
g, 90 mmol) in dry THF (10 mL). After the mixture was
stirred at rt for 45 min, TBDPSCl (24.7 g, 90 mmol) in
THF (10 mL) was added. The mixture was stirred at rt
for 15 h before quenching with water (25 mL). The
solution was extracted with ether, dried over anhydrous
MgSO4, evaporated in vacuo, and purified by flash-
column chromatography (10% ethyl acetate/hexane) to
give 4 (21.9 g, 74%) as a colorless oil; IR (neat): 3389,
1
2961 cm−1; H NMR (CDCl3) l (ppm)=0.83 (d, J=6.8
Hz, 3H), 1.06 (s, 9H), 1.92–2.07 (m, 1H), 2.65 (br s,
1H), 3.60 (dd, J=10.3, 7.3 Hz, 1H), 3.66 (d, J=6.4 Hz,
2H), 3.71 (dd, J=10.3, 4.9 Hz, 1H), 7.37–7.43 (m, 6H),
7.66–7.68 (m, 4H); 13C NMR (CDCl3): l (ppm)=13.2,
19.1, 26.8, 37.3, 67.5, 68.6, 127.7, 129.8, 133.2, 135.6.
Anal. calcd for C20H28O2Si: C, 73.12; H, 8.59. Found:
C, 73.20; H, 8.67.
1
(neat): 2962, 1655, 1251, 1219, 850 cm−1; Z-isomer: H
NMR (CDCl3): l (ppm)=0.22 (s, 9H), 1.20 (t, J=7.1
Hz, 3H), 2.14 (s, 3H), 3.84 (q, J=7.1 Hz, 2H); E-
1
isomer: H NMR (CDCl3): l (ppm)=0.19 (s, 9H), 1.22
(t, J=7.1 Hz, 3H), 2.08 (s, 3H), 3.88 (q, J=7.1 Hz,
2H).

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S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
4.4. (2RS)-3-(tert-Butyldiphenylsiloxy)-2-methyl-
13.8, 19.2, 24.2, 26.9, 37.4, 62.3, 67.8, 68.2, 74.8, 127.7,
129.7, 133.5, 135.6, 170.7. Anal. calcd for
C25H35BrO4Si: C, 59.16; H, 6.95. Found: C, 59.20; H,
7.02. The enantiomeric excess of the product was deter-
mined to be 92% by HPLC analysis using Chiralcel
OD-H (eluent: hexane/2-propanol (99:1), 0.5 mL/min,
254 nm) (tR of peak 1: 13.50 min, peak 2: 15.14 min).
propanal 5
To a stirred and cooled (−78°C) solution of (COCl)2
(5.4 mL, 63 mmol) in CH2Cl2 (100 mL) was added
DMSO (8.3 mL, 117 mmol). After 10 min, alcohol 4
(12.9 g, 39 mmol) in dry CH2Cl2 (5 mL) was added.
The mixture was stirred for 20 min after which Et3N
(21.7 mL, 156 mmol) was added. The solution was then
allowed to rise to 0°C. After stirring for an additional
30 min, a mixture of water (13 mL), ether (50 mL) and
benzene (25 mL) was added to quench the reaction. The
organic phase was separated, washed with water and
brine, dried over anhydrous MgSO4 and evaporated in
vacuo. The residue was purified by flash-column chro-
matography (5% ethyl acetate/hexane) to give 5 (11.2 g,
88%) as a colorless oil; IR (neat): 2957, 2932, 2885,
4.5.2. Ethyl (2S,3R,4R)-2-bromo-5-(tert-butyldiphenyl-
siloxy)-3-hydroxy-4-methylpentanoate 7. [h]2D4=−16.1 (c
1.23, CHCl3); IR (neat): 3528, 2932, 1732 cm−1; 1H
NMR (CDCl3): l (ppm)=0.89 (d, J=7.3 Hz, 3H), 1.07
(s, 9H), 1.30 (t, J=7.1 Hz, 3H), 1.78–1.84 (m, 1H), 1.86
(s, 3H), 3.43 (d, J=3.9 Hz, 1H), 3.73 (dd, J=10.3, 4.9
Hz, 1H), 3.84 (dd, J=10.3, 4.4 Hz, 1H), 4.16–4.31 (m,
3H), 7.25–7.45 (m, 6H), 7.65–7.68 (m, 4H); 13C NMR
(CDCl3): l (ppm)=11.0, 13.7, 14.6, 19.2, 21.7, 26.9,
38.3, 62.0, 67.4, 68.6, 127.7, 129.8, 133.1, 135.6, 170.7.
Anal. calcd for C25H35BrO4Si: C, 59.16; H, 6.95.
Found: C, 59.25; H, 6.84. The enantiomeric excess of
the product was determined to be 91% by HPLC
analysis using Chiralcel OD-H (eluent: n-hexane/2-
propanol (99:1), 0.5 mL/min, 254 nm) (tR of peak 1:
13.68 min, peak 2: 16.78 min).
1
2858, 1730 cm−1; H NMR (CDCl3): l (ppm)=1.04 (s,
9H), 1.09 (d, J=7.3 Hz, 3H), 2.55–3.0 (m, 1H), 3.86
(dd, J=10.3, 5.4 Hz, 1H) [one of ABq in ABX], 3.90
(dd, J=10.3, 5.9 Hz, 1H) [one of ABq in ABX],
7.24–7.43 (m, 6H), 7.63–7.65 (m, 4H), 9.76 (s, 1H); 13C
NMR (CDCl3): l (ppm)=10.3, 19.2, 26.7, 48.8, 64.1,
127.7, 129.8, 133.2, 135.6, 204.4. Anal. calcd for
C20H26O2Si: C, 73.57; H, 8.03. Found: C, 73.45; H,
8.12.
4.6. Enantioselective aldol reaction of 5 in the presence
of chiral borane (R)-1
4.5. Enantioselective aldol reaction of 5 in the presence
of chiral borane (S)-1
The aldol condensation procedure described above for
the preparation of 6 and 7 was employed using (R)-1.
Under an argon atmosphere, to a stirred solution of
N-p-tosyl-(S)-valine (299 mg, 1.1 mmol) in dry CH2Cl2
(5 mL) at 0°C was added dropwise a 1 M solution of
BH3·THF in THF (1.02 mL, 1.02 mmol) over 5 min
after which it was stirred for a further 30 min at the
same temperature. The resulting solution was then
allowed to warm to ambient temperature and subse-
quently stirred for 30 min. The solution was then
cooled to −78°C where 5 (327 mg, 1 mmol) in CH2Cl2
(1 mL) was slowly added over 5 min. After 5 min, the
silyl nucleophile 2 (760 mg, 3 mmol) was slowly intro-
duced and stirred for 3 h at −78°C. The reaction was
quenched by adding a buffer solution (10 mL, pH 6.8),
extracted with ether, washed with a satd NaHCO3
solution, followed with a satd NaCl solution and then
dried over anhydrous MgSO4. After evaporation of the
solvent, the crude was evaporated, and purified by flash
column chromatography (7% AcOEt in hexane) to
afford a mixture of aldol adducts, 6 and 7, (381 mg,
75%) and minor isomers (ꢀ4%) as a colorless oil,
which was then separated into each isomer by silca-gel
flash-column chromatography.
4.6.1. Ethyl (2R,3S,4R)-2-bromo-5-(tert-butyldiphenyl-
siloxy)-3-hydroxy-4-methylpentanoate the enantiomer of
6. [h]2D4=−1.2 (c 0.93, CHCl3).
4.6.2. 2. Ethyl (2R,3S,4S)-2-bromo-5-(tert-butyldi-
phenylsiloxy)-3-hydroxy-4-methylpentanoate the enan-
tiomer of 7. [h]2D4=+15.1 (c 1.66, CHCl3).
4.7. Methoxymethyl protection of aldol products
4.7.1. Ethyl (2S,3R,4S)-2-bromo-5-(tert-butyldiphenyl-
siloxy)-3-hydroxy-4-methylpentanoate 8. Under an
argon atmosphere at rt, to a stirred solution of 6 (233
mg, 0.46 mmol) and dimethoxymethane (5 mL) in dry
CHCl3 (5 mL) was added P2O5 (500 mg). This solution
was then stirred at the same temperature for 3 h. The
reaction was quenched by the slow addition of water (5
mL) at 0°C, extracted with ether, washed with a satd
NaHCO3 solution and a satd NaCl solution, dried over
anhydrous MgSO4, and evaporated. The resulting oil
was purified by flash column chromatography (5%
AcOEt in hexane) to afford 8 (226 mg, 89%). [h]2D4=
+27.8 (c 1.50, CHCl3); IR (neat): 2957, 2885, 1735 cm−1;
1H NMR (CDCl3): l (ppm)=0.99 (d, J=6.8 Hz, 3H),
1.06 (s, 9H), 1.21 (t, J=7.1 Hz, 3H), 1.80–1.89 (m, 1H),
1.89 (s, 3H), 3.31 (s, 3H), 3.47 (dd, J=9.8, 7.8 Hz, 1H),
3.58 (dd, J=9.8, 7.3 Hz, 1H), 4.05–4.25 (m, 2H), 4.18
(d, J=2.0 Hz, 1H), 4.76 (ABq, J=6.3 Hz, Dw=15.0
Hz, 2H), 7.25–7.44 (m, 6H), 7.64–7.67 (m, 4H); 13C
NMR (CDCl3): l (ppm)=12.0, 13.8, 19.2, 24.0, 26.8,
38.3, 56.3, 62.1, 66.7, 67.1, 81.7, 99.3, 127.6, 129.6,
133.6, 135.6, 170.2. Anal. calcd for C27H39BrO5Si: C,
58.79; H, 7.13. Found: C, 58.69; H, 7.24.
4.5.1. Ethyl (2S,3R,4S)-2-bromo-5-(tert-butyldiphenyl-
siloxy)-3-hydroxy-4-methylpentanoate 6. [h]2D4=+1.4 (c
1.44, CHCl3); IR (neat): 3529, 2935, 1732 cm−1; 1H
NMR (CDCl3): l (ppm)=0.97 (d, J=6.8 Hz, 3H), 1.07
(s, 9H), 1.25 (t, J=7.1 Hz, 3H), 1.89 (s, 3H), 1.87–2.07
(m, 1H), 2.65 (d, J=4.9 Hz, 1H), 3.52 (dd, J=9.8, 5.9
Hz, 1H) [one of ABq in ABX], 3.58 (dd, J=9.8, 6.8 Hz,
1H) [one of ABq in ABX], 4.18 (dq, J=9.7, 7.3 Hz,
2H), 4.28 (dd, J=4.9, 2.5 Hz, 1H), 7.25–7.42 (m, 6H),
7.63–7.66 (m, 4H); 13C NMR (CDCl3): l (ppm)=11.0,

S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
2905
4.7.2. Ethyl (2S,3R,4R)-2-bromo-5-(tert-butyldiphenyl-
4.9. Radical debromination under chelation conditions
siloxy)-3-methoxymethoxy-4-methylpentanoate 9. Com-
pound 9 was prepared from 7 (91%) using the same
procedure as 8. [h]2D7=+23.7 (c 5.10, CHCl3); IR (neat):
2957, 2932, 2885, 1732 cm−1. 1H NMR (CDCl3): l
(ppm)=1.05 (s, 9H), 1.06 (d, J=6.8 Hz, 3H), 1.32 (t,
J=7.1 Hz, 3H), 1.65–1.74 (m, 1H), 1.74 (s, 3H), 3.20 (s,
3H), 3.56 (dd, J=10.3, 7.8 Hz, 1H), 3.80 (dd, J=10.3,
3.4 Hz, 1H), 4.05 (d, J=4.9 Hz, 1H), 4.25 (dq, J=7.3,
2.4 Hz, 2H), 4.73 (ABq, J=6.8 Hz, Dw=27.8 Hz, 2H),
7.25–7.43 (m, 6H), 7.62–7.67 (m, 4H); 13C NMR
(CDCl3): l (ppm)=13.8, 16.5, 19.3, 21.8, 26.9, 39.5,
56.4, 62.0, 65.6, 65.9, 85.0, 100.0, 127.6, 129.6, 133.7,
135.6, 170.3. Anal. calcd for C27H39BrO5Si: C, 58.79;
H, 7.13. Found: C, 58.67; H, 7.21.
4.9.1. Ethyl (2S,3R,4S)-5-(tert-butyldiphenylsiloxy)-3-
methoxymethoxy-2,4-dimethylpentanoate 11. Under an
argon atmosphere, Mg turnings (78 mg, 3.2 mmol) were
treated with 1,2-dibromoethane (603 mg, 3.2 mmol) at
rt in dry ether (7 mL) until the reaction went to
completion. To a stirred suspension of the residue and
MOM-protected bromide 8 (254 mg, 0.46 mmol) in
CH2Cl2 (6 mL) at −78°C was added Bu3SnH dropwise
(0.62 mL, 2.3 mmol) and then Et3B (0.46 mL, 0.46
mmol, 1 M soln in hexanes) in 1/3 portions every 15
min with the resulting mixture being left to stir for 15 h
at the same temperature. The reaction was then
quenched by the addition of water, extracted with
ether, washed with a satd NaCl solution, and dried over
anhydrous MgSO4. After evaporation of the solvent,
the residue was purified by flash-column chromatogra-
phy to afford compound 11 (195 mg, 77%). The ratio of
syn:anti was found to be 8:1 on the basis of NMR data.
[h]2D7=+9.3 (c 1.91%, CHCl3); IR (neat): 2957, 2930,
4.8. Radical debromination under dipole conditions
4.8.1. Ethyl (2R,3R,4S)-5-(tert-butyldiphenylsiloxy)-3-
methoxymethoxy-2,4-dimethylpentanoate 10. Under an
argon atmosphere, to a stirred solution of MOM-pro-
tected bromide 8 (552 mg, 1 mmol) in toluene (15 mL)
at −78°C was added dropwise Bu3SnH (0.8 mL, 3
mmol) and then Et3B (0.6 mL, 0.6 mmol, 1 M soln in
hexanes) in 1/3 portions every 15 min with the resulting
mixture being left to stir for 2 h at the same tempera-
ture. The reaction was then quenched by the addition
of water, extracted with ether, washed with a satd NaCl
solution, and dried over anhydrous MgSO4. After evap-
oration of the solvent, the residue was purified by
flash-column chromatography to afford compound 10
as a colorless oil (397 mg, 72%). The ratio of anti:syn
was found to be 15:1 on the basis of NMR data.
[h]2D7=+4.0 (c 7.50, CHCl3); IR (neat): 2958, 2932,
1
2885, 1728 cm−1; H NMR (CDCl3): l (ppm)=0.91 (d,
J=6.8 Hz, 3H), 1.06 (s, 9H), 1.19 (d, J=7.3 Hz, 3H),
1.25 (t, J=7.1 Hz, 3H), 1.77–1.91 (m, 1H), 2.72 (dq,
J=6.8, 6.3 Hz, 1H), 3.31 (s, 3H), 3.50 (dd, J=10.3, 5.4
Hz, 1H), 3.58 (dd, J=10.3, 6.8 Hz, 1H), 4.01 (dd,
J=6.4, 4.4 Hz, 1H), 4.15 (dq, J=6.8, 1.5 Hz, 1H), 4.64
(ABq, J=7.1 Hz, Dw=19.5 Hz, 2H), 7.35–7.43 (m, 6H),
7.64–7.72 (m, 4H); 13C NMR (CDCl3): l (ppm)=11.7,
12.8, 14.1, 19.2, 26.9, 39.0, 42.9, 56.1, 60.4, 66.1, 80.8,
98.5, 127.6, 129.6, 133.6, 135.6, 175.0. Anal. calcd for
C27H40O5Si: C, 68.61; H, 8.53. Found: C, 68.52; H,
8.64.
1
2885, 2858, 1726 cm−1; H NMR (CDCl3): l (ppm)=
4.9.2. Ethyl (2S,3R,4R)-5-(tert-butyldiphenylsiloxy)-3-
methoxymethoxy-2,4-dimethylpentanoate 13. Employing
the radical reduction procedure described for the prepa-
ration of 10, the reaction of 11 gave 13 (82%). The ratio
of anti:syn was found to be 5:1. [h]2D7=−6.0 (c 0.52,
CHCl3); IR (neat): 2959, 2931, 2885, 2858, 1730 cm−1;
1H NMR (CDCl3): l (ppm)=0.99 (d, J=6.8 Hz, 3H),
1.07 (s, 9H), 1.13 (d, J=7.3 Hz, 3H), 1.25 (t, J=7.1 Hz,
3H), 1.80–1.90 (m, 1H), 2.67 (dq, J=7.1, 3.9 Hz, 1H),
3.19 (s, 3H), 3.63 (dd, J=9.8, 5.9 Hz, 1H), 3.73 (dd,
J=9.8, 3.9 Hz, 1H), 3.96 (dd, J=7.8, 3.9 Hz, 1H), 4.12
(q, J=7.1 Hz, 2H), 4.49 (ABq, J=6.6 Hz, Dw=32.8
Hz, 2H), 7.25–7.43 (m, 6H), 7.62–7.67 (m, 4H); 13C
NMR (CDCl3): l (ppm)=10.1, 14.1, 14.4, 19.3, 26.9,
39.0, 41.7, 56.0, 60.4, 65.5, 81.7, 98.2, 127.6, 129.6,
133.8, 135.7, 175.1. Anal. calcd for C27H40O5Si: C,
68.61; H, 8.53. Found: C, 68.70; H, 8.45.
0.82 (d, J=6.8, 3H), 1.07 (s, 9H), 1.08 (d, J=6.8 Hz,
3H), 1.25 (t, J=7.1 Hz, 3H), 1.80–1.90 (m, 1H), 2.70
(dq, J=9.3, 7.3 Hz, 1H), 3.23 (s, 3H), 3.51 (dd, J=9.8,
6.4 Hz, 1H), 3.63 (dd, J=9.8, 7.3 Hz, 1H), 3.98 (dd,
J=9.8, 2.0 Hz, 1H), 4.08–4.18 (m, 2H), 4.59 (ABq,
J=6.8 Hz, Dw=11.7 Hz, 2H), 7.35–7.43 (m, 6H), 7.64–
7.72 (m, 4H); 13C NMR (CDCl3): l (ppm)=9.9, 14.1,
14.4, 19.2, 26.9, 37.1, 43.7, 55.9, 60.3, 66.1, 80.7, 98.5,
127.6, 129.6, 133.8, 135.6, 175.4. Anal. calcd for
C27H40O5Si: C, 68.61; H, 8.53. Found: C, 68.70; H,
8.61.
4.8.2. Ethyl (2R,3R,4R)-5-(tert-butyldiphenylsiloxy)-3-
methoxymethoxy-2,4-dimethylpentanoate 12. Employing
the radical reduction procedure described for the prepa-
ration of 10, the reaction of 9 gave 12 (85%). The ratio
of anti:syn was found to be 12:1. [h]2D7=−6.9 (c 2.52,
CHCl3); IR (neat): 2957, 2932, 2886, 1732 cm−1; 1H
NMR (CDCl3): l (ppm)=0.98 (d, J=6.8 Hz, 3H), 1.07
(s, 9H), 1.11 (d, J=7.3 Hz, 3H), 1.25 (t, J=7.1 Hz,
3H), 1.92–2.02 (m, 1H), 2.85 (dq, J=6.8, 6.8 Hz, 1H),
3.26 (s, 3H), 3.61 (dd, J=10.3, 6.4 Hz, 1H), 3.73 (dd,
J=9.8, 4.9 Hz, 1H), 3.77 (t, J=5.9 Hz, 1H), 4.12 (dq,
J=7.3, 2.0 Hz, 2H), 4.58 (s, 2H), 7.25–7.43 (m, 6H),
7.62–7.67 (m, 4H). 13C NMR (CDCl3): l (ppm)=12.9,
14.2, 14.3, 19.3, 26.9, 37.8, 42.9, 55.9, 60.3, 65.2, 83.1,
98.1, 127.6, 129.6, 133.8, 135.7, 174.8. Anal. calcd for
C27H40O5Si: C, 68.61; H, 8.53. Found: C, 68.72; H,
8.65.
4.10. Deprotection of the MOM group of 10–13 with
TiCl4
4.10.1. Ethyl (2R,3R,4S)-5-(tert-butyldiphenylsiloxy)-
2,4-dimethyl-3-hydroxypentanoate 14. To a stirred solu-
tion of the MOM-compound 10 (270 mg, 0.57 mmol) in
dry CH2Cl2 (5 mL) at rt was added dropwise a 1 M
solution of TiCl4 in CH2Cl2 (0.85 mL, 0.85 mmol). The
solution was stirred at the same temperature for 30
min. The reaction was then quenched with a buffer
solution (3 mL, pH 6.8), followed by the addition of

2906
S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
water (3 mL), extracted with ether (10 mL), dried over
anhydrous MgSO4, and evaporated. The resulting oil
was purified by flash-column chromatography (7%
ethylacetate/hexane) to give MOM-deprotected product
14 (218 mg, 89%). [h]2D6=−7.1 (c 3.35, CHCl3); IR
dry CH2Cl2 (150 mL) at 0°C was added dropwise a 1 M
solution of BH3·THF in THF (60 mL, 60 mmol) over a
period of 5 min after which it was left to stir at 0°C for
30 min. The resulting solution was then allowed to
warm to ambient temperature and subsequently stirred
for 30 min. The solution was then cooled to −78°C after
which benzaldehyde (6.1 mL, 60 mmol) in CH2Cl2 (10
mL) was slowly added over 5 min. After 5 min, 2 was
also introduced over 5 min and the resulting solution
stirred for 15 h at −78°C. The reaction mixture was
quenched by the addition of buffer solution (10 mL, pH
6.8), extracted with ether, and washed with a satd
NaHCO3 solution, followed by the addition of a satd
NaCl solution, dried over anhydrous MgSO4, and evap-
orated. The residue was purified by flash-column chro-
matography (7% AcOEt in hexane) to afford a mixture
of 18 and 19 (12.8 g, 73% yield), which could be
separated into each isomer. The ratio of syn:anti was
found to be 6.6:1): l (ppm)=13.7, 22.5, 62.4, 67.6, 77.1,
127.9, 128.0, 128.5, 136.8, 170.4. The enantiomeric
excess of the syn-isomer was determined to be 90% ee
by HPLC analysis using Chiralcel OD-H (tR of peak 1:
24.04 min; tR of peak 2: 27.31 min; eluent, hexane/2-
propanol=97.5:2.5, 0.5 mL/min). Anal. calcd for
C12H15O3Br: C, 50.17; H, 5.23. Found: C, 50.20; H,
5.21.
1
(neat): 3520, 2957, 2885, 1725 cm−1; H NMR (CDCl3):
l (ppm)=0.91 (d, J=7.3 Hz, 3H), 1.06 (s, 9H), 1.10 (d,
J=7.3 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H), 1.72–1.83 (m,
1H), 2.59 (dq, J=7.1, 6.8 Hz, 1H), 2.89 (d, J=4.4 Hz,
1H), 3.65–3.75 (m, 2H), 3.98–4.03 (m, 1H), 4.12–4.25
(m, 2H), 7.25–7.43 (m, 6H), 7.62–7.67 (m, 4H); 13C
NMR (CDCl3): l (ppm)=9.47, 14.1, 14.2, 19.2, 26.9,
36.7, 43.3, 60.5, 67.8, 74.3, 127.7, 129.7, 133.2, 135.6,
176.3. Anal. calcd for C25H36O4Si: C, 70.05; H, 8.47.
Found: C, 70.11; H, 8.38.
4.10.2. Ethyl (2S,3R,4S)-5-(tert-butyldiphenylsiloxy)-
2,4-dimethyl-3-hydroxypentanoate 15. [h]2D5=+10.1 (c
0.79, CHCl3); IR (neat): 3517, 2957, 2885, 1725 cm−1;
1H NMR (CDCl3): l (ppm)=1.01 (d, J=6.8 Hz, 3H),
1.06 (s, 9H), 1.24 (d, J=7.3 Hz, 3H), 1.24 (t, J=7.1 Hz,
3H), 1.67–1.78 (m, 1H), 2.65 (dq, J=7.3, 6.8 Hz, 1H),
2.98 (d, J=2.9 Hz, 1H), 3.61 (dd, J=10.3, 4.9 Hz, 1H),
3.72 (dd, J=10.3, 3.9 Hz, 1H), 3.99 (dt, J=7.3, 3.6 Hz,
1H), 4.12 (dq, J=7.3, 2.0 Hz, 2H), 7.25–7.43 (m, 6H),
7.62–7.67 (m, 4H); 13C NMR (CDCl3): l (ppm)=10.9,
13.2, 14.2, 19.2, 26.9, 37.4, 43.2, 60.4, 68.3, 74.8, 127.7,
129.8, 132.9, 135.6, 175.7. Anal. calcd for C25H36O4Si:
C, 70.05; H, 8.47. Found: C, 70.00; H, 8.52.
4.11.1. Ethyl (2R,3R)-2-bromo-3-hydroxy-2-methyl-3-
phenylpropionate 19. [h]2D6=−38.6 (c 3.00, CHCl3); IR
1
(neat): 3508, 1734 cm−1; H NMR (CDCl3): l (ppm)=
4.10.3. Ethyl (2R,3R,4R)-5-(tert-butyldiphenylsiloxy)-
2,4-dimethyl-3-hydroxypentanoate 16. [h]2D5=−16.7 (c
2.09, CHCl3); IR (neat): 3500, 2957, 2885, 1730 cm−1;
1H NMR (CDCl3): l (ppm)=0.99 (d, J=6.8 Hz, 3H),
1.06 (s, 9H), 1.20 (d, J=6.8 Hz, 3H), 1.27 (t, J=7.1 Hz,
3H), 1.82–1.93 (m, 1H), 2.75 (dq, J=7.1, 5.4 Hz, 1H),
3.42 (d, J=7.3 Hz, 1H), 3.63 (dt, J=6.8, 6.3 Hz, 1H),
3.73 (dq, J=10.3, 4.9 Hz, 2H), 4.12–4.21 (m, 2H),
7.25–7.43 (m, 6H), 7.62–7.67 (m, 4H); 13C NMR
(CDCl3): l (ppm)=14.2, 14.4, 14.5, 19.2, 26.8, 38.0.
42.9, 60.4, 66.8, 77.2, 127.7, 129.7, 133.1, 135.6, 175.7;
Anal. calcd for C25H36O4Si: C, 70.05; H, 8.47. Found:
C, 70.09; H, 8.53.
1.33 (t, J=7.1 Hz, 3H), 1.79 (s, 3H), 3.22 (d, J=5.1 Hz,
1H), 4.30 (dq, J=5.1, 7.1 Hz, 2H), 5.31 (d, J=5.1 Hz,
1H), 7.26–7.49 (m, 5H); 13C NMR (CDCl3): l (ppm)=
13.8, 22.1, 62.1, 62.5, 77.9, 127.7, 128.4, 128.5, 137.4,
171.2. The enantiomeric excess of the syn-isomer was
determined to be 90% ee by HPLC analysis using
Chiralcel OD-H (tR of peak 1: 19.76 min; tR of peak 2:
30.59 min; eluent, hexane/2-propanol=98:2, 1 mL/
min). Anal. calcd for C12H15O3Br: C, 50.17; H, 5.23.
Found: C, 50.15; H, 5.24.
4.12. Radical reduction of a mixture of 18 and 19
Under an argon atmosphere, to a stirred solution of
(2S,3R)- and (2R,3R)-2-bromo-3-hydroxy-2-methyl-3-
phenylpropionates in CH2Cl2 (6 mL) at −78°C was
added dropwise Bu3SnH (0.53 mL, 1.9 mmol) and then
Et3B (0.64 mL, 0.64 mmol, 1 M solution in THF) 1/3
portions every 15 min and then left to stir for 4 h at the
same temperature. The reaction was then quenched by
the addition of water, extracted with ether, washed with
a satd NaCl solution and dried over anhydrous MgSO4,
evaporated. The residue was purified by flash-column
chromatography (5% AcOEt in hexane) to afford 20
(30%) and 21 (49%), respectively.
4.10.4. Ethyl (2S,3R,4R)-5-(tert-butyldiphenylsiloxy)-
2,4-dimethyl-3-hydroxypentanoate 17. [h]2D5=−9.8 (c
1.50, CHCl3); IR (neat): 3495, 2957, 2885, 1728 cm−1;
1H NMR (CDCl3): l (ppm)=0.88 (d, J=6.8 Hz, 3H),
1.06 (s, 9H), 1.20 (d, J=7.3 Hz, 3H), 1.26 (t, J=7.1 Hz,
3H), 1.72–1.83 (m, 1H), 2.61 (dq, J=6.8, 3.9 Hz, 1H),
3.51 (d, J=3.4 Hz, 1H), 3.71 (dd, J=10.3, 5.9 Hz, 1H),
3.83 (dd, J=9.8, 3.9 Hz, 1H), 3.96 (dt, J=12.0, 3.9 Hz,
1H), 4.16 (q, J=6.8 Hz, 1H), 7.25–7.43 (m, 6H), 7.62–
7.67 (m, 4H); 13C NMR (CDCl3): l (ppm)=9.8, 13.7,
14.2, 19.2, 26.9, 37.4, 42.4, 60.5, 67.9, 75.3, 127.7, 129.7,
133.0, 135.6, 175.9. Anal. calcd for C25H36O4Si: C,
70.05; H, 8.47. Found: C, 70.12; H, 8.40.
4.12.1. Ethyl (2S,3S)-3-methoxy-2-methyl-3-phenylpropi-
onate 20. [h]2D3=−15.7 (c 2.10, CHCl3); IR (neat): 3477,
1728 cm−1; 1H NMR (CDCl3): l (ppm)=1.13 (d, J=7.0
Hz, 3H), 1.21 (t, J=7.0 Hz, 3H), 2.77 (dq, J=2.9, 7.0
Hz, 1H), 2.98 (d, J=3.1 Hz, 1H), 4.12 (dq, J=4.1, 7.0
Hz, 2H), 5.09 (dd, J=3.4, 4.1 Hz, 1H), 7.25–7.68 (m,
5H); 13C NMR (CDCl3): l (ppm)=10.8, 14.0, 46.4,
4.11. Enantioselective aldol reaction of a benzaldehyde
with 2 in the presence of (S)-1
Under an argon atmosphere, to a stirred solution of
N-(p-toluenesulfonyl)-(S)-valine (19.5 g, 72 mmol) in

S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
2907
60.0, 70.3, 125.9, 127.4, 128.1, 141.4, 175.7. The enan-
tiomeric excess of the syn-isomer was determined to be
90% ee by HPLC analysis using Chiralcel OD-H (tR of
peak 1: 11.64 min; tR of peak 2: 12.47 min; eluent,
hexane/2-propanol=97:3, 1 mL/min). Anal. calcd for
C12H16O3: C, 69.23; H, 7.69. Found: C, 69.31; H, 7.70.
ing solution was then stirred at the same temperature
for 2 h. The reaction was quenched by the slow addi-
tion of MeOH (1 mL). After addition of water (5 mL),
the solution was extracted with ether, washed with a
satd NaCl solution, dried over anhydrous MgSO4 and
evaporated. The residue was purified by flash-column
chromatography (10% AcOEt in hexane) to afford 24
(798 mg, 68%). [h]2D4=−61.2 (c 0.98, CHCl3); IR (neat):
4.12.2. Ethyl (2R,3S)-3-methoxy-2-methyl-3-phenylpro-
pionate 21. [h]2D3=−42.3 (c 2.50, CHCl3); IR (neat):
1
2986, 1726 cm−1; H NMR (CDCl3): l (ppm)=1.06 (d,
1
3458, 1732 cm−1; H NMR (CDCl3): l (ppm)=1.00 (d,
J=7.0 Hz, 3H), 1.22 (ddq, J=1.2, 4.8, 7.0 Hz, 1H),
4.60 (d, J=4.8 Hz, 1H), 7.25–7.39 (m, 5H), 9.81 (d,
J=2.9 Hz, 1H); 13C NMR (CDCl3): l (ppm)=8.41,
53.0, 57.1, 82.4, 126.8, 127.8, 128.4, 138.9, 203.5.
J=7.3 Hz, 3H), 1.25 (t, J=7.3 Hz, 3H), 2.79 (dq,
J=1.0, 7.3 Hz, 1H), 2.98 (d, J=4.4 Hz, 1H), 4.18 (q,
J=7.3 Hz, 2H), 4.75 (dd, J=4.4, 8.2 Hz, 1H), 7.26–
7.37 (m, 5H); 13C NMR (CDCl3): l (ppm)=14.0, 14.4,
47.1, 60.6, 76.2, 126.6, 127.9, 128.3 141.6, 175.7. The
enantiomeric excess of the syn-isomer was determined
to be 90% ee by HPLC analysis using Chiralcel OD-H
(tR of peak 1: 15.09 min; tR of peak 2: 25.43 min;
eluent, hexane/2-propanol=97:3, 1 mL/min). Anal.
calcd for C12H16O3: C, 69.23; H, 7.69. Found: C, 69.18;
H, 7.71.
4.14.2. (2R,3S)-3-Methoxy-2-methyl-3-phenylpropanal
25. [h]2D3=−89.0 (c 1.14, CHCl3); IR (neat): 3030, 2982,
1736 cm−1; 1H NMR (CDCl3): l (ppm)=0.83 (d, J=7.0
Hz, 3H), 2.71 (ddq, J=1.1, 7.0, 9.0 Hz, 1H), 3.18 (s,
3H), 4.27 (d, J=9 Hz, 1H), 7.29–7.40 (m, 5H), 9.81 (d,
J=2.9 Hz, 1H); 13C NMR (CDCl3): l (ppm)=10.9,
52.6, 56.7, 84.8, 127.3 128.2, 128.5, 138.7, 204.0.
4.13. Methyl protection of 20 and 21
4.15. syn-Selective BF3·OEt2-promoted aldol reaction
of syn-24 and anti-25
4.13.1. Ethyl (2R,3S)-3-methoxy-2-methyl-3-phenylpro-
pionate 22. To a stirred solution of 20 (2.51 g, 12.5
mmol) in dry CH2Cl2 (20 mL) at room temperature was
added methyl iodide (3.9 mL) and stirred for 15 min.
Silver oxide (14.7 mg, 61.2 mmol) was added and the
solution left to stir for 15 h. Methyl iodide (3.9 mL)
was added and the solution stirred for 1 h at the same
temperture. After addition of ether (20 mL), the solu-
tion was washed with a satd NH4Cl solution, dried over
anhydrous MgSO4, and evaporated. The residue was
purified by flash-column chromatography (4% AcOEt
in hexane) to afford 22 (85%). [h]2D5=−34.0 (c 1.00,
4.15.1.
Ethyl
(2S,3R,4R,5S)-2-bromo-3-hydroxy-5-
methoxy-2,4-dimethyl-5-phenylpentanoate 26. Under an
argon atmosphere, to a stirred solution of BF3·OEt2
(0.88 mL, 7.01 mmol) in dry CH2Cl2 (35 mL) at −78°C
was added dropwise the aldehyde syn-24 (1.25 g, 7.01
mmol) over 5 min. After stirring at the same tempera-
ture for 15 min, bromo silyl nucleophile 2 (2.66 g, 10.5
mmol) was introduced over 10 min and the resulting
solution stirred for an additional 1 h at −78°C. The
reaction was quenched with a buffer solution (10 mL,
pH 6.8), extracted with ether, washed with a satd NaCl
solution, and dried over anhydrous MgSO4. After evap-
oration of the solvent, the crude residue was purified by
flash-column chromatography (8% AcOEt in n-hexane)
to afford 26 as a single isomer (2.19 g, 87%). [h]2D0=
−17.0 (c 1.06, CHCl3); IR (neat): 3497, 2984, 1730 cm−1;
1H NMR (CDCl3): l (ppm)=0.92 (d, J=7.1 Hz, 3H),
1.32 (t, J=7.1 Hz, 3H), 1.87 (s, 3H), 1.92 (ddq, J=1.4,
2.4, 4.6 Hz, 1H), 3.02 (d, J=3.2 Hz, 1H), 3.29 (s, 3H),
4.25 (dq, J=2.2, 7.1 Hz, 2H), 4.27 (d, J=1.7 Hz, 1H),
4.28 (dd, J=4.9, 8.8 Hz, 1H), 7.21–7.38 (m, 5H); 13C
NMR (CDCl3) l (ppm)=8.0, 13.9, 23.8, 41.9, 57.5,
62.3, 66.6, 77.2, 88.3, 126.9, 127.6, 128.2, 139.5, 170.7.
Anal. calcd for C16H23O4Br: C, 53.48; H, 6.41. Found:
C, 53.52; H, 6.39.
1
CHCl3); IR (neat): 2984, 1734 cm−1; H NMR (CDCl3):
l (ppm)=1.07 (d, J=7.0 Hz, 3H), 1.22 (t, J=6.8 Hz,
3H), 2.73 (quin, J=7.0 Hz, 1H), 3.22 (s, 3H), 3.98 (Abq
in ABX3, J=7.0, 10.8 Hz, Dw=14.8 Hz, 2H), 4.40 (d,
J=7.0 Hz, 1H), 7.29–7.38 (m, 5H); 13C NMR (CDCl3):
l (ppm)=12.5, 13.9, 47.4, 57.1, 60.2, 84.5, 127.1, 127.7,
128.1, 139.7, 173.9. Anal. calcd for C13H18O3: C, 70.27;
H, 8.10. Found: C, 70.20; H, 8.08.
4.13.2. Ethyl (2S,3S)-3-methoxy-2-methyl-3-phenylpropi-
onate 23. [h]2D5=−51.9 (c 1.56, CHCl3); IR (neat): 2982,
1736 cm−1; 1H NMR (CDCl3): l (ppm)=0.86 (d, J=7.0
Hz, 3H), 1.30 (t, J=7.0 Hz, 3H), 2.73 (dq, J=7.3, 9.7
Hz, 1H), 3.15 (s, 3H), 4.22 (Abq in ABX3, J=7.0, 11.3
Hz, Dw=22.9 Hz, 2H), 4.24 (d, J=10.0 Hz, 1H), 7.29–
7.38 (m, 5H); 13C NMR (CDCl3): l (ppm)=14.0, 14.2,
47.1, 56.7, 60.4, 85.9, 127.6, 128.1, 128.3, 138.9, 175.3.
Anal. calcd for C13H18O3: C, 70.27; H, 8.10. Found: C,
70.09; H, 8.11.
4.15.2.
Ethyl
(2R,3S,4S,5S)-2-bromo-3-hydroxy-5-
27. The
methoxy-2,4-dimethyl-5-phenylpentanoate
bromo-aldol adducts of 27 and the isomer at C-2 were
obtained from the reaction of the anti-25 (2:1 ratio)
(92%). [h]2D7=−29.5 (c 0.78, CHCl3); IR (neat): 3526,
1
4.14. DIBAL reduction of 22 and 23
2984, 1732 cm−1; H NMR (CDCl3): l (ppm)=0.92 (d,
J=7.1 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H), 1.88 (s 3H),
1.91 (m, 1H), 3.03 (d, J=3.2 Hz, 1H), 3.29 (s, 3H), 4.25
(dq, J=4.2, 6.8 Hz, 2H), 4.27 (d, J=3.4 Hz, 1H), 4.28
(dd, J=4.9, 9.1 Hz, 1H), 7.19–7.38 (m, 5H); 13C NMR
(CDCl3): l (ppm)=8.0, 13.9, 23.7, 41.9, 57.5, 62.2,
66.6, 77.2, 88.3, 126.8, 127.6, 128.3, 139.5, 170.7. Anal.
4.14.1. (2S,3S)-3-Methoxy-2-methyl-3-phenylpropanal
24. Under an argon atmosphere, to a stirred solution of
22 (1.46 g, 6.56 mmol) in dry CH2Cl2 (25 mL) at −78°C
was added dropwise a 1 M solution of DIBAL in
toluene (19.6 mL, 19.6 mmol) over 30 min. The result-

2908
S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
1
calcd for C16H23O4Br: C, 53.48; H, 6.41. Found: C,
53.54; H, 6.45.
4.16.2.1. The C-2 isomer of 29. H NMR (CDCl3): l
(ppm)=0.54 (d, J=7.0 Hz, 3H), 1.24 (t, J=7.3 Hz,
3H), 1.92 (s, 3H), 2.12 (m, 1H), 3.17 (s, 3H), 4.21 (m,
2H), 4.25 (m, 2H), 4.66 (d, J=3.9 Hz, 1H), 7.25–7.38
(m, 5H); 13C NMR (CDCl3): l (ppm)=8.9, 14.26, 24.6,
45.9, 61.4, 64.7, 80.7, 86.93, 126.8, 127.6, 127.8, 128.2,
140.2, 173.6.
4.15.3.
Ethyl
(2S,3S,4S,5S)-2-bromo-3-hydroxy-5-
methoxy-2,4-dimethyl-5-phenylpentanoate the isomer of
27. [h]2D5=−64.6 (c 1.01, CHCl3); IR (neat): 3349, 2982,
1734 cm−1; 1H NMR (CDCl3): l (ppm)=0.65 (d, J=6.8
Hz, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.92 (s, 3H), 2.24
(ddq, J=1.2, 6B, 8.3 Hz, 1H), 3.21 (s, 3H), 3.38 (d,
J=7.3 Hz, 1H), 4.08 (d, J=8.0 Hz, 1H), 4.24 (ABq in
ABX3, J=7.1, 10.9 Hz, Dw=10.0 Hz, 2H), 4.61 (dd,
J=7.1, 1.5 Hz, 1H), 7.26–7.38 (m, 5H); 13C NMR
(CDCl3): l (ppm)=10.7, 13.8, 24.9, 40.6, 57.1, 62.4,
63.5, 74.9, 86.5, 127.5, 127.8, 128.3, 140.4, 171.6.
4.17. A typical procedure of a syn-selective radical
debromination reaction from 26–29 to 42, 44, 46, and
48
4.17.1. Ethyl (2S,3R,4R,5S)-3-hydroxy-2,4-dimethyl-5-
methoxy-5-phenylpentanoate 42. Under an argon atmo-
sphere, Mg turnings (78 mg, 3.2 mmol) were treated
with 1,2-dibromoethane (603 mg, 3.2 mmol) at rt in dry
ether (7 mL) until the reaction went to completion. To
a stirred suspension of the residue and MOM-protected
bromide 30 (193 mg, 0.46 mmol), which was prepared
from 26 according to the standard procedure for 8
(85%) and used without further purification, in CH2Cl2
(6 mL) at −78°C was added dropwise Bu3SnH (0.62
mL, 2.3 mmol) and then Et3B (0.46 mL, 0.46 mmol, 1
M soln in hexanes) in 1/3 portions every 15 min with
the resulting mixture being left to stir for 15 h at the
temperature. The reaction was quenched by the addi-
tion of water, extracted with ether, washed with a satd
NaCl solution, and dried over anhydrous MgSO4. After
evaporation of the solvent, the residue was purified by
flash-column chromatography to afford compound 34
(140 mg, 95%). The ratio of syn:anti was found to be
>30:1 on the basis of NMR data. Compound 34 (136
mg, 0.4 mmol) was then dissolved in a solution of THF
(1 mL), water (1 mL), and 6 M hydrochloric acid (1
mL). After being stirred at rt for 3 h, the solution was
extracted with ether, washed with a satd Na2CO3 solu-
tion, and dried over anhydrous MgSO4. After evapora-
tion of the solvent, the residue was purified by
flash-column chromatography (15% AcOEt in hexane)
to afford 42 (91 mg, 85%). [h]2D8=−44.6 (c 0.56, CHCl3);
4.16. anti-Selective TiCl4-promoted aldol reaction of
syn-24 and anti-25
4.16.1.
Ethyl
(3S,4S,5S)-2-bromo-2,4-dimethyl-3-
hydroxy-5-methoxy-5-phenylpropionate 28. Under an
argon atmosphere, to a stirred solution of TiCl4 (0.36
mL, 3.29 mmol) in dry CH2Cl2 (15 mL) at −78°C was
added dropwise the aldehyde syn-24 (278 mg, 1.64
mmol) over 5 min. After stirring at the temperature for
an additional 30 min, silylketene acetal 2 (624 mg, 2.47
mmol) was introduced over 5 min and the resulting
solution stirred for another hour at −78°C. The reac-
tion was quenched with a buffer solution (3 mL, pH
6.8), extracted with ether, washed with a satd NaCl
solution and dried over anhydrous MgSO4. After evap-
oration of the solvent, the crude residue was purified by
flash-column chromatography (10% AcOEt in hexane)
to afford a mixture of 28 and the C-2 isomer (10:1
ratio) (363 mg, 73%), accompanied by a small amount
1
of 3,4-syn isomers. H NMR (CDCl3): l (ppm)=0.69
(d, J=7.3 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H), 1.90 (s,
3H), 2.01 (m, 1H), 3.31 (s, 3H), 3.57 (dd, J=2.6, 3.4
Hz, 1H), 4.22 (m, 2H), 4.33 (dd, J=3.4, 7.3 Hz, 1H),
4.83 (d, J=2.2 Hz, 1H), 7.23–7.37 (m, 5H). Anal. calcd
for C16H23O4Br: C, 53.48; H, 6.41. Found: C, 53.46; H,
6.43.
1
IR (neat): 3489, 2980, 1730 cm−1; H NMR (CDCl3): l
(ppm)=0.84 (d, J=7.0 Hz, 3H), 1.22 (t, J=7.3 Hz,
3H), 1.29 (d, J=6.8 Hz, 3H), 1.73 (ddq, J=2.2, 3.4, 7.0
Hz, 1H), 2.61 (dq, J=6.8, 9.0 Hz, 1H), 3.30 (s, 3H),
3.46 (d, J=1.7 Hz, 1H), 3.98 (ddd, J=1.7, 2.2, 9.2 Hz,
1H), 4.10 (ABq in ABX3, J=7.3, 10.8 Hz, Dw=9.3 Hz,
2H), 4.43 (d, J=3.4 Hz, 1H), 7.20–7.37 (m, 5H); 13C
NMR (CDCl3): l (ppm)=5.8, 14.1, 14.4, 42.4, 43.7,
57.1, 60.2, 76.3, 88.4, 126.5, 127.4, 128.2, 139.6, 175.1.
Anal. calcd for C16H24O4: C, 68.57; H, 8.57. Found: C,
68.61; H, 8.59.
1
4.16.1.1. The C-2 isomer of 28. H NMR (CDCl3): l
(ppm)=0.93 (d, J=7.3 Hz, 3H), 1.28 (t, J=7.3 Hz,
3H), 2.05 (s, 3H), 2.14 (ddq, J=2.2, 4.6, 7.0 Hz, 1H),
3.30 (s, 3H), 4.08 (t, J=5.2 Hz, 1H), 4.24 (q, J=7.0 Hz,
2H), 4.27 (d, J=5.4 Hz, 1H), 4.90 (d, J=2.4 Hz, 1H),
7.24–7.38 (m, 5H).
4.16.2.
Ethyl
(3R,4R,5S)-2-bromo-2,4-dimethyl-3-
hydroxy-5-methoxy-5-phenylpropionate 29. The bromo-
aldol adducts were obtained from the reaction of the
anti-25 as a mixture at C-2 (9:1 ratio) (75%). [h]2D7=
−48.1 (c 0.54, CHCl3); IR (neat): 3447, 2984, 1736 cm−1;
1H NMR (CDCl3): l (ppm)=0.70 (d, J=6.8 Hz, 3H),
1.33 (t, J=7.0 Hz, 3H), 2.03 (s, 3H), 2.27 (ddq, J=4.6,
7.0, 10.0 Hz, 1H), 2.98 (s, 3H), 4.10 (d, J=7.3 Hz, 1H),
4.12 (t, J=4.9 Hz, 1H), 4.27 (ABq in ABH3, J=7.0,
10.7 Hz, Dw=38 Hz, 2H), 5.16 (d, J=7.8 Hz, 1H),
7.25–7.38 (m, 5H); 13C NMR (CDCl3): l (ppm)=13.7,
16.9, 25.0, 41.8, 55.3, 62.0, 81.3, 86.2, 126.4, 127.7,
128.1, 128.4, 139.7, 171.3. Anal. calcd for C16H23O4Br:
C, 53.48; H, 6.41. Found: C, 53.54; H, 6.45.
4.17.2. Ethyl (2R,3S,4S,5S)-3-hydroxy-2,4-dimethyl-5-
methoxy-5-phenylpentanoate 44. [h]2D8=−57.1 (c 0.98,
1
CHCl3); IR (neat): 3504, 2980, 1733 cm−1; H NMR
(CDCl3): l (ppm)=0.90 (d, J=7.0 Hz, 3H), 1.12 (t,
J=7.3 Hz, 3H), 1.24 (d, J=6.9 Hz, 3H), 1.85 (ddq,
J=1.9, 7.0, 7.2 Hz, 1H), 2.60 (dq, J=6.8, 9.0 Hz, 1H),
3.07 (d, J=4.1 Hz, 1H), 3.24 (s, 3H), 3.94 (ddd, J=1.9,
3.9, 9.0 Hz, 1H), 4.01 (ABq in ABX3, J=3.6, 7.0 Hz,
Dw=7.1 Hz, 2H), 4.21 (d, J=6.1 Hz, 1H), 7.24–7.38
(m, 5H); 13C NMR (CDCl3) l (ppm)=11.3, 14.0, 14.5,
42.6, 43.9, 57.4, 60.1, 72.0, 87.7, 126.8, 127.6, 128.3,
140.2, 174.9.

S. Kiyooka / Tetrahedron: Asymmetry 14 (2003) 2897–2910
2909
4.17.3. Ethyl (2R,3S,4R,5S)-3-hydroxy-2,4-dimethyl-5-
methoxy-5-phenylpentanoate 46. [h]2D8=−72.4 (c 0.69,
4.18.2. Ethyl (2S,3S,4S,5S)-3-hydroxy-2,4-dimethyl-5-
methoxy-5-phenylpentanoate 45. [h]2D8=−66.9 (c 1.18,
1
1
CHCl3); IR (neat): 3493, 2980, 1728 cm−1; H NMR
CHCl3); IR (neat): 3508, 2978, 1732 cm−1; H NMR
(CDCl3) l (ppm)=0.76 (d, J=7.0 Hz, 3H), 1.24 (d,
J=6.8 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H), 1.76 (ddq,
J=2.6, 7.3, 7.5 Hz, 1H), 2.65 (dq, J=5.1, 7.0 Hz, 1H),
3.31 (s, 3H), 3.59 (d, J=5.1 Hz, 1H), 3.92 (dt, J=5.3,
7.0 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H), 4.78 (d, J=2.4
Hz, 1H), 7.22–7.37 (m, 5H); 13C NMR (CDCl3): l
(ppm)=10.0, 11.1, 14.1, 41.9, 42.9, 57.3, 60.5, 74.0,
83.2, 126.7, 127.0, 128.1, 140.0, 176.1.
(CDCl3): l (ppm)=0.74 (d, J=7.1 Hz, 3H), 1.05 (d,
J=7.1 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H), 1.87 (ddq,
J=2.0, 7.4, 7.6 Hz, 1H), 2.58 (dq, J=7.3, 9.5 Hz, 1H),
3.03 (d, J=4.2 Hz, 1H), 3.20 (s, 3H), 4.16 (d, J=7.8
Hz, 1H), 4.17 (dq, J=0.5, 7.0 Hz, 2H), 4.22 (ddd,
J=2.0, 4.2, 9.5 Hz, 1H), 7.25–7.34 (m, 5H); 13C NMR
(CDCl3): l (ppm)=9.7, 14.0, 14.1, 41.0, 43.5, 57.1,
60.5, 71.6, 86.3, 127.3, 127.6, 128.3, 140.7, 176.3.
4.17.4. Ethyl (2S,3R,4S,5S)-3-hydroxy-2,4-dimethyl-5-
methoxy-5-phenylpentanoate 48. [h]2D8=−41.6 (c 1.44,
4.18.3. Ethyl (2S,3S,4R,5S)-3-hydroxy-2,4-dimethyl-5-
methoxy-5-phenylpentanoate 47. [h]2D8=−50.0 (c 1.32,
1
1
CHCl3); IR (neat): 3468, 3063, 1732 cm−1; H NMR
CHCl3); IR (neat): 3503, 2980, 1732 cm−1; H NMR
(CDCl3): l (ppm)=0.58 (d, J=6.8 Hz, 3H), 1.18 (d,
J=7.0 Hz, 3H), 1.20 (t, J=7.0 Hz, 3H), 2.01 (ddq,
J=7.0, 7.9, 9.0 Hz, 1H), 2.59 (dq, J=2.6, 7.3 Hz, 1H),
3.17 (s, 3H), 3.99 (ddd, J=1.7, 2.4, 9.0 Hz, 1H), 4.18
(ABq in ABX3, J=7.3, 9.0 Hz, Dw=8.0 Hz, 2H), 4.24
(d, J=8.0 Hz, 1H), 4.48 (dd, J=1.2, 1.7 Hz, 1H),
7.20–7.38 (m, 5H); 13C NMR (CDCl3): l (ppm)=8.6,
12.3, 14.1, 41.5, 42.0, 56.3, 60.5, 75.6, 88.6, 127.8, 127.9,
128.2, 139.3, 175.6.
(CDCl3): l (ppm)=0.81 (d, J=7.1 Hz, 3H), 1.25 (t,
J=7.1 Hz, 3H), 1.31 (d, J=7.1 Hz, 3H), 1.80 (dquin,
J=2.4, 7.1 Hz, 1H), 2.74 (dq, J=2.0, 7.1 Hz, 1H), 3.32
(s, 3H), 3.57 (d, J=3.2 Hz, 1H), 3.68 (ddd, J=2.0, 3.9,
7.1 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 4.72 (d, J=2.4
Hz, 1H), 7.24–7.38 (m, 5H); 13C NMR (CDCl3): l
(ppm)=10.2, 14.2, 15.1, 42.7, 43.4, 57.4, 60.5, 76.2,
83.0, 126.6, 127.1, 128.2, 140.3, 176.0.
4.18.4. Ethyl (2R,3R,4S,5S)-3-hydroxy-2,4-dimethyl-5-
methoxy-5-phenylpentanoate 49. [h]2D8=−67.0 (c 1.18,
4.18. A typical procedure of anti-selective radical
1
debromination reaction from 26–29 to 43, 45, 47, and
CHCl3); IR (neat): 3481, 2980, 1728 cm−1; H NMR
49
(CDCl3): l (ppm)=0.65 (d, J=7.1 Hz, 3H), 1.28 (t,
J=7.1 Hz, 3H), 1.28 (d, J=7.3 Hz, 3H), 2.13 (dq,
J=7.0, 7.6 Hz, 1H), 2.76 (dq, J=3.7, 6.8 Hz, 1H), 3.17
(s, 3H), 3.51 (ddd, J=3.7, 6.1, 8.0 Hz, 1H), 4.08 (d,
J=6.1 Hz, 1H), 4.18 (ABq in ABX3, J=7.1, 9.4 Hz,
Dw=7.6 Hz, 2H), 4.31 (d, J=7.6 Hz, 1H), 7.26–7.37
(m, 5H); 13C NMR (CDCl3): l (ppm)=13.0, 14.2, 14.7,
42.3, 42.8, 56.4, 60.4, 77.5, 86.9, 127.8, 127.9, 128.2,
139.6, 175.6.
4.18.1. Ethyl (2R,3R,4R,5S)-3-hydroxy-2,4-dimethyl-5-
methoxy-5-phenylpentanoate 43. Under an argon atmo-
sphere, to a stirred solution of 30 (92 mg, 0.22 mmol),
which was prepared from 26 according to the standard
procedure for 8 (85%) and used without further purifi-
cation, in toluene (3 mL) at −78°C was added dropwise
Bu3SnH (0.2 mL, 0.88 mmol) and then Et3B (0.22 mL,
0.22 mmol, 1 M soln in hexanes) in 1/3 portions every
15 min and the resulting mixture left to stir for 2 h at
the temperature. The reaction was then quenched by
the addition of water, extracted with ether, washed with
a satd NaCl solution, and dried over anhydrous
MgSO4. After evaporation of the solvent, the residue
was purified by flash column chromatography to afford
compound 35 (73 mg, 97%). The ratio of syn:anti was
found to be 16:1 on the basis of NMR data. Compound
35 (51 mg, 0.15 mmol) was dissolved in a solution of
THF (1 mL), water (1 mL), and 6 M hydrochloric acid
(0.5 mL). The solution was stirred at rt for 3 h,
extracted with ether, washed with a satd Na2CO3 solu-
tion, and dried over anhydrous MgSO4. After evapora-
tion of the solvent, the residue was purified by
flash-column chromatography (15% AcOEt in hexane)
to afford 43 (38 mg, 90%). [h]2D8=−34.6 (c 0.78, CHCl3);
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports and Culture of Japan.
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