Superior substrate control on diastereoselection in boric Lewis acid-promoted aldol reactions. Asymmetric synthesis of a 3,4-syn homologous series of ethyl 3,5-dihydroxy-2,4-dimethyl-5-phenylpentanoates

Article abstract of DOI:10.1016/S0957-4166(01)00405-0

The BF₃·OEt₂-promoted aldol reaction of chiral syn- and anti-α-methyl-β-siloxy aldehydes with a silyl ketene acetal resulted in essentially complete syn Felkin selection. Even in the asymmetric aldol reaction using chiral oxazaboroli

Full text of DOI:10.1016/S0957-4166(01)00405-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2343–2349
Superior substrate control on diastereoselection in boric Lewis
acid-promoted aldol reactions. Asymmetric synthesis of a
3,4-syn homologous series of ethyl
3,5-dihydroxy-2,4-dimethyl-5-phenylpentanoates
Syun-ichi Kiyooka,a,* Kazi A. Shahid,b Kazunori Murai,a Yong-Nan Li,a Momotoshi Okazakib and
Yoshihiro Shutob
aDepartment of Chemistry, Faculty of Science, Kochi University, 2-5-1 Akebono-cho, Kochi 780-8520, Japan
bThe United Graduate School of Agricultural Sciences, Ehime University, 3-5-7 Tarumi, Matsuyama 790-8566, Japan
Received 14 August 2001; accepted 11 September 2001
Abstract—The BF3·OEt2-promoted aldol reaction of chiral syn- and anti-a-methyl-b-siloxy aldehydes with a silyl ketene acetal
resulted in essentially complete syn Felkin selection. Even in the asymmetric aldol reaction using chiral oxazaborolidinones, the
substrate control with respect to diastereoselection was found to overcome the promoter (catalyst) control which would normally
occur depending on the stereocenter of the chiral boranes. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
drance caused by the aldehyde, the nucleophile and the
promoter (Scheme 3). Consequently, we attempted to
employ the silyl ketene acetal 5, instead of using 2 in
order to examine the potential of the aldol strategy for
use in polypropionate synthesis.
In previous reports, we described that essentially enan-
tiopure syn- and anti-propionate aldol adducts can be
divergently prepared by using a reaction sequence
which is comprises the highly enantioselective oxaza-
borolidinone (
L
-1 or -1)-promoted aldol reaction with
D
a silyl ketene acetal 2, derived from ethyl 2-bromopro-
pionate, and followed by a highly diastereoselective
radical debromination reaction (Scheme 1).1,2 These
findings led us to extend the divergent aldol strategy to
the diastereoselective construction of polypropionate
units, which are building blocks for the synthesis of a
variety of macrolides.
If the reaction sequence is repeatedly applicable to
polypropionate synthesis, the iterative aldol strategy
might provide an ideal approach to the synthesis of
polypropionate units involving various combinations of
stereogenic centers (Scheme 2). However, the aldol
reaction of a-methyl-b-siloxy aldehydes with silyl nucle-
ophile 2 failed to proceed in the presence of the chiral
oxazaborolidinones because of excessive steric hin-
* Corresponding author. Tel.: +81-88-844-8295; fax: +81-88-844-8359;
e-mail: kiyo@cc.kochi-u.ac.jp
Scheme 1.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00405-0

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S. Kiyooka et al. / Tetrahedron: Asymmetry 12 (2001) 2343–2349
configurations.3–5 In the case of chiral oxazaborolidi-
none-promoted asymmetric aldol reactions of a-chiral
aldehydes, e.g. 2-phenylpropanal, with silyl ketene
acetals, the newly generated stereogenic center is known
to be constructed through the control induced by the
stereogenic center of the promoter used, and is indepen-
dent of the a-stereocenter of the aldehydes, that is, the
so-called promoter (catalyst) control on acyclic stereose-
lection, as depicted in Fig. 1.6 In the case of aldehydes
having no a-substituents, the promoter control works
more effectively in the enantioselective CꢀC bond form-
ing reactions, supplying essentially pure 1,3-syn- and
anti-polyol units, suitable for diastereoselective poly-
acetate synthesis.7 However, the promoter control is
prone to be diminished when the steric bulk of the
a-substituent of the aldehyde is increased.8 If promoter
control can be realized in the present aldehyde system,
which involves both a-methyl and b-siloxy substituents,
the expected iterative aldol reactions toward the
polypropionate synthesis might provide an ideal and
straightforward strategy.
Scheme 2. Iterative aldol strategy toward polypropionate
units.
Scheme 3.
The three types of relative stereochemical relationships
in the present aldol products should be considered, as
follows; (1) C(2)–C(3): 1,2-syn-/anti-diastereoselection,
(2) C(3)–C(4): Felkin or anti-Felkin selection, and (3)
C(3)–C(5): 1,3-diol-syn-/anti-diastereoselection (Scheme
4). Homochiral a-methyl-b-siloxy aldehydes were pre-
pared using our chiral oxazaborolidinone-promoted
asymmetric aldol reactions, as shown in Scheme 5.2 The
reaction of benzaldehyde with bromo silyl nucleophile 2
2. Results and discussion
The aldol reaction of chiral aldehydes having a-methyl
and b-siloxy substituents represents a plausible model
reaction for exploring the possibility that polypropi-
onate units might be constructed using an iterative
enantioselective and/or diastereoselective aldol strategy.
The stereochemical prediction, however, is not so
difficult in the Lewis acid-promoted Mukaiyama-type
aldol reactions of aldehydes, which involve separately
a-alkyl or b-siloxy substituents, from the standpoint of
chelate-syn, chelate-anti, Felkin-syn, and Felkin-anti
in the presence of oxazaborolidinone,
L
-1, resulted in
the essentially enantiopure aldol production of a mix-
ture of syn- and anti-isomers 6 (ratio=7:1) in good
yield. The non-diastereoselective debromination of 6
Figure 1.
Scheme 4. Relative stereochemical relationship appeared in
the present aldol reaction. C(2)–C(3): 1,2-syn-/anti-
diastereoselection; C(3)–C(4): Felkin or anti-Felkin selection;
C(3)–C(5): 1,3-diol-syn-/anti-diastereoselection.
Scheme 5.

S. Kiyooka et al. / Tetrahedron: Asymmetry 12 (2001) 2343–2349
2345
was carried out to give separable isomers of syn-7 and
anti-71,9 (syn/anti=1:1.7), both of which are available
for the present synthesis, by treatment with Bu3SnH
containing a catalytic amount of Et3B. After TMS
protection of the b-hydroxyl group of syn-7 and anti-7,
starting aldehydes (syn-10 and anti-10) were obtained
by DIBAL reduction and subsequent Swern oxidation.
using an achiral Lewis acid in order to obtain direct
evidence for the existence of such substrate control in
this system. A clear result was obtained in the reaction
using BF3·OEt2, which gave a 1:1 mixture of 11 and 12
in high yield. This finding supports that a highly reli-
able substrate control in the Felkin selection presents
where the face of the aldehyde carbonyl allowed by
mutual interactions with a- and b-substituents is being
attacked by the incoming nucleophile. Moreover, it was
found that the effectiveness of BF3·OEt2 is noteworthy
in the attainment of high 3,4-syn selection in the present
system. Even in the case of aldol reactions in which
anti-a-methyl-b-siloxy aldehyde (anti-10) is used, simi-
lar results were obtained (Table 2).
The Lewis acid-mediated aldol reaction of TMS-pro-
tected aldehydes (syn-10 and anti-10) with silyl ketene
acetal 5 was examined. After aldol reactions, the TMS-
aldol adducts could be separated by silica-gel chro-
matography and the isomeric ratios in the aldol
reactions were determined. Then, desilylation of the
products was carried out to give the corresponding
diols, followed by acetonization. The stereochemistry of
the products of 11, 12, 15, and 16 was confirmed by
NOESY experiments, using the corresponding ace-
tonides, 19, 20, 21, and 22, respectively. The aldol
reaction of syn-a-methyl-b-siloxy aldehyde (syn-10) in
In comparison with syn-10, the reactions with anti-10
in the presence of both chiral oxazaborolidinones pro-
ceeded in extremely low yields, which are presumably
caused by the shielding of the allowed face of the
aldehyde carbonyl with the bulk of the promoter and a
slight difference in the ratio of 3,4-syn products (the
2,3-anti isomer 15 is preferred) was observed in the
the presence of -1 resulted in a 1:1 mixture of 11 and
L
12, having 3,4-syn configuration, in 67% yield (Table 1).
reaction in the presence of -1. As expected from the
L
This seemed to be normal and typical because the
substrate control, the aldol reaction of syn-10 using
BF3·OEt2 also gave the syn-isomers in excellent yield.
promoter control, effected by -1, would be expected to
L
produce the same configuration at C(3) via re facial
selection. In addition, the random selection at C(2) on
the 2,3-syn and anti-relationship also lies within the
general tendency for reactions with the silyl nucleophile
5.10 Surprisingly, however, the aldol reaction in the
A similar system has been investigated consisting of
(2R,3R)- and (2S,3R)-2,4-dimethyl-3-[(4-methoxyben-
zyl)pentanals 23 and 24 and enol silanes, 25 (Fig. 2), in
BF3·OEt2-mediated aldol reactions where Evans pro-
posed the revised 1,3-asymmetric induction polar model
in order to explain the influence of the electrostatic
nature of the b-substituent on the facial selection of the
carbonyl moiety, in addition to the Felkin–Anh predic-
tion exerted on the a-substituent.3 The observed
diastereoselectivity was dependent on the size of nucle-
presence of
D
-1 gave a mixture of 11 and 12, not a
mixture of 13 and 14 as would be anticipated from the
promoter control. These results strongly suggest that
the configuration of the newly created stereogenic cen-
ter at C(3) can be attributed to the effect of the existing
stereocenters of syn-10. As a result, a reinvestigation of
the stereochemistry of the reaction was then carried out
Table 1.
Entry
Promoter
Yield (%)
Product ratios
11
12
13
14
1
2
3
L
-1 (
-1 (
BF3·OEt2
L
-Ts-Val)
-Ts-Val)
67
61
82
1
1.6
1
1
1
1
–
–
–
–
–
–
D
D

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S. Kiyooka et al. / Tetrahedron: Asymmetry 12 (2001) 2343–2349
Table 2.
Entry
Promoter
Yield (%)
Product ratios
15
16
17
18
1
2
3
L
-1 (
-1 (
BF3·OEt2
L
-Ts-Val)
21
24
93
1.7
2
1
1
1
1
–
–
–
–
–
–
D
D-Ts-Val)
structure of aldehydes available for acyclic stereoselec-
tion under promoter (catalyst) control in chiral oxaza-
borolidinone-promoted asymmetric aldol reactions.
However, for these aldehydes, BF3·OEt2 was found to
be a quite effective Lewis acid for essentially complete
3,4-syn stereoselection from the standpoint of substrate
control. BF3·OEt2 would be useful as an alternative
Lewis acid for use in the iterative aldol strategy to
achieve the expected polypropionate synthesis. A study
of the diastereoselective construction between C(2) and
C(3) in the system is currently underway.
Figure 2.
ophiles and the stereochemistry at the b position of
aldehydes was subsequently recognized to affect the
total diastereoselection as a merged 1,2- and 1,3-asym-
metric induction. However, the diastereofacial selection
in our present system of syn-10 and anti-10 can be
effectively accounted for using only the Felkin–Anh
model without any consideration of a specific influence
of b-substituents. The stereochemical outcome of the
present reaction can be explained with some confidence
using transition state models; A from syn-10 and B
from anti-10, as depicted in Fig. 3.
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 with a JEOL JNM-
LA 400 spectrometer. Chemical shifts are expressed in
ppm downfield from internal tetramethylsilane. 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. Optical rotations
were determined with a JASCO DIP-370 digital polar-
imeter. Merck silica gel 60 (230–400 mesh) was used for
flash-column chromatography and for thin-layer chro-
matography Merck silica gel 60 TLC aluminum sheets
were used.
3. Conclusions
The stereogenic center at C(3) of the aldol products
obtained from syn- and anti-10 could not be controlled
by the stereogenic center of the oxazaborolidinone
used. The fact provides a serious limitation on the
4.2. Ethyl (2S,3S)-2-methyl-3-phenyl-3-trimethylsiloxy-
propionate syn-8
To a stirred solution of ethyl (2S,3S)-3-hydroxy-2-
methyl-3-phenylpropionate (907 mg, 4.36 mmol) in dry
Figure 3.

S. Kiyooka et al. / Tetrahedron: Asymmetry 12 (2001) 2343–2349
2347
4.4. Oxidation procedure: (2S,3S)-2-methyl-3-phenyl-3-
trimethylsiloxypropanal syn-10
CH2Cl2 (35 mL) at rt was added 2,6-lutidine (2.03 mL,
17.4 mmol) and the resulting mixture stirred for 15 min.
Then, TMSOTf (1.13 mL, 6.54 mmol) was added and
stirred for 2.5 h at the same temperature. Reaction was
quenched by slow addition of satd NaCl (10 mL),
extracted with ether, washed with satd NaCl, and dried
over anhydrous MgSO4. After evaporation of the sol-
vent, the crude product was purified by flash-column
chromatography (1% AcOEt in n-hexane) to afford 8
(93%); [h]3D0 −45.1 (c 1.02, CHCl3); IR (neat): 2959,
Under an argon atmosphere, to a stirred solution of
(COCl)2 (0.38 mL, 4.38 mmol) in dry CH2Cl2 at −78°C
was added dropwise DMSO (0.58 mL, 8.22 mmol) over
5 min. After stirring for 10 min at the same tempera-
ture, syn-9 (650 mg, 2.74 mmol) was added and the
mixture was stirred for 20 min before Et3N (1.53 mL,
10.96 mmol) was added. The reaction mixture was
allowed to warm up to 0°C and additionally stirred for
30 min before quenched with a mixture of water (1.0
mL), ether (4.0 mL), and benzene (2.0 mL). The
organic phase was separated, washed with water fol-
lowed with satd NaCl, and dried over anhydrous
MgSO4. After evaporation of the solvent, the crude
product was purified by flash-column chromatography
(5% AcOEt in n-hexane) to afford syn-10 (480 mg,
74%); [h]2D0 −37.9 (c 2.19, CHCl3); IR (neat): 2959, 1726
1
1732 cm−1; H NMR (CDCl3): l (ppm)=0.0 (s, 9H),
1.08 (t, J=7.1 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H), 2.66
(dq, J=7.1, 6.8 Hz, 1H), 3.91–4.04 (m, 2H), 4.94 (d,
J=6.3 Hz, 1H), 7.19–7.30 (m, 5H); 13C NMR (CDCl3):
l (ppm)=0.0, 12.0, 14.0, 49.0, 60.2, 75.9, 126.4, 127.3,
127.9, 143.1, 174.3. Anal. calcd for C15H24O3Si: C,
64.25; H, 8.63. Found: C, 64.36; H, 8.57%.
1
cm−1; H NMR (CDCl3): l (ppm)=0.0 (s, 9H), 1.0 (d,
4.2.1. Ethyl (2R,3S) - 2 - methyl - 3 - phenyl - 3 - trimethyl-
siloxypropionate anti-8. [h]3D0 −19.1 (c 1.00, CHCl3); IR
J=7.1 Hz, 3H), 2.53–2.62 (m, 1H), 5.13 (d, J=4.4 Hz,
1H), 7.20–7.32 (m, 5H), 9.71 (d, J=1.5 Hz, 1H); 13C
NMR (CDCl3): l (ppm)=0.0, 8.0, 54.5, 73.9, 126.1,
127.4, 128.2, 142.3, 204.3.
1
(neat): 2961, 1736 cm−1; H NMR (CDCl3): l (ppm)=0
(s, 9H), 0.91 (d, J=7.1 Hz, 3H), 1.36 (t, J=7.1 Hz,
3H), 2.78 (dq, J=9.5, 7.1 Hz, 1H), 4.19–4.32 (m, 2H),
4.75 (d, J=9.3 Hz, 1H), 7.32–7.40 (m, 5H); 13C NMR
(CDCl3): l (ppm)=0.0, 14.0, 14.4, 49.3, 60.4, 77.8,
127.1, 127.8, 128.2, 142.2, 175.5. Anal. calcd for
C15H24O3Si: C, 64.25; H, 8.63. Found: C, 64.19; H,
8.66%.
4.4.1. (2R,3S)-2-Methyl-3-phenyl-3-trimethylsiloxyprop-
anal anti-10. [h]1D91 −95.6 (c 1.21, CHCl3); IR (neat):
2961, 1728 cm−1; H NMR (CDCl3): l (ppm)=0.0 (s,
9H), 0.89 (d, J=7.1 Hz, 3H), 2.67–2.77 (m, 1H), 4.77
(d, J=7.8 Hz, 1H), 7.27–7.37 (m, 5H), 9.80 (d, J=2.4
Hz, 1H); 13C NMR (CDCl3): l (ppm)=0.0, 11.1, 54.2,
76.6, 126.6, 127.8, 128.4, 142.2, 204.7.
4.3. Reduction procedure: (2R,3S)-2-methyl-3-phenyl-3-
trimethylsiloxypropanol syn-9
4.5. General procedure: chiral oxazaborolidinone-
promoted asymmetric aldol reaction of syn-10
Under an argon atmosphere, to a stirred solution of
syn-8 (750 mg, 2.67 mmol) in dry CH2Cl2 (20 mL) at
−78°C was added dropwise a solution of DIBAL in
toluene (1 M, 8.01 mL, 8.01 mmol) over 30 min and
was stirred at the same temperature for 2 h. The
reaction was quenched by slow addition of MeOH (5
mL), followed by addition of distilled water (20 mL),
extracted with ether, washed with satd NaCl, and dried
over anhydrous MgSO4. After evaporation of the sol-
vent, the crude product was purified by flash-column
chromatography (15% AcOEt in n-hexane) to afford
syn-9 (546 mg, 86%); [h]2D4 −33.3 (c 1.14, CHCl3); IR
Under an argon atmosphere, to a stirred solution of
N-p-tosyl-(S)-valine (331 mg, 1.22 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, and was further stirred for 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 and syn-10 (240 mg, 1.02 mmol) in
CH2Cl2 (1 mL) was added slowly over 5 min. After 5
min,
1-ethoxy-2-methyl-1-trimethylsiloxy-1-propene
1
(neat): 3380, 2961 cm−1; H NMR (CDCl3): l (ppm)=
(267 mg, 1.53 mmol) was introduced slowly and stirred
for 15 h at −78°C. The reaction was quenched by
adding a buffer solution (10 mL, pH 6.8), extracted
with ether, washed with satd NaHCO3 solution, fol-
lowed with satd NaCl solution, and dried over anhy-
drous MgSO4. After evaporation of the solvent, the
crude was evaporated, and purified by flash-column
chromatography (7% AcOEt in n-hexane) to afford a
mixture of aldol adducts in 1: 1 ratio (197 mg, 57%).
0.0 (s, 9H), 0.75 (d, J=7.1 Hz, 3H), 1.96–2.05 (m, 1H),
2.37 (dd, J=6.1, 4.6 Hz, 1H), 3.40–3.47 (m, 1H),
3.51–3.57 (m, 1H), 4.80 (d, J=4.4 Hz, 1H), 7.19–7.31
(m, 5H); 13C NMR (CDCl3): l (ppm)=0.0, 11.8, 42.7,
65.7, 77.3, 126.7, 127.1, 127.9, 142.5.
4.3.1. (2S,3S)-2-Methyl-3-phenyl-3-trimethylsiloxyprop-
anol anti-9. [h]2D9 −60.5 (c 1.00, CHCl3); IR (neat): 3420,
1
2961 cm−1; H NMR (CDCl3): l (ppm)=0.0 (s, 9H),
4.6. Ethyl (2R,3R,4R,5S)-3-hydroxy-2,4-dimethyl-5-
phenyl-5-trimethylsiloxypentanoate 11-OTMS
0.79 (d, J=7.1 Hz, 3H), 1.91–2.04 (m, 1H), 3.18 (dd,
J=6.8, 4.1 Hz, 1H), 3.58–3.69 (m, 2H), 4.54 (d, J=7.3
Hz, 1H), 7.24–7.34 (m, 5H); 13C NMR (CDCl3): l
(ppm)=0.0, 14.2, 42.8, 66.9, 81.4, 126.7, 127.5, 128.2,
143.4.
[h]1D9 −28.0 (c 1.11, CHCl3); IR (neat): 3516, 2976, 2900,
1
1732 cm−1; H NMR (CDCl3): l (ppm)=0.0 (s, 9H),
0.92 (d, J=7.1 Hz, 3H), 1.01 (d, J=7.3 Hz, 3H), 1.25

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S. Kiyooka et al. / Tetrahedron: Asymmetry 12 (2001) 2343–2349
(t, J=7.1 Hz, 3H), 1.79 (dq, J=6.8, 2.2 Hz, 1H), 2.58
(dq, J=9.3, 7.1 Hz, 1H), 3.04 (d, J=3.4 Hz, 1H), 3.65
(ddd, J=9.0, 3.2, 2.2 Hz, 1H), 4.07–4.20 (m, 2H), 4.79
(d, J=5.8 Hz, 1H), 7.21–7.32 (m, 5H); 13C NMR
(CDCl3): l (ppm)=0.0, 7.0, 13.8, 14.1, 42.3, 43.5, 60.5,
74.7, 78.7, 126.5, 127.2, 128.0, 143.2, 176.1.
(ppm)=0.82 (d, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz,
3H), 1.28 (d, J=6.8 Hz, 3H), 1.77–1.84 (m, 1H), 2.65
(dq, J=8.6, 7.1 Hz, 1H), 3.08 (br s, 1H), 3.36 (d, J=3.2
Hz, 1H), 4.0–4.08 (m, 1H), 4.12 (dq, J=7.1, 2.2 Hz,
1H), 4.98 (s, 1H), 7.23–7.35 (m, 5H); 13C NMR
(CDCl3): l (ppm)=5.0, 14.1, 14.2, 42.1, 43.7, 60.5,
76.9, 78.2, 125.6, 127.2, 128.2, 143.0, 175.2. Anal. calcd
for C15H22O4: C, 67.64; H, 8.33. Found: C, 67.54; H,
8.28%.
4.6.1. Ethyl (2S,3R,4R,5S) - 3 - hydroxy - 2,4 - dimethyl-
5-phenyl-5-trimethylsiloxypentanoate 12-OTMS. [h]D22
−33.2 (c 0.84, CHCl3); IR (neat): 3510, 2978, 2889, 1732
1
cm−1; H NMR (CDCl3): l (ppm)=0.0 (s, 9H), 0.79 (d,
4.8.2. Ethyl (2S,3S,4S,5S)-3,5-dihydroxy-2,4-dimethyl-5-
phenylpentanoate 15-OH. [h]2D6 −24.0 (c 0.25, CHCl3);
IR (neat): 3414, 2988, 2939, 1730 cm−1; 1H NMR
(CDCl3): l (ppm)=0.98 (d, J=7.1 Hz, 3H), 1.18 (t,
J=7.1 Hz, 3H), 1.22 (d, J=6.8 Hz, 3H), 1.89–1.96 (m,
1H), 2.64 (dq, J=8.8, 7.1 Hz, 1H), 2.73 (d, J=4.4 Hz,
1H), 2.89 (d, J=4.6 Hz, 1H), 3.96 (ddd, J=8.8, 4.9, 2.2
Hz, 1H), 4.06 (dq, J=7.1, 2.9 Hz, 2H), 4.75 (t, J=5.1
Hz, 1H), 7.12–7.37 (m, 5H); 13C NMR (CDCl3): l
(ppm)=11.0, 14.1, 14.3, 42.1, 43.7, 60.4, 72.2, 78.2,
126.0, 127.5, 128.4, 143.4, 175.0. Anal. calcd for
C15H22O4: C, 67.64; H, 8.33. Found: C, 67.37; H,
8.41%.
J=7.1 Hz, 3H), 1.19 (d, J=7.1 Hz, 3H), 1.22 (t, J=6.8
Hz, 3H), 1.63–1.71 (m, 1H), 2.59 (dq, J=8.8, 7.1 Hz,
1H), 2.99 (d, J=2.4 Hz, 1H), 3.85 (dt, J=8.5, 2.2 Hz,
1H), 4.01–4.12 (m, 2H), 4.85 (d, J=3.9 Hz, 1H), 7.17–
7.37 (m, 5H); 13C NMR (CDCl3): l (ppm)=0.0, 6.3,
13.9, 14.1, 43.1, 43.7, 60.2, 75.5, 79.1, 126.2, 127.0,
127.9, 142.9, 175.2.
4.7. General procedure: BF3·OEt2-mediated aldol
reaction of anti-10
Under an argon atmosphere, to a stirred solution of
anti-10 (710 mg, 3.0 mmol) in dry CH2Cl2 (10 mL) at
−78°C was added dropwise BF3·OEt2 (0.38 mL, 3.0
mmol) over 5 min. After stirring at the same tempera-
ture for 10 min, 1-ethoxy-2-methyl-1-trimethylsiloxy-1-
propene (1.1 g, 6.0 mmol) was introduced over 5 min
and 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 satd NaCl solution,
and dried over anhydrous MgSO4. After evaporation of
the solvent, the crude was evaporated, and purified by
flash-column chromatography (20% AcOEt in n-hex-
ane) to afford a mixture of 15-OH and 16-OH in a 1:1
ratio (738 mg, 93%).
4.8.3. Ethyl (2R,3S,4S,5S)-3,5-dihydroxy-2,4-dimethyl-
5-phenylpentanoate 16-OH. [h]2D5 −50.0 (c 0.50, CHCl3);
IR (neat): 3445, 2978, 2939, 1714 cm−1; 1H NMR
(CDCl3): l (ppm)=0.98 (d, J=7.1 Hz, 3H), 1.02 (d,
J=7.1 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H), 1.91–1.98 (m,
1H), 2.58 (dq, J=9.3, 7.1 Hz, 1H), 3.30 (d, J=5.9 Hz,
1H), 3.36 (d, J=3.6 Hz, 1H), 4.01 (ddd, J=9.5, 3.6, 2.2
Hz, 1H), 4.13 (dq, J=11.7, 7.1 Hz, 2H), 4.76 (t, J=5.8
Hz, 1H), 7.22–7.33 (m, 5H); 13C NMR (CDCl3): l
(ppm)=10.1, 13.7, 14.1, 40.4, 43.2, 60.8, 72.0, 77.7,
126.0, 127.3, 128.4, 143.8, 176.3. Anal. calcd for
C15H22O4: C, 67.64; H, 8.33. Found: C, 67.55; H,
8.25%.
4.8. Desilylation procedure: ethyl (2R,3R,4R,5S)-3,5-
dihydroxy-2,4-dimethyl-5-phenylpentanoate 11-OH
Under an argon atmosphere, to a stirred solution of
11-OTMS (108 mg, 0.32 mmol) in dry MeOH (5 mL) at
rt was added citric acid (403 mg, 1.92 mmol) and was
stirred at rt for 30 min. The reaction was quenched with
water, extracted with ether, washed with satd NaHCO3,
followed with satd NaCl, and dried over anhydrous
MgSO4. After evaporation of the solvent, the crude was
evaporated, and purified by flash-column chromatogra-
phy (13% AcOEt in n-hexane) to afford 11-OH (80 mg,
94%); [h]2D2 −5.5 (c 1.83, CHCl3); IR (neat): 3441, 2980,
1730 cm−1; 1H NMR (CDCl3): l (ppm)=0.82 (d, J=7.1
Hz, 3H), 1.12 (d, J=7.3 Hz, 3H), 1.28 (t, J=7.1 Hz,
3H), 1.81–1.90 (m, 1H), 2.62 (dq, J=9.0, 7.1 Hz, 1H),
3.58 (d, J=1.4 Hz, 1H), 3.65 (d, J=3.2 Hz, 1H), 4.19
(q, J=7.1 Hz, 2H), 5.04 (br s, 1H), 7.22–7.37 (m, 5H);
13C NMR (CDCl3): l (ppm)=4.3, 13.8, 14.1, 40.9, 43.4,
60.9, 77.4, 78.1, 125.8, 127.0, 128.1, 143.2, 176.3. Anal.
calcd for C15H22O4: C, 67.64; H, 8.33. Found: C, 67.89;
H, 8.31%.
4.9. General procedure for the acetonide preparation:
ethyl (2R,3R,4R,5S)-3,5-dihydroxy-3,5-O-isopropyli-
dene-2,4-dimethyl-5-phenylpentanoate 19
Under a nitrogen atmosphere, to a stirred solution of
11-OH (57 mg, 0.21 mmol) in dry acetone (5 mL) and
2,2-dimethoxypropane (0.13 mL, 1.06 mmol) at rt was
added camphor-10-sulphonic acid (5 mg) and was
stirred for 20 min. Reaction was quenched by slow
addition of Et3N (0.1 mL) followed with distilled water,
extracted with ether, washed with satd NaCl, and dried
over anhydrous MgSO4. After evaporation of the sol-
vent, the crude product was purified by flash-column
chromatography (5% AcOEt in n-hexane) to afford 19
(55 mg, 85%); [h]2D0 −35.6 (c 1.04, CHCl3); IR (neat):
1
2984, 1736 cm−1; H NMR (CDCl3): l (ppm)=0.62 (d,
J=6.8 Hz, 3H), 1.09 (d, J=7.1 Hz, 3H), 1.27 (t, J=7.1
Hz, 3H), 1.48 (s, 3H), 1.49 (s, 3H), 1.73–1.80 (m, 1H),
2.57 (dq, J=10.2, 7.1 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H),
4.29 (dd, J=10.2, 2.2 Hz, 1H), 5.11 (d, J=2.4 Hz, 1H),
7.22–7.40 (m, 5H); 13C NMR (CDCl3): l (ppm)=4.8,
12.5, 14.3, 19.3, 29.8, 34.4, 42.5, 60.3, 74.7, 74.9, 99.3,
125.6, 126.9, 128.1, 140.9, 175.4. Anal. calcd for
4.8.1. Ethyl (2S,3R,4R,5S)-3,5-dihydroxy-2,4-dimethyl-
5-phenylpentanoate 12-OH. [h]2D2 −8.3 (c 1.08, CHCl3);
1
IR (neat): 3434, 2980, 1713 cm−1; H NMR (CDCl3): l

S. Kiyooka et al. / Tetrahedron: Asymmetry 12 (2001) 2343–2349
2349
C18H26O4: C, 70.56; H, 8.55. Found: C, 71.02; H,
8.63%.
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.
4.9.1. Ethyl (2S,3R,4R,5S) - 3,5 - dihydroxy - 3,5 - O - iso-
propylidene-2,4-dimethyl-5-phenylpentanoate 20. [h]D22
1
−10.7 (c 1.31, CHCl3); IR (neat): 2990, 1732 cm−1; H
NMR (CDCl3): l (ppm)=0.62 (d, J=7.1 Hz, 3H), 1.18
(t, J=7.1 Hz, 3H), 1.22 (d, J=6.8 Hz, 3H), 1.47 (s,
6H), 1.67–1.73 (m, 1H), 2.58 (dq, J=10.0, 6.8 Hz, 1H),
4.04–4.13 (m, 3H), 5.04 (d, J=2.4 Hz, 1H), 7.15–7.29
(m, 5H); 13C NMR (CDCl3): l (ppm)=5.3, 14.1, 15.1,
19.6, 29.9, 35.8, 42.4, 60.3, 74.5, 74.8, 99.5, 125.5, 126.8,
128.0, 140.8, 174.6. Anal. calcd for C18H26O4: C, 70.56;
H, 8.55. Found: C, 70.77; H, 8.32%.
References
1. (a) Kiyooka, S.-i.; Shahid, K. A. Tetrahedron: Asymmetry
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909.
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propylidene-2,4-dimethyl-5-phenylpentanoate 21. [h]D19
1
−56.6 (c 0.32, CHCl3); IR (neat): 2984, 1738 cm−1; H
NMR (CDCl3): l (ppm)=0.94 (d, J=6.8 Hz, 3H), 1.08
(d, J=6.8 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.38 (s,
3H), 1.40 (s, 3H), 2.04–2.12 (m, 1H), 2.61 (dq, J=11.0,
6.8 Hz, 1H), 4.09–4.25 (m, 4H), 7.26–7.42 (m, 5H); 13C
NMR (CDCl3): l (ppm)=11.1, 13.3, 14.2, 23.6, 24.5,
39.7, 41.3, 60.3, 70.9, 77.6, 101.5, 126.8, 127.7, 128.5,
141.9, 175.1. Anal. calcd for C18H26O4: C, 70.56; H,
8.55. Found: C, 70.82; H, 8.37%.
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1,3-asymmetric inductions applied to natural product
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2000, 41, 6599–6603.
4.9.3. Ethyl (2R,3S,4S,5S) - 3,5 - dihydroxy - 3,5 - O - iso-
propylidene-2,4-dimethyl-5-phenylpentanoate 22. [h]D20
1
−24.4 (c 0.16, CHCl3); IR (neat): 2986, 1732 cm−1; H
NMR (CDCl3): l (ppm)=0.87 (d, J=6.8 Hz, 3H), 1.23
(t, J=7.1 Hz, 3H), 1.29 (d, J=6.8 Hz, 3H), 1.44 (s,
3H), 1.45 (s, 3H), 2.16–2.24 (m, 1H), 2.61 (dq, J=10.7,
6.8 Hz, 1H), 4.11 (q, J=7.1 Hz, 3H), 4.15 (dd, J=10.8,
5.12 Hz, 1H), 4.19 (d, J=8.3 Hz, 1H), 7.23–7.41 (m,
5H); 13C NMR (CDCl3): l (ppm)=11.5, 14.1, 15.7,
23.9, 24.5, 40.7, 40.8, 60.4, 70.9, 77.8, 101.5, 127.2,
127.8, 128.5, 141.6, 174.8. Anal. calcd for C18H26O4: C,
70.56; H, 8.55. Found: C, 71.42; H, 8.60%.
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