Stereoselective Construction of Entire Diastereomeric Stereotetrads Based on an Asymmetric Morita–Baylis–Hillman Reaction

Article abstract of DOI:10.1002/ejoc.201700337

A method for the enantio- and diastereoselective construction of all possible stereoisomers of a polypropionate stereotetrad having four contiguous stereogenic centers has been developed. The approach features an iterative sequence of cinchona-alkaloid-ca

Full text of DOI:10.1002/ejoc.201700337

A Journal of
Accepted Article
Title: Stereoselective Construction of Entire Diastereomeric
Stereotetrads Based on an Asymmetric Morita-Baylis-Hillman
Reaction
Authors: Hikaru Yoshimura, Jun Ishihara, and Susumi Hatakeyama
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700337
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10.1002/ejoc.201700337
European Journal of Organic Chemistry
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Stereoselective Construction of Entire Diastereomeric
Stereotetrads Based on an Asymmetric Morita-Baylis-Hillman
Reaction
Hikaru Yoshimura,[a] Jun Ishihara,[a] and Susumi Hatakeyama*[b]
Abstract: A methodology for the enantio- and diastereoselective
construction of all possible stereoisomers of a polypropionate
stereotetrad having four contiguous stereogenic centers has been
developed, which features an iterative sequence of a cinchona
alkaloid-catalyzed Morita-Baylis-Hillman reaction and subsequent
diastereoselective hydrogenation. By this method, benzaldehyde
was successfully converted to eight diastereoisomeric 3,5-dihydroxy-
2,4-dimethyl-5-phenylpentanoic acid ester derivatives with high
enantiomeric purities (99% ee) in 25-67% overall yield (8 steps) in a
reagent-controlled manner.
a few methods applicable to the synthesis of all stereoisomers
utilizing cyclic substrates for stereocontrol,[7] but there is no
satisfying method for acyclic substrates.[8]
Introduction
For many decades, natural products have contributed to a broad
field of drug discovery and development.[1] Polyketides, which
are a class of secondary metabolites produced by certain living
organisms such as bacteria, fungi, or plants, are known as one
of the most fascinating subgroups of natural products because
of their intriguing structures and beneficial biological activities
(Figure 1).[2] It is said that about 1% of polyketides have a
potential for drug-like activity which are five times higher than
average.[3] The important structural motif of polyketides is a
polypropionate chain consisting of alternating methyl and
hydroxy groups within an aliphatic framework.[4] The unit having
three, four, or five contiguous stereogenic centers is each called
as stereotriad, stereotetrad, or stereopentad. In Figure 1, the
stereotetrads are highlighted, and seven stereotetrads among
eight possible diastereomers are actually seen in natural
products.[2] From a synthetic point of view, the stereoselective
construction of polypropionates is highly challenging mainly
because of the stereochemical issues. Firstly, the stereoisomers
exponentially increase as the stereogenic centers increase.
Secondly, the stereoselective formation of a new stereogenic
center is often largely affected by the exsiting stereogenic
centers of the substrate. Thus, the stereoselective assembly of
polypropionate structures has attracted great interest among
synthetic chemists.[5] As for stereotriads, the stereoselective
construction of all possible stereoisomers has been achieved by
Figure 1. Examples of polyketide naturalproducts.
We have established both S- and R-selective asymmetric
Morita-Baylis-Hillman (MBH) reactions of aldehydes with
hexafluoroisopropyl acrylate (HFIPA) employing -isocupreidine
(-ICD) and -isocupreine (-ICPN) as a catalyst, respectively
(Scheme 1).[9] In addition, we have achieved the total syntheses
of bioactive natural products utilizing these MBH reactions.[10]
Recently, in the synthesis of the tirandamycin family of
antibiotics, we devised an effective methodology to construct the
essential anti,anti,syn-stereotetrad unit by taking advantage of
our MBH reactions (Scheme 2).[11] Thus, aldehyde 1 was
converted to the enantiopure adduct 2 (99% ee) by -ICD-
catalyzed MBH reaction and then the olefinic double bond was
hydrogenated syn-selectively.[12] After conversion of
3 to
aldehyde 4, -ICPN-catalyzed MBH reaction of 4 produced the
desired adduct 5 in high diastereoselectivity (>50:1). The
subsequent anti-selective hydrogenation[13] of 5 furnished the
desired stereotetrad 6. With this result, we then became
interested in probing the possibility that the combination of the
MBH reactions and syn- or anti-selective hydrogenation would
enable us to secure all stereoisomers of a polypropionate
stereotetrad from an aldehyde in high enantio- and
diastereoselectivities. We herein report the first organocatalytic
asymmetric synthesis of all diastereometric stereotetrads
starting from benzaldehyde.
[a]
[b]
Graduate School of Biomedical Sciences, Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Medical Innovation Center, Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
E-mail: susumi@nagasaki-u.ac.jp
http://www.ph.nagasaki-u.ac.jp/lab/manufac/index-j.html
Supporting information for this article is given via a link at the end of
the document.
many methods based on an aldol reaction and a crotylation
reaction.[4a,b,6] On the other hand, as for stereotetrads, there are
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10.1002/ejoc.201700337
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Scheme 1. Cinchona alkaloid-catalyzed Morita-Baylis-Hillman reactions.
Scheme 3. Preparation of syn- and anti-aldehydes from MBH adducts.
Scheme 2. Stereoselective construction of stereotetrad 6 in the synthesis of
We then investigated the synthesis of all possible eight
stereotriads from syn-aldehydes 9a,b and anti-aldehydes 11a,b
(Scheme 4). As reported previously,[11] the standard conditions
using 1.3 equiv of HFIPA and 0.2 equiv of -ICD or-ICPN in
DMF at –55 °C afforded the corresponding MBH adducts in poor
tirandamycin.[13]
Results and Discussion
yields
di(hexafluoroisopropyl)
due
to
the
competitive
2-methyleneglutarate.
production
of
Our examination began with methyl esters (R)-7a (98% ee) and
(S)-7b (87% ee) which were synthesized by -ICD- and -ICPN-
catalyzed MBH reactions of benzaldehyde (Scheme 3).[9c,e] Thus,
compounds 7a and 7b were hydrogenated under the conditions
using H2 (1 atm), 1.5 equiv of MgBr2, and 50% wt of Pd/C in
CH2Cl2 at room temperature to give 8a and 8b in excellent syn-
selectivity, respectively.[12] On the other hand, anti-selective
hydrogenations of 7a and 7b were conducted under the
conditions using H2 (1atm), 0.04 eq of rhodium catalyst A[13] in
CH2Cl2 at room temperature to afford 10a and 10b in excellent
anti-selectivity. Hydroxy esters 8a,b and 10a,b[14] were then
converted to TES-protected aldehyde 9a,b and 11a,b by
triethylsilylation followed by DIBAL-H reduction at –94°C in 85-
93% yield.
However,
increasing the amount of HFIPA to 4 equiv led to the production
of the MBH adducts in acceptable yields and good to excellent
diastereoselectivities. As a result, except for anti,anti-isomers
12d and 12h, other syn,syn-, anti,syn-, and syn,anti-stereotriads
were successfully constructed. All of these stereoisomers were
chromatographically separable and diastereomerically pure 12a-
h could be obtained. It is important to note that, although the
aldehydes were recovered in most cases, no epimerization was
detected after isolation.[15]
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Scheme 4. MBH reactions of TES-protected syn- and anti-aldehydes.
For the preparation of anti,anti-stereotriads, it was found that
replacing the protecting group from TES to TBDPS improves the
yield and diastereoselectivity (Scheme 5). At this stage, although
the reactivity and selectivity were somewhat affected by a
protecting group, we succeeded in the stereoselective
construction of all possible stereoisomers of stereotriads in a
catalyst-controlled manner.
Scheme 6. Diastereoselective hydrogenations giving sterotetrads.
The stereostructures of these products were unambiguously
determined as shown in Scheme 7. Compounds 17a and 17b
were converted to the known diols 19a and 19b respectively, the
spectral data and specific rotations of which were in good
agreement with those reported.[17] For other isomers 17c-h, the
stereochemistries of C3-hydroxyl groups were determined by
applying Rychnovsky’s method[18] to acetonides 20d,f,h. The
stereochemistries of C2-methyl groups were determined based
1
on J2,3 values and NOEs in H NMR spectra of acetonides 21c-
h.[16] The stereochemistries of 18a-d were determined by
converting to the corresponding diols and directly compared with
the diols obtained from 17e-h.
Scheme 5. MBH reactions of TBDPS-protected anti-aldehydes.
Finally, after ethanolysis of HFIP esters 12a-d and 14a,c to
15a-d and 16a,c, their syn- and anti-selective hydrogenations
were examined under the same conditions as shown in Scheme
3 (Scheme 6). As a result, in all cases, the reactions proceeded
in complete diastereoselectivities to give all patterns of
stereotetrads 17a-h and 18a-d in good to excellent yields.
Compounds 15a-d and 16a,c derived all the way from 7a (98%
ee) were found to be enantiomerically almost pure (99% ee) by
HPLC analysis on a chiral stationary phase.[16] Interestingly, the
enantiomers of 15a-d and 16a,c derived from 7b (87% ee)
turned out to be also enantiomerically pure (99% ee). These
results mean that the enantiomers of 17a-h and 18a-d are also
available in an enantiomerically pure form.
Scheme 7. Determination of the stereochemistries.
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To a solution of the HFIP ester (2.3 g, 7 mmol) in MeOH (35 mL) was
added NaHCO3 (0.9 g, 11 mmol). After being stirred at room temperature
for 24 h, the mixture was diluted with water (35 mL), extracted with
AcOEt, washed with brine, dried, concentrated, and chromatographed
(SiO2 50 g, hexane/AcOEt = 5:1) to afford 7b (1.3 g, 7 mmol, 100%) as a
colorless oil. The enantiomeric purity of 7b was determined to be 87% ee
by HPLC analysis as described for 7a. The spectral data were identical
with those reported.[9e]
Conclusions
We have developed a new methodology for the enantio- and
diastereoselective synthesis of the polypropionate stereotetrads
by taking advantage of our cinchona alkaloid-catalyzed
asymmetric MBH reaction. The present method enables us to
construct their all pattern of configurations in a reagent-
controlled manner, for the first time. Its application to the
synthesis of longer polypropionate chains as well as natural
products is under progress in our laboratory.
Methyl (2S,3S)-3-Hydroxy-2-methyl-3-phenylpropanoate (8a): To a
solution of 7a (1.36 g, 7.1 mmol) (98% ee) in CH2Cl2 (57 mL) were added
MgBr2 (1.9 g, 10.6 mmol) and 10% Pd/C (680 mg). After being stirred
under hydrogen atmosphere at room temperature for 6 h, the mixture
was filtered through Celite which was washed with CH2Cl2. The
combined filtrate and washings were washed with saturated NaHCO3 and
brine, dried, concentrated, and chromatographed (SiO2 40 g,
hexane/AcOEt = 8:1) to give 8a (1.36 g, 7.1 mmol, 100%) as a colorless
Experimental Section
General Information: Where appropriate, reactions were performed in
flame-dried glassware under argon atmosphere. All extracts were dried
over MgSO4 and concentrated by rotary evaporation below 30 °C at 25
Torr unless otherwise noted. Commercial reagents and solvents were
used as supplied with following exceptions. Dichrolomethane (CH2Cl2)
and N,N-dimethylformamide (DMF) were distilled from CaH2. Thin layer
chromatography (TLC) was performed using precoated silica gel plates
(0.2 or 0.5 mm thickness). Column chromatography was performed using
silica gel (particle size 100-210 µm (regular) or 40-50 µm (flash)). Optical
rotations were recorded on digital polarimeter at ambient temperature.
Infrared spectra (FTIR) were measured on a Fourier transform infrared
spectrometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
measured using CDCl3 and bezene-d6 as solvent, and chemical shifts are
reported as δ values in ppm based on internal CHCl3 (1H: 7.26 ppm; 13C:
77.0 ppm) and bezene-d6 (1H: 7.16 ppm; 13C: 128.1 ppm). Mass (MS)
and high resolution mass (HRMS) spectra were taken in EI or FAB mode.
23
oil: [α]D –21.1 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36-7.24
(m, 5H), 5.10 (t, J = 3.2 Hz, 1H), 3.66 (s, 3H), 2.98 (d, J = 3.2 Hz, 1H),
2.78 (dq, J = 3.2, 6.8 Hz, 1H), 1.12 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 176.1, 141.4, 128.2, 127.5, 125.9, 73.6, 51.8, 46.4, 10.7;
FTIR (neat) 3486, 2990, 1733, 1455, 1348, 1201, 1032 cm-1; MS (EI) m/z
77, 79, 88, 105, 107, 131, 163, 176, 194 (M+); HRMS (EI) calcd for
C11H14O3 (M+) 194.0943, found 194.0942. The 1H NMR spectrum was in
good agreement with that reported for the racemic compound.[12]
Methyl
(2R,3R)-3-Hydroxy-2-methyl-3-phenylpropanoate
(8b):
Compound 8b, [α]D23 +20.2 (c 1.00, CHCl3), was obtained as a colorless
oil (1.36 g, 7.1 mmol, 100%) from 7b (1.36 g, 7.1 mmol, 87% ee) in the
same manner as described for the synthesis of 8a. The spectral data
were identical with those of the enantiomer shown above.
Methyl (2R,3S)-3-Hydroxy-2-methyl-3-phenylpropanoate (10a):
mixture of 7a (1.36 g, 7.1 mmol) (98% ee) and (bicyclo[2.2.1]hepta-2,5-
diene)[1,4-bis(diphenylphosphino)butane]rhodium(I)
A
Methyl 2-((R)-Hydroxy(phenyl)methyl)acrylate (7a): β-ICD (2.2 g, 7.1
mmol) was dissolved in THF (10 mL) and the solution was evaporated at
room temperature. After repeating this operation three times, the
amorphous residue was dried under vacuum at room temperature for 10
min. A solution of the dried β-ICD and benzaldehyde (7.8 mL, 71 mmol)
in DMF (237 mL) was cooled to –55 °C, and HFIPA (15.2 mL, 91 mmol)
was then added. After stirring at –55 °C for 24 h, the reaction was
quenched by the addition of 0.1 M HCl (140 mL). The mixture was
extracted with AcOEt, washed with saturated NaHCO3 and brine, dried,
concentrated and chromatographed (SiO2 300 g, hexane/AcOEt = 10:1)
to give the corresponding HFIP ester (21.0 g, 64 mmol, 90%) as a
colorless oil.
trifluoromethanesulfonate (220 mg, 0.28 mmol) in CH2Cl2 (24 mL) was
stirred at room temperature under a hydrogen atmosphere. After being
stirred for 1 h, the mixture was filtered through SiO2 which was washed
with AcOEt. The filtrate and washings were concentrated and
chromatographed (SiO2 30 g, hexane/AcOEt = 8:1) to give 10a (1.36 g,
7.1 mmol, 100%) as a colorless oil: [α]D24 –51.1 (c 1.00, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 4.72 (dd, J = 4.0, 8.0 Hz, 1H),
3.72 (s, 3H), 3.09 (d, J = 4.0 Hz, 1H), 3.00 (dq, J = 7.2, 8.0 Hz, 1H), 0.99
(d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.2, 141.5, 128.4,
127.9, 126.6, 76.3, 51.8, 47.1, 14.4; FTIR (neat) 3460, 2948, 1733, 1455,
1372, 1250, 1023 cm-1; MS (EI) m/z 77, 79, 88, 105, 107, 131, 176, 194
(M+); HRMS (EI) calcd for C11H14O3 (M+) 194.0943, found 194.0942. The
1H NMR spectrum was in good agreement with that reported for the
racemic compound.[12]
To a solution of the HFIP ester (3.3 g, 10 mmol) in MeOH (50 mL) was
added NaHCO3 (1.3 g, 15 mmol). After being stirred at room temperature
for 24 h, the mixture was diluted with water (50 mL), extracted with
AcOEt, washed with brine, dried, concentrated, and chromatographed
(SiO2 50 g, hexane/AcOEt = 5:1) to afford 7a (1.9 g, 10 mmol, 100%) as
colorless oil. The enantiomeric purity of 7a was determined to be 98% ee
by HPLC analysis; Danicel Chiralcel OJ-H, 2-propanol/hexane = 1/100 (1
mL/min), tR = 22.7 min (7a) and 24.7 min (7b). The spectral data were
identical with those reported.[9d]
Methyl
(2S,3R)-3-Hydroxy-2-methyl-3-phenylpropanoate
(10b):
Compound 10b, [α]D23 +49.2 (c 1.00, CHCl3), was obtained as a colorless
oil (1.36 g, 7.1 mmol, 100%) from 7b (1.36 g, 7.1 mmol, 87% ee) in the
same manner as described for the synthesis of 10a. The spectral data
were identical with those of the enantiomer shown above.
Methyl 2-((S)-Hydroxy(phenyl)methyl)acrylate (7b): α-ICPN (620 mg,
2.0 mmol) was dissolved in THF (3 mL) and the solution was evaporated
at room temperature. After repeating this operation three times, the
amorphous residue was dried under vacuum at room temperature for 10
min. A solution of the dried α-ICPN and benzaldehyde (1.0 mL, 10 mmol)
in DMF (33 mL) was cooled to –55 °C, and HFIPA (2.2 mL, 13 mmol)
was then added. After stirring at –55 °C for 24 h, the reaction was
quenched by the addition of 0.1 M HCl (20 mL). The mixture was
extracted with AcOEt, washed with saturated NaHCO3 and brine, dried,
concentrated and chromatographed (SiO2 100 g, hexane/AcOEt = 10:1)
to give the corresponding HFIP ester (3 g, 9.1 mmol, 91%) as a colorless
oil.
Methyl (2S,3S)-3-Triethylsiloxy-2-methyl-3-phenylpropanoate: To an
ice-cooled solution of 8a (1.31 g, 7.1 mmol) in CH2Cl2 (14 mL) were
added TESCl (2.4 mL, 14.2 mmol), DIPEA (4.8 mL, 28.3 mmol), and
DMAP (86 mg, 0.7 mmol), and the mixture was stirred at 0 °C for 30 min.
The mixture was diluted with CH2Cl2, and washed with saturated NH4Cl,
dried, concentrated, and chromatographed (SiO2 50 g, hexane/AcOEt =
70:1) to give the TES ether (2.08 g, 6.9 mmol, 97%) as a colorless oil:
24
[α]D –23.1 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32-7.21 (m,
5H), 5.00 (d, J = 6.0 Hz, 1H), 3.55 (s, 3H), 2.67 (dq, J = 6.0, 6.8 Hz, 1H),
1.17 (d, J = 6.8 Hz, 3H), 0.86 (t, J = 7.2 Hz, 9H), 0.51 (q, J = 7.2 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 174.7, 143.2, 127.8, 127.3, 126.2, 75.8,
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10.1002/ejoc.201700337
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51.4, 49.1, 11.7, 6.7, 4.7; FTIR (neat) 2953, 2879, 1740, 1361, 1257,
1167, 1072 cm-1; MS (EI) m/z 87, 89, 117, 173, 221, 279 (100), 308 (M+);
HRMS (EI) calcd for C17H28O3Si (M+) 308.1808, found 308.1809.
(2R,3S)-3-Triethylsiloxy-2-methyl-3-phenylpropanal (11a): Prepared
from the TES ether of 10a in the same manner as described for the
25
synthesis of 9a, 95%, a colorless oil; [α]D –87.2 (c 2.00, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 9.83 (d, J = 2.8 Hz, 1H), 7.32-7.26 (m, 5H),
4.78 (d, J = 8.0 Hz, 1H), 2.70 (m, 1H), 0.90-0.78 (m, 12H), 0.50-0.42 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 204.6, 142.4, 128.1, 127.8, 126.6,
76.6, 54.7, 10.9, 6.6, 4.7; FTIR (neat) 2956, 2878, 1725, 1455, 1236,
1072, 1009 cm-1; MS (EI) m/z 87, 115, 143, 221, 249, 278 (M+); HRMS
(EI) calcd for C16H26O2Si (M+) 278.1702, found 278.1703.
Methyl (2R,3R)-3-Triethylsiloxy-2-methyl-3-phenylpropanoate: Prepared
from 8b in the same manner as described for TES-protection of 8a, 100%,
a colorless oil; [α]D +22.5 (c 1.00, CHCl3). The spectral data were
23
identical with those of the enantiomer shown above.
Methyl
(2R,3S)-3-Triethylsiloxy-2-methyl-3-phenylpropanoate:
(2S,3R)-3-Triethylsiloxy-2-methyl-3-phenylpropanal (11b): Prepared
from the TES ether of 10b in the same manner as described for the
synthesis of 9a, 86%, a colorless oil; [α]D +85.6 (c 2.00, CHCl3). The
Prepared from 10a in the same manner as described for TES-protection
of 8a, 98%, a colorless oil; [α]D –68.6 (c 1.00, CHCl3); 1H NMR (400
25
26
MHz, CDCl3) δ 7.32-7.24 (m, 5H), 4.73 (d, J = 10.0 Hz, 1H), 3.72 (s, 3H),
3.00 (dq, J = 9.6, 10.0 Hz, 1H), 0.85-0.77 (m, 12H), 0.50-0.37 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 175.8, 142.2, 128.1, 127.8, 127.0, 77.5,
51.4, 49.2, 13.8, 6.5, 4.6; FTIR (neat) 2953, 2879, 1740, 1361, 1257,
1167, 1072 cm-1; MS (EI) m/z 87, 89, 117, 173, 221, 279 (100), 308 (M+);
HRMS (EI) calcd for C17H28O3Si (M+) 308.1808, found 308.1812.
spectral data were identical with those of the enantiomer 11a.
(2R,3S)-3-tert-Butyldiphenylsiloxy-2-methyl-3-phenylpropanal (13a):
Prepared from the TBDPS ether of 10a in the same as manner described
for the synthesis of 9a, 92%, a colorless oil; [α]D28 –83.2 (c 2.00, CHCl3);
1H NMR (400 MHz, CDCl3) δ 9.60 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 8.0 Hz,
2H), 7.45-7.30 (m, 6H), 7.22-7.15 (m, 7H), 4.88 (d, J = 7.2 Hz, 1H), 2.75
(dq, J = 7.2, 8.0 Hz, 1H), 1.00 (s, 9H), 0.76 (d, J = 8.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 203.9, 141.1, 135.9, 133.3, 132.9, 129.8, 129.5,
128.1, 127.7, 127.3, 126.9, 76.7, 54.6, 26.8, 19.3, 10.3; FTIR (neat) 2934,
2858, 1726, 1108 cm-1; MS (FAB) m/z 77, 107, 136, 154, 199, 239, 307,
402 (M+); HRMS (EI) calcd for C26H30O2Si (M+) 402.2015, found
402.2015.
Methyl
(2S,3R)-3-Triethylsiloxy-2-methyl-3-phenylpropanoate:
Prepared from 10b in the same manner as described for TES-protection
of 8a,100%, a colorless oil; [α]D +71.0 (c 1.00, CHCl3). The spectral
data were identical with those of the enantiomer shown above.
25
Methyl
(2R,3S)-3-tert-Butyldiphenylsiloxy-2-methyl-3-
phenylpropanoate: Prepared from 10a in the same manner described
for TES-protection of 8a, 94%, a colorless oil; [α]D –68.4 (c 1.00,
25
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 6.0 Hz, 2H), 7.42-7.30
(m, 7H), 7.22 (dd, J = 6.0, 6.0 Hz, 1H), 7.19-7.02 (m, 5H), 4.86 (d, J = 8.4
Hz, 1H), 3.56 (s, 3H), 2.93 (dq, J = 8.0, 8.4 Hz, 1H), 0.95 (s, 9H), 0.79 (d,
J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2, 141.0, 135.98,
135.91, 133.8, 133.2, 129.4, 129.3, 127.9, 127.6, 127.32, 127.31, 127.1,
78.0, 51.4, 48.5, 26.8, 19.3, 13.2; FTIR (neat) 2942, 2857, 1740, 1361,
1262, 1167, 1066 cm-1; MS (FAB) m/z 89, 121, 135, 197, 213, 355,
375(100), 432 (M+), 455 [(M+Na)+]; HRMS (FAB) calcd for C27H32O3SiNa
[(M+Na)+] 455.2018, found 455.2018.
(2S,3R)-3-tert-Butyldiphenylsiloxy-2-methyl-3-phenylpropanal (13b):
Prepared from the TBDPS ether of 10b in the same manner as described
for the synthesis of 9a, 83%, a colorless oil; [α]D26 +80.5 (c 1.00, CHCl3).
The spectral data were identical with those of the enantiomer 13a.
1,1,1,3,3,3-Hexafluoropropan-2-yl
(3R,4R,5S)-3-Hydroxy-5-
triethylsiloxy-4-methyl-2-methylene-5-phenylpentanoate (12a): β-ICD
(124 mg, 0.4 mmol) was dissolved in THF (2 mL) and the solution was
evaporated at room temperature. After repeating this operation three
times, the amorphous residue was dried under vacuum at room
temperature for 10 min. A solution of the dried β-ICD and 9a (560 mg, 2.0
mmol) in DMF (6.6 mL) was cooled to –55 °C, and HFIPA (870 μL, 5.2
mmol) was then added. After stirring at –55 °C for 36 h, HFIPA (470 μL,
2.8 mmol) was added. The mixture was further stirred at –55 °C for 36 h,
and the reaction was quenched by the addition of 0.1 M HCl (6 mL). The
mixture was extracted with AcOEt, washed with saturated NaHCO3 and
brine, dried, and concentrated. Purification of the residue by flash
chromatography (SiO2 6 g, hexane/AcOEt = 100:1 to 20:1) to give 9a
(170 mg, 30%), 12a (558 mg, 1.12 mmol, 56%), and 12b (70 mg, 0.14
mmol, 7%) each as a colorless oil. As a result, the MBH adducts 12b and
12b were obtained in 63% total yield (90% brsm) and an 8:1
diastereomeric ratio. 12a: [α]D26 –47.4 (c 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.36-7.24 (m, 5H), 6.59 (s, 1H), 6.26 (s, 1H), 5.82 (septet, J =
6.4 Hz, 1H), 5.09 (d, J = 3.2 Hz, 1H), 4.88 (s, 1H), 3.52 (s, 1H), 1.95-1.85
(m, 1H), 0.90 (t, J = 8.0 Hz, 9H), 0.70 (d, J = 7.2 Hz, 3H), 0.55 (q, J = 8.0
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 162.4, 142.7, 138.5, 130.2, 130.0,
Methyl
(2S,3R)-3-tert-Butyldiphenylsiloxy-2-methyl-3-
phenylpropanoate: Prepared from 10b in the same manner described
24
for TES-protection of 8a, 100%, a colorless oil; [α]D +66.2 (c 1.00,
CHCl3). The spectral data were identical with those of the enantiomer
shown above.
(2S,3S)-3-Triethylsiloxy-2-methyl-3-phenylpropanal (9a): To a solution
of the TES ether of 8a (1.2 g, 6.8 mmol) in CH2Cl2 (65 mL) was added
DIBAL-H (1.02 M in hexane, 11.4 mL, 11.6 mmol) at –94 oC. After stirring
at –94 oC for 1 h, the reaction was quenched by the addition of
isopropanol (2 M in CH2Cl2, 60 mL, 120 mmol) and the mixture was
allowed to warm to 0 °C. Saturated Rochelle salt (60 mL) was added and
the mixture was vigorously stirred at room temperature for 6 h. The
mixture was extracted with AcOEt, dried over Na2SO4, concentrated, and
chromatographed (SiO2 50 g, hexane/AcOEt = 50:1) to afford 9a (1.56 g,
24
6.0 mmol, 88%) as a colorless oil: [α]D –26.3 (c 1.00, CHCl3); 1H NMR
1
2
127.4, 126.2, 120.5 (q, JC,F = 281 Hz), 80.0, 72.9, 66.6 (septet, JC,F
=
(400 MHz, CDCl3) δ 9.77 (s, 1H), 7.32-7.21 (m, 5H), 5.14 (d, J = 4.0 Hz,
1H), 2.60 (dq, J = 4.0, 6.8 Hz, 1H), 1.04 (d, J = 6.8 Hz, 3H), 0.86 (t, J =
8.0 Hz, 9H), 0.52 (q, J = 8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 204.4,
142.4, 128.1, 127.4, 126.1, 74.2, 54.7, 8.1, 6.6, 4.7; FTIR (neat) 2953,
2879, 1740, 1361, 1257, 1167, 1072 cm-1; MS (EI) m/z 87, 115, 143, 221,
249, 278 (M+); HRMS (EI) calcd for C16H26O2Si (M+) 278.1702, found
278.1703.
35 Hz), 43.1, 6.6, 4.8, 4.5; FTIR (neat) 3498, 2960, 1752, 1385, 1234,
1109, 1001 cm-1; MS (FAB) m/z 75, 103, 209, 221, 249, 353, 500 (M+);
HRMS (EI) calcd for C22H30F6O4Si (M+) 500.1818, found 500.1820.
1,1,1,3,3,3-Hexafluoropropan-2-yl
triethylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(3S,4R,5S)-Hydroxy-5-
(12b):
Prepared by α-ICPN-catalyzed MBH reaction of 9a in the same manner
as described for the synthesis of 12a. Compound 12b was obtained as a
colorless oil in 64% yield together with 12a (6%) and recovered 9a (28%).
The MBH adducts 12b and 12a were obtained in 70% total yield (97%
brsm) and a 10:1 diastereomeric ratio. 12b: [α]D26 –20.2 (c 2.00, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 6.51 (s, 1H), 6.12 (s, 1H),
5.81 (septet, J = 6.4 Hz, 1H), 5.03 (d, J = 2.4 Hz, 1H), 4.42 (dd, J = 4.4,
(2R,3R)-3-Triethylsiloxy-2-methyl-3-phenylpropanal (9b): Prepared
from the TES ether of 8b in the same manner as described for the
synthesis of 9a, 86%, a colorless oil; [α]D +26.8 (c 1.00, CHCl3). The
24
spectral data were identical with those of the enantiomer 9a.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700337
European Journal of Organic Chemistry
FULL PAPER
8.4 Hz, 1H), 4.31 (d, J = 4.4 Hz, 1H), 2.20-2.11 (m, 1H), 0.90 (t, J = 8.4
Hz, 9H), 0.67 (d, J = 7.2 Hz, 3H), 0.55 (q, J = 8.4 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 162.8, 141.4, 140.2, 130.6, 127.9, 127.4, 126.7, 120.4 (q,
1,1,1,3,3,3-Hexafluoropropan-2-yl
triethylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(3S,4R,5R)-3-Hydroxy-5-
(12h):
Prepared by α-ICPN-catalyzed MBH reaction of 11b in the same manner
as described for the synthesis of 12a. Compound 12h was obtained as a
colorless oil in 14% yield together with 12g (5%) and recovered 11b
(72%). The MBH adducts 12h and 12g were obtained in 19% total yield
(67% brsm) and a 3:1 diastereomeric ratio. Compound 12h, [α]D26 +42.0
(c 1.00, CHCl3), exhibited identical spectral data with those of the
enantiomer 12d.
1JC,F = 280 Hz), 77.0, 73.8, 66.5 (septet, JC,F = 35 Hz), 44.9, 11.6, 6.6,
2
4.7; FTIR (neat) 3447, 2960, 1755, 1455, 1385, 1234, 1125 cm-1; MS
(FAB) m/z 75, 103, 209, 221, 249, 353, 500 (M+); HRMS (EI) calcd for
C22H30F6O4Si (M+) 500.1818, found 500.1819.
1,1,1,3,3,3-Hexafluoropropan-2-yl
triethylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(3S,4S,5S)-3-Hydroxy-5-
(12c):
Prepared by α-ICPN-catalyzed MBH reaction of 9b in the same manner
as described for the synthesis of 12a. Compound 12c, a colorless oil,
was obtained as a single diastereomer in 65% (100% brsm) together with
1,1,1,3,3,3-Hexafluoropropan-2-yl
(3S,4S,5S)-3-Hydroxy-5-tert-
butyldiphenylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(14a): Prepared by α-ICPN-catalyzed MBH reaction of 13a in the same
manner as described for the synthesis of 12a. Compound 14a was
obtained as a single diastereomer in 40% (74% brsm) together with
26
recovered 9b (35%). 12c: [α]D –36.3 (c 1.00, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.36-7.24 (m, 5H), 6.56 (d, J = 1.6 Hz, 1H), 6.26 (d, J =
1.6 Hz, 1H), 5.71 (septet, J = 6.4 Hz, 1H), 4.94 (d, J = 3.2 Hz, 1H), 4.74
(s, 1H), 4.16 (s, 1H), 2.12-1.96 (m, 1H), 0.98-0.87 (m, 12H), 0.58 (q, J =
8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 162.2, 142.5, 138.8, 130.4,
29
recovered 13a (46%). 14a, a colorless oil; [α]D –36.1 (c 1.00, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 6.8 Hz, 2H), 7.48-7.30 (m, 6H),
7.29-7.18 (m, 7H), 6.51 (s, 1H), 6.14 (s, 1H), 5.80 (septet, J = 6.4 Hz, 1H),
4.99 (s, 1H), 4.71 (d, J = 6.4 Hz, 1H), 2.21 (s, 1H), 1.99 (dq, J = 6.4, 6.4
Hz, 1H), 1.05 (s, 9H), 0.51 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.2, 142.7, 139.1, 136.1, 136.0, 133.5, 132.3, 130.0, 129.9,
1
128.2, 127.4, 125.4, 120.5 (q, JC,F = 281 Hz), 79.9, 68.3, 66.3 (septet,
2JC,F = 37 Hz), 41.9, 10.6, 6.7, 4.6; FTIR (neat) 3470, 2960, 2880, 1753,
1386, 1356, 1234, 1112, 1005 cm-1; MS (FAB) m/z 75, 103, 209, 221, 249,
353, 500 (M+); HRMS (EI) calcd for C22H30F6O4Si (M+) 500.1818, found
500.1827.
1
129.6, 128.1, 127.8, 127.3, 126.9, 120.5 (q, JC,F = 281 Hz), 79.9, 67.9,
66.5 (septet, 2JC,F = 37 Hz), 43.2, 27.0, 19.3, 9.2; FTIR (neat) 3482, 2935,
2860, 1753, 1386, 1358, 1268, 1109, 1054 cm-1; MS (FAB) m/z 75, 135,
199, 305, 449, 449, 567, 624 (M+), 647 [(M+Na)+]; HRMS (FAB) calcd for
C27H32O3SiNa [(M+Na)+] 647.2028, found 647.2024.
1,1,1,3,3,3-Hexafluoropropan-2-yl
triethylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(3R,4S,5S)-3-Hydroxy-5-
(12d):
Prepared by β-ICD-catalyzed MBH reaction of 9b in the same manner as
described for the synthesis of 12a. Compound 12d was obtained as a
colorless oil in 14.5% yield together with 12c (3.5%) and recovered 9b
(58%). The MBH adducts 12d and 12c were obtained in 18% total yield
1,1,1,3,3,3-Hexafluoropropan-2-yl
(3R,4R,5R)-3-Hydroxy-5-tert-
butyldiphenylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(14b): Prepared by β-ICD-catalyzed MBH reaction of 13b in the same
manner as described for the synthesis of 12a. Compound 14b was
obtained as a single diastereomer in 39% (86% brsm) together with
recovered 13b (55%). Compound 14b, a colorless oil, [α]D +35.9 (c
1.00, CHCl3), exhibited identical spectral data with those of 14a.
27
(43% brsm) and a 4:1 diastereomeric ratio. [α]D –42.0 (c 1.00, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 6.50 (s, 1H), 6.21 (s, 1H),
5.83 (septet, J = 6.4 Hz, 1H), 5.02 (d, J = 1.2 Hz, 1H), 4.61 (d, J = 8.8 Hz,
1H), 4.57 (d, J = 8.8 Hz, 1H), 2.20-2.10 (m, 1H), 0.86 (t, J = 8.0 Hz, 9H),
0.55-0.41 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 162.8, 142.6, 139.9,
28
1
130.7, 128.2, 127.9, 127.2, 125.4, 120.5 (q, JC,F = 281 Hz), 81.9, 75.4,
1,1,1,3,3,3-Hexafluoropropan-2-yl
(3R,4S,5S)-3-Hydroxy-5-tert-
66.6 (septet, 2JC,F = 37 Hz), 47.1, 13.3, 6.5, 4.6; FTIR (neat) 3453, 2960,
1753, 1386, 1234, 1114 cm-1; MS (FAB) m/z 75, 103, 209, 221, 249, 353,
500 (M+); HRMS (EI) calcd for C22H30F6O4Si (M+) 500.1818, found
500.1819.
butyldiphenylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(14c): Prepared by β-ICD-catalyzed MBH reaction of 13a in the same
manner as described for the synthesis of 12a. Compound 14c was
obtained in 58% yield together with 14d (3%) and recovered 13a (34%)
each as a colorless oil. The MBH adducts 14c and 14d were obtained in
28
1,1,1,3,3,3-Hexafluoropropan-2-yl
triethylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(3S,4S,5R)-3-Hydroxy-5-
(12e):
61% total yield (93% brsm) and a 20:1 diastereomer ratio. 14c, [α]D
–
33.9 (c 2.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 6.0 Hz,
2H), 7.45-7.32 (m, 6H), 7.25-7.18 (m, 7H), 6.36 (s, 1H), 5.86 (s, 1H), 5.77
(septet, J = 6.4 Hz, 1H), 5.03 (d, J = 6.0 Hz, 1H), 4.00 (dd, J = 6.0, 10.0
Hz, 1H), 3.13 (d, J = 6.0 Hz, 1H), 2.11 (ddq, J = 6.0, 10.0, 10.0 Hz, 1H),
1.06 (s, 9H), 0.53 (d, J = 10.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
163.4, 141.5, 139.9, 136.7, 134.4, 133.9, 131.5, 130.6, 130.3, 128.5,
Prepared by α-ICPN-catalyzed MBH reaction of 11a in the same manner
as described for the synthesis of 12a. Compound 12e was obtained as a
colorless oil in 58% yield together with 12f (6%) and recovered 11a
(22%). The MBH adducts 12e and 12f were obtained in 64% total yield
(97% brsm) and a 10:1 diastereomeric ratio. Compound 12e, [α]D27 +47.1
(c 1.00, CHCl3), exhibited identical spectral data with those of the
enantiomer 12a.
1
128.3, 128.2, 128.1, 120.5 (q, JC,F = 281 Hz), 78.4, 75.6, 67.2 (septet,
2JC,F = 37 Hz), 46.9, 27.8, 20.1, 12.1; FTIR (neat) 3560, 2960, 1750,
1460, 1386, 1237, 1116 cm-1; MS (FAB) m/z 75, 135, 199, 305, 449, 449,
567, 624 (M+), 647 [(M+Na)+]; HRMS (FAB) calcd for C27H32O3SiNa
[(M+Na)+] 647.2028, found 647.2024.
1,1,1,3,3,3-Hexafluoropropan-2-yl
triethylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(3R,4S,5R)-Hydroxy-5-
(12f):
Prepared by β-ICD-catalyzed MBH reaction of 11a in the same manner
as described for the synthesis of 12a. Compound 12f, a colorless oil,
[α]D +21.0 (c 1.00, CHCl3), was obtained as a single diastereomer in
87% yield. The spectral data were identical with those of the enantiomer
12b.
1,1,1,3,3,3-Hexafluoropropan-2-yl
(3S,4R,5R)-3-Hydroxy-5-tert-
26
butyldiphenylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(14d): Prepared by α-ICPN-catalyzed MBH reaction of 13b in the same
manner as described for the synthesis of 12a. Compound 14d was
obtained in 29% together with 14c (3%) and recovered 13b (68%) each
as a colorless oil. The MBH adducts 14d and 14c were obtained in 32%
total yield (100% brsm) and a 10:1 diastereomer ratio. Compound 14d,
1,1,1,3,3,3-Hexafluoropropan-2-yl
triethylsiloxy-4-methyl-2-methylene-5-phenylpentanoate
(3R,4R,5R)-3-Hydroxy-5-
(12g):
28
[α]D +35.9 (c 1.00, CHCl3), exhibited identical spectral data with those
Prepared by β-ICD-catalyzed MBH reaction of 11b in the same manner
as described for the synthesis of 12a. Compound 12g, a colorless oil,
[α]D26 +36.1 (c 1.00, CHCl3), was obtained as a single diastereomer in
43% yield (65% brsm) together with recovered 11b (34%). The spectral
data were identical with those of the enantiomer 12c.
of the enantiomer 14c.
Ethyl (3R,4R,5S)-3-Hydroxy-5-triethylsiloxy-4-methyl-2-methylene-5-
phenylpentanoate (15a): To a solution of 12a (333 mg, 0.67 mmol) in
EtOH (5 mL) was added NaHCO3 (112 mg, 1.33 mmol). After being
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700337
European Journal of Organic Chemistry
FULL PAPER
stirred at room temperature for 24 h, the mixture was diluted with water
(15 mL), extracted with AcOEt, washed with brine, dried, and
(d, J = 8.0 Hz, 2H), 7.45-7.30 (m, 6H), 7.25-7.18 (m, 7H), 6.28 (s, 1H),
5.80 (s, 1H), 4.98 (s, 1H), 4.73 (d, J = 6.0 Hz, 1H), 4.18-4.08 (m, 2H),
2.19 (d, J = 2.8 Hz, 1H), 2.05 (dq, J = 6.0, 7.6 Hz, 1H), 2.05-1.98 (m, 1H),
1.17 (t, J = 7.6 Hz, 3H), 1.05 (s, 9H), 0.54 (d, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.5, 142.6, 141.3, 135.6, 133.1, 132.6, 129.3,
129.1, 127.5, 127.2, 126.8, 126.5, 124.8, 78.8, 67.7, 59.9, 43.0, 26.6,
18.9, 13.6, 8.9; FTIR (neat) 3513, 2934, 1715, 1272, 1157, 819 cm-1; MS
(FAB) m/z 77, 91, 129, 154, 327, 345, 445, 502 (M+); HRMS (FAB) calcd
for C31H38O4Si (M+) 502.2539, found 502.2531. HPLC conditions: Danicel
Chiralcel AD-H, 2-propanol/hexane = 1/100 (1 mL/min), tR = 6.6 min (16a)
concentrated. Purification by chromatography (SiO2 10 g, hexane/AcOEt
= 8:1) afforded 15a (253 mg, 0.67 mmol, 100%) as a colorless oil: [α]D
26
–
54.9 (c 1.00, CHCl3) (99% ee); 1H NMR (400 MHz, CDCl3) δ 7.32-7.21
(m, 5H), 6.33 (s, 1H), 5.93 (s, 1H), 5.07 (d, J = 4.4 Hz, 1H), 4.79 (s, 1H),
4.25-4.12 (m, 2H), 3.34 (d, J = 1.2 Hz, 1H), 2.05-1.95 (m, 1H), 1.29 (t, J =
7.2 Hz, 3H), 0.86 (t, J = 8.4 Hz, 9H), 0.71 (d, J = 7.6 Hz, 3H), 0.55 (q, J =
8.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 166.1, 143.2, 141.2, 127.8,
127.1, 126.3, 125.2, 79.9, 73.1, 60.5, 43.4, 14.1, 6.8, 5.0, 4.8; FTIR
(neat) 3514, 2957, 1714, 1456, 1265, 1173, 1094 cm-1; MS (EI) m/z 75,
103, 209, 221, 249, 272, 349 (100), 378 (M+); HRMS (EI) calcd for
C21H34O4Si (M+) 378.2226, found 378.2242. HPLC conditions: Danicel
Chiralcel AD-H, 2-propanol/hexane = 1/100 (1 mL/min), tR = 9.1 min (15a)
22
and 7.4 min (enantiomer). The enantiomer of 16a: [α]D +48.9 (c 1.00,
CHCl3) (99% ee).
Ethyl
(3R,4S,5S)-3-Hydroxy-5-tert-butyldiphenylsiloxy-4-methyl-2-
23
and 7.3 min (enantiomer). The enantiomer of 15a: [α]D +56.3 (c 1.00,
methylene-5-phenylpentanoate (16c): Prepared from 14c in the same
manner as described for the synthesis of 15a, 100%, a colorless oil;
[α]D27 –38.2 (c 1.00, CHCl3) (99% ee); 1H NMR (400 MHz, CDCl3) δ 7.69
(d, J = 7.6 Hz, 2H), 7.45-7.18 (m, 13H), 6.08 (s, 1H), 5.43 (s, 1H), 5.27 (d,
J = 4.4 Hz, 1H), 4.61 (d, J = 4.0 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.69
(dd, J = 9.2, 9.2 Hz, 1H), 3.11 (d, J = 9.2 Hz, 1H), 2.19 (ddq, J = 4.4, 6.8,
9.2 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H), 1.07 (s, 9H), 0.60 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 140.5, 135.8, 134.1, 133.5,
129.6, 129.4, 127.7, 127.5, 127.4, 127.3, 126.9, 126.7, 75.8, 75.7, 60.7,
45.3, 27.0, 19.4, 14.1, 10.9; FTIR (neat) 3523, 2934, 1703, 1457, 1174,
1108 cm-1; MS (FAB) m/z 77, 91, 129, 154, 327, 345, 445, 502 (M+);
HRMS (FAB) calcd for C31H38O4Si (M+) 502.2539, found 502.2521. HPLC
conditions: Danicel Chiralcel AD-H, 2-propanol/hexane = 1/100 (1 mL
/min), tR = 8.4 min (16c) and 7.8 min (enantiomer). The enantiomer of
16c: [α]D22 +39.0 (c 1.00, CHCl3) (99% ee).
CHCl3) (99% ee).
Ethyl (3S,4R,5S)-3-Hydroxy-5-triethylsiloxy-4-methyl-2-methylene-5-
phenylpentanoate (15b): Prepared from 12b in the same manner as
described for the synthesis of 15a, 100%, a colorless oil; [α]D –27.8 (c
26
2.00, CHCl3) (99% ee); 1H NMR (400 MHz, CDCl3) δ 7.33-7.21 (m, 5H),
6.25 (s, 1H), 5.79 (s, 1H), 5.20 (d, J = 2.4 Hz, 1H), 4.30 (dd, J = 7.6, 8.0
Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.89 (d, J = 7.6 Hz, 1H), 2.06 (ddq, J =
7.2, 7.6, 8.0 Hz, 1H), 1.27 (t, J = 6.8 Hz, 3H), 0.91 (t, J = 8.0 Hz, 9H),
0.64 (d, J = 6.8 Hz, 3H), 0.57 (q, J = 8.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 166.7, 143.2, 141.7, 127.7, 126.8, 126.5, 126.4, 74.9, 60.7,
45.5, 14.1, 10.6, 6.8, 4.8; FTIR (neat) 3518, 2957, 1714, 1456, 1375,
1326, 1098, 1021 cm-1; MS (EI) m/z 75, 103, 209, 221, 249, 272, 349
(100), 378 (M+); HRMS (EI) calcd for C21H34O4Si (M+) 378.2226, found
378.2252. HPLC conditions: Danicel Chiralcel AD-H, 2-propanol/hexane
= 1/100 (1 mL/min), tR = 7.4 min (enantiomer) and 7.8 min (15b). The
enantiomer of 15b: [α]D22 +27.2 (c 1.00, CHCl3) (99% ee).
Ethyl
(2S,3R,4R,5S)-3-Hydroxy-5-triethylsiloxy-2,4-dimethyl-5-
phenylpentanoate (17a): Prepared from 15a by syn-selective
hydrogenation in the same manner as described for the synthesis of 8a,
26
Ethyl (3S,4S,5S)-3-Hydroxy-5-triethylsiloxy-4-methyl-2-methylene-5-
phenylpentanoate (15c): Prepared from 12c in the same manner as
described for the synthesis of 15a, 100%, a colorless oil; [α]D –64.1 (c
84%, a colorless oil; [α]D –36.8 (c 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.32-7.21 (m, 5H), 4.88 (d, J = 4.0 Hz, 1H), 4.11 (q, J = 7.2 Hz,
2H), 3.87 (d, J = 8.0 Hz, 1H), 2.94 (s, 1H), 2.63 (dq, J = 7.6, 8.0 Hz, 1H),
1.72-1.65 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 0.90-
0.81 (m, 12H), 0.52 (q, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
175.2, 143.2, 127.8, 127.1, 126.3, 79.2, 75.3, 60.5, 43.8, 43.4, 14.1, 13.9,
6.8, 6.5, 4.8; FT-R (neat) 3514, 2955, 1729, 1456, 1243, 1176, 1053 cm-
1; MS (EI) m/z 75, 87, 103, 157, 209, 221, 233, 274, 351, 380 (M+);
HRMS (EI) calcd for C21H36O4Si (M+) 380.2383, found 380.2383.
25
1.00, CHCl3) (99% ee); 1H NMR (400 MHz, CDCl3) δ 7.35-7.21 (m, 5H),
6.32 (s, 1H), 5.92 (s, 1H), 4.92 (d, J = 3.6 Hz, 1H), 4.76 (s, 1H), 4.00 (q, J
= 7.6 Hz, 2H), 3.94 (s, 1H), 2.05-1.98 (m, 1H), 1.06 (t, J = 7.6 Hz, 3H),
0.96-0.88 (m, 12H), 0.57 (q, J = 8.4 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ 165.8, 143.1, 141.5, 128.0, 127.2, 125.9, 125.5, 79.9, 68.2, 60.2, 42.2,
13.8, 10.6, 6.7, 4.7; FTIR (neat) 3493, 2957, 1719, 1456, 1276, 1091,
1007 cm-1; MS (EI) m/z 75, 103, 209, 221, 249, 272, 349 (100), 378 (M+);
HRMS (EI) calcd for C21H34O4Si (M+) 378.2226, found 378.2240. HPLC
Ethyl
(2R,3R,4R,5S)-3-Hydroxy-5-triethylsiloxy-2,4-dimethyl-5-
conditions: Danicel Chiralcel OD-H, 2-propanol/hexane
mL/min), tR = 5.2 min (enantiomer) and 5.8 min (15c). The enantiomer of
15c: [α]D23 +63.0 (c 1.00, CHCl3) (99% ee).
= 1/100 (1
phenylpentanoate (17b): Prepared from 15a by anti-selective
hydrogenation in the same manner as described for the synthesis of 10a,
27
89%, a colorless oil; [α]D –30.9 (c 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.33-7.21 (m, 5H), 4.78 (d, J = 6.0 Hz, 1H), 4.19-4.08 (m, 2H),
3.62 (ddd, J = 4.0, 4.0, 7.6 Hz, 1H), 2.91 (d, J = 4.0 Hz, 1H), 2.58 (dq, J =
7.2, 7.6 Hz, 1H), 1.81 (ddq, J = 4.0, 6.0, 7.2 Hz, 1H), 1.25 (t, J = 7.2 Hz,
3H), 1.00 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.84 (t, J = 6.8 Hz,
9H), 0.52-0.42 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 176.1, 143.5,
127.9, 127.2, 126.6, 78.6, 74.3, 60.5, 43.3, 42.6, 14.1, 13.8, 7.4, 6.6, 4.8;
FTIR (neat) 3519, 2955, 1723, 1456, 1240, 1182, 1061 cm-1; MS (EI) m/z
75, 87, 103, 157, 209, 221, 233, 274, 351, 380 (M+); HRMS (EI) calcd for
C21H36O4Si (M+) 380.2383, found 380.2383.
Ethyl (3R,4S,5S)-3-Hydroxy-5-triethylsiloxy-4-methyl-2-methylene-5-
phenylpentanoate (15d): Prepared from 12d in the same manner as
described for the synthesis of 15a, 100%, a colorless oil; [α]D –49.1 (c
25
1.00, CHCl3) (99% ee); 1H NMR (400 MHz, CDCl3) δ 7.35-7.21 (m, 5H),
6.24 (s, 1H), 5.81 (s, 1H), 4.77 (d, J = 7.2 Hz, 1H), 4.61 (d, J = 4.0 Hz,
1H), 4.35 (dd, J = 4.0, 8.0 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 2.19 (ddq, J
= 7.2, 7.2, 7.6 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H), 0.84 (t, J = 7.2 Hz, 9H),
0.62-0.40 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 166.7, 142.6, 141.9,
127.9, 127.5, 127.4, 126.5, 80.0, 75.8, 60.7, 46.8, 14.1, 12.8, 6.7, 4.7;
FTIR (neat) 3477, 2957, 1716, 1456, 1276, 1155, 1092, 1033 cm-1; MS
(EI) m/z 75, 103, 209, 221, 249, 272, 349 (100), 378 (M+); HRMS (EI)
calcd for C21H34O4Si (M+) 378.2226, found 378.2222. HPLC conditions:
Danicel Chiralcel OD-H, 2-propanol/hexane = 1/100 (1 mL/min), tR = 5.5
min (15d) and 6.2 min (enantiomer). The enantiomer of 15d: [α]D23 +50.0
(c 1.00, CHCl3) (99% ee).
Ethyl
(2R,3S,4R,5S)-3-Hydroxy-5-triethylsiloxy-2,4-dimethyl-5-
phenylpentanoate (17c): Prepared from 15b by syn-selective
hydrogenation in the same manner as described for the synthesis of 8a,
25
84%, a colorless oil; [α]D –40.2 (c 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.34-7.21 (m, 5H), 5.21 (d, J = 2.4 Hz, 1H), 4.22-4.15 (m, 2H),
3.99 (ddd, J = 2.8, 2.8, 7.6 Hz, 1H), 3.74 (d, J = 2.8 Hz, 1H), 2.58 (dq, J =
2.4, 7.2 Hz, 1H), 1.78 (ddq, J = 2.4, 2.8, 7.2 Hz, 1H), 1.28 (t, J = 7.2 Hz,
3H), 1.18 (d, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 9H), 0.67 (d, J = 7.2 Hz,
3H), 0.55 (q, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.4, 143.1,
127.7, 126.8 126.6, 75.2, 72.4, 60.5, 42.8, 41.7, 14.1, 9.9, 9.1, 6.7, 4.8;
FTIR (neat) 3516, 2954, 1717, 1456, 1376, 1193, 1063 cm-1; MS (EI) m/z
Ethyl
(3S,4S,5S)-3-Hydroxy-5-tert-butyldiphenylsiloxy-4-methyl-2-
methylene-5-phenylpentanoate (16a): Prepared from 14a in the same
manner as described for the synthesis of 15a, 100%, a colorless oil;
[α]D27 –48.4 (c 2.00, CHCl3) (99% ee); 1H NMR (400 MHz, CDCl3) δ 7.72
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700337
European Journal of Organic Chemistry
FULL PAPER
75, 87, 103, 157, 209, 221, 233, 274, 351, 380 (M+); HRMS (EI) calcd for
C21H36O4Si (M+) 380.2383, found 380.2385.
3H), 0.52-0.42 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 175.8, 142.4,
127.7, 127.4 127.2, 77.2, 76.7, 60.4, 45.1, 41.7, 14.7, 14.2, 11.8, 6.7, 4.7;
FTIR (neat) 3509, 2956, 1713, 1456, 1378, 1181, 1061 cm-1; MS (EI) m/z
75, 87, 103, 157, 209, 221, 233, 274, 351, 380 (M+); HRMS (EI) calcd for
C21H36O4Si (M+) 380.2383, found 380.2363.
Ethyl
(2S,3S,4R,5S)-3-Hydroxy-5-triethylsiloxy-2,4-dimethyl-5-
phenylpentanoate (17d): Prepared from 15b by anti-selective
hydrogenation in the same manner as described for the synthesis of 10a,
89%, a colorless oil; [α]D –23.8 (c 1.00, CHCl3); 1H NMR (400 MHz,
26
Ethyl
(2R,3S,4S,5S)-3-Hydroxy-5-tert-butyldiphenylsiloxy-2,4-
CDCl3) δ 7.32-7.20 (m, 5H), 5.20 (d, J = 2.4 Hz, 1H), 4.17-4.09 (m, 2H),
3.77 (d, J = 8.0 Hz, 1H), 3.52 (ddd, J = 4.0, 8.0, 8.0 Hz, 1H), 2.67 (dq, J =
4.0, 6.8 Hz, 1H), 1.81 (ddq, J = 2.4, 6.8, 8.0 Hz, 1H), 1.30 (d, J = 6.8 Hz,
3H), 1.22 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 8.0 Hz, 9H), 0.73 (d, J = 6.8 Hz,
3H), 0.55 (q, J = 8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 175.7, 143.2,
127.7, 126.8, 126.5, 75.4, 75.3, 60.3, 44.9, 41.7, 15.1, 14.1, 10.3, 6.7,
4.7; FTIR (neat) 3516, 2956, 1714, 1456, 1378, 1184, 1045 cm-1; MS (EI)
m/z 75, 87, 103, 157, 209, 221, 233, 274, 351, 380 (M+); HRMS (EI)
calcd for C21H36O4Si (M+) 380.2383, found 380.2384.
dimethyl-5-phenylpentanoate (18a): Prepared from 16a by syn-
selective hydrogenation in the same manner as described for the
29
synthesis of 8a, 82%, a colorless oil; [α]D –48.3 (c 1.00, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.71 (d, J = 6.8 Hz, 2H), 7.48-7.38 (m, 3H),
7.35-7.18 (m, 10H), 4.57 (d, J = 8.4 Hz, 1H), 4.22-4.10 (m, 3H), 2.48 (dq,
J = 7.2, 8.4 Hz, 1H), 1.86 (dq, J = 7.2, 7.2 Hz, 1H), 1.66 (d, J = 4.4 Hz,
1H), 1.23 (t, J = 7.2 Hz, 3H), 1.08-1.01 (m, 12H), 0.50 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 176.0, 143.3, 136.1, 136.0, 133.7, 133.3,
129.7, 129.3, 127.9, 127.3, 127.2, 127.1, 78.1, 71.0, 60.3, 43.8, 42.3,
27.1, 19.3, 14.1, 14.0, 8.8; FTIR (neat) 3589, 2935, 1730, 1484, 1181,
1058 cm-1; MS (FAB) m/z 75, 131, 135, 199, 329, 345, 447, 504 (M+);
HRMS (FAB) calcd for C31H40O4Si (M+) 504.2696, found 504.2668.
Ethyl
(2R,3S,4S,5S)-3-Hydroxy-5-triethylsiloxy-2,4-dimethyl-5-
phenylpentanoate (17e): Prepared from 15c by syn-selective
hydrogenation in the same manner as described for the synthesis of 8a,
25
81%, colorless oil; [α]D –50.3 (c 1.00, CHCl3); 1H NMR (400 MHz,
Ethyl
(2S,3S,4S,5S)-3-Hydroxy-5-tert-butyldiphenylsiloxy-2,4-
CDCl3) δ 7.35-7.20 (m, 5H), 4.84 (d, J = 3.6 Hz, 1H), 3.98-3.92 (m, 2H),
3.81 (d, J = 9.6 Hz, 1H), 3.67 (brs, 1H), 2.56 (dq, J = 7.2, 9.6 Hz, 1H),
1.72-1.69 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.06
(t, J = 6.8 Hz, 3H), 0.89 (t, J = 8.0 Hz, 9H), 0.55 (q, J = 8.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 174.6, 143.0, 128.1, 127.2 125.8, 80.3, 71.4,
60.8, 44.2, 42.5, 14.4, 13.9, 11.4, 6.7, 4.6; FTIR (neat) 3503, 2956, 1731,
1457, 1374, 1177, 1053 cm-1; MS (EI) m/z 75, 87, 103, 157, 209, 221,
233, 274, 351, 380 (M+); HRMS (EI) calcd for C21H36O4Si (M+) 380.2383,
found 380.2373.
dimethyl-5-phenylpentanoate (18b): Prepared from 16a by anti-
selective hydrogenation in the same manner as described for the
24
synthesis of 10a, 93%, a colorless oil; [α]D –77.2 (c 1.00, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 6.0 Hz, 2H), 7.48-7.38 (m, 3H),
7.35-7.18 (m, 10H), 4.60 (d, J = 6.8 Hz, 1H), 4.04 (q, J = 7.6 Hz, 2H),
3.90 (ddd, J = 2.8, 6.8, 7.0 Hz, 1H), 2.48 (dq, J = 6.8, 7.0 Hz, 1H), 1.78-
1.70 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.04 (s,
9H), 0.66 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.2, 142.8,
136.1, 133.7, 133.1, 129.9, 129.5, 127.9, 127.3, 127.0, 78.7, 71.2, 60.1,
43.9, 43.8, 27.1, 19.3, 14.4, 14.1, 9.7; FTIR (neat) 3594, 2935, 1729,
1457, 1371, 1177, 1107, 1053 cm-1; MS (FAB) m/z 75, 131, 135, 199, 329,
345, 447, 504 (M+); HRMS (FAB) calcd for C31H40O4Si (M+) 504.2696,
found 504.2698.
Ethyl
(2S,3S,4S,5S)-3-Hydroxy-5-triethylsiloxy-2,4-dimethyl-5-
phenylpentanoate (17f): Prepared from 15c by anti-selective
hydrogenation in the same manner as described for the synthesis of 10a,
25
95%, a colorless oil; [α]D –62.3 (c 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.35-7.20 (m, 5H), 4.79 (d, J = 5.2 Hz, 1H), 4.20-4.10 (m, 2H),
4.06 (d, J = 9.6 Hz, 1H), 3.45 (brs, 1H), 2.53 (dq, J = 7.2, 9.6 Hz, 1H),
1.76 (dq, J = 5.2, 7.2 Hz, 1H), 1.25 (t, J = 6.8 Hz, 3H), 0.93 (d, J = 7.2 Hz,
3H), 0.89 (d, J = 7.2 Hz, 3H), 0.86 (t, J = 8.0 Hz, 9H), 0.51 (q, J = 8.0 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 176.1, 143.4, 128.1, 127.2 126.2,
79.2, 71.5, 60.4, 43.6, 41.2, 14.1, 13.6, 10.3, 6.7, 4.6; FTIR (neat) 3511,
2956, 1731, 1457, 1379, 1182, 1061 cm-1; MS (EI) m/z 75, 87, 103, 157,
209, 221, 233, 274, 351, 380 (M+); HRMS (EI) calcd for C21H36O4Si (M+)
380.2383, found 380.2383.
Ethyl
(2S,3R,4S,5S)-3-Hydroxy-5-tert-butyldiphenylsiloxy-2,4-
dimethyl-5-phenylpentanoate (18c): Prepared from 16c by syn-
selective hydrogenation in the same manner as described for the
synthesis of 8a, 86%, a colorless oil; [α]D –27.7 (c 1.00, CHCl3); 1H
28
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 6.8 Hz, 2H), 7.48-7.32 (m, 8H),
7.28-7.18 (m, 5H), 5.28 (d, J = 4.4 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 3.90
(d, J = 10.0 Hz, 1H), 2.70 (d, J = 1.2 Hz, 1H), 2.37 (q, J = 6.8 Hz, 1H),
1.82 (ddq, J = 4.4, 6.8, 10.0 Hz, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.08 (s, 9H),
0.91 (d, J = 6.8 Hz, 3H), 0.68 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 176.7, 140.8, 135.9, 135.8, 134.3, 133.6, 129.6, 129.4, 127.6,
127.5, 127.4, 127.3, 126.8, 75.1, 72.1, 60.5, 42.1, 40.6, 27.1, 19.3, 14.1,
9.3, 8.5; FTIR (neat) 3526, 2935, 2857, 1713, 1459, 1381, 1191, 1108
cm-1; MS (FAB) m/z 75, 131, 135, 199, 329, 345, 447, 504 (M+); HRMS
(FAB) calcd for C31H40O4Si (M+) 504.2696, found 504.2699.
Ethyl
(2S,3R,4S,5S)-3-Hydroxy-5-triethylsiloxy-2,4-dimethyl-5-
phenylpentanoate (17g): Prepared from 15d by syn-selective
hydrogenation in the same manner as described for the synthesis of 8a,
27
85%, a colorless oil; [α]D –42.6 (c 0.50, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.35-7.20 (m, 5H), 4.76 (d, J = 7.6 Hz, 1H), 4.25 (brs, 1H), 4.22-
4.10 (m, 2H), 3.93 (d, J = 9.6 Hz, 1H), 2.56 (dq, J = 6.8, 9.6 Hz, 1H), 1.94
(dq, J = 6.8, 7.2 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H),
0.84 (t, J = 8.0 Hz, 9H), 0.81 (d, J = 6.8 Hz, 3H), 0.58-0.41 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 175.9, 142.7, 127.8, 127.5 127.4, 79.4, 74.7,
60.4, 43.3, 41.7, 14.1, 11.7, 8.7, 6.6, 4.6; FTIR (neat) 3504, 2956, 1715,
1457, 1376, 1191, 1059 cm-1; MS (EI) m/z 75, 87, 103, 157, 209, 221,
233, 274, 351, 380 (M+); HRMS (EI) calcd for C21H36O4Si (M+) 380.2383,
found 380.2383.
Ethyl
(2R,3R,4S,5S)-3-Hydroxy-5-tert-butyldiphenylsiloxy-2,4-
dimethyl-5-phenylpentanoate (18d): Prepared from 16c by anti-
selective hydrogenation in the same manner as described for the
synthesis of 10a, 96%, a colorless oil; [α]D –45.1 (c 1.00, CHCl3); 1H
28
NMR (400 MHz, CDCl3) δ 7.67 (d, J = 6.8 Hz, 2H), 7.48-7.20 (m, 13H),
5.32 (d, J = 4.0 Hz, 1H), 4.07 (m, 2H), 2.88 (ddd, J = 2.4, 10.0, 10.0 Hz,
1H), 2.62 (d, J = 10.0 Hz, 1H), 2.50 (dq, J = 2.4, 6.8 Hz, 1H), 1.82 (ddq, J
= 4.0, 7.2, 10.0 Hz, 1H), 1.20 (t, J = 6.8 Hz, 3H), 1.14 (d, J = 7.2 Hz, 3H),
1.10 (s, 9H), 0.77 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
176.0, 140.6, 135.8, 135.7, 134.3, 133.7, 129.6, 129.4, 127.6, 127.5,
127.4, 127.3, 126.8, 75.3, 74.5, 60.4, 45.6, 40.6, 27.0, 19.3, 15.2, 14.1,
9.8; FTIR (neat) 3517, 2934, 2857, 1712, 1458, 1426, 1378, 1182, 1108,
1060 cm-1; MS (FAB) m/z 75, 131, 135, 199, 329, 345, 447, 504 (M+);
HRMS (FAB) calcd for C31H40O4Si (M+) 504.2696, found 504.2678.
Ethyl
(2R,3R,4S,5S)-3-Hydroxy-5-triethylsiloxy-2,4-dimethyl-5-
phenylpentanoate (17h): Prepared from 15d by anti-selective
hydrogenation in the same manner as described for the synthesis of 10a,
27
100%, a colorless oil; [α]D –40.8 (c 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.35-7.20 (m, 5H), 4.92 (d, J = 6.4 Hz, 1H), 4.23-4.12 (m, 2H),
3.85 (d, J = 6.8 Hz, 1H), 3.40 (ddd, J = 2.8, 6.8, 6.8 Hz, 1H), 2.73 (dq, J =
2.8, 6.8 Hz, 1H), 2.02 (ddq, J = 6.4, 6.8, 6.8 Hz, 1H), 1.28 (t, J = 6.8 Hz,
3H), 1.26 (d, J = 7.2 Hz, 3H), 0.85 (t, J = 8.0 Hz, 9H), 0.68 (d, J = 6.8 Hz,
Ethyl (2S,3R,4R,5S)-3,5-Dihydroxy-2,4-dimethyl-5-phenylpentanoate
(19a): To a solution of 17a (43 mg, 114 μmol) in THF (2 mL) was added
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700337
European Journal of Organic Chemistry
FULL PAPER
TBAF (1.0 M in THF, 0.23 mL, 0.23 mmol) and AcOH (4 μL, 68 μmol) at 0
oC. After stirring at 0 oC for 30 min, the reaction was quenched by the
addition of saturated NaHCO3 (2 mL). The mixture was extracted with
AcOEt, washed with brine, dried, concentrated, and purified by
preparative TLC (hexane/AcOEt = 3:1) to give 19a (22 mg, 81 μmol,
1H), 2.76 (dq, J = 2.4, 6.8 Hz, 1H), 1.95 (ddq, J = 7.6, 10.2, 10.4 Hz, 1H),
1.54 (s, 3H), 1.44 (s, 3H), 1.29 (t, J = 6.8 Hz, 3H), 1.23 (d, J = 7.6 Hz,
3H), 0.63 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.4, 140.4,
128.3, 128.1, 127.8, 98.8, 78.5, 60.3, 41.9, 37.9, 30.1, 19.4, 14.3, 12.8,
11.9; FTIR (neat) 2984, 1733, 1458, 1387, 1196, 949 cm-1; MS (EI) m/z
69, 107, 118, 127, 203, 248, 291, 306 (M+); HRMS (EI) calcd for
C18H26O4 (M+) 306.1831, found 306.1830.
71%) as a colorless oil: [α]D –8.6 (c 1.00, CHCl3) (lit.[17] [α]D −8.3 (c
1.08, CHCl3)); 1H NMR (400 MHz, CDCl3) δ 7.36-7.23 (m, 5H), 4.99 (d, J
= 2.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.07 (d, J = 8.8 Hz, 1H), 3.33 (brs,
1H), 3.02 (brs, 1H), 2.66 (dq, J = 7.2, 8.6 Hz, 1H), 1.75-1.78 (m, 1H),
1.28 (d, J = 6.8 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 175.2, 142.9, 128.2, 127.2, 125.6, 78.2,
76.9, 60.5, 43.7, 42.1, 14.1, 5.0; FTIR (neat) 3406, 2972, 1712, 1455,
1383, 1256, 1180, 1045 cm-1; MS (EI) m/z 57, 65, 91, 107, 118, 142, 160,
220, 248, 266 (M+); HRMS (EI) calcd for C15H22O4 (M+) 266.1518, found
266.1516.
28
22
(4R,5S)-4-((1S,2R)-1-Triethylsiloxy-1-phenylpropan-2-yl)-2,2,5-
trimethyl-1,3-dioxane (21c): To a solution of 17c (38 mg, 100 μmol) in
THF (2 mL) was added LiAlH4 (8 mg, 200 μmol) at 0 oC. After stirring at 0
oC for 1 h, the reaction was quenched by the addition of saturated
Rochelle salt (5 mL), and the mixture was vigorously stirred at room
temperature for 6 h. The mixture was extracted with AcOEt, dried over
Na2SO4, concentrated to give diol (30 mg). The crude diol was dissolved
in acetone (1 mL), and 2,2-dimethoxypropane (0.25 mL, 2 mmol) and
PPTS (2.5 mg, 10 μmol) were added at room temperature. After stirring
for 30 min at room temperature, the reaction was quenched by the
addition of saturated NaHCO3 (1 mL). The mixture was extracted with
AcOEt, dried, concentrated, and purified by preparative TLC
(hexane/AcOEt = 5:1) to give 21c (10.2 mg, 32 μmol, 32%, 2 steps) as a
Ethyl (2R,3R,4R,5S)-3,5-Dihydroxy-2,4-dimethyl-5-phenylpentanoate
(19b): Prepared from 17b in the same manner as described for the
synthesis of 19a, 70%, a colorless oil; [α]D –7.2 (c 2.30, CHCl3) (lit.[17]
24
22
[α]D −5.5 (c 1.83, CHCl3)); 1H NMR (400 MHz, CDCl3) δ 7.35-7.24 (m,
5H), 5.03 (d, J = 3.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 4.09 (d, J = 7.6 Hz,
1H), 3.69 (brs, 2H), 2.62 (dq, J = 7.2, 7.6 Hz, 1H), 1.89-1.81 (m, 1H),
1.29 (t, J = 7.2 Hz, 1H), 1.12 (d, J = 7.2 Hz, 3H), 0.82 (d, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 176.3, 143.2, 128.1, 126.9, 125.8, 78.1,
77.4, 60.9, 43.4, 40.8, 14.1, 13.8, 4.3; FTIR (neat) 3434, 2978, 1717,
1455, 1383, 1248, 1187, 973 cm-1; MS (EI) m/z 57, 65, 91, 107, 118, 142,
160, 220, 248, 266 (M+); HRMS (EI) calcd for C15H22O4 (M+) 266.1518,
found 266.1516.
27
colorless oil: [α]D –27.8 (c 0.25, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.30-7.18 (m, 5H), 5.17 (s, 1H), 4.14 (dd, J = 2.4, 11.2 Hz, 1H), 3.88 (dd,
J = 2.0, 8.4 Hz, 1H), 3.62 (d, J = 11.2 Hz, 1H), 1.55-1.46 (m, 8H), 1.00 (d,
J = 7.6 Hz, 3H), 0.88 (t, J = 7.2 Hz, 9H), 0.67 (d, J = 7.2 Hz, 3H), 0.55-
0.48 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 145.5, 127.5, 126.4, 126.3,
98.5, 71.9, 67.2, 44.1, 30.1, 29.9, 19.5, 10.3, 6.9, 6.4, 5.1; FTIR (neat)
2956, 1456, 1381, 1238, 1198, 1101, 1007, 958 cm-1; MS (EI) m/z 87,
115, 143, 171, 221, 249, 291, 320, 363, 378 (M+); HRMS (EI) calcd for
C22H38O3Si (M+) 378.2590, found 378.2576.
Ethyl
(S)-2-((4S,5R,6S)-2,2,5-Trimethyl-6-phenyl-1,3-dioxan-4-
yl)propanoate (20d): To a solution of 17d (21 mg, 56 μmol) in THF (2
mL) was added TBAF (1.0 M in THF, 0.11 mL, 0.11 mmol) and AcOH (2
μL, 34 μmol) at 0 oC. After stirring at 0 oC for 30 min, the reaction was
quenched by the addition of saturated NaHCO3 (2 mL). The mixture was
extracted with AcOEt, washed with brine, dried, and concentrated to give
the corresponding diol (16 mg). The crude diol was dissolved in acetone
(1 mL), and 2,2-dimethoxypropane (0.14 mL, 1.12 mmol) and PPTS (1.4
mg, 6 μmol) were added. After stirring for 30 min, the reaction was
quenched by the addition of saturated NaHCO3 (1 mL). The mixture was
extracted with AcOEt, dried, concentrated, and purified by preparative
TLC (hexane/AcOEt = 3:1) to give 20d (12.2 mg, 40 μmol, 72%, 2 steps)
(4R,5R)-4-((1S,2R)-1-Triethylsiloxy-1-phenylpropan-2-yl)-2,2,5-
trimethyl-1,3- dioxane (21d): Prepared from 17d in the same manner as
described for the synthesis of 21c, 33% (2 steps), a colorless oil: [α]D
25
–
25.7 (c 0.25, CHCl3); 1H NMR (400 MHz, benzene-d6) δ 7.45 (d, J = 8.8
Hz, 2H), 7.19 (dd, J = 7.2, 8.0 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H), 5.01 (d, J
= 6.4 Hz, 1H), 3.46 (dd, J = 4.8, 11.2 Hz, 1H), 3.35 (dd, J = 3.6, 11.2 Hz,
1H), 3.13 (dd, J = 9.6, 11.2 Hz, 1H), 2.10 (ddq, J = 3.6, 6.4, 6.8 Hz, 1H),
1.53 (s, 3H), 1.40-1.29 (m, 4H), 1.24 (d, J = 6.8 Hz, 3H), 0.96 (t, J = 8.0
Hz, 9H), 0.59 (q, J = 6.8 Hz, 6H), 0.44 (d, J = 2.4, 7.2 Hz, 3H); 13C NMR
(100 MHz, benzene-d6) δ 146.0, 127.8, 127.5, 127.4, 98.4, 78.1, 75.3,
66.1, 45.2, 32.1, 29.5, 19.7, 13.9, 13.7, 7.1, 5.5; FTIR (neat) 2957, 1457,
1375, 1198, 1062, 1001, 836 cm-1; MS (EI) m/z 87, 115, 143, 171, 221,
249, 291, 320, 363, 378 (M+); HRMS (EI) calcd for C22H38O3Si (M+)
378.2590, found 378.2590.
27
as a colorless oil: [α]D –60.7 (c 0.50, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.36-7.20 (m, 5H), 5.07 (d, J = 4.8 Hz, 1H), 4.21-4.14 (m, 2H),
3.62 (dd, J = 6.8, 6.8 Hz, 1H), 2.66 (dq, J = 6.8, 6.8 Hz, 1H), 2.15 (ddq, J
= 4.8, 6.8, 6.8 Hz, 1H), 1.44 (s, 3H), 1.36 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H),
1.21 (d, J = 7.2 Hz, 3H), 0.60 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.5, 139.8, 127.9, 126.6, 125.8, 101.0, 76.5, 60.3, 45.2, 39.2,
25.5, 23.5, 14.3, 13.7, 13.1; FTIR (neat) 2984, 1736, 1458, 1379, 1221,
1172, 1033 cm-1; MS (EI) m/z 69, 107, 118, 127, 203, 248, 291, 306 (M+);
HRMS (EI) calcd for C18H26O4 (M+) 306.1831, found 306.1830.
(4R,5S)-4-((1S,2S)-1-Triethylsiloxy-1-phenylpropan-2-yl)-2,2,5-
trimethyl-1,3-dioxane (21e): Prepared from 17e in the same manner as
described for the synthesis of 21c, 35% (2 steps), a colorless oil: [α]D
27
–
35.0 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.30-7.20 (m, 5H),
4.59 (d, J = 6.4 Hz, 1H), 4.06 (dd, J = 2.8, 11.6 Hz, 1H), 3.72 (dd, J = 2.0,
8.0 Hz, 1H), 3.57 (dd, J = 1.2, 11.6 Hz, 1H), 2.01 (ddq, J = 6.4, 6.8, 8.0
Hz, 1H), 1.80-1.72 (m, 1H), 1.36 (s, 3H), 1.34 (s, 3H), 1.12 (d, J = 6.8 Hz,
3H), 0.86 (t, J = 8.0 Hz, 9H), 0.75 (d, J = 6.8 Hz, 3H), 0.51-0.41 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 143.2, 127.7, 127.1, 98.7, 75.7, 72.5, 67.2,
43.0, 32.2, 29.7, 19.1, 11.5, 11.4, 6.7, 4.8; FTIR (neat) 2957, 1457, 1380,
1240, 1197, 1063, 1006, 851, 740 cm-1; MS (EI) m/z 87, 115, 143, 171,
221, 249, 291, 320, 363, 378 (M+); HRMS (EI) calcd for C22H38O3Si (M+)
378.2590, found 378.2586.
Ethyl
(S)-2-((4S,5S,6S)-2,2,5-Trimethyl-6-phenyl-1,3-dioxan-4-
yl)propanoate (20f): Prepared from 17f in the same manner as
24
described for the synthesis of 20d, 63% (2 steps), a colorless oil; [α]D
–
70.0 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36-7.19 (m, 5H),
4.18-4.05 (m, 4H), 2.55 (dq, J = 6.0, 6.8 Hz, 1H), 2.01 (dq, J = 3.6, 7.2,
7.6 Hz, 1H), 1.34 (s, 3H), 1.32 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H), 1.02 (d, J
= 7.6 Hz, 3H), 0.88 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
175.1, 141.9, 128.5, 127.8, 126.8, 101.5, 70.9, 60.4, 41.3, 39.7, 24.5,
23.6, 14.2, 13.3, 11.1; FTIR (neat) 2983, 1737, 1456, 1378, 1228, 1182,
887, 761 cm-1; MS (EI) m/z 69, 107, 118, 127, 203, 248, 291, 306 (M+);
HRMS (EI) calcd for C18H26O4 (M+) 306.1831, found 306.1833.
(4R,5R)-4-((1S,2S)-1-Triethylsiloxy-1-phenylpropan-2-yl)-2,2,5-
trimethyl-1,3-dioxane (21f): Prepared from 17f in the same manner as
described for the synthesis of 21c, 40% (2 steps), a colorless oil; [α]D
25
–
Ethyl
(R)-2-((4R,5S,6S)-2,2,5-Trimethyl-6-phenyl-1,3-dioxan-4-
67.5 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.31-7.22 (m, 5H),
4.45 (d, J = 9.2 Hz, 1H), 4.11 (dd, J = 1.2, 10.8 Hz, 1H), 3.72 (dd, J = 4.8,
11.6 Hz, 1H), 3.56 (dd, J = 10.8, 11.6 Hz, 1H), 1.93-1.80 (m, 2H), 1.50 (s,
3H), 1.40 (s, 3H), 0.83 (t, J = 8.0 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H), 0.51
(d, J = 7.6 Hz, 3H), 0.45-0.33 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
yl)propanoate (20h): Prepared from 17h in the same manner as
described for the synthesis of 20d, 50% (2 steps), a colorless oil; [α]D
49.5 (c 0.25, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35-7.26 (m, 5H),
4.00 (d, J = 10.4 Hz, 1H), 4.27-4.12 (m, 2H), 3.89 (dd, J = 2.4, 10.2 Hz,
27
–
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700337
European Journal of Organic Chemistry
FULL PAPER
144.8, 127.9, 127.4, 127.2, 97.9, 75.7, 72.8, 66.4, 42.0, 30.4, 29.8, 19.4,
12.5, 9.3, 6.9, 5.0; FTIR (neat) 2954, 1458, 1378, 1236, 1198, 1063,
1009, 834 cm-1; MS (EI) m/z 87, 115, 143, 171, 221, 249, 291, 320, 363,
378 (M+); HRMS (EI) calcd for C22H38O3Si (M+) 378.2590, found
378.2576.
565; k) T. Kano, H. Sugimoto, K. Maruoka, J. Am. Chem. Soc. 2011,
133, 18130-18133; l) W. Torres, G. Torres, J. A. Prieto, Synthesis. 2012,
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2012, 51, 1942-1946; n) D. E. Ward, A. Kazemeini, J. Org. Chem. 2012,
77, 10789-10803; o) M. Turks, S. Laclef, P. Vogel in Stereoselective
Synthesis of Drugs and Natural Products (Eds.: V. Andrushko, N.
Andrushko), John Wiley & Sons, Hoboken, 2013, Vol. 2, pp. 271-318
and references cited therein; p) J. M. Ketcham, I. Shin, T. P.
Montgomery, M. J. Krische, Angew. Chem. In. Ed. 2014, 53, 9142-
9150; q) L. Lin, K. Yamamoto, H. Mitsunuma, Y. Kanzaki, S. Matsunaga,
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Chem. Front. 2016, 3, 1383-1391.
(4S,5R)-4-((1S,2S)-1-Triethylsiloxy-1-phenylpropan-2-yl)-2,2,5-
trimethyl-1,3-dioxane (21g): Prepared from 17g in the same manner as
described for the synthesis of 21c, 33% (2 steps), a colorless oil; [α]D
26
–
0.31 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28-7.20 (m, 5H),
5.14 (d, J = 3.6 Hz, 1H), 3.95 (dd, J = 3.6, 12.0 Hz, 1H), 3.54 (d, J = 12.0
Hz, 1H), 3.30 (dd, J = 2.0, 10.4 Hz, 1H), 2.02 (ddq, J = 3.6, 6.8, 12.0 Hz,
1H), 1.46 (s, 3H), 1.32 (s, 3H), 1.36-1.28 (m, 1H), 1.09 (d, J = 6.8 Hz, 3H),
0.89 (t, J = 8.4 Hz, 9H), 0.67 (d, J = 6.8 Hz, 3H), 0.51-0.48 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 141.8, 127.6, 127.1, 126.7, 98.3, 75.7, 72.3,
67.1, 42.7, 30.0, 29.5, 19.4, 10.6, 7.9, 6.8, 4.9; FTIR (neat) 2957, 1457,
1381, 1195, 1090, 1007, 853, 771 cm-1; MS (EI) m/z 87, 115, 143, 171,
221, 249, 291, 320, 363, 378 (M+); HRMS (EI) calcd for C22H38O3Si (M+)
378.2590, found 378.2581.
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Brown, K. S. Bhat, R. S. Randad, J. Org. Chem. 1989, 54, 1570-1576;
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[8]
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a) O. Arjona, R. Menchaca, J. Plumet, J. Org. Chem. 2001, 66, 2400-
2413; b) A. El-Awa, X. M. du Jourdin, P. L. Fuchs, J. Am. Chem. Soc.
2007, 129, 9086-9093.
(4S,5S)-4-((1S,2S)-1-Triethylsiloxy-1-phenylpropan-2-yl)-2,2,5-
trimethyl-1,3-dioxane (21h): Prepared from 17h in the same manner as
described for the synthesis of 21c, 28% (2 steps), a colorless oil; [α]D
a) T. Hanamoto, T. Katsuki, M. Yamaguchi, Bull. Chem. Soc. Jpn. 1990,
63, 1039-1048; b) S. Kiyooka, Tetrahedron Asymmetry. 2003, 14, 2897-
2910.
26
–
17.5 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.29-7.22 (m, 5H),
4.76 (d, J = 8.4 Hz, 1H), 3.70 (dd, J = 4.8, 11.6 Hz, 1H), 3.58 (dd, J = 3.2,
10.0 Hz, 1H), 3.44 (dd, J = 11.6, 11.6 Hz, 1H), 2.31-2.22 (m, 1H), 2.09
(ddq, J = 3.2, 6.8, 8.4 Hz, 1H), 1.42 (s, 3H), 1.40 (s, 3H), 0.92-0.82 (m,
12H), 0.60 (d, J = 6.8 Hz, 3H), 0.48-0.38 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 144.5, 127.1, 127.3, 127.0, 98.3, 77.3, 76.6, 75.8, 66.7, 43.6,
32.3, 29.5, 19.3, 13.9, 13.6, 6.8, 4.9; FT-IR (neat) 2954, 1458, 1377,
1198, 1063, 1009, 820 cm-1; MS (EI) m/z 87, 115, 143, 171, 221, 249,
291, 320, 363, 378 (M+); HRMS (EI) calcd for C22H38O3Si (M+) 378.2590,
found 378.2606.
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Acknowledgements
This work was supported by the Grant-in-Aid for Scientific
Research (B) (16H05074) from JSPS and the Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysis” (No. 2304) (26105747)
from MEXT. H.Y. thanks a JSPS Research Fellowship for Young
Scientists.
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comparison of the 1H NMR spectra with those reported for racemic 8
and 10.[12]
[15] The 1H and 13C NMR spectra clearly showed that the recovered
aldehydes did not contain the corresponding epimers, respectively.
[16] See Supporting Information.
Keywords: Asymmetric synthesis• Organocatalysis •
Polyketides
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Tetrahedron Assymetry. 2001, 12, 2343-2349.
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700337
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Asymmetric Synthesis
Hikaru Yoshimura, Jun Ishihara and
Susumi Hatakeyama*
Page No. – Page No.
Stereoselective Construction of
Entire Diastereomeric Stereotetrads
Based on an Asymmetric Morita-
Baylis-Hillman Reaction
Described is a highly enantio- and diastereoselective approach to all possible
stereoisomers of a polypropionate stereotetrad, which features an iterative
sequence of a cinchona alkaloid-catalyzed Morita-Baylis-Hillman reaction and
diastereoselective hydrogenation.
This article is protected by copyright. All rights reserved.