Enantioselective evans-tishchenko reduction of β-hydroxyketone catalyzed by lithium binaphtholate

Article abstract of DOI:10.3390/molecules16065008

Lithium diphenylbinaphtholate catalyzed the enantioselective Evans-Tishchenko reduction of achiral β-hydroxyketones to afford monoacyl-protected 1,3-diols with high stereoselectivities. In the reaction of racemic β-hydroxyketones, kinetic optical resolution occurred in a highly stereoselective manner.

Full text of DOI:10.3390/molecules16065008

Molecules 2011, 16, 5008-5019; doi:10.3390/molecules16065008
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molecules
ISSN 1420-3049
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Article
Enantioselective Evans-Tishchenko Reduction of
β-Hydroxyketone Catalyzed by Lithium Binaphtholate
Tomonori Ichibakase, Masato Nakatsu and Makoto Nakajima *
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi,
Kumamoto 862-0973, Japan
* Author to whom correspondence should be addressed; E-Mail: nakajima@gpo.kumamoto-u.ac.jp;
Tel.: +81-96-371-4680; Fax: +81-96-362-7692.
Received: 1 June 2011; in revised form: 10 June 2011 / Accepted: 15 June 2011 /
Published: 17 June 2011
Abstract: Lithium diphenylbinaphtholate catalyzed the enantioselective Evans-Tishchenko
reduction of achiral β-hydroxyketones to afford monoacyl-protected 1,3-diols with high
stereoselectivities. In the reaction of racemic β-hydroxyketones, kinetic optical resolution
occurred in a highly stereoselective manner.
Keywords: Evans-Tishchenko reduction; lithium binaphtholate; β-hydroxyketone;
1,3-diol; enantioselectivity
1. Introduction
Stereoselective synthesis of 1,3-diols is an important subject in synthetic organic chemistry because
numerous biologically active compounds include such units [1,2]. One method to prepare chiral 1,3-diol
is the reduction of β-hydroxyketones, and various metal hydride reagents have been applied to the
syntheses of biologically active compounds using this method. Recently, acetalization of a β-hydroxy
group with an aldehyde followed by a hydride shift to the carbonyl carbon, the so called
Evans-Tishchenko reduction (Scheme 1) [3-5], has received much attention because it does not require
the use of metal hydride reagents. Although the literature contains numerous examples using
the Evans-Tishchenko reduction in the synthesis of biologically active compounds [6-13], the
enantioselective Evans-Tishchenko reduction of an achiral β-hydroxyketone had not been reported
prior to our preliminary study [14].

Molecules 2011, 16
5009
Scheme 1. Evans-Tishchenko reduction of β-hydroxyketone.
OH
O
O
H
O
OH
O
O
R2
OH
O
R2
R2
H
R1
R1
R1
acetalization
hydride shift
H
We have previously reported that an enantioselective aldol-Tishchenko reaction [14-21] catalyzed
by lithium binaphtholate [22-30], affords 1,3-diol derivatives from a ketone and an aldehyde. Herein
we report an enantioselective Evans-Tishchenko reduction, which yields optically active mono-acyl
protected 1,3-diols from the reaction of achiral β-hydroxyketones with aldehydes catalyzed by
lithium binaphtholate.
2. Results and Discussion
2.1. Optimization of Reaction Conditions
First we investigated the Evans-Tishchenko reduction of α,α-dimethyl-β-hydroxypropiophenone
(2a) with benzaldehyde (3a) in THF at r.t. using lithium binaphtholate 1a, prepared in situ from
binaphthol and BuLi, as a catalyst (Table 1, entry 1). The reaction gave the corresponding
monobenzoyl 1,3-diol 4aa, but with low chemical yield (36%) and enantioselectivity (2% ee).
Screening binaphthol derivatives revealed that introducing substituents to the 3,3’-positions of the
catalyst dramatically increased both the chemical yield and enantioselectivity (entries 2–6). Among the
various substituents surveyed, phenyl groups gave the best result (entry 4, 82% yield, 96% ee).
Compared to THF, the use of ether or toluene as solvent gave unsatisfactory results (entries 7 and 8).
Although lowering the reaction temperature increased the enantioselectivity (entry 9), the reaction did
not proceeded smoothly at −78 °C (entry 10).
Table 1. Evans-Tishchenko reduction of α,α-dimethyl-β-hydroxypropiophenone.
R
O
O
OH
O
OH
O
Ph
1 (10 mol %)
OLi
OLi
+
Ph
Ph
H
Ph
THF, rt
R
2a
3a
4aa
1
Entry
Catalyst
Conditions
rt, 24 h
Solvent
THF
THF
THF
THF
THF
THF
Et2O
toluene
THF
Yield, % a
ee, % b
2
1
2
3
4
5
6
7
8
9
1a (R = H)
1b (R = Me)
1c (R = Br)
1d (R = Ph)
36
91
76
82
80
84
73
63
87
56
rt, 24 h
rt, 24 h
79
83
96
89
20
56
63
99
rt, 0.5 h
rt, 0.5 h
rt, 0.5 h
rt, 0.5 h
rt, 0.5 h
1e (R = 4-MeC6H4)
1f (R = 3,5-Me2C6H3)
1d (R = Ph)
1d (R = Ph)
1d (R = Ph)
1d (R = Ph)
−40 °C, 0.5 h
−78 °C, 48 h
10
THF
99
a Isolated yield; b Determined by HPLC analysis.

Molecules 2011, 16
5010
2.2. Evans-Tishchenko Reduction of Various Achiral β-Hydroxy ketones
With the optimum conditions in hand, we next examined the Evans-Tishchenko reduction of
various β-hydroxyketones and aldehydes. The reaction of 2a with pivalaldehyde (3b) as a hydride
source, which should afford pivaloyl ester, gave the corresponding product 4ab with the same absolute
configuration as that with benzaldehyde in high yield at 0 °C, but was accompanied by the side product
5ab (5% yield), which was formed by transesterification of 4ab (Table 2, entry 2). The obtained
enantioselectivity decreased to 90% ee, probably due to the higher reaction temperature (0 °C in entry
2 vs. −40 °C in entry 1). β-Hydroxyketone 2b, with cyclohexane at the α-position gave similar results
as 2a with benzaldehyde (3a) or pivaldehyde (3b) (entries 3 and 4). Isopropyl ketone 2c gave the
product 4ca in high enantioselectivity, but accompanied by 31% of the transesterification product 5ca
(entry 5). Under the reaction conditions, either 4ca or 5ca was isomerized into a mixture of 4ca and
5ca (4ca:5ca = 2:1) without losing the enantioselectivity. The reaction of methyl ketone 2d and
benzaldehyde (3a) gave excellent results, however, the products 4da and 5da (4da:5da = 2:1) were
isolated as a single dibenzoyl ester 7da after benzoylation of the mixture of 4da and 5da (entry 6),
because the monobenzoyl products 4da and 5da could not be separated.
Table 2. Evans-Tishchenko reduction of various achiral β-hydroxy ketones.
O
O
O
OH
OH
O
R3
R3
O
OH
1d (10 mol %)
R3CHO
+
+
R1
R1
R1
THF
R2 R2
R2 R2
R2 R2
2
3
4
5
Entry
2
3
Conditions
4
Yield of 4 (5) % a ee of 4 (5) % b
1
2
3
4
5
2a
2a
2b
2b
2c
3a
3b
3a
3b
3a
−40 °C, 0.5 h 4aa
87 (0)
93 (5)
96 (0)
82 (13)
64 (31)
91 c
99
90 (90)
98
83
93 (93)
0 °C, 1 h
4ab
−40 °C, 0.5 h 4ba
0 °C, 4 h
rt, 4 h
4bb
4ca
6
2d
3a
−40 °C, 6 h
4da
99 c
[4da:5da = 2:1]
a Isolated yield; b Determined by HPLC analysis; c Isolated as dibenzoyl ester 7da. Ratio of 4da to
5da was calculated from the crude NMR before benzoylation.
O
O
O
OH
O
OH
OH OH Ph
O
O
Ph
O
OH
O
OH
3a: PhCHO
Ph
Ph
Ph
3b: t-BuCHO
2a
2b
2c
2d
6a
7da
2.3. Evans-Tishchenko Reduction of Chiral β-Hydroxypropiophenone
Using chiral β-hydroxyketones under the above conditions, a kinetic optical resolution occurred in a
highly enantioselective manner (Scheme 2). The reaction of racemic α-methyl-β-hydroxyketone 8 and

Molecules 2011, 16
5011
benzaldehyde (3a) at −45 °C for 24 h afforded monobenzoyl 1,3-diol 9 in 48% yield with 86% ee, and
the unreacted starting material 8 was recovered in 42% yield with 88% ee. The stereochemistry of 9
was determined by the conversion to the stereochemically-known diol 10 [31] by debenzoylation with
sodium methoxide in methanol. Scheme 3 explains the 1,2-syn stereochemistry using bicyclic
transition model A for the reaction of 8 and benzaldehyde 3a. The α-methyl group preferred the
equatorial position over the axial position, producing 1,2-syn product predominantly.
Scheme 2. Kinetic resolution of chiral β-hydroxyketone.
Scheme 3. Plausible reaction pathway.
O
Li
H
Li
H
O
O
O
O
O
O
OH
OH O
Ph
PhCHO
H+
2
1
1
1
Ph
Ph
Ph
Me
Ph
Ph
Me
Ph
Ph
Ph
1d
O
O
O
2
2
H
H
R-8
A
B
9
Li
H
O
O
OH
PhCHO
1
Ph
2 H
1d
Me
S-8
A'
2.4. Reaction of An α-Unsubstituted-β-Hydroxypropiophenone
In the reaction of α-unsubstituted-β-hydroxypropiophenone 11, the Evans-Tishchenko product
was not observed, but rather the monobenzoyl triol 12 was obtained in high yield with a high
enantioselectivity (Scheme 4). Compound 12 may be formed by the transesterification of the
aldol-Tishchenko adduct 13. It is interesting that the Evans-Tishchenko reduction proceeded
exclusively in methyl ketone 2d, while β-hydroxypropiophenone (11) gave predominantly the
aldol-Tishchenko adduct, although both hydroxyketones have enolizable positions. This may be
because the Li-coordinated cyclic structure promoted the enolate formation or the approach of the
aldehyde, though the detail is not clear. The absolute configuration of 12 was determined by
conversion to stereochemically-known triol 14 [32].

Molecules 2011, 16
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Scheme 4. The reaction of an α-unsubstituted-β-hydroxyketone.
3. Experimental
3.1. General
1H-NMR and 13C-NMR spectra were recorded using a JEOL JNM-ECX-400 (1H, 400 MHz;
13C, 100 MHz) spectrometer. Chemical shift values are expressed in ppm relative to internal
tetramethylsilane. Coupling constants (J) are reported in Hz. Abbreviations are as follows: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad. Infrared spectra were recorded using a JASCO
FT/IR-5300. HPLC was performed on a JASCO PU-1580 with a JASCO UV-1575 (λ = 254 nm), and
chiral separations were performed using Daicel Chiralpak or Chiralcel columns (φ 0.46 × 25 cm) with
mixtures of hexane/isopropyl alcohol (hex/IPA) as eluents. Optical rotations were obtained using a
JASCO DIP-370 digital polarimeter. β-Hydroxyketones 2, 6 and 8 were prepared according to the
literature [33-36], as were the binaphthol derivatives [37].
3.2. Enantioselective Evans-Tishchenko Reduction of β-Hydroxyketones
3.2.1. (S)-2,2-Dimethyl-1-phenyl-1,3-propanediol 3-O-benzoate (4aa) [38]
Under an argon atmosphere, n-BuLi (0.094 mmol, 20 mol %) in hexane (0.17 M, 0.55 mL) was
added to a solution of (R)-3,3’-diphenylbinaphthol (21 mg, 0.047 mmol, 10 mol %) in THF at −45 °C,
and the mixture was stirred for 5 min. Then solutions of benzaldehyde (3a, 75 mg, 0.708 mmol,
1.5 equiv.) and 3-hydroxy-2,2-dimethyl-1-phenylpropan-1-one (2a, 84 mg, 0.472 mmol, 1.0 equiv.)
were successively added to the above mixture. After 0.5 h, the reaction was quenched with sat. NH4Cl
aq. and the mixture was stirred for an additional 10 min at r.t. The aqueous layer was extracted
with ethyl acetate and the combined organic layer was washed with brine. After drying over Na2SO4
and evaporating the solvent, the residue was purified by silica gel column chromatography
(dichloromethane) to afford diol derivative 4aa (114 mg, 87% yield, 99% ee) as colorless prisms. Mp
73–74 °C. 1H-NMR (CDCl3): δ 0.97 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.45 (brs, 1H, –OH), 4.02 (d, 1H,
J = 11.0 Hz, OCH2), 4.43 (d, 1H, J = 11.0 Hz, OCH2), 4.69 (s, 1H, CHPh), 7.25–7.48 (m, 7H, ArH),
7.56–7.60 (m, 1H, ArH), 8.04–8.06 (m, 2H, ArH). HPLC (Daicel Chiralpak AD-H, hex/IPA = 9/1,
1.0 mL/min): tR 8.8 (S), 12.8 min (R). [α]30D −23.1 (c 1.13, CHCl3) for 99% ee.

Molecules 2011, 16
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Determination of the absolute configuration of 4aa.
To a solution of 4aa (114 mg, 0.401 mmol, 1.0 equiv.) in MeOH (2 mL), NaOMe (0.05 mmol,
12 mol %) in MeOH (0.1 mL) was added and the resulting homogeneous mixture was stirred for 3 h.
The mixture was diluted with ethyl acetate (20 mL), and washed with water (5 mL). The aqueous layer
was extracted twice with ethyl acetate (10 mL × 2). The combined organic layers were washed with
brine (10 mL) and dried over Na2SO4. After concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/ethyl acetate = 4/1) to give diol 6a (70 mg, 96% yield, 99% ee) as
colorless needles. The optical rotation data shows (+)-6a had an S-configuration, indicating (−)-4aa
1
has an S-configuration. Mp 62–63 °C. H-NMR (CDCl3) δ 0.79 (s, 3H, CH3), 0.84 (s, 3H, CH3), 3.43
(d, 1H, J = 10.6 Hz, OCH2), 3.50–3.58 (m, 2H, OCH2 and CHPh), 3.77 (brs, 1H, OH), 4.57 (s, 1H,
OH), 7.32–7.35 (m, 5H, ArH). [α]30D +44.7 (c 1.00, CHCl3) for 99% ee (S). [lit. 39: [α]D30 +21.7 (c 1.17,
CHCl3) for 55% ee (S)].
3.2.2. (S)-2,2-Dimethyl-1-phenyl-1,3-propanediol 3-O-pivaloate (4ab)
1H-NMR (CDCl3): δ 0.87 (s, 3H, C(CH3)2), 0.95 (s, 3H, C(CH3)2), 1.26 (s, 9H, C(CH3)3), 2.39 (d,
1H, J = 3.2 Hz, –OH), 3.74 (d, 1H, J = 11 Hz, CH2), 4.19 (d, 1H, J = 11 Hz, CH2), 4.57 (d, 1H, J = 3.2 Hz,
13
PhCH), 7.26–7.33 (m, 5H, ArH). C-NMR: δ 19.4, 21.3, 27.2, 39.0, 39.3, 70.5, 78.0, 127.5, 127.6,
127.7, 140.9, 178.6. IR (CHCl3): 3480, 1715 cm−1. MS (FAB): m/z 173, 287 ([M+Na]+). HRMS: calcd
for C16H24O3Na 287.1623, found 287.1619. HPLC (Daicel Chiralcel OD-H, hex/IPA = 9/1, 1.0 mL/min)
tR: 5.1 (R), 6.7 (S) min. [α]17 −7.5 (c 1.0, CHCl3) for 90% ee (S). The absolute configuration of 4ab
D
was determined by conversion to diol 6a. [α]21 +35.1 (c 1.37, CHCl3) for 90% ee (S). [lit. 39: [α]30
D
D
+21.7 (c 1.17, CHCl3) for 55% ee (S)].
3.2.3. (S)-2,2-Dimethyl-1-phenyl-1,3-propanediol 1-O-pivaloate (5ab)
1H-NMR (CDCl3): δ 0.88 (s, 3H, C(CH3)2), 0.89 (s, 3H, C(CH3)2), 1.25 (s, 9H, C(CH3)3), 2.34 (brs,
1H, OH), 3.24 (d, 1H, J = 11 Hz, CH2), 3.42 (d, 1H, J = 11 Hz, CH2), 5.77 (s, 1H, PhCH), 7.28–7.35
(m, 5H, ArH). 13C-NMR: δ 19.2, 21.6, 27.2, 39.0, 40.2, 69.1, 78.5, 127.66, 127.72, 127.8, 137.5,
178.2. IR (neat): 3458, 1730 cm−1. MS (FAB, NBA+NaI): m/z 287 ([M+Na]+). HRMS: calcd for
C16H24O3Na 287.1623, found 287.1628. [α]17D +51.4 (c 0.6, CHCl3).
3.2.4. (−)-2,2-Pentamethylene-1-phenyl-1,3-propanediol 3-O-benzoate (4ba)
1H-NMR (CDCl3): δ 1.17–1.26 (m, 1H, CCH2C), 1.37–1.61 (m, 9H, CCH2C), 2.50 (brs, 1H, OH),
4.21 (d, 1H, J = 11.4 Hz, OCH2), 4.47 (d, 1H, J = 11.4 Hz, OCH2), 4.74 (s, 1H, PhCH), 7.21–7.32
(m, 5H, ArH), 7.41–7.44 (m, 2H, ArH), 7.54–7.58 (m, 1H, ArH), 7.94–7.96 (m, 2H, ArH). 13C-NMR:
δ 21.3, 21.4, 25.8, 28.2, 28.3, 41.3, 65.2, 78.2, 127.3, 127.6, 127.7, 128.3, 129.5, 130.1, 132.9, 141.0,
166.4. IR (neat): 3502, 1716 cm−1. MS (FAB, NBA+NaI): m/z 347 ([M+Na]+). HRMS: calcd for
C21H24O3Na 347.1623, found 347.1643. HPLC (Daicel Chiralpak AD-H, hex/IPA = 49/1, 1 mL/min)
tR: 13.0 (major), 14.4 (minor) min. [α]18D −11.4 (c 1.13, CHCl3) for 98% ee.

Molecules 2011, 16
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3.2.5. (+)-2,2-Pentamethylene-1-phenyl-1,3-propanediol 3-O-pivaloate (4bb)
1H-NMR (CDCl3): δ 1.22 (s, 9H, C(CH3)3), 1.34-1.58 (m, 10H, CCH2C), 2.54 (brs, 1H, OH), 3.94
(d, 1H, J = 11.4 Hz, OCH2), 4.21 (d, 1H, J = 11.4 Hz, OCH2), 4.62 (s, 1H, PhCH), 7.25–7.32 (m, 5H,
ArH). 13C-NMR: δ 21.2, 21.4, 25.8, 27.2, 28.2, 28.3, 38.9, 41.1, 64.9, 78.5, 127.3, 127.6, 127.7, 140.9,
178.3. IR (KBr): 3498, 1711 cm−1. MS (FAB, NBA+NaI): m/z 287, 327 ([M+Na]+). HRMS: calcd for
C19H28O3Na 327.1936, found 327.1929. HPLC (Daicel Chiralpak AD-H, hex/IPA = 49/1, 1 mL/min)
tR: 28.1 (minor), 33.0 (major) min. [α]17D +6.0 (c 1.36, CHCl3) for 83% ee.
3.2.6. (+)-2,2-Pentamethylene-1-phenyl-1,3-propanediol 1-O-pivaloate (5bb)
1H-NMR (CDCl3): δ 1.12-1.59 (m, 9H, CCH2C), 1.24 (s, 9H, C(CH3)3), 1.69–1.72 (m, 1H,
CCH2C), 2.07 (brs, 1H, OH), 3.49 (d, 1H, J = 11.9 Hz, OCH2), 3.63 (d, 1H, J = 11.9 Hz, OCH2), 5.78
(s, 1H, PhCH), 7.26–7.33 (m, 5H, ArH). 13C-NMR: δ 21.1, 21.3, 25.9, 27.2, 28.2, 28.4, 39.0, 41.9, 62.9,
79.8, 127.7, 127.8, 127.9, 137.3, 177.6. IR (neat): 3513, 1732 cm−1. MS (FAB, NBA+NaI): m/z 57, 91,
305 ([M+H]+). HRMS: calcd for C19H29O3 305.2117, found 305.2128. [α]17D +23.3 (c 1.47, CHCl3).
3.2.7. (S)-2,2,4-Trimethyl-1,3-pentanediol 1-O-benzoate (4ca)
1H-NMR (CDCl3): δ 0.97 (d, 3H, J = 6.9 Hz, CH(CH3)2), 1.02 (d, 3H, J = 6.9 Hz, CH(CH3)2), 1.05
(s, 3H, C(CH3)2), 1.07 (s, 3H, C(CH3)2), 1.97–2.00 (m, 2H, OH, CH(CH3)2), 3.38 (s, 1H, CHOH), 4.02
(d, 1H, J = 11 Hz, CH2), 4.38 (d, 1H, J = 11 Hz, CH2), 7.43–7.47 (m, 2H, ArH), 7.55–7.59 (m, 1H,
ArH), 8.03–8.05 (m, 2H, ArH). 13C-NMR: δ 17.9, 19.7, 22.3, 23.0, 28.6, 40.3, 70.0, 80.3, 128.5, 129.8,
129.9, 133.2, 167.6. IR (KBr): 3340, 1724 cm−1. MS (FAB, NBA+NaI): m/z 77, 105, 273 ([M+Na]+).
HRMS calcd for C15H22O3Na 273.1467, found 273.1458. HPLC (Daicel Chiralpak AD-H, hex/IPA = 39/1,
1.0 mL/min) tR: 14.4 (S), 15.7 (R) min. [α]17 +9.5 (c 2.14, benzene) for 93% ee, (S). The absolute
D
configuration of 4ca was determined by conversion to diol 6a. [α]29 −11.3 (c 1.54, CH2Cl2) for 93%
D
ee. [lit. 40: [α]30D −9.5 (c 1.0, CH2Cl2) for 75% ee, (S)].
3.2.8. (S)-2,2,4-Trimethyl-1,3-pentanediol 3-O-benzoate (5ca)
1H-NMR (CDCl3): δ 0.95 (s, 3H, C(CH3)2), 1.01 (d, 3H, J = 6.9 Hz, CH(CH3)2), 1.09 (d, 3H, J = 6.9 Hz,
CH(CH3)2), 1.10 (s, 3H, C(CH3)2), 2.17–2.21 (m, 1H, CH(CH3)2), 2.79 (brs, 1H, OH), 3.09 (d, 1H,
J = 11.9 Hz, CH2), 3.34 (d, 1H, J = 11.9 Hz, CH2), 5.04 (d, 1H, J = 2.8 Hz, OCH), 7.45–7.49 (m, 2H,
ArH), 7.58–7.61 (m, 1H, ArH), 8.08–8.10 (d, 2H, J = 7.3 Hz, ArH). 13C-NMR: δ 17.9, 19.7, 22.3, 23.0,
28.6, 40.3, 70.0, 80.3, 128.5, 129.8, 129.9, 133.2, 167.6. IR (neat): 3493, 1720 cm−1. MS (FAB,
NBA+NaI): m/z 105, 273 ([M+Na]+). HRMS calcd for C H O Na 273.1467, found 273.1447. HPLC
：
15 22
3
(Daicel Chiralpak AD-H, hex/IPA = 39/1, 1 mL/min) tR: 13.5 (S), 14.8 (R) min. [α]17 −15.4 (c 1.15,
D
CHCl3) for 93% ee, (S).
Treatment of 4ca (93% ee) with 10 mol % of 1d for 3 h at rt afforded 5ca (32% yield, 92% ee) with
unreacted 4ca (63% yield, 93% ee). Treatment of 5ca (93% ee) with 10 mol % of 1d for 3 h at r.t.
afforded 4ca (58% yield, 93% ee) with unreacted 5ca (32% yield, 93% ee).

Molecules 2011, 16
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3.2.9. (+)-2,2-Dimethyl-1,3-butanediol dibenzoate (7da)
Starting from 2d (0.057 mL, 0.470 mmol, 1.0 equiv.) and 3a (75 mg, 0.708 mmol, 1.5 equiv.), a
mixture of 4da and 5da was obtained by the above method. To the solution of the mixture in
dichloromethane (2 mL), benzoyl chloride (0.820 mL, 0.710 mmol, 1.5 equiv.), Et3N (0.147 mL,
1.41 mmol, 3.0 equiv.) and DMAP (11.5 mg, 0.094 mmol, 10 mol %) were added successively. After
being stirred for 12 h at r.t., the reaction mixture was quenched by diethylamine (0.1 mL) and was
diluted with ethyl acetate. The organic layer were washed with HCl aq., NaHCO3 aq. and brine (10 mL)
successively, and dried over Na2SO4. After concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/dichloromethane = 1/1) to give dibenzoate 7da (141 mg, 92%
1
yield, 99% ee) as as oil. H-NMR (CDCl3) δ 1.13 (s, 3H, CCH3), 1.17 (s, 3H, CCH3), 1.37 (d, 3H,
J = 6.4 Hz, CHCH3), 4.22 (d, 1H, J = 11.5 Hz, CH2), 4.26 (d, 1H, J = 11.5 Hz, CH2), 5.28 (q, 1H,
J = 6.4 Hz, CH), 7.39–7.44 (m, 4H, ArH), 7.51–7.55 (m, 2H, ArH), 8.03–8.06 (m, 4H, ArH).
13C-NMR (CDCl3) δ 14.70, 20.38, 21.33, 38.07, 70.02, 74.50, 128.24, 128.28, 129.39, 129.45, 130.02,
130.42, 132.76, 132.83, 165.66, 166.28. IR (neat): 1720 cm−1. MS (FAB, NBA+NaI) 327 ((M+H)+),
205, 154, 137, 105, 83, 77. HRMS (FAB) calcd for C20H23O4 ((M+H)+) 327.1602, found 327.1597.
[α]29 +66.6 (c 1.47, CHCl3) for 99% ee. HPLC (Daicel Chiralpak AD-H, hex/IPA = 200/1,
D
1.0 mL/min): tR: 19.3 (minor), 20.7 (major) min.
3.3. Kinetic Optical Resolution of 3-Hydroxy-2-methyl-1-phenylpropan-1-one (8)
Under an argon atmosphere, n-BuLi (0.094 mmol, 20 mol %) in hexane (0.19 M, 0.49 mL) was
added to a solution of (R)-3,3’-diphenylbinaphthol (21 mg, 0.047 mmol, 10 mol %) in THF at −45 °C,
and the mixture was stirred for 5 min. Then solutions of benzaldehyde (3a, 50 mg, 0.470 mmol,
1.0 equiv.) and racemic 3-hydroxy-2-methyl-1-phenylpropan-1-one (8, 77 mg, 0.470 mmol, 1.0 equiv.)
were successively added to the above mixture. After 24 h, the reaction was quenched with sat. NH4Cl
aq. and the mixture was stirred for 20 min at r.t. The aqueous layer was extracted twice with
dichloromethane and the combined organic layers were washed with brine. After drying over Na2SO4
and evaporating the solvent, the residue was purified by silica gel column chromatography
(hexane/ethyl acetate = 6/1 ~ 2/1) to afford the diol derivative 9 (61 mg, 48% yield, 86% ee) and
unreacted starting material 8 (32 mg, 42%, 88% ee).
3.3.1. (1R,2S)-2-Methyl-1-phenyl-1,3-propanediol 3-O-benzoate (9)
1H-NMR (CDCl3): δ 1.03 (d, 3H, J = 6.9 Hz, CH3), 2.16 (dd, 1H, J = 1.4, 3.6 Hz, OH), 2.28–2.36
(m, 1H, CHCH3), 4.14 (dd, 1H, J = 6.0, 11 Hz, CH2), 4.43 (dd, 1H, J = 6.7, 11 Hz, CH2), 4.84–4.86
(m, 1H, PhCH), 7.26–2.29 (m, 1H, ArH), 7.34–7.36 (m, 4H, ArH), 7.43−7.47 (m, 2H, ArH), 7.56–7.59
(m, 1H, ArH), 8.01−8.03 (m, 2H, ArH). 13C-NMR: δ 11.2, 40.1, 67.1, 74.3, 126.0, 127.4, 128.3, 128.4,
130.0, 130.1, 133.0, 142.7, 166.7. IR (neat): 3492, 1722 cm−1. MS (FAB, NBA+NaI): m/z 77, 105,
154, 271 ([M+H]+). HRMS: calcd for C17H19O30 271.1334 found 271.1356. HPLC (Daicel Chiralpak
AD-H, hex/IPA = 9/1, 1.0 mL/min) tR: 9.8 (1R,2S), 11.2 (1S,2R) min. [α]18D −17.4 (c 1.45, CHCl3) for 88%
ee, (1R,2S). The relative and absolute configuration of 9 were determined by conversion to diol 10. [α]21
+39.2 (c 0.88, CHCl3) for 88% ee (1R,2S). [lit. 31:[α]27D +56.1 (c 0.75, CHCl3) for >99% ee, (1R,2S)].
D

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5016
3.3.2. (S)-3-Hydroxy-2-methyl-1-phenylpropan-1-one (8)
HPLC (Daicel Chiralpak AD-H, hex/IPA = 19/1, 1 mL/min) tR: 17.6 (R), 19.7 (S) min. [α]29D −37.9
(c 0.86, EtOH) for 86% ee (S). [lit. 41: [α]23D +41.2 (c 0.90, EtOH) for 91% ee, (R)].
3.4. The Aldol-Tishchenko Reaction of An α-Unsubstituted-β-Hydroxypropiophenone
(1R,3R)-2-Benzoyloxymethyl-1,3-diphenyl-1,3-propanediol (12)
Under an argon atmosphere, n-BuLi (0.094 mmol, 20 mol %) in hexane (0.19 M, 0.49 mL) was
added to a solution of (R)-3,3’-diphenylbinaphthol (21 mg, 0.047 mmol, 10 mol %) in THF at −45 °C,
and the mixture was stirred for 5 min. Then solutions of benzaldehyde (3a, 76 mg, 0.716 mmol,
1.5 equiv.) and 3-hydroxy-1-phenylpropan-1-one (11, 70 mg, 0.470 mmol, 1.0 equiv.) were
successively added to the above mixture. After 24 h, the reaction was quenched with sat. NH4Cl aq.
and the mixture was stirred for 20 min at r.t. The aqueous layer was extracted twice with
dichloromethane and the combined organic layers were washed with brine. After drying over Na2SO4
and evaporating the solvent, the residue was purified by silica gel column chromatography
(hexane/ethyl acetate = 1/1 then dichloromethane) to afford the diol derivative 12 (158 mg, 93% yield,
90% ee) as colorless needles. Mp 119–120 °C. 1H-NMR (CDCl3): δ 2.45–2.50 (m, 1H, CCHC), 3.89 (d,
1H, J = 6.7 Hz, OH), 3.90 (d, 1H, J = 4.6 Hz, OH), 4.20 (dd, 1H, J = 5.5, 11.5 Hz, BzOCH2), 4.65 (dd,
1H, J = 8.3, 11.5 Hz, BzOCH2), 5.33–5.57 (m, 1H, HOCH), 5.11 (dd, 1H, J = 4.6, 4.6 Hz, HOCH),
7.16–7.20 (m, 3H, ArH), 7.24–7.30 (m, 3H, ArH), 7.35–7.43 (m, 6H, ArH), 7.50–7.54 (m, 1H, ArH),
7.80–7.83 (m, 2H, ArH). 13C-NMR: δ 50.7, 61.7, 71.6, 73.5, 125.4, 125.7, 127.0, 127.6, 128.2, 128.6,
129.5, 129.7, 133.0, 141.9, 142.2, 166.8. IR (neat): 3477, 1713 cm−1. MS (FAB, NBA+NaI) 385
((M+Na)+), 326, 323, 242, 176, 173, 92, 77. HRMS (FAB) calcd for C23H22O4Na ((M+Na)+) 385.1420,
found 385.1416. HPLC (Daicel Chiralpak AD-H, hex/IPA = 9/1, 1.0 mL/min) tR: 19.3 (S,S), 25.1 (R,R)
min. [α]29D +44.1 (c 1.04, CHCl3) for 92% ee, (S,S).
The absolute configuration of 12 was determined by the conversion to triol 14. 1H-NMR (CDCl3) δ
1.91 (brs, 1H, OH), 3.25 (brs, 1H, J = 10.6 Hz, CH2), 3.65 (dd, 1H, J = 5.48, 11.44 Hz, CH), 4.18 (brs,
1H, OH), 4.43 (d, 1H, J = 4.12 Hz, CH2), 7.16–7.19 (m, 3H, ArH), 7.22–7.25 (m, 3H, ArH), 7.27–7.33
(m, 3H, ArH). [α]18D −35.0 (c 2.16, CH2Cl2) for 92% ee [lit. 32: [α]20D −39 (c 0.97, CH2Cl2) for >99%
ee, (R,R)].
4. Conclusions
We have demonstrated that lithium diphenylbinaphtholate catalyzes the enantioselective
Evans-Tishchenko reduction of β-hydroxyketones, affording monoacyl-protected 1,3-diols in high
stereoselectivities. In the reaction of racemic β-hydroxyketone, kinetic optical resolution occurs in a
highly stereoselective manner. Further investigations to expand the substrate scope and to explore the
reaction mechanism are currently underway.

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