Efficient preparation of 1,3-Diol derivatives with three contiguous stereocenters by an enantioselective direct aldol-tishchenko reaction

Article abstract of DOI:10.1055/s-0031-1291138

1,3-Diol derivatives with three contiguous stereocenters were efficiently prepared by an enantioselective direct aldol-Tishchenko reaction catalyzed by dilithium 3,3-diphenylbinaphtholate. The reactions of acyclic ketones as aldol donors gave 1,2-syn-1,3-

Full text of DOI:10.1055/s-0031-1291138

PRACTICAL SYNTHETIC PROCEDURES
▌3145
pErafctficiacliseynnthtetiPc prroecepduarersation of 1,3-Diol Derivatives with Three Contiguous Stereo-
centers by an Enantioselective Direct Aldol–Tishchenko Reaction
Synthesis of 1,3-Diols with Three Contiguous Stereocenters
Tomonori Ichibakase, Makoto Nakajima*
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi,
Kumamoto 862-0973, Japan
Fax +81(96)3627692; E-mail: nakajima@gpo.kumamoto-u.ac.jp
PSP
Received: 29.02.2012; Accepted: 21.03.2012
No234
Abstract: 1,3-Diol derivatives with three contiguous stereocenters were efficiently prepared by an enantioselective direct aldol–Tishchenko
reaction catalyzed by dilithium 3,3′-diphenylbinaphtholate. The reactions of acyclic ketones as aldol donors gave 1,2-syn-1,3-anti-diol de-
rivatives, whereas the reactions of cyclic ketones as aldol donors gave 1,2-anti-1,3-anti-diol derivatives. Sequential aldol–aldol–Tishchenko
reactions gave a triol derivative with five consecutive chiral centers.
Key words: aldol reaction, asymmetric catalysis, enantioselectivity, stereoselectivity, tandem reaction
O
O
OH OH
3
(10 mol%)
NaOMe
MeOH
+
+
Ph
H
Ph
THF
2a
(2.5 equiv)
1a
6aa
81% yield, 93% ee
Ph
O
O
OH OH
Ph
3
OLi
OLi
(10 mol%)
NaOMe
MeOH
Ph
H
THF
2a
(2.5 equiv)
1h
6ha
Ph
91% yield, 90% ee
3
O
O
OH OH OH
3
1) Me2C(OMe)2
PPTS
(10 mol%)
+
Ph
H
Ph
Ph
THF
2) separation
3) NaOMe
then HCl
2a
(3.5 equiv)
1j
10
65% yield, 99% ee
Scheme 1
Introduction
however, the observed enantioselectivities were low. Later,
the research groups of Morken,6 Shibasaki,7 Mlynarski,8
and Mahrwald9 developed a highly enantioselective al-
dol–Tishchenko reaction using, respectively, yttrium, lan-
thanum, ytterbium, and titanium complexes as catalysts.
We previously reported that dilithium binaphtholate10,11
catalyzes an enantioselective direct aldol reaction and the
subsequent Tishchenko reaction.12 Here, we present a
practical synthetic procedure for the preparation of 1,3-
diol derivatives with three contiguous stereocenters.
The efficient preparation of 1,3-diol derivatives with three
contiguous stereocenters by an enantioselective direct
aldol–Tishchenko reaction starting from two carbonyl
compounds is described (Scheme 1). The enantioselective
synthesis of 1,3-diols is important in synthetic organic
chemistry because numerous biologically active com-
pounds include 1,3-diol units.1 Direct aldol–Tishchenko
reactions2 are cascade reactions3 consisting of a direct al-
dol process,4 an acetalization, and a hydride shift (Scheme
2). The sequence of these conversions affords monoacyl- Scope and Limitations
protected 1,3-diols with three contiguous asymmetric cen-
In the initial study, we investigated the aldol–Tishchenko
ters from two carbonyl compounds. The first enantiose-
lective aldol–Tishchenko reaction was reported by Loog
and Mäeorg,5 who used a monolithium salt of binaphthol;
reaction using pentan-3-one (1a) and benzaldehyde (2a)
as substrates with dilithium 3,3′-diphenylbinaphtholate as
a catalyst (Scheme 3). The reaction proceeded to afford
the product as a mixture of 3-O-ester 4aa and 1-O-ester
5aa having the same sense and magnitude of absolute and
relative configurations (1,2-syn-1,3-anti). As expected,
the isolated 3-O-ester 4aa and 1-O-ester 5aa easily inter-
SYNTHESIS 2012, 44, 3145–3151
Advanced online publication: 29.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1291138; Art ID: SS-2012-Z0209-PSP
© Georg Thieme Verlag Stuttgart · New York

3146
T. Ichibakase, M. Nakajima
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Aldol–Tishchenko Reaction of Pentan-3-one with Various
Aldehydes
OH
R3
H
O
O
O
O
O
OH
R3
O
R3
O
O
OH OH
3
R3
H
R3
H
(10 mol%)
NaOMe
MeOH
R1
R1
R1
+
R
H
R
R2
R2
R2
THF
0 °C, 48 h
2
1a
6
direct aldol reaction
acetalization
hydride shift
O
Entry
R
Product
Yield (%) ee (%)
1
2
3
4
5
6
7
Ph (2a)
6aa
6ab
6ac
6ad
6ae
6af
81
87
81
80
61
0
93
95
95
88
94
–
OH
*
O
R3
4-MeC6H4 (2b)
4-MeOC6H4 (2c)
4-BrC6H4 (2d)
PhCH=CH (2e)
PhCH2CH2 (2f)
t-Bu (2g)
*
R1
R3
*
H
R2
aldol–Tishchenko product
Scheme 2
converted via isomerization under the reaction conditions,
which suggested that 1-O-ester 5aa formed via a trans-
esterification from the 3-O-ester 4aa after the Tishchenko
process. Therefore, prior to isolating the product, we re-
moved the benzoyl group to obtain the product as a single
diastereomer for data collection.
6ag
0
–
OH
HO
Ph
Ph
7
Ph
Figure 1
OLi
OLi
O
O
High enantioselectivities were obtained using other ke-
tones as aldol donors (Table 2). In the reactions involving
acyclic ketone aldol donors and benzaldehyde as the aldol
acceptor, 1,2-syn-1,3-anti-diols were obtained as single
diastereomers with high chemical and optical yields (en-
tries 1–3). It should be noted that this is the highest level
of enantioselectivity yet reported for an aldol–Tishchenko
reaction using simple aliphatic ketones as aldol donors.
Aromatic ketones were less reactive and gave the corre-
sponding diols in high chemical yields at room tempera-
ture; the enantioselectivities, however, were slightly
lower (entries 4 and 5) than those obtained from aliphatic
ketones. The sterically congestesd ketone 1f did not react
at all (entry 6). In the reaction of hexan-3-one (1g), which
includes two reactive sites, the diol 6ga (upon reaction at
the ethyl site) and the diol 8ga (upon reaction at the propyl
site) were obtained in a ratio of 4.4 to 1 (entry 7). It is in-
teresting that the present reaction selectively distin-
guished between the ethyl and propyl groups, which do
not differ significantly in bulk or reactivity.
Ph
O
OH
O
Ph Ph
+
O
OH
3
(10 mol%)
2
2
2
1
1
1
3
3
+
PhCHO
Ph
Ph
THF, r.t., 3 h
1a
2a
3-O-ester
1-O-ester
4aa
5aa
44% yield, 85% ee
23% yield, 85% ee
NaOMe, MeOH
OH OH
Ph
6aa
Scheme 3
The results obtained in the aldol–Tishchenko reactions of
pentan-3-one (1a) with various aldehydes at 0 °C are list-
ed in Table 1. Although a slight decrease in the selectivity
was observed in the reaction of p-bromobenzaldehyde
(2d) (entry 4), both p-tolualdehyde (2b) and p-anisalde-
hyde (2c) gave a selectivity of 95% ee (entries 2 and 3),
similar to that obtained from the reaction of benzaldehyde
(2a). The reaction of cinnamaldehyde (2e) gave a slightly
lower chemical yield, but with a high selectivity (entry 5).
Hydrocinnamaldehyde (2f) did not give the correspond-
ing adduct (entry 6), although the self-aldol–Tishchenko
product 7 was obtained in 83% in racemic form (Figure
1). Sterically bulky pivalaldehyde (2g) did not react at all
(entry 7).
The reactions of cyclic ketones as aldol donors, such as
cyclohexanone (1h) and cyclohex-2-en-1-one (1i), afford-
ed 1,2-anti-1,3-anti-diols as single diastereomers with
high chemical and optical yields (Table 2, entries 8 and 9).
Transition-state model A, proposed by early pioneers,13
can explain the formation of the 1,2-syn-1,3-anti-isomer
from an acyclic aldol donor, whereas the reaction of a cy-
clic ketone may proceed via a tricyclic transition state B,
proposed by Fang and co-workers,13f to afford the 1,2-
anti-1,3-anti-isomer (Scheme 4).
Synthesis 2012, 44, 3145–3151
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of 1,3-Diols with Three Contiguous Stereocenters
3147
Table 2 Aldol–Tishchenko Reaction of Benzaldehyde with Various Ketones
Entry
1
Ketone
Conditions
0 °C, 48 h
Product
Yield (%) ee (%)
OH OH
O
Ph
81
71
93
91
1a
1b
6aa
O
O
OH OH
Ph
Ph
2
0 °C, 48 h
6ba
6ca
OH OH
3
4
5
6
0 °C, 48 h
r.t., 48 h
r.t., 48 h
r.t., 48 h
80
80
91
0
87
72
70
–
1c
OH OH
O
Ph
Ph
Ph
1d
6da
OH OH
O
Ph
Ph
Ph
1e
6ea
O
–
1f
OH OH
Ph
O
6ga
70 (6ga)
16 (8ga)
94 (6ga)
97 (8ga)
7
–10 °C, 48 h
OH OH
1g
Ph
8ga
6ga/8ga = 4.4:1
OH OH
O
Ph
8
9
0 °C, 24 h
91
88
90
85
6ha
1h
OH OH
O
Ph
–23 °C, 24 h
1i
6ia
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3145–3151

3148
T. Ichibakase, M. Nakajima
PRACTICAL SYNTHETIC PROCEDURES
method described in the literature.14 Yields refer to isolated com-
pounds estimated to be >95% pure, as determined by 1H NMR spec-
troscopy. IR spectra were recorded on a JEOL JIR 6500-W
O
Li
O
OH
O
Ph
Ph
O
O
1
spectrophotometer. H and 13C NMR spectra were determined for
3 O
2
1
3
Ph
Ph
Ph
Ph
solutions in CDCl3 with Me4Si as internal standard on a JEOL JNM-
ECX 400 instrument. HRMS data were measured on a JEOL JMS-
DX303HF mass spectrometer. Optical rotations were recorded on a
JASCO P-1010.
H
1
2 Et
1,2-syn-1,3-anti
A
O
Li
O
(1R,2R,3S)-2-Methyl-1-phenylpentane-1,3-diol (6aa);8d Typical
Procedure for the Aldol–Tishchenko Reaction
OH
O
3 O
Ph
2
2
1
3
Ph
H
1
Under an argon atmosphere, n-BuLi (0.094 mmol, 20 mol%) in hex-
ane (0.17 M, 0.55 mL) was added to a soln of (R)-3,3′-diphenylbi-
naphthol (20.7 mg, 0.047 mmol, 10 mol%) in THF (1 mL) at 0 °C,
and the mixture was stirred for 5 min. Benzaldehyde (2a) (0.12 mL,
1.18 mmol, 2.5 equiv) and pentan-3-one (1a) (41 mg, 0.47 mmol)
in THF (0.5 mL) were successively added to the above mixture, and
the mixture was stirred for 48 h. The reaction was quenched with
sat. NH4Cl (2 mL) and the mixture was stirred at r.t. for 5 min. The
aqueous layer was extracted with EtOAc (3 × 10 mL) and the com-
B
1,2-anti-1,3-anti
Scheme 4
In the reaction of cyclopentanone (1j), a highly enolizable
aldol donor, the byproduct derived from the sequential
double aldol and Tishchenko reaction (aldol–aldol– bined organic layers were washed with brine (3 mL), dried
Tishchenko reaction)9,13d was favored, even in the pres-
ence of 2.5 equivalents of benzaldehyde (2a) at –23 °C.
Therefore, we employed 3.5 equivalents of benzaldehyde
(2a) as aldol acceptor to afford a mixture of two insepara-
(Na2SO4), and concentrated under reduced pressure. The residue
was dissolved in MeOH (2 mL) and treated with NaOMe (0.05
mmol, 11 mol%) in MeOH (0.5 M, 0.1 mL). After 3 h, the mixture
was diluted with EtOAc (20 mL), and washed with H2O (5 mL). The
aqueous layer was extracted with EtOAc (2 × 10 mL) and the com-
ble diastereomers (3:1). As the isomers could not be sep-
arated, we converted the isomers into acetonides, which
could be separated by silica gel chromatography. The se-
quential deprotection of benzoyl and acetonide groups af-
forded a triol 10 with five consecutive chiral centers with
extremely high enantioselectivity (Scheme 5). Although
the relative configurations of the other isomers are not yet
known, the configuration of the major product 10 was de-
termined by X-ray crystallographic analysis (CCDC
848047).
bined organic layers were washed with brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane–EtOAc,
4:1) to give diol 6aa as a colorless oil; yield: 74 mg (81%).
[α]D29 +45.4 (c 1.22, CHCl3; 93% ee), [α]D29 +43.6 (c 1.01, CH2Cl2;
93% ee) [Lit.8d [α]D –36.2 (c 0.60, CH2Cl2; 75% ee (1S,2S,3R))].
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH (19:1), 1.0
mL/min): tR (min) = 14.7 (major, 1R,2R,3S), 20.3 (minor, 1S,2S,3R)
[Lit.8d AD-H, hexane–i-PrOH (9:1), 1.0 mL/min: tR (min) = 7.8
(1R,2R,3S), 10.1 (1S,2S,3R)].
1H NMR (400 MHz, CDCl3): δ = 0.85 (d, J = 6.8 Hz, 3 H, CHCH3),
0.89 (t, J = 7.3 Hz, 3 H, CH2CH3), 1.36–1.56 (m, 2 H, CH2CH3),
1.88–1.95 (m, 1 H, CHCH3), 2.91 (br s, 1 H, OH), 3.54 (br s, 1 H,
OH), 3.70 (ddd, J = 8.7, 4.6, 2.3 Hz, 1 H, HOCH), 4.67 (d, J = 6.9
Hz, 1 H, HOCHPh), 7.22–7.36 (m, 5 H, ArH).
O
O
OH OH OH
1) Me2C(OMe)2
PPTS
3
(10 mol%)
+
Ph
H
Ph
Ph
THF
–23 °C, 24 h
2) separation
3) NaOMe
then HCl
2a
1j
10
(1R,2R,3S)-2-Methyl-1-(4-methylphenyl)pentane-1,3-diol
(6ab)8d
65% yield, 99% ee
Following the typical procedure, the reaction of p-tolualdehyde (2b)
(0.14 mL, 1.18 mmol, 2.5 equiv) and pentan-3-one (1a) (41 mg,
0.47 mmol) gave diol 6ab as a colorless oil; yield: 85 mg (87%).
[α]D29 +41.0 (c 1.05, CHCl3; 95% ee).
Scheme 5
In conclusion, we have provided a new, efficient method
for preparing 1,3-diol derivatives with three contiguous
stereocenters by an enantioselective direct aldol–
Tishchenko reaction. The catalyst is easily prepared from
common reagents and does not contain rare metals. The
reactions of acyclic ketones as aldol donors produced 1,2-
syn-1,3-anti-diol derivatives, whereas the reactions of cy-
clic ketones as aldol donors produced 1,2-anti-1,3-anti-
diol derivatives. In the case of cyclopentanone, a single
manipulation controlled five consecutive chiral centers.
The design of chiral catalysts to further enhance the reac-
tion enantioselectivity, in addition to studies toward the
synthesis of biologically active compounds, is currently in
progress.
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH (29:1), 1.0
mL/min): tR (min) = 24.6 (major, 1R,2R,3S), 29.4 (minor, 1S,2S,3R)
[Lit.8d AD-H, hexane–i-PrOH (9:1), 1.0 mL/min: tR (min) = 8.4
(1R,2R,3S), 9.1 (1S,2S,3R)].
1H NMR (400 MHz, CDCl3): δ = 0.81 (d, J = 7.3 Hz, 3 H, CHCH3),
0.89 (t, J = 7.3 Hz, 3 H, CH2CH3), 1.35–1.58 (m, 2 H, CH2CH3),
1.85–1.92 (m, 1 H, CHCH3), 2.33 (s, 3 H, ArCH3), 3.07 (br s, 1 H,
OH), 3.53 (br s, 1 H, OH), 3.69 (ddd, J = 8.7, 4.6, 1.8 Hz, 1 H,
HOCH), 4.62 (d, J = 6.8 Hz, 1 H, HOCHAr), 7.13 (d, J = 7.8 Hz, 2
H, ArH), 7.20 (d, J = 7.8 Hz, 2 H, ArH).
(1R,2R,3S)-1-(4-Methoxyphenyl)-2-methylpentane-1,3-diol
(6ac)8d
Following the typical procedure, the reaction of p-anisaldehyde (2c)
(0.14 mL, 1.18 mmol, 2.5 equiv) and pentan-3-one (1a) (41 mg,
0.47 mmol) gave diol 6ac as a colorless oil; yield: 85 mg (81%).
[α]D29 +41.8 (c 0.75, CHCl3; 95% ee).
All reactions were carried out under an argon atmosphere using
dried glassware. All starting materials were purchased from com-
mercial suppliers and were used without purification, unless other-
wise stated. 3,3′-Diphenylbinaphthol was prepared according to the
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH (9:1), 1.0
mL/min): tR (min) = 11.0 (major, 1R,2R,3S), 12.4 (minor, 1S,2S,3R)
Synthesis 2012, 44, 3145–3151
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of 1,3-Diols with Three Contiguous Stereocenters
(1R,2R,3S,4E)-2-Methyl-1-phenylhex-4-ene-1,3-diol (6ca)
3149
[Lit.8d AD-H, hexane–i-PrOH (9:1), 1.0 mL/min: tR (min) = 11.3
(1R,2R,3S), 12.7 (1S,2S,3R)].
Following the typical procedure, the reaction of benzaldehyde (2a)
(0.12 mL, 1.18 mmol, 2.5 equiv) and hex-4-en-3-one (1c) (46 mg,
0.47 mmol) gave diol 6ca as a colorless oil; yield: 78 mg (80%).
[α]D28 +5.7 (c 1.34, CHCl3; 87% ee).
1H NMR (400 MHz, CDCl3): δ = 0.79 (d, J = 7.4 Hz, 3 H, CHCH3),
0.90 (t, J = 7.3 Hz, 3 H, CH2CH3), 1.38–1.58 (m, 2 H, CH2CH3),
1.83–1.91 (m, 1 H, CHCH3), 3.12 (br s, 1 H, OH), 3.62 (br s, 1 H,
OH), 3.69 (ddd, J = 8.2, 4.1, 1.8 Hz, 1 H, HOCH), 3.78 (s, 3 H,
OCH3), 4.60 (d, J = 7.3 Hz, 1 H, HOCHAr), 6.84–6.88 (m, 2 H,
ArH), 7.21–7.25 (m, 2 H, ArH).
HPLC (Daicel Chiralcel OD-H, hexane–i-PrOH (19:1), 1.0
mL/min): tR (min) = 11.1 (minor, 1S,2S,3R), 12.2 (major,
1R,2R,3S).
IR (neat): 3354 cm–1.
(1R,2R,3S)-1-(4-Bromophenyl)-2-methylpentane-1,3-diol
(6ad)8d
Following the typical procedure, the reaction of p-bromobenzalde-
hyde (2d) (212 mg, 1.18 mmol, 2.5 equiv) and pentan-3-one (1a)
(41 mg, 0.47 mmol) gave diol 6ad as colorless prisms; yield: 103
mg (80%); mp 96–97 °C.
1H NMR (400 MHz, CDCl3): δ = 0.69 (d, J = 7.3 Hz, 3 H, CHCH3),
1.72 (d, J = 5.5 Hz, 3 H, CH=CHCH3), 1.96–2.04 (m, 1 H, CHCH3),
3.42 (br s, 1 H, OH), 3.87 (br s, 1 H, OH), 4.20–4.23 (m, 1 H,
HOCH), 4.57 (d, J = 8.3 Hz, 1 H, HOCHPh), 5.56–5.89 (m, 2 H,
CH=CH), 7.23–7.34 (m, 5 H, ArH).
[α]D29 +34.5 (c 1.05, CHCl3; 88% ee).
13C NMR (100 MHz, CDCl3): δ = 12.5, 17.8, 44.2, 75.0, 77.9,
HPLC (Daicel Chiralpak AS-H, hexane–i-PrOH (9:1), 1.0
mL/min): tR (min) = 7.2 (major, 1R,2R,3S), 10.2 (minor, 1S,2S,3R)
[Lit.8d AS-H, hexane–i-PrOH (9:1), 1.0 mL/min: tR (min) = 6.3
(1R,2R,3S), 10.1 (1S,2S,3R)].
1H NMR (400 MHz, CDCl3): δ = 0.84–0.89 (m, 6 H, CHCH3,
CH2CH3), 1.34–1.54 (m, 2 H, CH2CH3), 1.80–1.87 (m, 1 H,
CHCH3), 3.04 (br s, 1 H, OH), 3.63 (ddd, J = 8.7, 5.0, 2.3 Hz, 1 H,
HOCH), 4.08 (br s, 1 H, OH), 4.60 (d, J = 6.4 Hz, 1 H, HOCHAr),
7.15–7.19 (m, 2 H, ArH), 7.43–7.46 (m, 2 H, ArH).
126.6, 127.5, 127.7, 128.3, 130.7, 143.6.
LRMS–FAB (CHCl3 + NBA + NaI): m/z = 229 (100) [M + Na]+,
173, 149, 107, 55.
HRMS–FAB: m/z [M + Na]+ calcd for C13H18O2Na: 229.1204;
found: 229.1200.
(1R,3R)-2-Methyl-1,3-diphenylpropane-1,3-diol (6da)8d
Following the typical procedure, the reaction of benzaldehyde (2a)
(0.12 mL, 1.18 mmol, 2.5 equiv) and propiophenone (1d) (63 mg,
0.47 mmol) gave diol 6ba as a colorless oil; yield: 91 mg (80%).
(1E,3S,4R,5S)-4-Methyl-1-phenylhept-1-ene-3,5-diol (6ae)
Following the typical procedure, the reaction of trans-cinnamalde-
hyde (2e) (0.15 mL, 1.18 mmol, 2.5 equiv) and pentan-3-one (1a)
(41 mg, 0.47 mmol) gave diol 6ae as a colorless oil; yield: 63 mg
(61%).
[α]D29 +6.9 (c 1.27, CHCl3; 94% ee), [α]D31 +15.4 (c 1.14, benzene;
94% ee).
[α]D17 +15.1 (c 1.20, CHCl3; 72% ee), [α]D17 +13.8 (c 1.20, CH2Cl2;
72% ee) [Lit.8d [α]D28 −13.0 (c 0.60, CH2Cl2; 75% ee (1S, 3S)].
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH (9:1), 1.0
mL/min): tR (min) = 11.6 (major, 1R,3R), 14.4 (minor, 1S,3S) [Lit.8d
hexane–i-PrOH (9:1), 1.0 mL/min: tR (min) = 11.4 (1R,3R), 14.5
(1S,3S)].
1H NMR (400 MHz, CDCl3): δ = 0.71 (d, J = 7.1 Hz, 3 H, CH3),
2.14 (m, 1 H), 3.05 (d, J = 3.4 Hz, 1 H, OH), 3.15 (d, J = 3.4 Hz, 1
H, OH), 4.64 (dd, J = 3.6, 6.6 Hz, 1 H, HOCHPh), 4.96 (t, J = 3.1
Hz, 1 H, HOCHPh), 7.20–7.40 (m, 10 H, ArH).
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH (19:1), 1.0
mL/min): tR (min) = 18.5 (major, 3S,4R,5S), 21.2 (minor,
3R,4S,5R).
IR (neat): 3552 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.92–0.98 (m, 6 H, CHCH3,
CH2CH3), 1.49–1.61 (m, 2 H, CH2CH3), 1.73–1.80 (m, 1 H,
CHCH3), 2.85 (br s, 1 H, OH), 3.29 (br s, 1 H, OH), 3.84–3.88 (m,
1 H, HOCH), 4.30 (t, J = 6.4 Hz, 1 H, HOCH), 6.25 (dd, J = 16.0,
6.4 Hz, 1 H, PhCH=CH), 6.62 (d, J = 15.6 Hz, 1 H, PhCH=CH),
7.21–7.39 (m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 10.63, 11.02, 26.71, 41.78, 74.10,
76.61, 126.41, 127.52, 128.50, 130.74, 131.60, 136.68.
LRMS–FAB (CHCl3 + NBA + NaI): m/z = 243 [M + Na]+, 241,
176 (100), 145, 136, 55.
(1R,2R,3S,4E)-2-Methyl-1,5-diphenylpent-4-ene-1,3-diol (6ea)
Following the typical procedure, the reaction of benzaldehyde (2a)
(0.12 mL, 1.18 mmol, 2.5 equiv) and 1-phenylpent-1-en-3-one (1e)
(75 mg, 0.47 mmol) gave diol 6ea as a colorless oil; yield: 115 mg
(91%).
[α]D18 –23.4 (c 0.42, CHCl3; 70% ee).
HPLC (Daicel Chiralcel OD-H, hexane–i-PrOH (9:1), 1.0 mL/min):
tR (min) = 17.4 (major, 1R,2R,3S), 24.9 (minor, 1S,2S,3R).
IR (CHCl3): 3604, 3477 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.77 (d, J = 7.3 Hz, 3 H, CH3),
2.08–2.16 (m, 1 H, CHCH3), 4.48 (d, J = 5.5 Hz, 1 H, HOCH), 4.65
(d, J = 7.8 Hz, 1 H, HOCH), 6.30 (dd, J = 5.9, 15.6 Hz, 1 H,
CH=CH), 6.58 (d, J = 15.6 Hz, 1 H, CH=CH), 7.18–7.42 (m, 10 H,
ArH).
HRMS–FAB: m/z [M + Na]+ calcd for C14H20O2Na: 243.1361;
found: 243.1340.
(1R,2R,3S)-2-Ethyl-1-phenylhexane-1,3-diol (6ba)8d
Following the typical procedure, the reaction of benzaldehyde (2a)
(0.12 mL, 1.18 mmol, 2.5 equiv) and heptan-4-one (1b) (54 mg,
0.47 mmol) gave diol 6ba as a colorless oil; yield: 74 mg (71%).
13C NMR (100 MHz, CDCl3): δ = 12.6, 44.5, 74.7, 78.1, 126.4,
126.5, 127.5, 127.7, 128.4, 128.5, 129.4, 130.9, 136.7, 143.3.
LRMS–FAB (CHCl3 + NBA + NaI): m/z = 291 [M + Na]+, 73
(100).
HRMS–FAB: m/z [M + Na]+ calcd for C18H20O2Na: 291.1361;
found: 291.1355.
[α]D28 +37.6 (c 0.99, CHCl3; 91% ee).
HPLC (Daicel Chiralpak AS-H, hexane–i-PrOH (19:1), 1.0
mL/min): tR (min) = 8.6 (major, 1R,2R,3S), 11.4 (minor, 1S,2S,3R)
[Lit.8d Daicel Chiralpak AS-H, hexane–i-PrOH (9:1), 1.0 mL/min:
tR (min) = 5.1 (1R,2R,3S), 5.7 (1S,2S,3R)].
1H NMR (400 MHz, CDCl3): δ = 0.82 (t, J = 6.9 Hz, 3 H,
CHCH2CH3), 0.91 (t, J = 7.3 Hz, 3 H, CH2CH2CH3), 1.16–1.63 (m,
7 H, CHCH2CH3, CH2CH2CH3), 3.32 (br s, 1 H, OH), 3.74 (ddd,
J = 9.2, 4.1, 1.8 Hz, 1 H, HOCH), 3.89 (br s, 1 H, OH), 4.85 (d,
J = 5.5 Hz, 1 H, HOCHPh), 7.22–7.35 (m, 5 H, ArH).
(1R,2R,3S)-2-Methyl-1-phenylhexane-1,3-diol (6ga)15 and
(1R,2R,3S)-2-Ethyl-1-phenylpentane-1,3-diol (8ga)
Following the typical procedure, the reaction of benzaldehyde (2a)
(0.12 mL, 1.18 mmol, 2.5 equiv) and hexan-3-one (1g) (47 mg, 0.47
mmol) gave diols 6ga [yield: 69 mg (70%)] and 8ga [yield: 16 mg
(16%)] as colorless oils.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3145–3151

3150
6ga
T. Ichibakase, M. Nakajima
PRACTICAL SYNTHETIC PROCEDURES
1H NMR (400 MHz, CDCl3): δ = 1.15–1.24 (m, 1 H, CH2), 1.62–
1.67 (m, 1 H, CH2), 1.93–2.09 (m, 3 H, CH + CH2), 2.71 (br s, 1 H,
OH), 3.12 (br s, 1 H, OH), 4.24 (d, J = 8.7 Hz, 1 H, =CHCHOH),
4.98 (s, 1 H, PhCH), 5.56–5.60 (m, 1 H, CH=CH), 5.70–5.72 (m, 1
H, CH=CH), 7.26–7.38 (m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 22.2, 25.0, 47.4, 68.1, 76.2,
126.5, 127.4, 128.1, 128.8, 130.3, 142.0.
LRMS–FAB (CHCl3 + NBA + NaI): m/z = 227 (100) [M + Na]+,
173, 149, 107, 77.
HRMS–FAB: m/z [M + Na]+ calcd for C13H16O2Na: 227.1048;
[α]D14 +35.3 (c 0.91, CHCl3; 94% ee).
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH (9:1), 1.0
mL/min): tR (min) = 7.8 (major, 1R,2R,3S), 9.1 (minor, 1S,2S,3R).
IR (CHCl3): 3608, 3446 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.82 (d, J = 7.3 Hz, 3 H, CHCH3),
0.87 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.19–1.61 (m, 4 H, CH2CH2),
1.84–1.92 (m, 1 H, CHCH3), 3.06 (br s, 1 H, OH), 3.71–3.73 (m, 1
H, HOCH), 3.75 (br s, 1 H, OH), 4.65 (d, J = 6.9 Hz, 1 H, HOCH),
7.20–7.36 (m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 11.5, 14.0, 19.4, 35.7, 43.5, 72.4,
found: 227.1030.
78.2, 126.2, 127.3, 128.3, 143.8.
LRMS–FAB (CHCl3 + NBA + NaI): m/z = 231 (100) [M + Na]+,
(+)-rel-(α1R,α3R,1R,3S)-2-Hydroxy-α,α′-diphenyl-1,3-cyclopen-
tanedimethanol (10)
Under an argon atmosphere, n-BuLi (0.094 mmol, 20 mol%) in hex-
ane (0.17 M, 0.55 mL) was added to a soln of (R)-3,3′-diphenylbi-
naphthol (20.7 mg, 0.047 mmol, 10 mol%) in THF (3 mL) at –23 °C,
and the mixture was stirred for 5 min. Then, benzaldehyde (2a)
(0.17 mL, 1.65 mmol, 3.5 equiv) and cyclopentanone (1j) (40 mg,
0.47 mmol) in THF (0.3 mL) were added to the above mixture. Af-
ter 24 h, the reaction was quenched with sat. NH4Cl (2 mL) and the
mixture was stirred at r.t. for 5 min. The aqueous layer was extract-
ed with EtOAc (3 × 10 mL) and the combined organic layers were
washed with brine (3 mL), dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (CH2Cl2) to give an inseparable mixture of triol
monoesters as a colorless oil.
119, 23.
HRMS–FAB: m/z [M + Na]+ calcd for C13H20O2Na: 231.1361;
found: 231.1359.
8ga
[α]D14 +51.9 (c 0.52, CHCl3; 97% ee).
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH (9:1), 1.0
mL/min): tR (min) = 7.2 (major, 1R,2R,3S), 10.2 (minor, 1S,2S,3R).
IR (CHCl3): 3608, 3481 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 7.4 Hz, 3 H, CH2CH3),
0.95 (t, J = 7.3 Hz, 3 H, CH2CH3), 1.36–1.67 (m, 5 H,
2 × CH2 + CH), 2.90 (br s, 1 H, OH), 3.51 (br s, 1 H, OH), 3.63–
3.68 (m, 1 H, HOCH), 4.91 (d, J = 3.6 Hz, 1 H, HOCHPh), 7.24–
7.39 (m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 10.7, 12.5, 18.2, 26.4, 50.0, 73.6,
75.6, 126.1, 127.2, 128.3, 144.0.
LRMS–FAB (CHCl3 + NBA + NaI): m/z = 231 [M + Na]+, 83, 55
(100), 41.
To the solution of the monoesters, PPTS (12 mg, 0.047 mmol, 10
mol%) and 2,2-dimethoxypropane (0.09 mL, 0.71 mmol, 1.5 equiv)
were added, and the mixture was stirred for 12 h, then diluted with
EtOAc (20 mL). The mixture was washed with H2O (3 × 5 mL) and
brine (10 mL), dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (hexane–toluene, 1:1) to give acetonide 9 [yield: 137 mg
(66%, 2 steps), [α]D27 –8.2 (c 1.01, CHCl3; 99% ee), HPLC (Daicel
Chiralpak AD-H, hexane–i-PrOH (99:1), 1.0 mL/min): tR (min) =
14.4 (major), 17.4 (minor)] as colorless needles and its diastereomer
9′ [yield: 46 mg (22%, 2 steps)] as colorless needles.
HRMS–FAB: m/z [M + Na]+ calcd for C13H20O2Na: 231.1361;
found: 231.1353.
(αR)-α-[(1S,2S)-2-Hydroxycyclohexyl]benzenemethanol (6ha)16
Following the typical procedure, the reaction of benzaldehyde (2a)
(0.12 mL, 1.18 mmol, 2.5 equiv) and cyclohexanone (1h) (46 mg,
0.47 mmol) in THF (3 mL) gave diol 6ha as colorless needles;
yield: 88 mg (91%); mp 122–124 °C.
To a soln of 9 in MeOH (2 mL), NaOMe (0.05 mmol, 11 mol%) in
MeOH (0.5 M, 0.1 mL) was added, and the resulting homogeneous
mixture was stirred for 12 h. The reaction was quenched with concd
aq HCl (5 mL) and the mixture was stirred at r.t. for 1 h. The mixture
was diluted with EtOAc (20 mL), and washed with H2O (5 mL). The
aqueous layer was extracted with EtOAc (2 × 10 mL) and the com-
bined organic layers were washed with brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane–EtOAc,
3:2) to give triol 10 as colorless prisms; yield: 88 mg [65%, from cy-
clopentanone (1j)]; mp 136–137 °C.
27
[α]D +27.6 (c 1.02, CHCl3; 90% ee) [Lit.16 [α]D +32 (c 0.95,
CHCl3; 99% ee (1S,2S,αR))].
HPLC (Daicel Chiralcel OD-H, hexane–i-PrOH (9:1), 1.0 mL/min):
tR (min) = 7.3 (minor, 1R,2R,αS), 8.7 (major, 1S,2S,αR).
1H NMR (400 MHz, CDCl3): δ = 0.78–0.92 (m, 1 H, CH2), 1.02–
1.15 (m, 2 H, CH2), 1.25–1.35 (m, 1 H, CH2), 1.50–1.65 (m, 3 H,
CH2), 1.74–1.81 (m, 1 H, CH2), 1.89–1.93 (m, 1 H, CH), 3.23 (br s,
1 H, OH), 3.49 (dt, J = 10.5, 4.6 Hz, 1 H, CH2CHOH), 3.70 (br s, 1
H, OH), 4.92 (s, 1 H, PhCH), 7.24–7.36 (m, 5 H, ArH).
[α]D30 +55.5 (c 1.01, CHCl3).
IR (KBr): 3302 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.04–1.14 (m, 1 H, CH2), 1.23–
1.32 (m, 1 H, CH2), 1.45–1.61 (m, 2 H, CH2), 2.09–2.18 (m, 1 H,
CH), 2.30 (ddd, J = 18.8, 9.2, 5.0 Hz, 1 H, CH), 2.61 (d, J = 3.6 Hz,
1 H, OH), 3.05 (s, 1 H, OH), 3.10 (s, 1 H, OH), 4.01 (t, J = 9.2 Hz,
1 H, CHCHOH), 4.48 (d, J = 9.6 Hz, 1 H, PhCH), 4.86–4.88 (m, 1
H, PhCH), 7.24–7.37 (m, 10 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 21.68, 23.85, 52.51, 52.71, 74.44,
79.14, 80.49, 126.30, 126.42, 127.52, 127.91, 128.37, 128.45,
142.95, 143.30.
(αR)-α-[(1S,2S)-2-Hydroxycyclohex-3-en-1-yl]benzenemeth-
anol (6ia)
Following the typical procedure, the reaction of benzaldehyde (2a)
(0.12 mL, 1.18 mmol, 2.5 equiv) and cyclohex-2-en-1-one (1i) (45
mg, 0.47 mmol) in THF (3 mL) at –23 °C gave diol 6ia as colorless
needles; yield: 84 mg (88%); mp 135–137 °C. The absolute and rel-
ative configurations of 6ia were determined by 1H NMR spectros-
copy and from the specific rotation after the conversion into 6ha by
hydrogenation.
[α]D27 –11.4 (c 0.99, CHCl3; 85% ee).
LRMS–FAB (CHCl3 + NBA + NaI): m/z = 321 [M + Na]+, 263,
245, 176, 154 (100), 136, 107, 69.
HRMS–FAB: m/z [M + Na]+ calcd for C19H22O3Na: 321.1467;
found: 321.1475.
HPLC (Daicel Chiralcel OD-H, hexane–i-PrOH (9:1), 1.0 mL/min):
tR (min) = 8.8 (minor, 1R,2R,αS), 11.3 (major, 1S,2S,αR).
IR (KBr): 3313 cm–1.
Synthesis 2012, 44, 3145–3151
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3145–3151