Asymmetric cycloetherifications by bifunctional aminothiourea catalysts: The importance of hydrogen bonding

Article abstract of DOI:10.1055/s-0032-1316920

Chiral oxacyclic frameworks are prevalent in many natural products and bioactive compounds. In addition, a number of them are important synthetic intermediates. Thus, the synthesis of such structures is a significant goal in the field of organic chemistry. However, the development of catalytic asymmetric cycloetherification for the straightforward synthesis of these compounds remains a challenge. In this study, we propose the use of aminothiourea catalysis as an effective way to accomplish such a challenge. The asymmetric synthesis of chiral oxygen heterocycles, including tetrahydrofurans, tetrahydropyrans, and 1,3-dioxolanes, is demonstrated herein using intramolecular oxy-Michael addition mediated by bifunctional aminothiourea catalysts. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316920

SPECIAL TOPIC
▌1627
sApesciyalmtopmic etric Cycloetherifications by Bifunctional Aminothiourea Catalysts:
The Importance of Hydrogen Bonding
Asymmetric Cycloetherifications by Bifunctional Aminothiourea Catalysts
Yukihiro Fukata, Ryota Miyaji, Takaaki Okamura, Keisuke Asano,* Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510,
Japan
Fax +81(75)3832438; E-mail: keisuke.asano@t03kr913mk.mbox.media.kyoto-u.ac.jp; E-mail: matsubara.seijiro.2e@kyoto-u.ac.jp
Received: 21.02.2013; Accepted after revision: 20.03.2013
oxycyclization
azacyclization
Abstract: Chiral oxacyclic frameworks are prevalent in many nat-
ural products and bioactive compounds. In addition, a number of
them are important synthetic intermediates. Thus, the synthesis of
such structures is a significant goal in the field of organic chemistry.
However, the development of catalytic asymmetric cycloetherifica-
tion for the straightforward synthesis of these compounds remains a
challenge. In this study, we propose the use of aminothiourea catal-
ysis as an effective way to accomplish such a challenge. The asym-
metric synthesis of chiral oxygen heterocycles, including
tetrahydrofurans, tetrahydropyrans, and 1,3-dioxolanes, is demon-
strated herein using intramolecular oxy-Michael addition mediated
by bifunctional aminothiourea catalysts.
interaction with PG
(steric repulsion, π-interaction, etc.)
interaction via hydrogen bonding
chiral
catalyst
chiral
catalyst
PG
PG
H
O
HN
R
R
Scheme 1 Strategies for asymmetric aza- and oxycyclizations
Evidence for the validity of this concept can be found in
some recent reports on catalytic asymmetric halolactoni-
zations using bifunctional organocatalysts. These allow
multipoint interactions in the reaction transition states,
one of which is hydrogen bonding with the pendant car-
boxy group.6 In addition, a number of other highly enan-
tioselective oxycyclizations using organocatalysts have
been developed, where hydrogen bonding is thought to
have played a role in controlling the chirality.7–10
Key words: oxycyclization, cycloetherification, hydrogen bond-
ing, bifunctional aminothiourea catalyst, oxy-Michael addition
Cyclization from unsaturated substrates that bear a pen-
dant nucleophilic oxygen atom is a straightforward way to
synthesize chiral oxacyclic compounds. However, asym-
metric oxycyclization reactions are highly challenging be-
cause of the difficulty in installing a suitable chiral
environment during the rapid intramolecular process. On
the other hand, several asymmetric azacyclizations have
successfully been developed, including enantioselective
intramolecular aza-Michael additions using a proline-
derived catalyst1 or a chiral phase-transfer catalyst.2 The
enantioselection of these azacyclizations is largely controlled
by the effects of the substituents on the nucleophilic nitro-
gen atom through steric repulsion or π-interactions.
Meanwhile, because such a substituent is lacking in the
oxycyclization substrates, these strategies can only be ap-
plied to starting materials that bear an appropriate substit-
uent in the vicinity of the alcohol.3,4 Therefore, a novel
strategy is required to obtain an efficient asymmetric ox-
ycyclization reaction. In this context, hydrogen bonding is
an interaction with the potential to be able to control the
behavior of a pendant hydroxy group (Scheme 1). Thus,
the use of organocatalysts that utilize hydrogen bonding5
is a promising approach to realizing enantioselective oxy-
cyclization. Moreover, multipoint recognition by an
asymmetric catalyst would be favorable in the achieve-
ment of effective transfer of chiral information during the
cyclization process (Scheme 1).
However, whereas recently an increasing number of
methods for asymmetric cyclolactonizations have been
reported,6 examples of cycloetherifications are still limit-
ed.3,7,9,10 In particular, catalytic enantioselective cyclo-
etherifications are extremely challenging because of the
higher nucleophilicity of hydroxy groups compared to
carboxy groups. In fact, several of the previously reported
cycloetherifications demonstrated only moderate enantio-
selectivity, resulting from background racemic reactions
that occurred, even at low temperatures. They therefore
required a stoichiometric or extremely high loading of
chiral mediators in order to achieve acceptable selectivi-
ty.11 To overcome such drawbacks, we have developed an
intramolecular oxy-Michael addition reaction12 by em-
ploying bifunctional aminothiourea catalysts13 that utilize
hydrogen bonding at both catalytic sites. It was hypothe-
sized that the mild character of hydrogen bonding facili-
tates concerted catalysis through multipoint recognition,
even with highly reactive substrates, for cycloetherifica-
tion (Scheme 2).7a,b
Herein, we describe a highly enantioselective catalytic cy-
cloetherification for the synthesis of 2-substituted tetrahy-
drofurans (Table 1) and tetrahydropyrans (Table 2).14 An
intramolecular oxy-Michael addition reaction from ε- or
ξ-hydroxy-α,β-unsaturated ketones is performed in a
highly enantioselective fashion by using cinchona alka-
loid–thiourea-based bifunctional organocatalyst 3a (Fig-
SYNTHESIS 2013, 45, 1627–1634
Advanced online publication: 16.04.2013
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DOI: 10.1055/s-0032-1316920; Art ID: SS-2013-C0153-ST
© Georg Thieme Verlag Stuttgart · New York

1628
Y. Fukata et al.
SPECIAL TOPIC
Table 1 Asymmetric Synthesis of 2-Substituted Tetrahydrofurans
via Cycloetherification Using Bifunctional Organocatalystsa
chiral scaffold
S
O
NR2
O
R
3a (3 mol%)
Ar
mild activation
••
N
H
N
OH
mild activation
O
H
R
CPME, 25 °C, 24 h
H
O
1
O
2
R
Entry
R
2
Yieldb (%)
ee (%)
Scheme 2 Asymmetric cycloetherification via intramolecular oxy-
Michael addition reaction mediated by bifunctional organocatalyst
1
Ph
Ph
Ph
2a
99
99
95
99
93
98
99
99
97
95
96
96
94
85
91
93
92
90
2c
3d
4
ent-2a
2a
ure 1). Through the solvent optimization process, ethereal
solvents proved to be relatively efficient for the enantiose-
lectivity, and cyclopentyl methyl ether (CPME) was iden-
tified as the most suitable solvent from the viewpoints of
both yield and stereoselectivity. Screening of the catalysts
shown in Figure 1 further demonstrated that 3c is an effi-
cient catalyst to obtain the opposite enantiomer ent-2a in
excellent yield with high enantioselectivity (Table 1, entry
2). Moreover, the catalytic loading could be decreased to
as low as 1 mol% in the tetrahydrofuran synthesis, while
still giving excellent enantioselectivity (Table 1, entry 3).
This catalytic process is a highly practical cycloetherifica-
tion method that provides excellent enantioselectivities,
even with low catalyst loadings at ambient temperature.
4-MeOC6H4
4-F3CC6H4
2-naphthyl
4-MeC6H4
4-BrC6H4
(CH2)2Ph
2b
2c
5e
6
2d
2e
7
8
2f
9f
2g
a Reaction conditions: 1 (0.25 mmol), 3a (0.0075 mmol), CPME (0.5
mL).
b Isolated yields.
c Reaction was run using 3c instead of 3a.
d Reaction was run using 1 mol% 3a (0.0025 mmol).
e Reaction was run on a 0.125-mmol scale.
f Reaction was run for 120 h.
Although the reactions were slower, similar reaction con-
ditions also led to the highly enantioselective synthesis of
2-substituted tetrahydropyrans 5 (Table 2).
The obtained tetrahydrofuran product 2b could be further
transformed into the corresponding ester 6 by Baeyer–
Villiger oxidation with 3-chloroperoxybenzoic acid in the
presence of trifluoroacetic acid in 92% yield without loss
of optical purity (Scheme 3). Subsequent reduction of 6
with lithium aluminum hydride afforded (R)-2-(tetrahy-
drofuran-2-yl)ethanol (7), which is a valuable synthetic
intermediate (Scheme 3).15
These results subsequently motivated us to exploit this ef-
ficient oxycyclization protocol for the development of a
catalytic formal [3+2]-cycloaddition reaction starting
from γ-hydroxy-α,β-unsaturated carbonyls16 with alde-
hydes or ketones (Scheme 4). This method led to the suc-
cessful divergent synthesis of chiral 1,3-dioxolanes.17 In
Ar
Ar
NH
NH
MeO
NH
NH
H
H
S
S
N
N
H
N
H
N
H
NH
H
NH
H
H
N
N
N
N
S
S
NH
Ar
NH
Ar
OMe
3a
3b
3c
3d
Ar = 3,5-(CF3)2C6H3
Figure 1 Cinchona alkaloid derived aminothiourea catalysts
O
O
HO
LiAlH4
m-CPBA, TFA
O
O
2b
94% ee
Et2O, –40 °C, 2 h
94%
CH2Cl2, r.t., 8 h
MeO
92%
7
6
94% ee
94% ee
Scheme 3 Transformation of 2b
Synthesis 2013, 45, 1627–1634
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Asymmetric Cycloetherifications by Bifunctional Aminothiourea Catalysts
1629
Table 2 Asymmetric Synthesis of 2-Substituted Tetrahydropyrans
Table 3 Asymmetric Synthesis of 1,3-Dioxolanes by Organocatalyt-
via Cycloetherification Using Bifunctional Organocatalystsa
ic Formal [3+2] Cycloadditiona
R
O
R2
R3
3a (5 mol%)
O
3a (10 mol%)
O
O
O
O
O
O
+
CPME, 25 °C, 24 h
R
OH
OH
R1
R2
R3
R1
CPME, 25 °C, 24 h
4
10
8
9
5
Entry R1
R2
R3 10
Yieldb drc
(%)
eed
(%)
Entry
R
5
Yieldb (%) ee (%)
1
Ph
5a
5b
5c
5d
5e
5f
90
56
95
80
76
99
58
91
94
85
94
94
94
95
1
Ph
Ph
Cy
Cy
H
H
H
H
H
H
H
H
H
H
H
H
10aa
95
3.0:1 96
4.0:1 93
3.4:1 96
2.5:1 95
4.7:1 96
3.3:1 91
2.9:1 90
3.3:1 98
3.3:1 96
3.0:1 94
2.7:1 93
2.6:1 94
1.2:1 70
2
4-MeOC6H4
4-CF3C6H4
2-naphthyl
4-MeC6H4
4-BrC6H4
(CH2)2Ph
2e
3f
4
ent-10aa 91
3c
4
4-MeOC6H4 Cy
10ba
10ca
10da
10ea
10fa
10ga
10ha
10ab
10ac
10ad
93
83
88
71
82
84
82
94
92
84
99
4-F3CC6H4
4-BrC6H4
2-MeC6H4
1-naphthyl
2-thienyl
(CH2)2Ph
Ph
Cy
Cy
Cy
Cy
Cy
Cy
Et
5
5
6
6
7d
5g
7
a Reaction conditions: 1 (0.15 mmol), 3a (0.0075 mmol), CPME (0.3
8
mL).
b Isolated yields.
9g
10
11
12h
13
c Reaction was run on a 0.1-mmol scale.
d Reaction was run for 120 h.
Ph
i-Pr
t-Bu
this reaction, the hemiacetal intermediate generated in situ
was the substrate for the cycloetherification mediated by
chiral aminothiourea.18,19
Ph
Ph
CF3 Ph 10ae
a Reaction conditions: 8 (0.25 mmol), 9 (0.3 mmol), 3a (0.025 mmol),
CPME (0.5 mL).
Employing the conditions described in Table 3, various
1,3-dioxolanes were stereoselectively obtained by the for-
mal cycloaddition reaction using 3a as a catalyst.20 In ad-
dition, catalyst screening identified 3c as an efficient
catalyst to obtain the opposite enantiomer ent-10aa in
good yield with high enantioselectivity (Table 3, entry 2).
b Isolated yields.
c Diastereomeric ratios were determined by 1H NMR.
d Values are for the major diastereomers of 10. See ref. 20 for minor
diastereomers.
e Reaction was run using 3c instead of 3a.
f Reaction was run for 48 h.
The utility of the products as synthetic intermediates was
demonstrated by performing the transformation of 10aa.
Reduction with lithium aluminum hydride in the presence
of lithium iodide afforded the corresponding alcohol 11
with high diastereoselectivity, and subsequent de-acetal-
ization gave optically active triol 12 (Scheme 5). In addi-
tion, treatment of 10aa with allyltrimethylsilane in the
presence of titanium tetrachloride led to allylative ring
cleavage to provide 13 in a regio- and diastereoselective
fashion while maintaining the optical purity (Scheme 6).
g Reaction was run for 96 h.
h Reaction was run for 120 h.
Cy
LiAlH4, LiI
p-TsOH·H2O
OH OH
OH
O
10aa
OH
O
96% ee
Et2O
MeOH–H O
80 °C, 12 h
95%
Ph
2
–78 °C, 10 h
Ph
12
97% ee
92%, dr = 14:1
11
97% ee
Scheme 5 Synthesis of chiral triol 12
O
R2
∗
OH
R2
R1
R3
HO
aminothiourea*
R3
O
∗
O
O
O
∗
+
O
R1
hemiacetal intermediate
O
R1
R2
R3
Scheme 4 Chiral 1,3-dioxolane synthesis via asymmetric cycloetherification using a bifunctional aminothiourea catalyst
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1627–1634

1630
Y. Fukata et al.
SPECIAL TOPIC
O
OH
carbonyl group. This cyclization protocol was therefore
applied to reactions using carboxylic acid derivatives as
substrates. There have been very few demonstrations of
asymmetric oxy-Michael additions to high oxidation state
substrates, such as α,β-unsaturated carboxylic acid deriv-
atives,22 despite their great synthetic importance.23
TMS
O
10aa
96% ee
Ph
TiCl4, CH2Cl2
–78 °C, 20 min
96%, dr = 4:1
Cy
13
97% ee
Scheme 6 Stereospecific ring cleavage of 10aa
By employing studies involving the optimization of sub-
strates and reaction conditions, 2,6-dimethylbenzenethiol
ester 14 was identified as the best substrate, and pivalal-
dehyde (9d) proved to be a good counterpart. The reaction
between these components, using 3a as a catalyst, gave a
diastereomer mixture of the desired products 15 and 15′ in
high yield, with excellent enantioselectivity for both dia-
stereomers (Scheme 9).24 Stereochemical analysis of the
products revealed that these diastereomers had the same
S-configuration at the β-position of the carbonyl group as
was expected.25
To gain further insight into the enantio-determining step,
formal [3+2]-cycloaddition reactions were investigated
using formaldehyde (9f) and acetone (9g) with 8a
(Scheme 7). Products 10af and 10ag were obtained enan-
tioselectively, regardless of the achirality of the forming
acetal carbon. These results strongly suggest that the in-
tramolecular oxy-Michael addition from the hemiacetal
intermediates proceeded with high enantioselectivity ac-
cording to our original hypothesis. This is also in agree-
ment with the consistent absolute configuration (the same
S-configuration) at the β-position of the carbonyl group in
both diastereomers of 10da (Scheme 8).
The easily removable acetal functionality enables this
oxy-Michael addition method to be useful as an enantiose-
lective formal hydration.26 In order to demonstrate this,
the obtained products were further extended to the asym-
metric syntheses of some β-hydroxy carboxyl compounds
(Scheme 10). Treatment of the diastereomer mixture of 15
and 15′ with titanium tetrachloride led to the generation of
free β,γ-dihydroxy compound 16 with high optical purity,
while keeping the thioester group intact. Alternatively,
treatment of the diastereomer mixture with p-toluenesul-
fonic acid in an aqueous medium gave β-hydroxy-γ-buty-
rolactone 17, a versatile chiral synthetic intermediate27
that could be transformed into L-carnitine (18), an impor-
tant bioactive agent, using a previously reported proce-
dure.28
R
R
O
O
4a (10 mol %)
O
O
+
O
OH
CPME, 25 °C, 24 h
R
Ph
R
Ph
8a
R = H (9f)a
R = Me (9g)
R = H (10af); 91%, 62% ee
R = Me (10ag); 4%, 98% ee
Scheme 7 Formal [3+2] cycloaddition with formaldehyde (9f) and
acetone (9g). a Reaction was run using 37% aqueous solution of form-
aldehyde.
Cy
O
Cy
O
4a (10 mol %)
O
O
O
O
8d + 9a
+
CPME, 25 °C, 24 h
88%, dr = 4.7:1
Ar
Ar
(S)
(S)
Taking advantage of the thioester functionality, we also
carried out functional group transformations of 15, and it
was found that the chiral acetal moiety was unchanged af-
ter the transformations (Scheme 11). Reduction of 15 with
lithium aluminum hydride afforded the corresponding pri-
mary alcohol 19 quantitatively, without any erosion of op-
tical purity. In addition, Liebeskind–Srogl cross coupling
enabled the replacement of the arylthio group of 15 to give
ketone 10ad,29 indicating that these thioester products can
be easily transformed into a wide variety of chiral com-
pounds.
10da
major diastereomer
96% ee
minor diastereomer
85% ee
Ar = 4-BrC6H4
Scheme 8 The absolute configurations of 10da, as determined by X-
ray crystal structure analysis for both diastereomers21
Considering these stereochemical outcomes, although the
diastereoselectivity was only moderate, these reactions
can be recognized as a way to achieve highly enantiose-
lective oxygen atom introduction at the β-position of the
O
OH
ArS
t-Bu
t-Bu
14
3a (13 mol%)
O
O
O
O
+
+
O
O
CPME, 25 °C, 48 h
85%, dr = 3.8:1
ArS
ArS
O
(S)
(S)
15
15'
t-Bu
H
major diastereomer
98.9% ee
minor diastereomer
97.1% ee
9d
Ar = 2,6-dimethylphenyl
Scheme 9 Asymmetric oxy-Michael addition to γ-hydroxy-α,β-unsaturated thioester 14
Synthesis 2013, 45, 1627–1634
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Asymmetric Cycloetherifications by Bifunctional Aminothiourea Catalysts
1631
1H and 13C NMR spectra were taken on a Varian Unity Inova 500
(1H, 500 MHz; 13C, 125.7 MHz) spectrometer using TMS as an in-
TiCl4
O
OH
OH
1
ternal standard for H NMR (δ = 0); 13C NMR used CDCl3 as an
CH2Cl2
–78 to –40 °C, 4 h
93%
ArS
16
98.7% ee
(from diastereomixture)
internal standard (δ = 77.0) and C6D6 as an internal standard (δ =
128.06). 19F NMR spectra were measured on a Varian Mercury 200
(19F, 188 MHz) spectrometer with hexafluorobenzene as an internal
standard (δ = 0). GC-MS analyses and HRMS were obtained with a
Jeol JMS-700 spectrometer by electron ionization at 70 eV. HPLC
was performed with a Shimadzu Prominence. IR spectra were deter-
mined on a Shimadzu IR Affinity-1 spectrophotometer. Melting
points were determined using a Yanako MP-500D. Optical rotations
were measured on a Horiba SEPA-200. X-ray data were taken on a
Bruker Smart APEX X-Ray diffractometer equipped with a large
area CCD detector. The structures were solved with the program
system SHELXS-97 and refined with SHELXL-97 package from
Bruker. TLC analyses were performed by means of Merck Kieselgel
60 F254 (0.25 mm) Plates. Visualization was accomplished with UV
light (254 nm) and/or such as an aqueous alkaline KMnO4 solution
followed by heating.
15
+
15'
98.9% ee 97.1% ee
diastereomixture
(15:15' = 3.8:1)
O
p-TsOH•H2O
O
ClCH2CH2Cl–H2O
90 °C, 8 d
84%
HO
17
98.7% ee
(from diastereomixture)
(1) MsCl, CH2Cl2
(2) H2SO4, H2O
(3) NaOH, H2O
(4) Me3N, H2O
Me
Me
OH
O
Flash column chromatography was carried out using Kanto Chemi-
cal silica gel (spherical, 40–50 μm). Unless otherwise noted, com-
mercially available reagents were used without purification.
N
10% (4 steps)
Me
O
L-carnitine (18)
[α]D27 –30.0 (c 0.50, H2O)
[lit.21b [α]D22 –30.0 (c 1.2, H2O)]
Bifunctional Aminothiourea Catalysts 3; General Procedure
Bifunctional organocatalysts 3 were prepared by the literature pro-
cedure.13c A cinchona alkaloid (5 mmol) and Ph3P (1.6 g, 6 mmol)
were dissolved in THF (25 mL), and the solution was cooled to 0
°C. DEAD (1.0 g, 6 mmol) was subsequently added. To the result-
ing solution was added dropwise a solution of diphenylphosphoryl
azide (1.3 mL, 6 mmol) in THF (10 mL) at 0 °C. The mixture was
allowed to warm to r.t. and stirred for 24 h; it was then heated to 50
°C and stirred for 10 h. Ph3P (1.7 g, 6.5 mmol) was added again, and
the mixture was stirred at 50 °C for an additional 15 h. The solution
was cooled to r.t., H2O (0.5 mL) was added, and the solution was
stirred for 24 h. The solvents were removed in vacuo, and the resi-
due was dissolved in CH2Cl2–10% aq HCl (1:1, 50 mL). The aque-
ous phase was separated and washed with CH2Cl2 (4 × 25 mL). It
was subsequently made alkaline with aq NH3, and the aqueous
phase was extracted with CH2Cl2 (4 × 25 mL). The combined organ-
ic layers were dried (Na2SO4), and concentrated in vacuo. Purifica-
tion by flash column chromatography (silica gel, EtOAc–MeOH,
9:1 then CHCl3–MeOH, 8:2) gave the corresponding 9-amino(9-de-
oxy)cinchona alkaloid. Next, to the solution of the obtained 9-ami-
no(9-deoxy)cinchona alkaloid in THF (6 mL) was slowly added a
solution of 3,5-bis(trifluoromethyl)phenyl isothiocyanate (1 equiv)
in THF (4 mL) at r.t. The mixture was stirred overnight, and the sol-
vents were removed in vacuo. Purification by flash column chroma-
tography (silica gel, EtOAc–MeOH, 95:5 to 97.5:2.5 or EtOAc)
gave the corresponding bifunctional organocatalyst 3.
Scheme 10 Syntheses of chiral β-hydroxy carboxy compounds
t-Bu
LiAlH4
O
O
Et2O, r.t., 1 h
99%
HO
19
99% ee
t-Bu
O
O
O
S
PhB(OH)2
Pd2(dba)3
P(2-furyl)3
CuTC
15
99% ee
t-Bu
O
O
O
THF, 50 °C, 60 h
50%
Ph
10ad
98% ee
Scheme 11 Transformations of the thioester group of 15
In summary, we have demonstrated asymmetric intramo-
lecular oxy-Michael addition reactions using cinchona al-
kaloid–thiourea-based bifunctional organocatalysts. The
developed methods afforded several important oxacyclic
compounds, including tetrahydrofurans, tetrahydropy-
rans, and 1,3-dioxolanes. A number of the resulting prod-
ucts were demonstrated to be useful synthetic
intermediates that could be further transformed into valu-
able bioactive compounds. This study indicates that the
approach based on the use of hydrogen bonding is an ef-
fective way to achieve enantioselective cycloetherifica-
tion. Further studies on the application of this
methodology to the synthesis of other chiral oxygen het-
erocycles are currently underway in our laboratory and
will be reported in due course.
Catalyst 3a
White solid; yield: 1.2 g (41%, 2 steps from quinidine); mp 125.0–
125.2 °C; [α]D23 +122.6 (c 1.33, CH2Cl2).
IR (KBr): 3221, 2944, 2361, 1735, 1623, 1511, 1475, 1384, 1278,
1177, 1134, 1034, 959, 916, 884, 850, 826, 682 cm–1.
1H NMR (CDCl3): δ = 8.65 (br s, 1 H), 8.02 (d, J = 9.0 Hz, 1 H),
7.86 (s, 2 H), 7.67 (s, 1 H), 7.59 (br s, 1 H), 7.40 (d, J = 9.0 Hz, 1
H), 7.23 (br s, 1 H), 5.86 (br s, 2 H), 5.19 (br s, 1 H), 5.15 (d, J = 9.5
Hz, 1 H), 3.97 (s, 3 H), 3.22 (br s, 1 H), 3.10 (br s, 1 H), 3.03 (m, 2
H), 2.94 (m, 1 H), 2.38 (m, 1 H), 1.70 (s, 1 H), 1.61 (m, 2 H), 1.27
(br s, 1 H), 1.02 (m, 1 H).
13C NMR (CDCl3): δ = 181.0, 158.1, 147.3, 144.7, 144.5, 140.1,
139.6, 132.5 (q, J = 33.6 Hz), 131.6, 128.0, 123.5, 122.9 (q, J =
273.0 Hz), 122.3, 118.7, 115.3, 101.7, 61.4, 55.6, 48.5, 47.1, 38.7,
27.1, 26.1, 25.0.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1627–1634

1632
Y. Fukata et al.
SPECIAL TOPIC
HRMS: m/z [M + H]+ calcd for C29H29F6N4OS: 595.1966; found:
595.1961.
raphy (silica gel, hexane–EtOAc, 3:1) afforded the corresponding
2-substituted tetrahydrofuran 2.
Catalyst 3b
Asymmetric Synthesis of 2-Substituted Tetrahydropyrans 5;
General Procedure
White solid; yield: 1.0 g (36%, 2 steps from cinchonine); mp 189.9–
190.3 °C; [α]D23 +163.3 (c 1.23, CH2Cl2).
In a 5-mL vial, ξ-hydroxy-α,β-unsaturated ketone 4 (0.15 mmol),
cyclopentyl methyl ether (0.3 mL), and quinidine-derived bifunc-
tional catalyst 3a (0.0075 mmol) were added sequentially. The mix-
ture was stirred in an oil bath maintained at 25 °C for 24 h. The
mixture was subsequently diluted with hexane–EtOAc (1:1), passed
through a short silica gel pad to remove 3a, and concentrated in vac-
uo. Purification of the reaction mixture by flash column chromatog-
raphy (silica gel, hexane–EtOAc, 3:1) afforded the corresponding
tetrahydropyran 5.
IR (KBr): 3428, 3246, 2944, 2360, 1622, 1588, 1512, 1474, 1386,
1281, 1183, 1126, 960, 882, 848, 752, 682 cm–1.
1H NMR (CDCl3): δ = 8.83 (br s, 1 H), 8.28 (br s, 1 H), 8.15 (d, J =
8.5 Hz, 1 H), 7.85 (br s, 2 H), 7.56 (dd, J = 7.5, 7.5 Hz, 1 H), 7.68
(s, 1 H), 7.64 (dd, J = 7.5, 7.5 Hz, 1 H), 7.29 (br s, 1 H), 5.81 (br s,
2 H), 5.14 (m, 2 H), 3.21 (br s, 1 H), 3.00 (m, 3 H), 2.92 (br s, 1 H),
2.36 (m, 1 H), 1.66 (s, 1 H), 1.59 (m, 2 H), 1.22 (br s, 1 H), 0.95 (m,
1 H).
1-Phenyl-2-(tetrahydro-2H-pyran-2-yl)ethanone (5a)
Colorless oil; yield: 27.1 mg (90%), 91% ee; [α]D26 +16.8 (c 2.53,
CH2Cl2); TLC: Rf = 0.45 (hexane–EtOAc, 3:1); HPLC (Daicel Chi-
ralcel OD-H, hexane–i-PrOH, 99:1, flow rate = 2.0 mL/min, λ = 254
nm, 40 °C): tR = 6.1 (minor), 8.0 min (major).
13C NMR (CDCl3): δ = 181.3, 150.0, 148.6, 145.8, 140.2, 139.3,
132.5 (q, J = 33.6 Hz), 130.5, 129.5, 127.1, 126.7, 123.4, 122.9 (q,
J = 273.1 Hz), 122.8, 119.0, 118.7, 115.5, 61.8, 55.7, 48.5, 47.0,
38.9, 27.3, 26.0, 24.9.
HRMS: m/z [M + H]+ calcd for C28H27F6N4S: 565.1861; found:
565.1855.
IR (neat): 3060, 2936, 2849, 1686, 1597, 1581, 1449, 1379, 1357,
1325, 1292, 1273, 1208, 1194, 1175, 1088, 1045, 1003, 971, 904,
810, 777, 751, 692, 661, 471 cm–1.
1H NMR (CDCl3): δ = 7.97 (m, 2 H), 7.56 (m, 1 H), 7.46 (m, 2 H),
3.96 (m, 2 H), 3.48 (m, 1 H), 3.29 (dd, J = 16.0, 6.5 Hz, 1 H), 2.92
(dd, J = 16.0, 5.5 Hz, 1 H), 1.84 (m, 1 H), 1.75 (m, 1 H), 1.57 (m, 2
H), 1.52 (m, 1 H), 1.36 (m, 1 H).
13C NMR (CDCl3): δ = 198.4, 137.4, 133.0, 128.5, 128.3, 74.4, 68.7,
45.4, 32.0, 25.9, 23.4.
HRMS: m/z [M + H]+ calcd for C13H17O2: 205.1229; found:
205.1227.
Catalyst 3c
White solid; yield: 0.80 g (27%, 2 steps from quinine); mp 121.0–
121.5 °C; [α]D23 –99.0 (c 1.24, CH2Cl2).
IR (neat): 3220, 2946, 2360, 1623, 1510, 1475, 1384, 1279, 1180,
1134, 1032, 959, 917, 885, 850, 683 cm–1.
1H NMR (CDCl3): δ = 8.60 (br s, 1 H), 8.00 (d, J = 8.5 Hz, 1 H),
7.82 (br s, 2 H), 7.68 (s, 1 H), 7.62 (br s, 1 H), 7.39 (d, J = 8.5 Hz,
1 H), 7.18 (br s, 1 H), 5.84 (br s, 1 H), 5.70 (m, 1 H), 5.01 (m, 2 H),
3.96 (s, 3 H), 3.37 (br s, 1 H), 3.30 (br s, 1 H), 3.18 (m, 1 H), 2.79
(br s, 2 H), 2.35 (br s, 1 H), 1.72 (s, 1 H), 1.68 (m, 2 H), 1.41 (m, 1
H), 0.92 (br s, 1 H).
13C NMR (CDCl3): δ = 181.0, 158.2, 147.4, 144.8, 144.0, 140.6,
140.0, 132.6 (q, J = 33.6 Hz), 131.8, 127.9, 123.6, 122.9 (q, J =
273.0 Hz), 122.0, 118.8, 115.1, 102.1, 61.2, 55.7, 54.9, 41.3, 39.0,
27.5, 27.1, 25.7.
1-(4-Methoxyphenyl)-2-(tetrahydro-2H-pyran-2-yl)ethanone
(5b)
Colorless oil; yield: 19.7 mg (56%); 94% ee; [α]D25 +20.8 (c 1.97,
CH2Cl2); TLC: Rf = 0.29 (hexane–EtOAc, 3:1); HPLC (Daicel Chi-
ralpak AD-H, hexane–i-PrOH, 98:2, flow rate = 0.5 mL/min, λ =
254 nm, 40 °C): tR = 34.6 (minor), 44.6 min (major).
HRMS: m/z [M + H]+ calcd for C29H29F6N4OS: 595.1966; found:
595.1961.
IR (neat): 2934, 2844, 1672, 1600, 1577, 1510, 1309, 1261, 1170,
1087, 1045, 1031, 843, 450 cm–1.
1H NMR (CDCl3): δ = 7.95 (m, 2 H), 6.91 (m, 2 H), 3.95 (m, 1 H),
3.93 (m, 1 H), 3.86 (s, 3 H), 3.47 (m, 1 H), 3.23 (dd, J = 16.0, 7.0
Hz, 1 H), 2.86 (dd, J = 16.0, 6.0 Hz, 1 H), 1.83 (m, 1 H), 1.73 (m, 1
H), 1.59–1.49 (m, 3 H), 1.34 (m, 1 H).
Catalyst 3d
White solid; yield: 1.2 g (44%, 2 steps from cinchonidine); mp
122.8–123.1 °C; [α]D23 –101.0 (c 1.24, CH2Cl2).
IR (neat): 3240, 3081, 2946, 2366, 1510, 1473, 1384, 1281, 1181,
1135, 990, 958, 884, 849, 755, 683 cm–1.
13C NMR (CDCl3): δ = 196.9, 163.4, 130.5, 130.1, 113.6, 74.4, 68.6,
55.4, 45.0, 32.0, 25.8, 23.3.
HRMS: m/z [M + H]+ calcd for C14H19O3: 235.1329; found:
235.1377.
1H NMR (CDCl3): δ = 8.80 (br s, 1 H), 8.35 (br s, 1 H), 8.14 (d, J =
8.5 Hz, 1 H), 7.80 (s, 2 H), 7.74 (dd, J = 8.0, 7.5 Hz, 1 H), 7.69 (s,
1 H), 7.63 (dd, J = 8.0, 7.5 Hz, 1 H), 7.27 (br s, 1 H), 5.78 (br s, 1
H), 5.67 (m, 1 H), 4.98 (m, 2 H), 3.26 (m, 1 H), 3.20 (br s, 1 H), 3.17
(dd, J = 13.5, 10.5 Hz, 1 H), 2.78 (m, 2 H), 2.33 (br s, 1 H), 1.70 (m,
2 H), 1.63 (m, 1 H), 1.33 (m, 1 H), 0.93 (br s, 1 H).
13C NMR (CDCl3): δ = 180.9, 149.9, 148.5, 145.9, 140.7, 139.9,
132.6 (q, J = 33.6 Hz), 130.4, 129.5, 127.0, 123.6, 122.9 (q, J =
273.0 Hz), 119.1, 118.9, 115.0, 61.5, 56.5, 54.9, 41.1, 39.2, 27.5,
27.1, 25.7.
2-(Tetrahydro-2H-pyran-2-yl)-1-[4-(trifluoromethyl)phe-
nyl]ethanone (5c)
Reaction was run on a 0.1-mmol scale; white solid; yield: 25.9 mg
(95% ); 85% ee; mp 51.5–52.5 °C; TLC: Rf = 0.49 (hexane–EtOAc,
3:1); [α]D25 +3.86 (c 2.59, CH2Cl2); HPLC (Daicel Chiralpak AD-
H, hexane–i-PrOH, 98:2, flow rate = 0.5 mL/min, λ = 254 nm, 40
°C): tR = 15.8 (minor), 18.9 min (major).
HRMS: m/z [M + H]+ calcd for C28H27F6N4S: 565.1861; found:
565.1855.
IR (KBr): 2946, 2936, 2925, 2857, 1681, 1412, 1334, 1323, 1213,
1170, 1158, 1134, 1124, 1113, 1107, 1084, 1070, 1006, 848, 829
cm–1.
1H NMR (CDCl3): δ = 8.06 (m, 2 H), 7.72 (m, 2 H), 3.95 (m, 1 H),
3.93 (m, 1 H), 3.50 (m, 1 H), 3.30 (dd, J = 16.0, 7.0 Hz, 1 H), 2.90
(dd, J = 16.0, 5.0 Hz, 1 H), 1.85 (m, 1 H), 1.73 (m, 1 H), 1.59 (m, 1
H), 1.55 (m, 1 H), 1.52 (m, 1 H), 1.39 (m, 1 H).
13C NMR (CDCl3): δ = 197.6, 139.9, 134.2 (q, J = 32.7 Hz), 128.6,
125.6 (q, J = 3.9), 123.5 (q, J = 272.6 Hz), 74.2, 68.6, 45.6, 31.9,
25.7, 23.3.
Asymmetric Synthesis of 2-Substituted Tetrahydrofurans 2;
General Procedure
In a 5-mL vial, ε-hydroxy-α,β-unsaturated ketone 1 (0.25 mmol),
cyclopentyl methyl ether (0.5 mL), and quinidine-derived bifunc-
tional catalyst 3a (0.0075 mmol) were added sequentially. The mix-
ture was stirred in an oil bath maintained at 25 °C for 24 h. The
mixture was subsequently diluted with hexane–EtOAc (1:1), passed
through a short silica gel pad to remove 3a, and concentrated in vac-
uo. Purification of the reaction mixture by flash column chromatog-
Synthesis 2013, 45, 1627–1634
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Asymmetric Cycloetherifications by Bifunctional Aminothiourea Catalysts
1633
19F NMR (CDCl3): δ = 98.7.
HRMS: m/z [M + H]+ calcd for C14H16F3O2: 273.1097; found:
1H NMR (CDCl3): δ = 7.27 (m, 2 H), 7.20–7.17 (m, 3 H), 3.92 (m,
1 H), 3.75 (m, 1 H), 3.42 (m, 1 H), 2.89 (m, 2 H), 2.79 (m, 2 H), 2.65
(dd, J = 15.5, 6.0 Hz, 1 H), 2.38 (dd, J = 15.5, 4.5 Hz, 1 H), 1.81 (m,
1 H), 1.58 (m, 1 H), 1.53–1.46 (m, 3 H), 1.25 (m, 1 H).
273.1106.
13C NMR (CDCl3): δ = 208.5, 141.1, 130.4, 128.3, 126.0, 74.1, 68.5,
49.6, 45.2, 31.7, 29.4, 25.7, 23.3.
HRMS: m/z [M + H]+ calcd for C15H21O2: 233.1536; found:
233.1545.
1-(Naphthalen-2-yl)-2-(tetrahydro-2H-pyran-2-yl)ethanone
(5d)
Colorless oil; yield: 30.5 mg (80%); 94% ee; [α]D25 +26.7 (c 3.05,
CH2Cl2); TLC: Rf = 0.36 (hexane–EtOAc, 3:1); HPLC (Daicel Chi-
ralpak AD-H, hexane–i-PrOH, 98.5:1.5, flow rate = 2.0 mL/min,
λ = 254 nm, 40 °C): tR = 35.1 (minor), 47.8 min (major).
Asymmetric Synthesis of 1,3-Dioxolanes 10; General Procedure
In a 5-mL vial, γ-hydroxy-α,β-unsaturated ketone 8 (0.25 mmol),
cyclopentyl methyl ether (0.5 mL), aldehyde or ketone 9 (0.3
mmol), and quinidine-derived bifunctional catalyst 3a (0.025
mmol) were added sequentially. The mixture was stirred in an oil
bath maintained at 25 °C for 24 h. The mixture was sequentially di-
luted with hexane–EtOAc (1:1), passed through a short silica gel
pad to remove 3a, and concentrated in vacuo. Purification of the
mixture by flash column chromatography (silica gel, hexane–
EtOAc, 10:1) afforded the corresponding 1,3-dioxolane 10 as a
mixture of diastereomers. In most cases, the diastereomers were fur-
ther separated by flash column chromatography (silica gel); see ref-
erence 20 for details.
IR (neat): 3508, 2935, 2848, 2739, 2667, 2314, 1680, 1636, 1469,
1387, 1355, 1295, 1209, 1087, 863, 821, 747, 677, 450 cm–1.
1H NMR (CDCl3): δ = 8.49 (m, 1 H), 8.04 (m, 1 H), 7.96 (d, J = 8.5
Hz, 1 H), 7.88 (m, 2 H), 7.58 (m, 1 H), 7.55 (m, 1 H), 4.02 (m, 1 H),
3.96 (m, 1 H), 3.51 (m, 1 H), 3.45 (dd, J = 16.0, 6.5 Hz, 1 H), 3.05
(dd, J = 16.0, 5.5 Hz, 1 H), 1.86 (m, 1 H), 1.78 (m, 1 H), 1.62–1.55
(m, 2 H), 1.51 (m, 1 H), 1.41 (m, 1 H).
13C NMR (CDCl3): δ = 198.3, 135.5, 134.5, 132.4, 130.1, 129.6,
128.43, 128.36, 127.7, 126.7, 123.9, 74.4, 68.6, 45.4, 32.0, 25.8,
23.4.
HRMS: m/z [M + H]+ calcd for C17H19O2: 255.1380; found:
255.1388.
Asymmetric Oxy-Michael Addition Reaction to γ-Hydroxy-α,β-
Unsaturated Thioester 14
1-(4-Methylphenyl)-2-(tetrahydro-2H-pyran-2-yl)ethanone
(5e)
In a 5-mL vial, γ-hydroxy-α,β-unsaturated thioester 14 (2.0 mmol),
cyclopentyl methyl ether (2.0 mL), pivalaldehyde (9d, 4.0 mmol),
and quinidine-derived bifunctional catalyst 3a (0.26 mmol) were
added sequentially. The mixture was stirred in an oil bath main-
tained at 25 °C for 48 h. The mixture was sequentially diluted with
hexane–EtOAc (1:1), passed through a short silica gel pad to re-
move 3a, and concentrated in vacuo. Purification of the reaction
mixture by flash column chromatography (silica gel, hexane–Et2O,
10:1) afforded the corresponding oxy-Michael adducts 15 and 15′
as a mixture of diastereomers.
Colorless oil; yield: 24.9 mg (76%); 94% ee; [α]D25 +14.9 (c 2.49,
CH2Cl2); TLC: Rf = 0.44 (hexane–EtOAc, 3:1); HPLC (Daicel Chi-
ralpak AD-H, hexane–i-PrOH, 98.5:1.5, flow rate = 0.5 mL/min,
λ = 254 nm, 40 °C): tR = 24.0 (minor), 30.7 min (major).
IR (neat): 2933, 2853, 2360, 2331, 1686, 1607, 1087, 1045, 971,
475, 448 cm–1.
1H NMR (CDCl3): δ = 7.86 (m, 2 H), 7.26 (m, 2 H), 3.95 (m, 1 H),
3.93 (m, 1 H), 3.47 (m, 1 H), 3.23 (dd, J = 16.0, 6.0 Hz, 1 H), 2.90
(dd, J = 16.0, 6.0 Hz, 1 H), 2.40 (s, 3 H), 1.83 (m, 1 H), 1.74 (m, 1
H), 1.58 (m, 1 H), 1.54 (m, 1 H), 1.49 (m, 1 H), 1.35 (m, 1 H).
See references 14, 20, and 24 for further details on the experimental
procedures and the characterization data of compounds.
13C NMR (CDCl3): δ = 198.0, 143.8, 134.7, 129.2, 128.4, 74.4, 68.6,
45.2, 32.0, 25.8, 23.4, 21.6.
HRMS: m/z [M + H]+ calcd for C14H19O2: 219.1380; found:
Acknowledgment
219.1389.
We thank Professor Takuya Kurahashi (Kyoto University) for X-
ray crystallographic analysis. This work was supported financially
by the Japanese Ministry of Education, Culture, Sports, Science,
and Technology.
1-(4-Bromophenyl)-2-(tetrahydro-2H-pyran-2-yl)ethanone (5f)
White solid; yield: 42.1 mg (99%); 94% ee; mp 55.3–55.5 °C; [α]D
+10.9 (c 4.21, CH2Cl2); TLC: Rf = 0.49 (hexane–EtOAc, 3:1);
HPLC (Daicel Chiralpak AD-H, hexane–i-PrOH, 98:2, flow rate =
2.0 mL/min, λ = 254 nm, 40 °C): tR = 21.7 (minor), 25.4 min (ma-
jor).
25
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
IR (KBr): 2960, 2937, 2924, 2845, 1684, 1584, 1400, 1207, 1087,
1072, 999, 973, 835, 807 cm–1.
References
1H NMR (CDCl3): δ = 7.81 (m, 2 H), 7.56 (m, 2 H), 3.92 (m, 1 H),
3.90 (m, 1 H), 3.41 (m, 1 H), 3.22 (dd, J = 16.0, 7.0 Hz, 1 H), 2.83
(dd, J = 16.0, 5.5 Hz, 1 H), 1.79 (m, 1 H), 1.70 (m, 1 H), 1.59–1.52
(m, 2 H), 1.48 (m, 1 H), 1.35 (m, 1 H).
13C NMR (CDCl3): δ = 197.4, 135.8, 131.7, 129.7, 128.2, 74.2, 68.5,
45.2, 31.9, 25.7, 23.3.
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4-Phenyl-1-(tetrahydro-2H-pyran-2-yl)butan-2-one (5g)
Colorless oil; yield: 20.0 mg (58%); 95% ee; [α]D25 +3.50 (c 2.00,
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1088, 1044, 747, 699, 456 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1627–1634

1634
Y. Fukata et al.
SPECIAL TOPIC
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Synthesis 2013, 45, 1627–1634
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