Asymmetric cycloetherification via the kinetic resolution of alcohols using chiral phosphoric acid catalysts

Article abstract of DOI:10.1246/cl.160727

In this study, novel asymmetric cycloetherification via the kinetic resolution of secondary or tertiary alcohols using chiral phosphoric acid catalysts was developed, affording tetrahydropyrans (THPs) with two stereogenic centers. The cyclization of the recovered optically active alcohols afforded other stereoisomers of THPs. These protocols offer efficient synthetic routes to various optically active THP derivatives, which are important structures found in a range of biologically active agents.

Full text of DOI:10.1246/cl.160727

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Asymmetric Cycloetherification via the Kinetic Resolution of Alcohols
Using Chiral Phosphoric Acid Catalysts
Naoki Yoneda, Akira Matsumoto, Keisuke Asano,* and Seijiro Matsubara*
Advance Publication on the web September 7, 2016
doi:10.1246/cl.160727
© 2016 The Chemical Society of Japan
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1
Asymmetric Cycloetherification via the Kinetic Resolution of Alcohols
Using Chiral PhosphoricAcid Catalysts
Naoki Yoneda, Akira Matsumoto, Keisuke Asano,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510,
Japan
(E-mail: asano.keisuke.5w@kyoto-u.ac.jp)
In this study, novel asymmetric cycloetherification via
the kinetic resolution of secondary or tertiary alcohols using
chiral phosphoric acid catalysts was developed, affording
tetrahydropyrans (THPs) with two stereogenic centers. The
cyclization of the recovered optically active alcohols afforded
other stereoisomers of THPs. These protocols offer efficient
synthetic routes to various optically active THP derivatives,
which are important structures found in
biologically active agents.
a range of
The kinetic resolution of chiral alcohols has been
extensively investigated because of their importance as a
feedstock for optically active materials.1 As chiral oxacycles
are versatile frameworks found in a wide range of natural
products and bioactive molecules (Figure 1),2 it is also
essential to develop enantioselective cycloetherification via
kinetic resolution starting from racemic secondary or tertiary
alcohols. However, few examples of such methodologies for
enabling the synthesis of chiral cyclic ethers are available.3
Meanwhile, we have recently reported several asymmetric
cycloetherification
reactions
using
bifunctional
amino(thio)urea catalysts.4,5 In these studies, the utilization of
the multipoint recognition of substrates using bifunctional
organocatalysts via hydrogen bonding6 for enantioselective
C–O bond formation via intramolecular oxy-Michael addition
has proven to be efficient.7 As a result, these insights have
stimulated us to use organocatalysts by utilizing hydrogen
Figure 1. Chiral THPs in natural products.
bonding
for
intramolecular
oxy-Michael
addition
accompanied by the kinetic resolution of racemic alcohols,
affording oxacycles bearing two stereogenic centers (Scheme
1). In this study, we demonstrate novel organocatalytic
asymmetric cycloetherification via the kinetic resolution of
secondary or tertiary alcohols, affording tetrahydropyrans
(THPs) with two asymmetric centers.
Initially, the reaction of (±)-(E)-7-hydroxy-1,7-
diphenylhept-2-en-1-one ((±)-1a) was performed at 0 °C
using bifunctional aminothiourea catalysts 3a and 3b, and the
observed selectivity factors were not satisfactory (Table 1,
entries 1 and 2, respectively).8 Next, we focused on chiral
phosphoric acid catalysts 3c–3e9 as they also contain both
acidic and basic sites, allowing for the multipoint recognition
of substrates via hydrogen bonding;10 on the other hand,
sterically bulky substituents near catalytic sites are well
known to help in the recognition of substituents on substrates,
thereby affording high stereoselectivity.11 In this context, we
envisioned that chiral phosphoric acid catalysts would be
more suitable for the kinetic resolution of alcohols.12
Scheme 1. Asymmetric intramolecular oxy-Michael addition via kinetic
resolution of chiral alcohols
As expected, phosphoric acid catalyst 3c13 with a BINOL
backbone performed significantly better than aminothiourea
catalysts (Table 1, entry 3), although other phosphoric acids
with different backbones gave less satisfactory results (Table
1, entries 4 and 5).14 With 3c, lower temperatures were
subsequently utilized. Although the stereoselectivity was not
improved for the reaction performed at –20 °C (Table 1, entry
6), the use of 4 Å molecular sieves (4 Å MS) as an additive
was found to dramatically accelerate the reaction (Table 1,
entry 7); in the presence of 4 Å MS, the reaction was
performed even at lower temperature, and the selectivity
factor was significantly improved (Table 1, entry 8).

2
Table 1. Optimization of conditionsa
reaction using (±)-1d increased to 39. A substrate with an
aliphatic substituent also participated in kinetic resolution,
affording moderate selectivity (Table 2, entry 6). In addition,
substrates with electron-rich and electron-poor enones were
also applicable, both of which exhibited high
stereoselectivities (Table 2, entries 7 and 8, respectively).
The absolute configurations of 2a and 2a’ were determined by
NOE and HPLC analyses (see the Supporting Information for
details), and the configurations of all other examples were
assigned analogously.
Catalyst Time Conv.
dr
ee (%)
2a, 2a’, 1a
70, 28, 72
–69, –7, –93
80, 80, 85
22, 10, 19
62, 31, 23
87, 61, 62
88, 79, 62
89, 87, 85
s
factorc
6.5
8.0
15
Table 2. Scope of secondary alcoholsa
Entry
(mol %)
3a (30)
3b (30)
3c (1)
(h)
48
48
2
(%)b
58
68
55
48
28
44
44
51
2a:2a’
4.3:1
2.1:1
16:1
24:1
24:1
19:1
19:1
24:1
1
2
3
4
3d (0.3)
3e (1)
3
1.8
4.7
16
5
24
12
2
6d
7d,e
8e,f
3c (1)
3c (1)
16
3c (5)
4
27
aReactions were run using (±)-1a (0.15 mmol) and the catalyst in
toluene (15 mL). bConversions were calculated from the ee values.
See the Supporting Information for details. cSelectivity factors (s)
were calculated from the dr and ee values (ref 8). See the Supporting
Information for details. dReactions were run at –20 °C. eReactions
f
were run using 4 Å MS (300 mg). Reaction was run at –40 °C.
Time Conv.
dr
ee (%)
s
factorc
27
3c
Entry
(±)-1
(mol %)
(h)
4
(%)b
51
63
52
49
58
53
52
57
2:2’
2, 2’, 1
1
2
(±)-1a
(±)-1b
(±)-1c
(±)-1d
(±)-1e
(±)-1f
(±)-1g
(±)-1h
5
5
5
1
1
5
5
5
24:1 89, 87, 85
4.3:1 58, 96, 50
16:1 90, 90, 87
50:1 90, 83, 84
17:1 79, 71, 98
14:1 82, 84, 81
19:1 90, 85, 89
12:1 86, 88, 97
36
4
1.8
26
3
4d
5d
6
2
39
1
26
2.5
4
15
7
30
Figure 2. Chiral organocatalysts.
8
7
26
aReactions were run using (±)-1 (0.15 mmol), 3c, and 4 Å MS (300 mg) in
toluene (15 mL). bConversions were calculated from the ee values. See
the Supporting Information for details. cSelectivity factors (s) were
calculated from the dr and ee values (ref 8). See the Supporting
Information for details. dReactions were run at 0 °C.
With the established optimal conditions, we explored the
substrate scope.
Although poor stereoselectivity was
observed for the reaction of a substrate containing an alcohol
with a p-methoxyphenyl group (Table 2, entry 2), in the case
of a substrate containing a p-trifluoromethyl group, a good
selectivity factor was obtained (Table 2, entry 3). Substrates
bearing larger substituents, such as 9-anthracenyl and 4-
pyrenyl groups, also exhibited high stereoselectivities (Table
2, entries 4 and 5, respectively); the selectivity factor of the

3
biphenyl group at the enone moiety also afforded the
corresponding products; the absolute configurations of 5c and
5c’ were determined by X-ray analysis (see the Supporting
Information for details), and the configurations of all other
examples were assigned analogously.
Scheme 2. Enantiodivergent synthesis of cis-2,6-disubstituted THPs
For demonstrating the utility of the recovered chiral
secondary alcohols, the cyclization of the recovered optically
active 1d was further performed (Scheme 2). The treatment
of the recovered (R)-1d with tetrafluoroboric acid afforded
ent-2d as a cis-isomer without the loss of enantiomeric purity.
In total, these protocols provided both enantiomers of cis-2,6-
disubstituted THPs by using 3c as the only chiral source.
Table 3. Kinetic resolution of tertiary alcoholsa
Scheme 3. Stereodivergent synthesis of 2,2,6-trisubstituted THPs
In contrast to the cyclization from the secondary alcohol
described in Scheme 2, that of the recovered tertiary alcohol
(R)-4a by treatment with tetrafluoroboric acid afforded 5a’,
which is the diastereomer of 5a, as the major product while
simultaneously maintaining enantiomeric purity (Scheme 3).
On the other hand, the treatment of (R)-4a with (R)-3c
afforded ent-5a, the enantiomer of 5a, as the major product
with 97% ee.
These results imply that not only
enantioselectivity but also diastereoselectivity is controlled by
using chiral phosphoric acid catalysts in these asymmetric
cycloetherification reactions utilizing steric interactions as
well as multipoint recognition via hydrogen bonding; as
cyclizations with chiral catalysts preferentially yield kinetic
products, the synthetic protocols involving tertiary alcohols
can facilitate synthetic routes to all possible stereoisomers of
the THPs with two chiral centers including a tetrasubstituted
carbon.
In summary, novel asymmetric cycloetherification,
accompanied by the kinetic resolution of secondary or tertiary
alcohols to afford THPs bearing two chiral centers, was
developed. The recovered optically active alcohols were also
transformed to other stereoisomers of the THPs. These
protocols provide efficient synthetic routes to various
stereoisomers of substituted THP derivatives, which would be
useful for constructing a library of such pharmaceutically
important compounds. Currently, further studies on the
application of these protocols to the asymmetric synthesis of
bioactive agents containing THP rings are underway in our
laboratory, and the results will be reported in due course.
Conv.
(%)b
48
dr
ee (%)
5, 5’, 4
s
factorc
54
Entry
(±)-4
5:5’
25:1
10:1
11:1
1d
2
(±)-4a
(±)-4b
(±)-4c
95, 10, 84
79, 76, 89
81, 74, 61
58
13
3
47
9.7
aReactions were run using (±)-4 (0.15 mmol), 3c (0.015
mmol), and Å MS (300 mg) in toluene (15 mL).
4
bConversions were calculated from the ee values. See the
Supporting Information for details. cSelectivity factors (s)
were calculated from the dr and ee values (ref 8). See the
Supporting Information for details. dReaction was run using
(±)-4a (0.3 mmol), 3c (0.03 mmol), and 4 Å MS (600 mg) in
toluene (30 mL).
Furthermore, this kinetic resolution method can also be
applied to tertiary alcohols (Table 3). The kinetic resolution
of (±)-4a afforded good stereoselectivity, with a selectivity
factor of 54 (Table 3, entry 1). In addition, an alcohol with
two different aliphatic substituents also successfully
completed the reaction (Table 3, entry 2). A substrate with a
We thank Dr. Hiroyasu Sato (RIGAKU) for X-ray
crystallographic analysis.
This work was supported
financially by the Japanese Ministry of Education, Culture,
Sports, Science and Technology (15H05845 and 16K13994).
K.A. also acknowledges the Asahi Glass Foundation, Toyota

4
11
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5
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14
15
Results of further screening of other catalysts, solvents, and
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Supporting Information is also available electronically on the CSJ-
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8
9
In this kinetic resolution, diastereomeric mixtures of cyclic
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