Catalytic asymmetric cycloetherification via intramolecular oxy-Michael addition of enols

Article abstract of DOI:10.1016/j.tet.2021.132381

Carbonyl compounds employed as carbon nucleophiles have played a dominant role in synthetic organic chemistry; however, there is very limited use of these compounds as oxygen nucleophiles. In particular, there are only a few reports on the oxy-Michael addition of the enol forms of carbonyl nucleophiles. In this study, we present the asymmetric cycloetherification of enols, which are generated in situ from enone-bearing ketones, using chiral bifunctional organocatalysts bearing amino and squaramide groups. This transformation chemo- and enantioselectively afforded dihydropyran derivatives, which are the core structures of building blocks for synthesizing glycans.

Full text of DOI:10.1016/j.tet.2021.132381

Tetrahedron 97 (2021) 132381
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic asymmetric cycloetherification via intramolecular oxy-
Michael addition of enols
Ryuichi Murata, Keisuke Asano*, Seijiro Matsubara**
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto, 615-8510, Japan
a r t i c l e i n f o
A
b s t r a c t
Article history:
Carbonyl compounds employed as carbon nucleophiles have played a dominant role in synthetic organic
chemistry; however, there is very limited use of these compounds as oxygen nucleophiles. In particular,
there are only a few reports on the oxy-Michael addition of the enol forms of carbonyl nucleophiles. In
this study, we present the asymmetric cycloetherification of enols, which are generated in situ from
enone-bearing ketones, using chiral bifunctional organocatalysts bearing amino and squaramide groups.
This transformation chemo- and enantioselectively afforded dihydropyran derivatives, which are the
core structures of building blocks for synthesizing glycans.
Received 20 April 2021
Received in revised form
31 July 2021
Accepted 3 August 2021
Available online 10 August 2021
Keywords:
© 2021 Elsevier Ltd. All rights reserved.
Asymmetric cycloetherification
Bifunctional organocatalyst
Squaramide
Enol
Dihydropyran
1. Introduction
electron-deficient ketones and water, intramolecular oxy-Michael
addition of the enol forms of the ketone substrates proceeded as
Carbonyl compounds as carbon nucleophiles have played a
dominant role in synthetic organic chemistry [1], but have not been
widely employed as oxygen nucleophiles [2]. In particular, the oxy-
Michael addition of the enol forms of carbonyl nucleophiles is
challenging, as strongly basic conditions should be avoided due to
the potential oligomerization of Michael acceptors and the intrinsic
reversibility of the reaction [3]. The sole enantioselective precedent
a side reaction [4f]. Inspired by these results, we then decided to
identify catalysts for selectively promoting the intramolecular oxy-
Michael addition via enol formation. In this study, we present the
asymmetric cycloetherification of enols, which are generated in situ
from enone-bearing ketones under mild conditions, using chiral
bifunctional organocatalysts bearing amino and squaramide groups
(Scheme 1b). This transformation chemo- and enantioselectively
afforded dihydropyran derivatives, which are the core structures of
building blocks for glycan synthesis [5].
employs highly enolizable
a-aryl aldehydes [2a]; however, for
promoting the formation of enol forms of ketones under nearly
neutral conditions, it is useful to introduce electron-withdrawing
groups for increasing the acidity at the a-position (Scheme 1a, A).
2. Results and discussions
However, this also accelerates competing nucleophilic additions to
the carbonyl group, providing transient saturated alcohols, which
serve as more nucleophilic oxygen nucleophiles to afford side
products (Scheme 1a, B). We have reported the organocatalytic
asymmetric cycloetherification reactions of such intermediary
saturated alcohols to synthesize optically active tetrahydropyran
derivatives [4]. In the course of the most recent study on the
cycloetherification of gem-diols, which are generated in situ from
2.1. Optimization of catalysts and reaction conditions
We began our investigations using ethyl (E)-8-(4-
methoxyphenyl)-2,8-dioxooct-6-enoate (1a) with 10 mol % of a
bifunctional organocatalyst (4ae4k, Fig. 1) [6] in CH2Cl2 at 25 ꢀC
(Table 1, entries 1e11). First, hydrogen bond donors in quinine-
derived bifunctional catalysts were screened (Table 1, entries
1e4). Thiourea catalyst 4a provided the desired product 2a in 72 %
yield with 86 % ee, along with 11 % yield of a side product 3a, which
was formed through cycloetherification of a gem-diol generated in
situ from 1a and trace amounts of water present even in dehydrated
solvents (Table 1, entry 1). The formation of 3a could not be
* Corresponding author.
** Corresponding author.
E-mail addresses: asano.keisuke.5w@kyoto-u.ac.jp (K. Asano), matsubara.seijiro.
2e@kyoto-u.ac.jp (S. Matsubara).
https://doi.org/10.1016/j.tet.2021.132381
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

R. Murata, K. Asano and S. Matsubara
Tetrahedron 97 (2021) 132381
Table 1
Optimization of conditions.a
entry
catalyst
solvent
yield of 2a (%)b
ee of 2a (%)
yield of 3a (%)b
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4i
4i
4i
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
toluene
hexane
THF
Et2O
EtOAc
MeCN
72
93
18
6
86
85
74
14
11
<1
16
19
2
Scheme 1. Asymmetric intramolecular oxy-Michael addition via formation of enol
forms of ketones.
91
92
95
89
91 (92c)
65
<1
81
45
26
62
33
51
53
86
ꢁ90
ꢁ85
ꢁ92
ꢁ93
ꢁ57
e
2
2
1
9
1 (1c)
8
10
11
12
13
14
15
16
17
18
<1
1
2
7
1
2
1
<1
ꢁ91
ꢁ89
ꢁ85
ꢁ92
ꢁ90
ꢁ92
ꢁ90
4i
4i
4i
4i
a
Reactions were run using 1a (0.15 mmol) and the catalyst (0.015 mmol) in the
solvent (0.30 mL).
b
NMR yields.
Isolated yields.
c
5e10). Other cinchona alkaloid derivatives 4ee4g resulted in
similarly efficient reactions (Table 1, entries 5e7), and quinidine-
and cinchonine-derived catalysts 4f and 4g afforded the opposite
enantiomer of 2a with high enantioselectivities. The electronic
properties of the squaramide groups of quinidine-derived catalysts
were also altered, and more electron-rich catalysts proved to be
more enantioselective while maintaining high yields of 2a (Table 1,
entries 6, 8, and 9). In contrast, catalyst 4j, which has a cyclo-
hexanediamine framework, afforded 2a in a lower yield and
enantioselectivity along with a higher amount of 3a (Table 1, entry
10). Thus, the efficiency of the current catalytic system is attributed
not only to the functionality of the squaramide group but also to the
chiral scaffolds of the catalysts [10]. In addition, catalyst 4k, which
has a significantly less basic nitrogen atom, did not provide 2a
(Table 1, entry 11), thus demonstrating the significance of the
bifunctionality of the catalyst containing hydrogen bond donor and
acceptor moieties. Various solvents were next investigated using 4i
as the catalyst (Table 1, entries 12e18); the use of CH2Cl2 led to
better results (Table 1, entry 9).
2.2. Mechanistic insights
To gain insights into the chemoselectivity, racemic 3a (rac-3a)
was exposed to the reaction conditions, and no dehydrated product
2a was obtained (Scheme 2). This result suggested that the for-
mation of 2a was kinetically controlled by 4i through the oxy-
Michael addition of the enol, and not through dehydration after
the formation of 3a [11].
Fig. 1. Organocatalysts.
inhibited even after the addition of various dehydrating agents (see
Table S1 in the SI for details). To solve this problem, the catalyst was
then modified. The use of squaramide [7] catalyst 4b selectively
afforded 2a in 93 % yield without the formation of 3a (Table 1, entry
2). Benzothiadiazine [8] 4c and sulfonamide [9] 4d were much less
effective (Table 1, entries 3 and 4). Next, squaramide catalysts
bearing various chiral structures were investigated (Table 1, entries
2.3. Substrate scope and gram-scale synthesis
With the optimized conditions in hand, we next explored the
substrate scope (Table 2). Not only electron-rich but also less
2

R. Murata, K. Asano and S. Matsubara
Tetrahedron 97 (2021) 132381
fluorinated dihydropyran derivative in high yield and enantiose-
lectivity (Table 2, 2h), even though the ketone of 1h was likely to be
hydrated [4f]. A bromodifluoromethyl ketone also provided the
desired product in moderate yield with high enantioselectivity
(Table 2, 2i). Such halodifluoromethyl groups give access to a wide
variety of difluoroalkylated compounds [14], which impart unique
pharmacological properties associated with fluorinated functional
groups. As another type of substrate, a 1,3-diketone yielded the
Scheme 2. Reaction of 3a.
Table 2
Substrate scope.a
electron-rich enones were tolerated under the reaction conditions,
affording the corresponding products in good yields with high
enantioselectivities (Table 2, 2ae2c). The halogen group is useful as
it can be converted to other functional groups (Table 2, 2c). An
enone bearing a 2-naphthyl group also provided the product in
high yield with good enantioselectivity (Table 2, 2d). An aliphatic
enone also yielded the product in moderate yield with good
corresponding product with moderate enantioselectivity, albeit in a
low yield (Table 2, 2j). Furthermore, the gram-scale synthesis of 2a
was carried out (Scheme 3). The reaction proceeded smoothly
when using 1.83 g (6.01 mmol) of 1a under the optimized condi-
tions, and 1.75 g (5.75 mmol, 96%) of 2a was obtained with 92 % ee.
enantioselectivity after 24 h (Table 2, 2e). In addition, an a,b-un-
saturated thioester, which is useful for further transformations
because of its higher oxidation state [12,13], afforded the desired
product in moderate yield and enantioselectivity after 24 h (Table 2,
2f), while an
a,b-unsaturated ester failed to furnish the product
even at higher temperatures and after longer reaction times
(Table 2, 2g). We also investigated the effect of substituents (R2) on
the ketones. A trifluoromethyl group-bearing ketone formed a
Scheme 3. Gram-scale synthesis of 2a.
3

R. Murata, K. Asano and S. Matsubara
Tetrahedron 97 (2021) 132381
The absolute configuration of 2h was determined by comparing the
optical rotation with the literature value [4f], and the configura-
tions of all other products 2 were assigned analogously.
light (254 nm) and/or such as an aqueous alkaline KMnO4 solution
followed by heating.
Flash column chromatography was carried out using Kanto
Chemical silica gel (spherical, 40e50 mm). Preparative recycling gel
permeation chromatography (GPC) was performed with LC-9160II
NEXT equipped with JAIGEL-1H column. Unless otherwise noted,
commercially available reagents were used without purification.
2.4. Transformations of the product
The utility of the dihydropyran derivatives was demonstrated by
the transformation of the products. In the presence of N-bromo-
succinimide in an aqueous medium, difunctionalization of the
unsaturated bond of 2a occurred efficiently to furnish bromohydrin
5 bearing a structure analogous to that of sialic acids, without
erosion of the enantiomeric purity (Scheme 4).
4.2. Experimental procedure
General procedure for asymmetric synthesis of dihydropyrans
2. Substrate 1 (0.15 mmol), CH2Cl2 (0.30 mL), and catalyst 4i
(7.9 mg, 0.015 mmol) were sequentially added to a 10-mL vial with
a screw cap. The mixture was stirred in an oil bath maintained at
25 ꢀC for 3 h. The reaction mixture was subsequently diluted with
EtOAc, passed through a short silica gel pad to remove 4i, and
concentrated in vacuo. Purification of the crude product by flash
silica gel column chromatography using hexane/EtOAc (v/
v ¼ 10:1e3:1) as an eluent afforded the corresponding dihy-
dropyran 2.
3. Conclusions
In conclusion, asymmetric cycloetherification via intra-
molecular oxy-Michael addition of enols, which are generated in
situ from enone-bearing ketones, was developed using chiral
bifunctional organocatalysts bearing amino and squaramide
groups. This transformation afforded dihydropyran derivatives,
that is artificial glycals, with high chemo- and enantioselectivities.
The product was also transformed through difunctionalization by
taking advantage of the presence of an unsaturated bond moiety.
Further studies to expand the scope of this methodology and its
application to the asymmetric synthesis of bioactive glycans are
underway in our laboratory.
Racemic dihydropyrans
2 were prepared using 1-(3,5-
bis(trifluoromethyl)phenyl)-3-(2-(dimethylamino)ethyl)thiourea
(4l) as a catalyst. The synthesis was carried out in an oil bath
maintained at 50 ꢀC for 24 h (10e60 % yields).
Procedure for bromohydroxylation of 2a. [15] A solution of 2a
(0.030 g, 0.10 mmol, 92 % ee) and NBS (20 mg, 0.11 mmol) in MeCN/
H2O (v/v ¼ 5:2, 0.66 mL) was stirred at ambient temperature for 2 h.
The mixture was dried over Na2SO4 and concentrated in vacuo.
Purification by flash silica gel column chromatography using hex-
ane/EtOAc (v/v ¼ 5:1) as an eluent gave bromohydrin 5.
4. Experimental section
4.1. Instrumentation and chemicals
1H and 13C Nuclear magnetic resonance spectra were taken on a
Varian UNITY INOVA 500 (1H, 500 MHz; 13C, 125.7 MHz) spec-
trometer using tetramethylsilane as an internal standard for 1H
4.3. Characterization data of products
Ethyl 2-(2-(4-methoxyphenyl)-2-oxoethyl)-3,4-dihydro-2H-
pyran-6-carboxylate (2a). Yield: 92 % (42 mg), 93 % ee, yellow oil,
NMR (
d
¼ 0 ppm) and CDCl3 as an internal standard for 13C NMR
¼ 77.0 ppm). When a13C NMR spectrum was measured using
yield of 3a: 1 %. [
a
]
18 þ14.8 (c 1.15, CH2Cl2). 1H NMR (CDCl3)
d 7.96
D
(
d
(d, J ¼ 8.5 Hz, 2H), 6.94 (d, J ¼ 8.5 Hz, 2H), 6.10 (dd, J ¼ 4.0, 4.0 Hz,
1H), 4.51 (m, 1H), 4.23 (q, J ¼ 7.0 Hz, 2H), 3.88 (s, 3H), 3.55 (dd,
J ¼ 16.5, 4.5 Hz, 1H), 3.17 (dd, J ¼ 16.5, 8.0 Hz, 1H), 2.30 (m, 1H), 2.20
(m, 1H), 2.10 (m, 1H), 1.61 (m, 1H), 1.29 (t, J ¼ 7.0 Hz, 3H). 13C NMR
DMSO-d6 as a solvent, DMSO-d6 was used as an internal standard
(
C6D6 as
(
shift, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
quint ¼ quintet, sext ¼ sextet, sept ¼ septet, br ¼ broad,
m ¼ multiplet), coupling constants (Hz), integration. 19F NMR
spectra were measured on a Varian Mercury 200 (19F, 188 MHz)
spectrometer with hexafluorobenzene as an internal standard
d
¼ 39.52 ppm). When a13C NMR spectrum was measured using
a solvent, C6D6 was used as an internal standard
d
¼ 128.06 ppm). 1H NMR data are reported as follows: chemical
(CDCl3)
d 195.9, 163.7, 162.9, 144.2, 130.5, 130.0, 113.8, 111.2, 73.0,
61.0, 55.5, 43.3, 26.5, 20.5, 14.2. TLC: Rf 0.20 (hexane/EtOAc ¼ 3:1).
IR (neat): 2935, 1736, 1679, 1654, 1601, 1576, 1521, 1267, 1173, 1105,
1029, 830, 748 cmꢁ1. HRMS Calcd for C17H20O5Na: [MþNa]þ,
327.1203. Found m/z 327.1204. HPLC (Daicel Chiralpak IA, hexane/i-
PrOH ¼ 96/4, flow rate ¼ 2.0 mL/min,
l
¼ 254 nm, 30 ꢀC):
(
d
¼ 0 ppm). Mass spectra were recorded on a SHIMADZU GCMS-
tminor ¼ 13.1 min, tmajor ¼ 15.7 min.
QP2010 Plus (EI) and a Thermo Scientific Exactive (ESI, APCI)
spectrometers. High performance liquid chromatography (HPLC)
was performed with a SHIMADZU Prominence. Infrared (IR) spectra
were determined on a SHIMADZU IR Affinity-1 spectrometer.
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 Rigaku XtaLAB mini diffractometer equipped with a CCD
detector. TLC analyses were performed by means of Merck Kieselgel
60 F254 (0.25 mm) Plates. Visualization was accomplished with UV
Ethyl 2-hydroxy-6-(2-(4-methoxyphenyl)-2-oxoethyl)tetra-
hydro-2H-pyran-2-carboxylate (3a). The diastereomers and un-
identified products could not be separated. Diastereomer mixture:
yield: 1 % (4.8 mg), ca.1:1 dr, orange oil. 1H NMR (CDCl3)
d 7.92e7.88
(m, 4H), 6.95e6.90 (m, 4H), 4.64e4.59 (m, 2H), 4.28e4.18 (m, 4H),
3.83 (s, 3H), 3.83 (s, 3H), 3.58e3.52 (m, 2H), 3.18e3.10 (m, 2H),
2.46e2.23 (m, 8H), 1.87e1.79 (m, 2H), 1.72e1.59 (m, 2H), 1.58e1.46
(m, 2H), 1.28e1.23 (m, 6H). 13C NMR (CDCl3)
d194.7 (2C), 167.9 (2C),
163.3 (2C), 130.7, 130. 5, 130.4, 130.3, 113.8, 113.7, 86.2, 86.1, 75.1,
75.0, 62.3 (2C), 55.4, 55.3, 42.6, 42.4, 31.9 (2C), 26.2, 26.1, 21.7, 21.6,
14.0 (2C). TLC: Rf 0.20 (hexane/EtOAc ¼ 1:1). IR (neat): 3540, 2936,
2842, 1788, 1671, 1599, 1508, 1466, 1432, 908, 856, 729 cmꢁ1. HRMS
Calcd for C17H22O6Na: [MþNa]þ, 345.1309. Found m/z 345.1310.
Ethyl
2-(2-oxo-2-phenylethyl)-3,4-dihydro-2H-pyran-6-
carboxylate (2b). Yield: 74 % (31 mg), 91 % ee, colorless oil, yield
of 3b: <1 %. [
a
]
18 ꢁ 1.81 (c 1.16, CH2Cl2). 1H NMR (CDCl3)
d 7.98 (d,
D
J ¼ 7.5 Hz, 2H), 7.58 (t, J ¼ 7.0 Hz, 1H), 7.48 (dd, J ¼ 7.5, 7.0 Hz, 2H),
Scheme 4. Bromohydroxylation of 2a.
6.11 (dd, J ¼ 4.0, 4.0 Hz, 1H), 4.54 (m, 1H), 4.23 (q, J ¼ 7.0 Hz, 2H),
4

R. Murata, K. Asano and S. Matsubara
Tetrahedron 97 (2021) 132381
3.61 (dd, J ¼ 17.0, 4.5 Hz, 1H), 3.23 (dd, J ¼ 17.0, 8.0 Hz, 1H), 2.34 (m,
1H), 2.20 (m, 1H), 2.12 (m, 1H), 1.62 (m, 1H), 1.29 (t, J ¼ 7.0 Hz, 3H).
yield of 3g: 17 %. [
a
]
18 ꢁ 24.3 (c 0.803, CH2Cl2). 1H NMR (C6D6)
d 7.69
D
(m, 2H), 7.11 (tt, J ¼ 7.0, 1.5 Hz, 1H), 7.02 (m, 2H), 5.15 (m, 1H), 4.34
13C NMR (CDCl3)
d 197.4,162.9,144.2,136.9,133.3,128.7,128.2,111.2,
(m, 1H), 3.02 (dd, J ¼ 17.0, 4.5 Hz, 1H), 2.42 (dd, J ¼ 17.0, 8.0 Hz, 1H),
73.0, 61.0, 43.6, 26.5, 20.5, 14.2. TLC: Rf 0.25 (hexane/EtOAc ¼ 3:1).
IR (neat): 2981, 2928, 1733, 1692, 1649, 1597, 1449, 1270, 1222, 1105,
1002, 756, 692 cmꢁ1. HRMS Calcd for C16H18O4Na: [MþNa]þ,
297.1097. Found m/z 297.1092. HPLC (Daicel Chiralpak IA, hexane/i-
1.66e1.56 (m, 2H),1.47 (m, 1H),1.11 (m, 1H). 13C NMR (C6D6)
d 195.6,
142.6 (q, J ¼ 34.6 Hz), 136.8, 132.8, 128.3, 127.9, 120.3 (q,
J ¼ 272.3 Hz), 102.7 (q, J ¼ 3.9 Hz), 73.1, 42.9, 26.1, 18.9. 19F NMR
(C6D6)
d
90.4 (s, 3F). Mp. 51.0e52.0 ꢀC. TLC: Rf 0.40 (hexane/
PrOH ¼ 90/10, flow rate ¼ 2.0 mL/min,
l
¼ 230 nm, 30 ꢀC):
EtOAc ¼ 3:1). IR (KBr): 2925, 1701, 1690, 1680, 1653, 1560, 1508,
tminor ¼ 4.1 min, tmajor ¼ 4.9 min.
1457, 1437, 1420, 1318, 1183, 1120, 1090, 947 cmꢁ1. HRMS Calcd for
Ethyl 2-(2-(4-bromophenyl)-2-oxoethyl)-3,4-dihydro-2H-py-
ran-6-carboxylate (2c). Yield: 78 % (41 mg), 85 % ee, white solid,
C
14H13F3O2Na: [MþNa]þ, 293.0760. Found: m/z 293.0759. HPLC
(Daicel Chiralpak IA, hexane/i-PrOH ¼ 99/1, flow rate ¼ 1.0 mL/min,
yield of 3c: <1 %. [
a
]
18 þ5.29 (c 1.21, CH2Cl2). 1H NMR (CDCl3)
d
7.85
l
¼ 225 nm, 30 ꢀC): tminor ¼ 6.7 min, tmajor ¼ 8.7 min.
D
(d, J ¼ 9.0 Hz, 2H), 7.62 (d, J ¼ 9.0 Hz, 2H), 6.11 (m, 1H), 4.51 (m, 1H),
4.22 (q, J ¼ 7.0 Hz, 2H), 3.55 (dd, J ¼ 17.0, 5.0 Hz, 1H), 3.16 (dd,
J ¼ 17.0, 8.0 Hz, 1H), 2.32 (m, 1H), 2.20 (m, 1H), 2.09 (m, 1H), 1.60 (m,
2-(6-(Bromodifluoromethyl)-3,4-dihydro-2H-pyran-2-yl)-1-
phenylethan-1-one (2i). Yield: 33 % (16 mg), 88 % ee, white solid,
yield of 3h: 22 %. [
18
a]
ꢁ 5.46 (c 0.513, CH2Cl2). 1H NMR (CDCl3)
D
1H), 1.29 (t, J ¼ 7.0 Hz, 3H). 13C NMR (CDCl3)
d
196.5, 162.8, 144.4,
d
7.99 (d, J ¼ 8.5 Hz, 2H), 7.59 (tt, J ¼ 7.0, 1.5 Hz, 1H), 7.48 (dd, J ¼ 8.5,
135.6, 132.0, 129.7, 128.6, 111.2, 72.8, 61.0, 43.6, 26.5, 20.5, 14.2. Mp.
59.5e60.5 ꢀC. TLC: Rf 0.25 (hexane/EtOAc ¼ 3:1). IR (KBr): 1722,
1689, 1641, 1585, 1459, 1398, 1264, 1220, 1125, 1093, 1071, 996,
962 cmꢁ1. HRMS Calcd for C16H17BrO4Na: [MþNa]þ, 375.0202.
Found m/z 375.0202. HPLC (Daicel Chiralpak IA, hexane/i-
7.0 Hz, 2H), 5.43 (m, 1H), 4.64 (m, 1H), 3.57 (dd, J ¼ 17.0, 5.5 Hz, 1H),
3.19 (dd, J ¼ 17.0, 7.5 Hz, 1H), 2.26 (m, 1H), 2.20e2.09 (m, 2H), 1.69
(m, 1H). 13C NMR (CDCl3)
d
197.1, 147.5 (t, J ¼ 38.7 Hz), 136.8, 133.4,
128.7,128.2,114.1 (t, J ¼ 452 Hz),100.4 (t, J ¼ 7.1 Hz), 73.4, 43.2, 26.6,
19.3. 19F NMR (CDCl3) 107.5 (s, 1F), 107.4 (s, 1F). Mp. 64.0e65.0 ꢀC.
d
PrOH ¼ 98/2, flow rate ¼ 2.0 mL/min,
l
¼ 230 nm, 30 ꢀC):
TLC: Rf 0.50 (hexane/EtOAc ¼ 3:1). IR (KBr): 1689, 1680, 1451, 1272,
1215, 1153, 1085, 880, 788 cmꢁ1. HRMS Calcd for C14H13BrF2O2Na:
[MþNa]þ, 352.9959. Found: m/z 352.9959. HPLC (Daicel Chiralpak
tminor ¼ 15.4 min, tmajor ¼ 23.2 min.
Ethyl
2-(2-(naphthalen-2-yl)-2-oxoethyl)-3,4-dihydro-2H-
pyran-6-carboxylate (2d). Yield: 87 % (42 mg), 86 % ee, colorless oil,
IA, hexane/i-PrOH ¼ 98/2, flow rate ¼ 2.0 mL/min,
30 ꢀC): tminor ¼ 3.2 min, tmajor ¼ 3.8 min.
l
¼ 230 nm,
yield of 3d: <1 %. [
a
]
18 þ29.1 (c 1.19, CH2Cl2). 1H NMR (CDCl3)
d 8.52
D
(s, 1H), 8.04 (d, J ¼ 8.5 Hz, 1H), 7.97 (d, J ¼ 8.0 Hz, 1H), 7.91e7.87 (m,
2H), 7.63e7.55 (m, 2H), 6.13 (m, 1H), 4.60 (m, 1H), 4.22 (q, J ¼ 7.0 Hz,
2H), 3.75 (dd, J ¼ 17.0, 4.5 Hz,1H), 3.35 (dd, J ¼ 17.0, 8.5 Hz,1H), 2.33
2-(5-Benzoyl-6-phenyl-3,4-dihydro-2H-pyran-2-yl)-1-
phenylethan-1-one (2j). Yield: 7 % (4.0 mg), 78 % ee, white solid.
18
[
a
]
þ40.5 (c 0.153, CH2Cl2, e36 % ee). 1H NMR (CDCl3)
d 8.03 (d,
D
(m, 1H), 2.24e2.14 (m, 2H), 1.67 (m, 1H), 1.27 (t, J ¼ 7.0 Hz, 3H). 13
C
J ¼ 7.0 Hz, 2H), 7.60 (t, J ¼ 7.0 Hz, 1H), 7.55 (d, J ¼ 7.5 Hz, 2H), 7.50
(dd, J ¼ 7.0, 7.0 Hz, 2H), 7.18 (t, J ¼ 7.5 Hz, 1H), 7.16 (d, J ¼ 7.0 Hz, 2H),
7.08 (dd, J ¼ 7.5, 7.5 Hz, 2H), 7.03 (t, J ¼ 7.0 Hz, 1H), 6.98 (dd, J ¼ 7.0,
7.0 Hz, 2H), 4.85 (m, 1H), 3.67 (dd, J ¼ 17.0, 7.5 Hz, 1H), 3.23 (dd,
J ¼ 17.0, 5.5 Hz, 1H), 2.99 (ddd, J ¼ 17.5, 6.0, 2.5 Hz, 1H), 2.51 (ddd,
J ¼ 17.5, 11.0, 7.0 Hz, 1H), 2.27 (dddd, J ¼ 13.5, 7.0, 2.5, 2.0 Hz, 1H),
NMR (CDCl3)
d 197.3, 162.9, 144.2, 135.7, 134.2, 132.5, 130.2, 129.7,
128.6, 128.5, 127.8, 126.8, 123.7, 111.2, 73.0, 61.0, 43.7, 26.5, 20.5,
14.2. TLC: Rf 0.25 (hexane/EtOAc ¼ 3:1). IR (neat): 2927, 1735, 1682,
1648, 1270, 1218, 1106, 748 cmꢁ1. HRMS Calcd for C20H20O4Na:
[MþNa]þ, 347.1254. Found m/z 347.1253. HPLC (Daicel Chiralpak IA,
hexane/i-PrOH ¼ 98/2, flow rate ¼ 2.0 mL/min,
tminor ¼ 17.2 min, tmajor ¼ 23.7 min.
l
¼ 230 nm, 30 ꢀC):
1.84 (m, 1H). 13C NMR (CDCl3)
d 198.7, 197.3, 160.9, 139.0, 136.9,
135.2, 133.4, 131.4, 129.5, 129.4, 129.3, 128.7, 128.2, 127.6 (2C), 112.1,
73.6, 43.5, 27.3, 23.8. Mp. 71.0e72.0 ꢀC. TLC: Rf 0.30 (hexane/
EtOAc ¼ 3:1). IR (KBr): 1685, 1645, 1623, 1597, 1448, 1351, 1288,
1163, 693 cmꢁ1. HRMS Calcd for C26H22O3Na: [MþNa]þ, 405.1461.
Found m/z 405.1452. HPLC (Daicel Chiralpak IA, hexane/i-
Ethyl
2-(2-oxo-4-phenylbutyl)-3,4-dihydro-2H-pyran-6-
carboxylate (2e). Yield: 60 % (27 mg), 78 % ee, colorless oil, yield
of 3e: <1 %. [
a
]
18 ꢁ 21.9 (c 0.913, CH2Cl2). 1H NMR (CDCl3)
d 7.27 (m,
D
2H), 7.19e7.17 (m, 3H), 6.06 (dd, J ¼ 4.0, 4.0 Hz, 1H), 4.31 (m, 1H),
4.22 (q, J ¼ 7.0 Hz, 2H), 2.98e2.77 (m, 5H), 2.60 (dd, J ¼ 16.0, 7.0 Hz,
1H), 2.27 (m, 1H), 2.14 (m, 1H), 1.92 (m, 1H), 1.53 (m, 1H), 1.28 (t,
PrOH ¼ 98/2, flow rate ¼ 2.0 mL/min,
l
¼ 254 nm, 30 ꢀC):
tminor ¼ 16.9 min, tmajor ¼ 18.8 min.
J ¼ 7.0 Hz, 3H). 13C NMR (CDCl3)
d
207.5, 162.8, 144.0, 140.9, 128.5,
Ethyl
3-bromo-2-hydroxy-6-(2-(4-methoxyphenyl)-2-
128.3, 126.1, 110.9, 72.5, 61.0, 47.8, 45.2, 29.5, 26.4, 20.4, 14.2. TLC: Rf
0.25 (hexane/EtOAc ¼ 3:1). IR (neat): 2928, 1722, 1648, 1372, 1300,
1270, 1220, 1105, 751, 700 cmꢁ1. HRMS Calcd for C18H22O4Na:
[MþNa]þ, 325.1410. Found m/z 325.1407. HPLC (Daicel Chiralpak IB,
oxoethyl)tetrahydro-2H-pyran-2-carboxylate. Yield: 99
(40 mg), 2.7:1 dr. Major diastereomer (5): 90 % ee, yellow oil.
%
[
a
]
18 þ19.1 (c 1.10, CH2Cl2). 1H NMR (CDCl3)
d
7.96 (d, J ¼ 9.0 Hz, 2H),
D
6.93 (d, J ¼ 9.0 Hz, 2H), 4.75 (dddd, J ¼ 12.0, 6.0, 6.0, 2.5 Hz,1H), 4.37
(dd, J ¼ 3.0, 3.0 Hz, 1H), 4.31e4.21 (m, 2H), 3.87 (s, 3H), 3.48 (dd,
J ¼ 17.5, 6.0 Hz, 1H), 3.06 (dd, J ¼ 17.5, 6.0 Hz, 1H), 2.65 (m, 1H), 2.06
hexane/i-PrOH ¼ 98/2, flow rate ¼ 2.0 mL/min,
tmajor ¼ 18.1 min, tminor ¼ 21.8 min.
l
¼ 254 nm, 30 ꢀC):
Ethyl 2-(2-oxo-2-(phenylthio)ethyl)-3,4-dihydro-2H-pyran-
6-carboxylate (2f). Yield: 62 % (31 mg), 68 % ee, yellow oil, yield of
(m, 1H), 1.93 (m, 1H), 1.68 (m, 1H), 1.30 (dd, J ¼ 7.0, 7.0 Hz, 3H). 13
C
NMR (CDCl3) d 196.4, 168.8, 163.7, 130.6,130.5,113.7, 95.3, 68.1, 62.2,
3e: 9 %. [
a
]
18 þ81.5 (c 0.130, CH2Cl2). 1H NMR (CDCl3)
d
7.42 (m, 5H),
55.5, 49.1, 44.0, 27.2, 25.0, 14.0. TLC: Rf 0.40 (hexane/EtOAc ¼ 1:1).
IR (neat): 3403, 2966, 1740, 1672, 1601, 1576, 1507, 1262, 1174, 844,
749 cmꢁ1. HRMS Calcd for C17H21BrO6Na: [MþNa]þ, 423.0414.
Found m/z 423.0418. HPLC (Daicel Chiralpak IC, hexane/i-
D
6.10 (dd, J ¼ 5.0, 5.0 Hz, 1H), 4.41 (m, 1H), 4.25 (q, J ¼ 7.0 Hz, 2H),
3.21 (dd, J ¼ 16.0, 6.0 Hz, 1H), 2.89 (dd, J ¼ 16.0, 7.5 Hz, 1H),
2.30e2.18 (m, 2H), 2.04 (m, 1H), 1.67 (m, 1H), 1.31 (t, J ¼ 7.0 Hz, 3H).
13C NMR (CDCl3)
d
194.5,162.7,143.9,134.7,129.6,129.2,127.4,111.0,
PrOH ¼ 80/20, flow rate ¼ 2.0 mL/min,
l
¼ 254 nm, 30 ꢀC):
72.6, 61.1, 48.0, 26.0, 20.1, 14.2. TLC: Rf 0.40 (hexane/EtOAc ¼ 3:1). IR
(neat): 2985, 2928, 1728, 1649, 1481, 1442, 1300, 1270, 1226, 1103,
987, 751 cmꢁ1. HRMS Calcd for C16H18O4SNa: [MþNa]þ, 329.0818.
Found m/z 329.0821. HPLC (Daicel Chiralpak IC, hexane/i-
tmajor ¼ 7.0 min, tminor ¼ 21.9 min. Minor diastereomer (5′): 92 % ee,
colorless oil. [
a
]
18 þ3.46 (c 0.693, CH2Cl2). 1H NMR (CDCl3)
d 7.91 (d,
D
J ¼ 9.0 Hz, 2H), 6.91 (d, J ¼ 9.0 Hz, 2H), 4.72 (dddd, J ¼ 12.0, 7.0, 7.0,
2.5 Hz, 1H), 4.41e4.36 (m, 2H), 4.27 (br s, 1H), 4.25 (dq, J ¼ 18.0,
7.0 Hz, 1H), 3.87 (s, 3H), 3.23 (dd, J ¼ 15.5, 7.0 Hz, 1H), 2.82 (dd,
J ¼ 15.5, 7.0 Hz, 1H), 2.43 (m, 1H), 2.21 (m, 1H), 1.97 (m, 1H), 1.63 (m,
PrOH ¼ 90/10, flow rate ¼ 2.0 mL/min,
l
¼ 225 nm, 30 ꢀC):
tminor ¼ 9.8 min, tmajor ¼ 10.7 min.
(R)-1-Phenyl-2-(6-(trifluoromethyl)-3,4-dihydro-2H-pyran-
2-yl)ethan-1-one (2h). Yield: 80 % (33 mg), 92 % ee, white solid,
1H), 1.33 (dd, J ¼ 7.0, 7.0 Hz, 3H). 13C NMR (CDCl3)
d 195.7, 168.7,
163.6, 130.5, 130.1, 113.7, 95.0, 67.4, 63.2, 55.5, 48.6, 43.7, 33.1, 29.4,
5

R. Murata, K. Asano and S. Matsubara
Tetrahedron 97 (2021) 132381
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(2017) 1397;
14.0. TLC: Rf 0.55 (hexane/EtOAc ¼ 1:1). IR (neat): 3457, 2952, 1753,
1676, 1600, 1264, 1213, 1173, 1054, 916, 839, 731 cmꢁ1. HRMS Calcd
for C17H21BrO6Na: [MþNa]þ, 423.0414. Found m/z 423.0415. HPLC
(Daicel Chiralpak IA, hexane/i-PrOH ¼ 90/10, flow rate ¼ 2.0 mL/
€
(b) A. Matsumoto, K. Asano, S. Matsubara, Chem. Asian J. 14 (2019) 116;
(c) Y. Kurimoto, T. Nasu, Y. Fujii, K. Asano, S. Matsubara, Org. Lett. 21 (2019)
2156;
min,
l
¼ 254 nm, 30 ꢀC): tminor ¼ 9.3 min, tmajor ¼ 18.3 min.
(d) A. Matsumoto, K. Asano, S. Matsubara, Org. Lett. 21 (2019) 2688;
(e) Y. Wada, R. Murata, Y. Fujii, K. Asano, S. Matsubara, Org. Lett. 22 (2020)
4710;
Declaration of competing interest
(f) R. Murata, A. Matsumoto, K. Asano, S. Matsubara, Chem. Commun. 56
(2020) 12335;
(g) K. Asano, Bull. Chem. Soc. Jpn. 94 (2021) 694.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[5] (a) R.J. Ferrier, N. Prasad, J. Chem. Soc. C (1969) 570;
(b) G.D. Daves Jr., Acc. Chem. Res. 23 (1990) 201;
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(e) W. Priebe, G. Grynkiewicz, Glycoscience 1 (2001) 749;
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Acknowledgments
This work was supported financially by the Japanese Ministry of
Education, Culture, Sports, Science and Technology, Japan
(JP15H05845, JP18K14214, JP18H04258, and JP20K05491). K.A. also
acknowledges Toyo Gosei Memorial Foundation, Japan, the Sumi-
tomo Foundation, Fukuoka Naohiko Memorial Foundation, Japan,
Inoue Foundation for Science, Mizuho Foundation for the Promo-
tion of Sciences, Japan, SPIRITS 2020 of Kyoto University Keisuke
Asano reports financial support was provided by Japan Association
for Chemical Innovation. R.M. also acknowledges the Japan Society
for the Promotion of Science for Young Scientists for the fellowship
support (JP21J23149).
(g) H. Kubota, J. Lim, K.M. Depew, S.L. Schreiber, Chem. Biol. 9 (2002) 265;
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(b) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am. Chem. Soc. 127
(2005) 119;
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(c) B. Vakulya, S. Varga, A. Csampai, T. Soos, Org. Lett. 7 (2005) 1967.
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[10] Even in the presence of 3.0 equiv of water, 3a was formed only in 2%, and 2a
was obtained in 73% yield with 91% ee (see Scheme S1 in the SI for details).
[11] The enantioselectivity gradually decreased as the reaction time increased (see
Scheme S2 in the SI for details). The reaction time of 3 h was the optimal from
the viewpoints of both yield and enantioselectivity. When racemic 2a was
exposed to the reaction conditions, the hydrated product 3a was obtained,
and 2a recovered in an optically active form (see Scheme S3 in the SI for
details). These results indicate the reversibility of the oxy-Michael addition of
the enol, even under such near-neutral conditions, implying the intrinsic
difficulty of the reaction. In addition, 4i selectively catalyzed the retro-
Michael addition from one enantiomer of 2a, which is the major enan-
tiomer of the product mentioned in Table 2, leading to a gradual change in the
optical purity of 2a.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132381.
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6