Synthesis of chiral tetrahydrofurans via catalytic asymmetric [3 + 2] cycloaddition of heterosubstituted alkenes with oxiranes

Article abstract of DOI:10.1021/acs.joc.5b02524

An efficient diastereo- and enantioselective [3 + 2] cycloaddition of heterosubstituted alkenes with oxiranes via selective C-C bond cleavage of epoxides has been developed. The reaction was catalyzed by a chiral N,N′-dioxide/Ni(II) catalyst, and a variety of chiral highly substituted tetrahydrofurans were obtained in up to 99% yield, 92/8 dr, and 99% ee.

Full text of DOI:10.1021/acs.joc.5b02524

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Note
Synthesis of chiral tetrahydrofurans via catalytic asymmetric
[3+2] cycloaddition of hetero-substituted alkenes with oxiranes
Xiao Yuan, Lili Lin, Weiliang Chen, Wangbin Wu, Xiaohua Liu, and Xiaoming Feng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02524 • Publication Date (Web): 14 Jan 2016
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Synthesis of chiral tetrahydrofurans via catalytic asymmetric
[3+2] cycloaddition of hetero-substituted alkenes with oxiranes
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Xiao Yuan,† Lili Lin,*, Weiliang Chen,† Wangbin Wu,† Xiaohua Liu,†
†
,
Xiaoming Feng*,
† ‡
†
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China.
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin)
‡
Abstract. An efficient diastereo- and enantioselective [3+2] cycloaddition of hetero-substituted
alkenes with oxiranes via selective C–C bond cleavage of epoxides has been developed. The
reaction was catalyzed by a chiral N,N'-dioxide/Ni(II) catalyst, and a variety of chiral highly
substituted tetrahydrofurans were obtained in up to 99% yield, 92/8 dr and 99% ee.
Tetrahydrofurans (THFs) represent a class of common heterocyclic scaffolds and are found
in myriads of natural products and biologically active molecules.1 Thus, considerable efforts
have been devoted to developing efficient methodologies for their synthesis.2 For the
synthesis of chiral tetrahydrofurans, asymmetric [3+2] cycloadditions (Scheme 1a and 1b),3-5
cyclization of alcohols,6 oxidative cyclization of olefins,7 intramolecular Michael
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addition/Lactonization8 (Scheme 1c) and sequential Henry reaction/iodocyclization9 (Scheme
1d) have been developed. Though great progress has been achieved, other efficient methods
are still desirable. Oxiranes have obviously become interesting reagents for the past few years.
Particularly, their selective C–C bond cleavage has been proved to be an atom-economical
approach to generate carbonyl ylides.10 Up to now, chemoselective [4+3] cycloadditions of
oxiranes with nitrones,11 tandem heterocyclization/[4+1] cycloaddition of oxiranes,12
ring-opening/Friedel–Crafts alkylation13 and a range of [3+2] cycloaddition of oxiranes14 have
been achieved. Recently, we demonstrated that our chiral N,N'-dioxide/metal complexes15
could realize the asymmetric cycloaddition of oxiranes with aldehydes,16 alkynes4 and
indoles5 for the first time. So, it is reasonable to predict that chiral N,N'-dioxide/metal
complexes would be workable for the catalytic asymmetric [3+2] cycloaddition of oxiranes
with hetero-substituted alkenes, which would offer a facile way to construct chiral furan
derivatives. Herein, we described our efforts in developing an efficient chiral
N,N'-dioxide-Ni(II) catalyst system for the asymmetric [3+2] cycloaddition of
hetero-substituted alkenes with oxiranes. A variety of chiral substituted tetrahydrofurans were
obtained in up to 99% yield, 92/8 dr and 99% ee.
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Scheme 1. Methods for catalytic asymmetric synthesis of highly substituted tetrahydrofurans.
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In our initial work, the [3+2] cycloaddition of oxirane 1a and hetero-substituted alkene 2a
was employed as the model reaction to optimize the reaction conditions. We firstly examined
various N,N'-dioxides derived from -ramipril (Ra) by complexing with Ni(BF4)2•6H2O. As
L
shown in Table 1, the steric hindrance at the ortho positions of the aniline of N,N'-dioxide
ligands affected the reaction greatly (Table 1, entries 1-4). When L-RaPh was employed,
only trace amount of the desired product was obtained and the ee value was only 11% (Table
1, entry 1). In the presence of L-RaMe2 bearing methyl groups, the yield was improved to
99% and the dr was improved to 72/28 albeit with still low ee value (Table 1, entry 2). When
it came to L-RaEt2 with ethyl groups, the dr value was further improved to 80/20 and the
configuration of the product was reversed (23% ee, Table 1, entry 3). Gratifyingly, L-RaPr2
bearing i-propyl groups increased sharply the ee to 87% and the dr to 92/8 (Table 1, entry 4).
Further optimization of reaction conditions revealed that solvents affected the reaction to a
great extent. When the reaction was performed in CHCl3, the ee increased slightly to 89%, but
the dr decreased a little (90/10) (Table 1, entry 5). When the reaction was performed in
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CH2ClCH2Cl, the ee further increased to 91% with the yield and dr maintained (Table 1, entry
6). Finally, the optimal reaction conditions were established as follows: 1a:2a = 1:1.2,
L-RaPr2:Ni(BF4)2•6H2O = 1.1:1 (10 mol %), LiNTf2 (10 mol %) and 20 mg 4 Å MS in
CH2ClCH2Cl (0.5 mL) under N2 at 35 oC for 24 h.
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Table 1. Optimization of the reaction conditions
Entrya
Ligand
Solvent
Yield (%)b
drc
cis/trans
56/44
72/28
80/20
92/8
ee (%)c
cis-3ae
-11d
-17 d
23
1
2
3
4
5
6
CH2Cl2
CH2Cl2
trace
99
L-RaPh
L-RaMe2
L-RaEt2
L-RaPr2
L-RaPr2
L-RaPr2
CH2Cl2
99
CH2Cl2
99
87
CHCl3
99
90/10
90/10
89
CH2ClCH2Cl
99
91
a Unless otherwise noted, all reactions were carried out with ligand-metal (1.1:1, 10 mol %), 1a (0.10
mmol), 2a (0.12 mmol, 1.2 eq.), LiNTf2 (10 mol %) and 20 mg 4 Å MS in solvent (0.5 mL) under N2 at
35 oC for 24 h. b Isolated yield. c Determined by HPLC analysis. d “-” represents that the optical rotation
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is opposite to the others. e Determined by NOESY.
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With the optimized conditions in hand, we investigated the scope of the reaction. With
respect to oxiranes (Table 2), aromatic (R1) substituted epoxides with either
electron-withdrawing or electron-donating substitutes at para position on the phenyl ring
transformed to the corresponding products in good to excellent yields (85 to 98%) with high
dr (>90/10) and ee values (91 to 93%) (Table 2, entries 2-6). Meanwhile, when
electron-donating group was at meta or ortho position, excellent outcomes also can be
obtained (Table 2, entries 7-10). Unfortunately, the aromatic oxiranes with
electron-withdrawing groups at meta or ortho position (1r, 1s) exhibited much lower
reactivity. We got only 71% and 66% yields even if we added 2 eq. 2a and prolonged the
reaction time to 48 h (Table 2, entries 18-19). What’s more, the desired products were very
difficult to separate from the starting materials.17 These problems may be due to the electronic
effects of the aryl group substituents. In addition, ring-fused epoxides 1k, 1l and
heteroaromatic epoxides 1m, 1n were also well tolerated, delivering the corresponding
products in 87 to 99% yields with 83/17 to 91/9 dr and 88 to 91% ee (Table 2, entries 11-14).
Remarkably, unsaturated oxirane 1o could also undergo this reaction smoothly, affording
product 3o in 98% yield with 92/8 dr and 90% ee (Table 2, entry 15). Moreover, we also
varied the substituent R2 on the acyl group, 1p, 1q were transformed to 3p, 3q in quantitative
yields with 90/10 dr and 88 to 92% ee (Table 2, entries 16-17).
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Table 2 Substrate scope of oxiranes
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Entrya
R1
R2
Yield (%)b
drc
cis/trans
90/10
91/9
ee (%)c
cis
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1
2
C6H5
C6H5
C6H5
99 (3a)
93 (3b)
91
1a
1b
93
4-FC6H4
3
C6H5
C6H5
C6H5
C6H5
C6H5
1c
1d
1e
1f
93 (3c)
85 (3d)
98 (3e)
97 (3f)
99 (3g)
90/10
90/10
92/8
91
91
93
93
90
4-ClC6H4
4-BrC6H4
4e,f
5
4-MeC6H4
4-MeOC6H4
6
91/9
7
1g
90/10
3-MeC6H4
3-MeOC6H4
3-PhOC6H4
8
9
C6H5
C6H5
98 (3h)
99 (3i)
90/10
91/9
88
90
1h
1i
10
C6H5
1j
93 (3j)
89/11
89
2-MeOC6H4
11
12
13
14
1-Naphthyl
2-Naphthyl
3-Furyl
C6H5
C6H5
C6H5
C6H5
99 (3k)
98 (3l)
83/17
91/9
91/9
91/9
88
90
91
91
1k
1l
87 (3m)
96 (3n)
1m
1n
3-Thienyl
15
16e,f
17
C6H5
4-MeC6H4
4-BrC6H4
C6H5
1o
1p
1q
1r
1s
98 (3o)
99 (3p)
99 (3q)
71 (3r)d
66 (3s)d
92/8
90
92
88
86
88
90/10
90/10
88/12
88/12
C6H5
C6H5
18e,f
19 e,f
3-FC6H4
2-FC6H4
C6H5
a Unless otherwise noted, all reactions were carried out with L-RaPr2-Ni(BF4)2•6H2O (10 mol %, 1.1 :
1), 1a (0.10 mmol), 2a (0.12 mmol, 1.2 eq.), LiNTf2 (10 mol %) and 20 mg 4 Å MS in CH2ClCH2Cl
(0.5 mL) under N2 at 35 oC for 24 h. b Isolated yield. c Determined by chiral HPLC analysis. d
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Determined by 1H NMR (CH2Br2 as a standard). e 2 eq. 2a was added. f The reaction time was
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Subsequently, we explored the scope of hetero-substituted alkenes (Figure 1). It was found
that large steric hindrance on vinyl ether was beneficial for the enantioselectivity but not for
diastereoselectivity. From 2b to 2e, enantioselectivity increased little by little as the steric
hindrance on hetero-substituted alkenes become larger. When 2e was employed, 99% ee of
3ae was obtained while the dr decreased sharply to 73/27. Besides, Cyclohexyl vinyl ether 2g
also proceeded the reaction well, giving 3ag in 97% yield with 90/10 dr and 96% ee. Cyclic
vinyl ether 1,4-dioxene 2f was also tested, generating 3af with three stereogenic centers in
90% yield, 89/11 dr, and 90% ee. Furthermore, the absolute configuration of 3af was
determined to be (4aR,7S,7aR) by X-ray analysis.18 Finally, allyl vinyl ether 2h and vinyl
sulfide 2i were examined, generating 3ah in 97% yield, 86/14 dr, 89% ee and 3ai in 99%
yield, 80/20 dr, 86% ee.
Figure 1. Substrate scope of hetero-substituted alkenes a
COPh
COPh
L-RaPr2-Ni(BF4
)2•6H2O
(1.1:1, 10 mo l%)
O
Ph
O
COPh
COPh
*
R3
*
X
Ph
R3
LiNTf2(10 mol %)
X
20 mg 4 Å MS, CH2ClCH2Cl
COPh
1a
3ab-3ai
2b-2i
COPh
COPh
COPh
O
O
O
COPh
O
COPh
O
O
iBu
3ad,d 92% yieldb
83/17 dr,c 93% eec
,
d 88% yieldb
3ac, 99% yieldb
91/9 dr,c 90% eec
COPh
3ab
86/14 dr c 89%
c
,
ee
COPh
COPh
COPh
O
O
O
O
tBu
O
, 93% yieldb
3af,d,f 90% yieldb
89/11 dr,c 90% eec
3ae
(4a ,7 ,7a )-
R
S
R
3af
73/27 dr c 99%
c
,
ee
COPh
COPh
COPh
COPh
COPh
O
COPh
O
O
O
O
S
3ag,d 97% yieldb
d,e 97% yieldb
3ah
, 99% yieldb
,
3ai
80/20 dr c 86%
c
90/10 dr c 96%
c
c
,
ee
86/14 dr c 89%
, ee
,
ee
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a Unless otherwise noted, all reactions were carried out with L-RaPr2-metal (1.1:1, 10 mol %), 1a (0.10
mmol), 2a (0.12 mmol, 1.2 eq.), LiNTf2 (10 mol %) and 20 mg 4 Å MS in CH2ClCH2Cl (0.5 mL)
under N2 at 35 oC for 24 h. b Isolated yield. c Determined by HPLC analysis. d 2 eq. 2a was added. e The
f
reaction time was prolonged to 48 h. The absolute configuration was determined to be (4aR,7S,7aR)
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by X-ray crystallographic analysis.
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To show the prospect of the methodology, a gram-scale synthesis of 3a was carried out. As
shown in Scheme 2, 3.0 mmol of oxirane 1a reacted smoothly with 3.6 mmol of
hetero-substituted alkenes 2a, affording 1.28 g of the corresponding product 3a (99% yield)
with 90/10 dr and 90% ee.
Scheme 2. Gram-scale synthesis of 3a.
Based on our previous study15 and the absolute configuration of 3af by X-ray analysis,18
a
possible transition-state was proposed in Figure 2. The prepared catalyst coordinates with the
two carbonyl groups of oxirane in a bidentate fashion, which leads to the formation of the
carbonyl ylide, forming a rigid octahedral complex. The 2,6-diisopropylaniline group
underneath the ligand shields the Si face of the carbonyl ylide. Therefore hetero-substituted
alkene attacks the Re face of the carbonyl ylide giving (4aR,7S,7aR)-configured 3af.
Figure 2. Proposed transition-state model and the absolute configuration of 3af.
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In summary, we have demonstrated a catalytic asymmetric [3+2] cycloaddition of
hetero-substituted alkenes with oxiranes via C–C bond cleavage of epoxides in the presence
of
a chiral N,N'-dioxide-Ni(II) complex. A variety of chiral highly substituted
tetrahydrofurans were furnished in good to excellent yields (up to 99%) with good to
excellent enantioselectivities and diastereoselectivities (up to 92/8 dr and 99% ee) under mild
reaction conditions.
EXPERIMENTAL SECTION
General Remarks. 1H NMR spectra were recorded on commercial instruments (400 MHz). Chemical
shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard
(CDCl3, δ = 7.26). Spectra are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), integration and assignment. 13
C
NMR spectra were collected on commercial instruments (100 MHz) with complete proton decoupling.
Chemical shifts are reported in ppm from the tetramethylsilane with the solvent resonance as internal
standard (CDCl3, δ = 77.0). The enantiomeric excesses (ee) were determined by HPLC analysis on
commercial chiral columns. Optical rotations were reported as follows: [a]T (c = g/100 mL, in
D
solvent). HRMS was recorded on a commercial apparatus (ESI Source). All reagents and solvents were
obtained from commercial suppliers and used without further purification except as indicated below.
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All catalytic reactions were run in dried glassware. Solvent was distilled over CaH2.
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General procedure for substrates.
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AcOH (10 mol %) and piperidine (10 mol %) were added to the solution of
1,3-Diphenyl-1,3-propanedione (5.6 g) and benzaldehyde (2.5 mL) in toluene (25 mL). After addition,
the mixture was heated to reflux for 4 h (separate the produced water from reaction system). Then the
solvent was removed under reduced pressure. The resulting residue was purified by silica gel column
chromatography eluting with PE/EA = 10:1. The white solid, crude unsaturated diketone, was obtained
in 86% yield. To a well-stirred solution of unsaturated diketone (22 mmol) in 1,2-dichloroethane (DCE,
15 mL) which was cooled in an ice bath, t-BuOOH (in DCE, 21 mL) and DBU (4 mL) were added.
Commercial t-BuOOH (70% in H2O, 13 mL) should be extracted with DCE (20 mL). The reaction
mixture was further stirred for 40 min. After removing the solvent DCE, the crude product 1 was
purified by silica gel column chromatography eluting with PE/EA = 10:1 and recrystallized in ethyl
acetate. Washed by Petroleum ether and dried under vacuum, the pure product was obtained. Substrate
2 was obtained from commercial suppliers.
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General procedure for chiral N,N'-dioxide preparation.
The N,N'-dioxides were prepared according to the methods reported in the literature.19
General procedure for the catalytic [3+2] cycloaddition.
A dry reaction tube was charged with L-RaPr2 (11 mol %), Ni(BF4)2•6H2O (10 mol %), LiNTf2 (10
mol %) and 20 mg 4 Å MS. CH2ClCH2Cl (0.5 mL) was added, and the mixture was stirred at 35 oC for
0.5 h until Ni(BF4)2•6H2O is solved entirely. Then, the hetero-substituted alkenes 2 (1.2 eq. or 2.0 eq.)
o
and oxiranes 1 (0.1 mmol) were added to the reaction mixture. After being stirred at 35 C for 24 h or
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48 h, the crude reaction mixture was purified by flash chromatography on silica gel (PE/EA = 10/1) to
afford the desired product.
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(3-butoxy-5-phenyltetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3a). Yield 42.7 mg, 99%; green
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viscous liquid; 91% ee, 90/10 dr; [α]13 = −137.9 (c = 0.75 in CH2Cl2); HPLC (Daicel chiralcel IE,
D
n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 7.257, t2 = 8.184, t3 =
1
10.029, t4 = 11.421; H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.7 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H),
7.54 – 7.47 (m, 3H), 7.46 – 7.34 (m, 5H), 7.33 – 7.26 (m, 3H), 5.33 (dd, J = 6.4, 3.4 Hz, 1H), 4.88 (t, J
= 8.0 Hz, 1H), 3.48 – 3.40 (m, 1H), 3.33 – 3.23 (m, 1H), 2.89 – 2.77 (m, 1H), 2.28 – 2.18 (m, 1H), 1.32
– 1.24 (m, 2H), 1.09 – 0.98 (m, 2H), 0.69 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 196.3,
194.8, 141.1, 136.7, 134.0, 133.3, 132.7, 130.2, 129.9, 128.5, 128.4, 128.0, 127.9, 126.7, 98.8, 83.7,
+
81.2, 69.9, 40.7, 31.5, 19.0, 13.7. HRMS (ESI-TOF): calcd for C28H28NaO4 ([M+Na+]) 451.1880,
found 451.1881.
(3-butoxy-5-(4-fluorophenyl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3b). Yield 41.8 mg, 93%;
green viscous liquid; 93% ee, 91/9 dr; [α]13D = −129.5 (c = 0.70 in CH2Cl2); HPLC (Daicel chiralcel IE,
n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 6.977, t2 = 7.816, t3 =
1
8.660, t4 = 11.512.; H NMR (400 MHz, CDCl3) δ 8.08 – 8.00 (m, 4H), 7.53 – 7.45 (m, 3H), 7.45 –
7.41 (m, 1H), 7.41 – 7.35 (m, 2H), 7.33 – 7.27 (m, 2H), 7.12 – 7.01 (m, 2H), 5.32 (dd, J = 6.0, 3.2 Hz,
1H), 4.90 (t, J = 7.6 Hz, 1H), 3.46 – 3.40 (m, 1H), 3.28 – 3.21 (m, 1H), 2.86 – 2.77 (m, 1H), 2.22 –
2.15 (m, 1H), 1.30 – 1.22 (m, 2H), 1.08 – 0.96 (m, 2H), 0.69 (t, J = 7.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ = 195.9, 194.7, 162.4 (d, J = 244 Hz), 137.1 (d, J = 3Hz), 136.5, 134.0, 133.4, 132.8, 130.2,
129.7, 128.5 (d, J = 8Hz), 128.4, 128.1, 115.3 (d, J = 22Hz), 98.8, 83.6, 80.7, 69.9, 40.5, 31.4, 19.0,
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13.6. HRMS (ESI-TOF): calcd for C28H27FNaO4+ ([M+Na+]) 469.1786, found 469.1799.
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(3-butoxy-5-(4-chlorophenyl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3c). Yield 43.1 mg, 93%;
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green viscous liquid; 91% ee, 90/10 dr; [α]13 = −112.4 (c = 0.86 in CH2Cl2); HPLC (Daicel chiralcel
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IE, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 6.787, t2 = 7.905,
t3 = 10.124, t4 = 13.239.; 1H NMR (400 MHz, CDCl3) δ 8.06 – 7.96 (m, 4H), 7.53 – 7.43 (m, 4H), 7.41
– 7.35 (m, 2H), 7.35 – 7.28 (m, 4H), 5.31 (dd, J = 6.0, 2.8 Hz, 1H), 4.91 (t, J = 7.6 Hz, 1H), 3.44 – 3.88
(m, 1H), 3.26 – 3.20 (m, 1H), 2.86 – 2.77 (m, 1H), 2.21 – 2.14 (m, 1H), 1.28 – 1.21 (m, 2H), 1.04 –
0.97 (m, 2H), 0.68 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 195.7, 194.6, 140.0, 136.5,
134.0, 133.5, 133.5, 132.8, 130.2, 129.7, 128.6, 128.4, 128.1, 128.1, 98.9, 83.6, 80.6, 69.8, 40.4, 31.4,
+
19.0, 13.6. HRMS (ESI-TOF): calcd for C28H2734.9689ClNaO4 ([M+Na+]) 485.1491, found 485.1493,
C28H2736.9659ClNaO4+ ([M+Na+]) 487.1461, found 487.1491.
(5-(4-bromophenyl)-3-butoxytetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3d). Yield 42.9 mg, 85%;
green viscous liquid; 91% ee, 90/10 dr; [α]13D = −94.5 (c = 0.86 in CH2Cl2); HPLC (Daicel chiralcel ID,
n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 6.874, t2 = 8.185, t3 =
1
10.269, t4 = 13.276.; H NMR (400 MHz, CDCl3) δ 7.99 – 7.88 (m, 4H), 7.44 – 7.38 (m, 3H), 7.37 –
7.27 (m, 5H), 7.25 – 7.20 (m, 2H), 5.23 (dd, J = 6.4, 3.2 Hz, 1H), 4.81 (t, J = 7.8 Hz, 1H), 3.37 – 3.28
(m, 1H), 3.20 – 3.11 (m, 1H), 2.79 – 2.67 (m, 1H), 2.14 – 2.04 (m, 1H), 1.20 – 1.12 (m, 2H), 0.97 –
0.86 (m, 2H), 0.60 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 194.7, 193.6, 139.5, 135.5,
133.0, 132.4, 131.7, 130.5, 129.2, 129.1, 128.6, 127.4, 127.4, 127.0, 120.6, 97.9, 82.6, 79.6, 68.8, 39.3,
+
30.4, 18.0, 12.6. HRMS (ESI-TOF): calcd for C28H2778.9183BrNaO4 ([M+Na+]) 529.0985, found
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529.0989, C28H2780.9163BrNaO4+ ([M+Na+]) 531.0965, found 531.0980.
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(3-butoxy-5-(p-tolyl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3e). Yield 43.6 mg, 98%; green
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viscous liquid; 93% ee, 92/8 dr; [α]13 = −122.9 (c = 0.83 in CH2Cl2); HPLC (Daicel chiralcel IE,
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n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 7.569, t2 = 8.638, t3 =
1
9.942, t4 = 12.374.; H NMR (400 MHz, CDCl3) δ 8.13 – 8.07 (m, 2H), 8.04 – 7.99 (m, 2H), 7.54 –
7.48 (m, 1H), 7.47 – 7.42 (m, 1H), 7.42 – 7.36 (m, 4H), 7.33 – 7.27 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H),
5.32 (dd, J = 6.4, 3.6 Hz, 1H), 4.83 (t, J = 8.0 Hz, 1H), 3.49 – 3.42 (m, 1H), 3.32 – 3.25 (m, 1H), 2.86 –
2.77 (m, 1H), 2.36 (s, 3H), 2.24 – 2.17 (m, 1H), 1.33 – 1.24 (m, 2H), 1.10 – 1.00 (m, 2H), 0.71 (t, J =
7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 196.5, 194.8, 137.9, 137.7, 136.7, 134.0, 133.3, 132.7,
130.2, 130.0, 129.1, 128.4, 128.0, 126.8, 98.6, 83.7, 81.2, 69.9, 40.7, 31.5, 21.2, 19.1, 13.7. HRMS
(ESI-TOF): calcd for C29H30NaO4+ ([M+Na+]) 465.2036, found 465.2041.
(3-butoxy-5-(4-methoxyphenyl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3f). Yield 44.7 mg,
97%; green viscous liquid; 93% ee, 91/9 dr; [α]13 = −113.0 (c = 0.72 in CH2Cl2); HPLC (Daicel
D
chiralcel IE, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 10.199,
t2 = 12.566, t3 = 13.767, t4 = 18.254.; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz, 2H), 8.00 (t, J
= 7.6 Hz, 2H), 7.53 – 7.50 (m, 1H), 7.46 – 7.35 (m, 5H), 7.33 – 7.26 (m, 2H), 6.90 (d, J = 8.4 Hz, 2H),
5.31 (dd, J = 6.4, 3.6 Hz, 1H), 4.83 (t, J = 8.0 Hz, 1H), 3.81 (s, 3H), 3.50 – 3.41 (m, 1H), 3.32 – 3.25
(m, 1H), 2.85 – 2.74 (m, 1H), 2.25 – 2.15 (m, 1H), 1.34 – 1.25 (m, 2H), 1.11 – 1.00 (m, 2H), 0.71 (t, J
= 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 196.5, 194.8, 159.4, 136.7, 134.0, 133.3, 133.0, 132.7,
130.2, 130.0, 128.4, 128.3, 128.0, 113.8, 98.6, 83.7, 81.1, 69.9, 55.3, 40.6, 31.5, 19.1, 13.7. HRMS
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(ESI-TOF): calcd for C29H30NaO5+ ([M+Na+]) 481.1985, found 481.1988.
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(3-butoxy-5-(m-tolyl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3g). Yield 44.7 mg, 99%; green
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viscous liquid; 90% ee, 90/10 dr; [α]16 = −100.3 (c = 0.89 in CH2Cl2); HPLC (Daicel chiralcel IE,
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n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 6.986, t2 = 8.237, t3 =
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9.144, t4 = 11.310.; H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz, 2H), 7.94 (d, J = 7.6 Hz, 2H),
7.47 – 7.40 (m, 1H), 7.39 – 7.27 (m, 3H), 7.27 – 7.14 (m, 5H), 7.06 – 6.97 (m, 1H), 5.24 (dd, J = 6.4,
3.2 Hz, 1H), 4.75 (t, J = 8.0 Hz, 1H), 3.42 – 3.32 (m, 1H), 3.26 – 3.16 (m, 1H), 2.79 – 2.68 (m, 1H),
2.28 (s, 3H), 2.17 – 2.09 (m, 1H), 1.25 – 1.16 (m, 2H), 1.04 – 0.92 (m, 2H), 0.62 (t, J = 7.4 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ = 196.5, 194.8, 140.9, 138.1, 136.8, 134.0, 133.3, 132.7, 130.2, 130.0,
128.7, 128.4, 128.4, 127.9, 127.5, 123.8, 98.8, 83.7, 81.3, 69.9, 40.7, 31.5, 21.5, 19.1, 13.7. HRMS
(ESI-TOF): calcd for C29H30NaO4+ ([M+Na+]) 465.2036, found 465.2046.
(3-butoxy-5-(3-methoxyphenyl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3h). Yield 45.1 mg,
98%; green viscous liquid; 88% ee, 90/10 dr; [α]15 = −116.4 (c = 0.67 in CH2Cl2); HPLC (Daicel
D
chiralcel IE, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 8.570, t2
1
= 9.699, t3 = 11.718, t4 = 15.257.; H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 2H), 8.02 (d, J =
7.6 Hz, 2H), 7.54 – 7.48 (m, 1H), 7.47 – 7.37 (m, 3H), 7.34 – 7.27 (m, 2H), 7.27 – 7.23 (m, 1H), 7.15
(s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.84 (dd, J = 8.0, 2.4 Hz, 1H), 5.31 (dd, J = 6.4, 3.2 Hz, 1H), 4.87 (t, J
= 7.8 Hz, 1H), 3.81 (s, 3H), 3.47 – 3.39 (m, 1H), 3.30 – 3.22 (m, 1H), 2.88 – 2.77 (m, 1H), 2.27 – 2.16
(m, 1H), 1.31 – 1.23 (m, 2H), 1.08 – 0.98 (m, 2H), 0.69 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ = 196.3, 194.7, 159.8, 142.8, 136.7, 134.0, 133.3, 132.7, 130.2, 129.9, 129.4, 128.4, 128.0,
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119.0, 113.8, 111.8, 98.9, 83.7, 81.3, 69.9, 55.2, 40.6, 31.5, 19.0, 13.6. HRMS (ESI-TOF): calcd for
C29H30NaO5+ ([M+Na+]) 481.1985, found 481.1993.
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(3-butoxy-5-(3-phenoxyphenyl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3i). Yield 53.3 mg,
99%; green viscous liquid; 90% ee, 91/9 dr; [α]13 = −92.4 (c = 1.07 in CH2Cl2); HPLC (Daicel
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chiralcel ID, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 8.162, t2
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= 9.504, t3 = 13.587, t4 = 24.142.; H NMR (400 MHz, CDCl3) δ 8.08 – 8.03 (m, 2H), 8.03 – 7.98 (m,
2H), 7.54 – 7.38 (m, 3H), 7.37 – 7.29 (m, 7H), 7.22 – 7.18 (m, 1H), 7.15 – 7.05 (m, 1H), 7.05 – 6.99
(m, 2H), 6.96 – 6.91 (m, 1H), 5.29 (dd, J = 6.4, 3.2 Hz, 1H), 4.86 (t, J = 7.8 Hz, 1H), 3.44 – 3.37 (m,
1H), 3.30 – 3.20 (m, 1H), 2.87 – 2.77 (m, 1H), 2.24 – 2.17 (m, 1H), 1.27 – 1.19 (m, 2H), 1.06 – 0.95
(m, 2H), 0.68 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 196.2, 194.7, 157.3, 157.2, 143.3,
136.6, 133.9, 133.4, 132.7, 130.2, 129.9, 129.8, 129.8, 128.4, 128.0, 123.3, 121.6, 118.9, 118.8, 118.2,
+
117.2, 98.9, 83.6, 80.9, 69.9, 40.5, 31.4, 19.0, 13.7. HRMS (ESI-TOF): calcd for C34H32NaO5
([M+Na+]) 543.2142, found 543.2141.
(3-butoxy-5-(2-methoxyphenyl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3j). Yield 42.7 mg,
93%; green viscous liquid; 89% ee, 89/11 dr; [α]15 = −141.5 (c = 0.85 in CH2Cl2); HPLC (Daicel
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chiralcel IE, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 7.888, t2
= 9.862, t3 = 12.255, t4 = 13.100.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 4H), 7.85 (d, J = 7.2 Hz, 1H),
7.53 (t, J = 7.3 Hz, 1H), 7.47 – 7.37 (m, 3H), 7.36 – 7.20 (m, 3H), 7.05 – 6.96 (m, 1H), 6.85 – 6.76 (m,
1H), 5.37 (dd, J = 6.4, 3.6 Hz, 1H), 5.12 (t, J = 8.0 Hz, 1H), 3.74 (s, 3H), 3.44 – 3.34 (m, 1H), 3.28 –
3.19 (m, 1H), 3.00 – 2.86 (m, 1H), 2.11 – 1.99 (m, 1H),1.29 – 1.18 (m, 2H), 1.05 – 0.92 (m, 2H), 0.66
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(t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 196.7, 195.0, 155.8, 136.7, 134.1, 133.2, 132.6,
130.3, 130.0, 129.9, 128.3, 128.0, 126.5, 120.7, 109.9, 98.3, 83.7, 76.0, 69.8, 55.2, 39.8, 31.5, 19.0,
13.6. HRMS (ESI-TOF): calcd for C29H30NaO5+ ([M+Na+]) 481.1985, found 481.1991.
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(3-butoxy-5-(naphthalen-1-yl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3k). Yield 49.7 mg,
99%; green viscous liquid; 88% ee, 83/17 dr; [α]13 = −116.4 (c = 0.99 in CH2Cl2); HPLC (Daicel
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chiralcel ID, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 7.471, t2
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= 8.822, t3 = 9.891, t4 = 14.883.; H NMR (400 MHz, CDCl3) δ 8.13 – 8.07 (m, 4H), 8.06 – 8.02 (m,
1H), 7.87 – 7.77 (m, 3H), 7.54 – 7.49 (m, 2H), 7.48 – 7.42 (m, 3H), 7.41 – 7.36 (m, 2H), 7.35 – 7.29
(m, 2H), 5.54 (t, J = 8.0 Hz, 1H), 5.47 (dd, J = 6.8, 3.6 Hz, 1H), 3.39 – 3.32 (m, 1H), 3.27 – 3.18 (m,
1H), 3.11 – 3.01 (m, 1H), 2.38 – 2.29 (m, 1H), 1.26 – 1.18 (m, 2H), 1.01 – 0.92 (m, 2H), 0.64 (t, J =
7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 195.8, 195.1, 136.6, 136.6, 134.1, 133.6, 133.5, 132.8,
130.3, 129.8, 128.8, 128.4, 128.1, 128.1, 126.0, 125.7, 125.5, 123.4, 123.3, 98.7, 83.7, 78.2, 69.8, 39.8,
31.4, 19.0, 13.6. HRMS (ESI-TOF): calcd for C32H30NaO4+ ([M+Na+]) 501.2037, found 501.2046.
(3-butoxy-5-(naphthalen-2-yl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3l). Yield 47.1 mg, 98%;
green viscous liquid; 90% ee, 91/9 dr; [α]16D = −89.0 (c = 0.94 in CH2Cl2); HPLC (Daicel chiralcel IE,
n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 8.857, t2 = 10.378, t3
= 11.720, t4 = 15.650.; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.2 Hz, 2H), 8.06 (d, J = 7.6 Hz, 2H),
7.88 (s, 1H), 7.87 – 7.78 (m, 2H), 7.72 – 7.64 (m, 1H), 7.54 – 7.45 (m, 3H), 7.44 – 7.35 (m, 3H), 7.30
(t, J = 7.8 Hz, 2H), 5.36 (dd, J = 6.3, 3.0 Hz, 1H), 5.06 (t, J = 7.8 Hz, 1H), 3.51 – 3.39 (m, 1H), 3.36 –
3.22 (m, 1H), 2.97 – 2.82 (m, 1H), 2.38 – 2.23 (m, 1H), 1.33 – 1.23 (m, 2H), 1.11 – 0.98 (m, 2H), 0.69
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(t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 196.3, 194.8, 138.5, 136.7, 134.0, 133.4, 133.2,
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133.1, 132.8, 130.2, 130.0, 128.4, 128.1, 128.0, 127.7, 126.2, 126.1, 125.7, 124.7, 99.0, 83.8, 81.5, 69.9,
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+
40.6, 31.5, 19.1, 13.7. HRMS (ESI-TOF): calcd for C32H30NaO4 ([M+Na+]) 501.2036, found
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501.2042.
(3-butoxy-5-(furan-3-yl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3m). Yield 36.5 mg, 87%;
green viscous liquid; 91% ee, 91/9 dr; [α]15D = −181.0 (c = 0.73 in CH2Cl2); HPLC (Daicel chiralcel IE,
n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 7.841, t2 = 8.787, t3 =
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10.943, t4 = 12.111.; H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.6 Hz, 2H), 7.98 (d, J = 7.6 Hz, 2H),
7.53 – 7.48 (m, 1H), 7.48 – 7.41 (m, 3H), 7.40 – 7.35 (m, 2H), 7.33 – 7.28 (m, 2H), 6.60 (s, 1H), 5.26
(dd, J = 6.0, 2.8 Hz, 1H), 4.95 (t, J = 7.6 Hz, 1H), 3.53 – 3.45 (m, 1H), 3.33 – 3.25 (m, 1H), 2.77 – 2.68
(m, 1H), 2.27 – 2.18 (m, 1H), 1.34 – 1.25 (m, 2H), 1.11 – 1.00 (m, 2H), 0.71 (t, J = 7.4 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ = 196.5, 194.6, 143.5, 140.3, 136.6, 133.9, 133.3, 132.7, 130.1, 130.0,
128.4, 127.9, 125.8, 109.5, 98.7, 83.9, 74.1, 70.0, 39.1, 31.5, 19.0, 13.7. HRMS (ESI-TOF): calcd for
C26H26NaO5+ ([M+Na+]) 441.1672, found 441.1673.
(3-butoxy-5-(thiophen-3-yl)tetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3n). Yield 41.9 mg, 96%;
green viscous liquid; 91% ee, 91/9 dr; [α]15D = −179.0 (c = 0.61 in CH2Cl2); HPLC (Daicel chiralcel IE,
n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 7.905, t2 = 8.952, t3 =
1
11.761, t4 = 12.813.; H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.6 Hz, 2H), 8.00 (d, J = 8.0 Hz, 2H),
7.53 – 7.41 (m, 2H), 7.41 – 7.35 (m, 2H), 7.35 – 7.22 (m, 5H), 5.29 (dd, J = 6.4, 3.2 Hz, 1H), 5.02 (t, J
= 7.6 Hz, 1H), 3.51 – 3.41 (m, 1H), 3.33 – 3.22 (m, 1H), 2.84 – 2.71 (m, 1H), 2.33 – 2.20 (m, 1H), 1.32
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– 1.24 (m, 2H), 1.11 – 0.97 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 196.4,
194.7, 142.3, 136.6, 133.9, 133.3, 132.7, 130.2, 130.0, 128.4, 128.0, 126.5, 126.2, 122.5, 98.7, 83.8,
77.6, 70.0, 39.7, 31.5, 19.0, 13.7. HRMS (ESI-TOF): calcd for C26H26NaO4S+ ([M+Na+]) 457.1444,
found 457.1447.
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(E)-(3-butoxy-5-styryltetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3o). Yield 44.7 mg, 98%; green
viscous liquid; 90% ee, 92/8 dr; [α]15 = −105.0 (c = 0.89 in CH2Cl2); HPLC (Daicel chiralcel IE,
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n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 8.088, t2 = 9.478, t3 =
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10.313, t4 = 14.035.; H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 2H), 8.00 (d, J = 7.6 Hz, 2H),
7.53 – 7.48 (m, 1H), 7.47 – 7.36 (m, 5H), 7.36 – 7.28 (m, 4H), 7.28 – 7.21 (m, 1H), 6.59 – 6.46 (m,
2H), 5.26 (dd, J = 5.8, 2.4 Hz, 1H), 4.67 (dd, J = 13.2, 6.8 Hz, 1H), 3.52 – 3.42 (m, 1H), 3.31 – 3.23 (m,
1H), 2.66 – 2.52 (m, 1H), 2.19 – 2.07 (m, 1H), 1.34 – 1.24 (m, 2H), 1.13 – 1.01 (m, 2H), 0.71 (t, J =
7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 196.5, 194.5, 136.6, 136.4, 134.0, 133.3, 132.7, 132.1,
130.2, 129.8, 129.5, 128.6, 128.4, 128.0, 127.9, 126.7, 98.8, 84.0, 81.7, 69.9, 38.4, 31.5, 19.1, 13.7.
HRMS (ESI-TOF): calcd for C30H30NaO4+ ([M+Na+]) 477.2036, found 477.2036.
(3-butoxy-5-phenyltetrahydrofuran-2,2-diyl)bis(p-tolylmethanone) (3p). Yield 48.7 mg, 99%; green
viscous liquid; 92% ee, 90/10 dr; [α]16 = −114.7 (c = 0.97 in CH2Cl2); HPLC (Daicel chiralcel IE,
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n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 10.899, t2 = 11.433, t3
= 15.380, t4 = 16.341.; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H),
7.51 (d, J = 7.2 Hz, 2H), 7.41 – 7.33 (m, 2H), 7.32 – 7.26 (m, 1H), 7.20 – 7.16 (m, 2H), 7.12 – 7.06 (m,
2H), 5.31 (dd, J = 6.4, 3.2 Hz, 1H), 4.86 (t, J = 7.8 Hz, 1H), 3.47 – 3.37 (m, 1H), 3.31 – 3.20 (m, 1H),
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2.89 – 2.75 (m, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 2.24 – 2.15 (m, 1H), 1.31 – 1.22 (m, 2H), 1.10 – 0.98
(m, 2H), 0.69 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 195.6, 194.6, 144.2, 143.4, 141.3,
134.1, 131.5, 130.4, 130.0, 129.08, 128.7, 128.4, 127.8, 126.7, 98.8, 83.6, 81.0, 69.8, 40.7, 31.5, 21.7,
21.7, 19.0, 13.7. HRMS (ESI-TOF): calcd for C30H32NaO4+ ([M+Na+]) 479.2193, found 479.2206.
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(3-butoxy-5-phenyltetrahydrofuran-2,2-diyl)bis((4-bromophenyl)methanone) (3q). Yield 59.7 mg, 99%;
green viscous liquid; 88% ee, 90/10 dr; [α]16 = −108.2 (c = 1.19 in CH2Cl2); HPLC (Daicel chiralcel
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ID, n-hexane/i-PrOH = 95/5, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 6.849, t2 = 7.537, t3
= 9.781, t4 = 10.499.; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.91 – 7.82 (m, 2H), 7.60
– 7.51 (m, 2H), 7.50 – 7.43 (m, 4H), 7.42 – 7.36 (m, 2H), 7.35 – 7.29 (m, 1H), 5.27 (dd, J = 6.4, 3.2 Hz,
1H), 4.86 (t, J = 8.0 Hz, 1H), 3.50 – 3.41 (m, 1H), 3.33 – 3.25 (m, 1H), 2.87 – 2.77 (m, 1H), 2.29 –
2.17 (m, 1H), 1.34 – 1.24 (m, 2H), 1.11 – 1.00 (m, 2H), 0.73 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ = 195.5, 193.6, 140.5, 135.1, 132.6, 131.8, 131.7, 131.6, 131.6, 131.4, 128.9, 128.6, 128.3,
128.1, 126.7, 98.6, 83.6, 81.6, 70.0, 40.3, 31.5, 19.1, 13.7. HRMS (ESI-TOF): calcd for
+
+
C28H2678.9183Br2NaO4 ([M+Na+]) 607.0090, found 607.0096, C28H2678.9183Br80.9163BrNaO4 ([M+Na+])
609.0070, found 609.0075.
(3-ethoxy-5-phenyltetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3ab). Yield 35.2 mg, 88%; green
viscous liquid; 89% ee, 86/14 dr; [α]28 = −181.6 (c = 0.83 in CH2Cl2); HPLC (Daicel chiralcel IE,
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n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 8.177, t2 = 9.201, t3 =
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11.727, t4 = 12.103.; H NMR (400 MHz, CDCl3) δ 8.10 – 8.05 (m, 2H), 8.04 – 8.00 (m, 2H), 7.53 –
7.47 (m, 3H), 7.46 – 7.40 (m, 2H), 7.39 – 7.34 (m, 3H), 7.33 – 7.27 (m, 3H), 5.36 (dd, J = 6.8, 4.0 Hz,
1H), 4.86 (t, J = 8.0 Hz, 1H), 3.57 – 3.46 (m, 1H), 3.40 – 3.30 (m, 1H), 2.90 – 2.80 (m, 1H), 2.27 –
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2.17 (m, 1H), 0.93 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 196.7, 194.8, 140.9, 136.8,
134.0, 133.3, 132.7, 130.2, 129.9, 128.5, 128.4, 128.4, 128.0, 127.9, 126.7, 98.7, 83.4, 81.2, 65.8, 40.9,
14.9. HRMS (ESI-TOF): calcd for C26H24NaO4+ ([M+Na+]) 423.1567, found 423.1572.
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(3-isobutoxy-5-phenyltetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3ac). Yield 45.2 mg, 99%;
green viscous liquid; 90% ee, 91/9 dr; [α]16D = −162.9 (c = 0.50 in CH2Cl2); HPLC (Daicel chiralcel ID,
n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 6.500, t2 = 7.810, t3 =
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8.875, t4 = 13.208.; H NMR (400 MHz, CDCl3) δ 8.14 – 8.09 (m, 2H), 8.04 – 8.00 (m, 2H), 7.54 –
7.47 (m, 3H), 7.47 – 7.40 (m, 2H), 7.39 – 7.35 (m, 3H), 7.33 – 7.27 (m, 3H), 5.32 (dd, J = 6.4, 3.2 Hz,
1H), 4.89 (t, J = 7.8 Hz, 1H), 3.26 – 3.19 (m, 1H), 3.09 – 2.99 (m, 1H), 2.88 – 2.76 (m, 1H), 2.28 –
2.17 (m, 1H), 1.61 – 1.53 (m, 1H), 0.61 (dd, J = 12.8, 6.4 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ =
196.1, 194.7, 141.1, 136.6, 134.0, 133.3, 132.8, 130.2, 130.0, 128.5, 128.4, 128.0, 128.0, 126.7, 98.9,
83.9, 81.3, 77.0, 40.4, 28.4, 19.2, 19.1. HRMS (ESI-TOF): calcd for C28H28NaO4+ ([M+Na+]) 451.1880,
found 451.1884.
(3-isopropoxy-5-phenyltetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3ad). Yield 38.3 mg, 92%;
green viscous liquid; 93% ee, 83/17 dr; [α]28 = −125.1 (c = 0.77 in CH2Cl2); HPLC (Daicel chiralcel
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IE, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 7.557, t2 = 8.453,
t3 = 10.296, t4 = 11.248.; 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.07 (m, 2H), 8.06 – 7.97 (m, 2H), 7.54
– 7.48 (m, 3H), 7.46 – 7.40 (m, 2H), 7.40 – 7.33 (m, 3H), 7.33 – 7.27 (m, 3H), 5.44 (dd, J = 6.4, 3.6 Hz,
1H), 4.84 (t, J = 8.0 Hz, 1H), 3.65 – 3.55 (m, 1H), 2.92 – 2.81 (m, 1H), 2.24 – 2.16 (m, 1H), 1.03 (d, J
= 6.2 Hz, 3H), 0.81 (d, J = 6.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 195.7, 193.9, 139.9, 135.7,
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133.0, 132.2, 131.6, 129.2, 129.1, 129.0, 127.4, 127.3, 127.1, 126.9, 126.8, 125.7, 124.7, 97.7, 80.2,
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80.1, 41.0, 21.4, 20.4. HRMS (ESI-TOF): calcd for C27H26NaO4 ([M+Na+]) 437.1723, found
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437.1730.
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(3-(tert-butoxy)-5-phenyltetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3ae). Yield 40.6 mg, 93%;
green viscous liquid; 99% ee, 73/27 dr; [α]17 = −101.6 (c = 1.54 in CH2Cl2); HPLC (Daicel chiralcel
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ADH, n-hexane/i-PrOH = 99/1, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 15.337, t2 =
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17.651, t3 = 25.061, t4 = 30.009.; H NMR (400 MHz, CDCl3) δ 8.16 – 8.11 (m, 2H), 8.00 – 7.94 (m,
2H), 7.55 – 7.48 (m, 3H), 7.47 – 7.40 (m, 3H), 7.40 – 7.34 (m, 2H), 7.32 – 7.29 (m, 2H), 7.19 – 7.15
(m, 1H), 5.61 (dd, J = 7.20, 4.00 Hz, 1H), 4.75 (t, J = 8.00 Hz, 1H), 2.94 – 2.83 (m, 1H), 2.24 – 2.15
(m, 1H), 1.06 (s, 9H). 13C NMR (100 MHz, CDCl3) δ = 195.7, 193.9, 140.0, 135.7, 133.0, 132.2, 131.6,
129.1, 129.1, 127.4, 127.3, 126.9, 126.8, 125.7, 97.8, 80.3, 80.1, 41.0, 31.5, 30.1, 24.5, 22.5, 22.4.
HRMS (ESI-TOF): calcd for C28H28NaO4+ ([M+Na+]) 451.1880, found 451.1885.
(7-phenylhexahydrofuro[3,4-b][1,4]dioxine-5,5-diyl)bis(phenylmethanone) (3af). Yield 37.2 mg, 90%;
a white amorphous solid, mp 154 − 156 °C; 90% ee, 89/11 dr; [α]28 = −54.7 (c = 0.74 in CH2Cl2);
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HPLC (Daicel chiralcel IE, n-hexane/i-PrOH = 95/5, flow rate 1.0 mL/min, λ = 254 nm) retention time:
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t1 = 26.050, t2 = 28.006, t3 = 46.858, t4 = 50.862.; H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.2 Hz,
2H), 8.04 – 7.98 (m, 2H), 7.63 (d, J = 7.2 Hz, 2H), 7.56 – 7.51 (m, 1H), 7.46 – 7.37 (m, 5H), 7.35 –
7.26 (m, 3H), 5.62 (d, J = 4.8 Hz, 1H), 5.02 (d, J = 5.6 Hz, 1H), 4.54 (m, 1H), 3.59 – 3.50 (m, 1H),
3.48 – 3.40 (m, 1H), 3.35 (t, J = 5.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 195.5, 193.8, 136.1, 135.9,
134.0, 133.5, 133.3, 130.3, 129.9, 128.5, 128.5, 128.4, 128.3, 128.1, 127.9, 127.2, 125.6, 95.9, 82.3,
+
78.2, 75.0, 62.4, 62.0. HRMS (ESI-TOF): calcd for C26H22NaO5 ([M+Na+]) 437.1359, found
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(3-(cyclohexyloxy)-5-phenyltetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3ag). Yield 44.2 mg, 97%;
green viscous liquid; 96% ee, 90/10 dr; [α]22D = −74.5 (c = 0.88 in CH2Cl2); HPLC (Daicel chiralcel ID,
n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 7.364, t2 = 8.513, t3 =
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11.040, t4 = 14.256.; H NMR (400 MHz, CDCl3) δ 8.16 – 8.09 (m, 2H), 8.07 – 7.97 (m, 2H), 7.54 –
7.48 (m, 3H), 7.46 – 7.40 (m, 2H), 7.39 – 7.33 (m, 3H), 7.32 – 7.26 (m, 3H), 5.47 (dd, J = 6.6, 3.2 Hz,
1H), 4.85 (t, J = 8.0 Hz, 1H), 3.36 – 3.28 (m, 1H), 2.91 – 2.79 (m, 1H), 2.25 – 2.18 (m, 1H), 1.74 –
1.71 (m, 1H), 1.53 – 1.41 (m, 3H), 1.29 – 1.16 (m, 4H), 1.11 – 1.03 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ = 196.8, 195.0, 141.1, 136.8, 134.1, 133.3, 132.6, 130.2, 130.1, 128.4, 128.4, 128.4, 127.9,
127.9, 126.8, 98.9, 81.3, 81.2, 77.3, 42.0, 32.5, 31.2, 25.6, 23.5, 23.4. HRMS (ESI-TOF): calcd for
C30H30NaO4+ ([M+Na+]) 477.2036, found 477.2042.
(3-(allyloxy)-5-phenyltetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3ah). Yield 40.0 mg, 97%;
green viscous liquid; 89% ee, 86/14 dr; [α]22 = −132.0 (c = 0.80 in CH2Cl2); HPLC (Daicel chiralcel
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IE, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 9.019, t2 = 10.706,
t3 = 13.810, t4 = 15.337.; 1H NMR (400 MHz, CDCl3) δ 8.13 – 8.08 (m, 2H), 8.05 – 7.98 (m, 2H), 7.54
– 7.47 (m, 3H), 7.47 – 7.43 (m, 1H), 7.43 – 7.41 (m, 1H), 7.41 – 7.36 (m, 3H), 7.33 – 7.27 (m, 3H),
5.68 – 5.57 (m, 1H), 5.43 (dd, J = 6.8, 4.0 Hz, 1H), 5.09 – 4.98 (m, 2H), 4.86 (t, J = 8.0 Hz, 1H), 4.03 –
3.93 (m, 1H), 3.92 – 3.80 (m, 1H), 2.92 – 2.79 (m, 1H), 2.30 – 2.19 (m, 1H). 13C NMR (100 MHz,
CDCl3) δ = 196.5, 194.7, 140.7, 136.6, 133.9, 133.8, 133.4, 132.8, 130.2, 130.0, 128.5, 128.4, 128.1,
128.0, 126.7, 117.0, 98.6, 83.0, 81.1, 71.0, 40.9. HRMS (ESI-TOF): C27H24NaO4+ ([M+Na+]) 435.1567,
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(3-(ethylthio)-5-phenyltetrahydrofuran-2,2-diyl)bis(phenylmethanone) (3ai). Yield 41.7 mg, 99%;
green viscous liquid; 86% ee, 80/20 dr; [α]28D = −52.2 (c = 0.90 in CH2Cl2); HPLC (Daicel chiralcel IE,
n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm) retention time: t1 = 7.051, t2 = 7.974, t3 =
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9.247, t4 = 15.366.; H NMR (400 MHz, CDCl3) δ 8.07 – 8.01 (m, 2H), 7.98 – 7.91 (m, 2H), 7.49 –
7.43 (m, 1H), 7.38 – 7.31 (m, 5H), 7.30 – 7.20 (m, 5H), 4.80 – 4.69 (m, 2H), 2.96 – 2.86 (m, 1H), 2.60
– 2.50 (m, 1H), 2.44 – 2.33 (m, 1H), 2.18 – 2.08 (m, 1H), 1.13 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ = 196.1, 194.0, 138.2, 135.5, 132.8, 132.1, 131.9, 129.4, 129.2, 128.6, 127.5, 127.4, 127.3,
127.1, 127.0, 125.2, 124.7, 97.2, 80.1, 45.4, 41.7, 26.2, 13.3. HRMS (ESI-TOF): calcd for
C26H24NaO3S+ ([M+Na+]) 439.1338, found 439.1349.
ASSOCATED CONTENT
Support Information
Optimization detail, X-ray data for compound 3af, HPLC data, 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*
E-mail: lililin@scu.edu.cn
*
E-mail: xmfeng@scu.edu.cn
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Notes
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The author declare no competing financial interest.
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ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (Nos. 21172151, 21321061 and 21432006) for
financial support.
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