Enantioselective desymmetrization of prochiral allenic diols via cooperative catalysis of Pd(OAc)2 and a chiral phosphoric acid

Article abstract of DOI:10.1016/j.tetasy.2015.08.010

The first non-enzymatic desymmetrization of prochiral allenic diols via cooperative binary catalysis of Pd(OAc)₂ and (R)-STRIP has been reported. This method allows easy access to a series of optically active disubstituted dihydrofurans through

Full text of DOI:10.1016/j.tetasy.2015.08.010

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective desymmetrization of prochiral allenic diols via
cooperative catalysis of Pd(OAc)2 and a chiral phosphoric acid
⇑
Kou-Sen Cao, Wen-Hua Zheng
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first non-enzymatic desymmetrization of prochiral allenic diols via cooperative binary catalysis of Pd
(OAc)2 and (R)-STRIP has been reported. This method allows easy access to a series of optically active
disubstituted dihydrofurans through palladium mediated 5-endo-trig cyclizations of allenic alcohol with
high yields and good to excellent enantioselectivity. A broad substrate scope has been demonstrated.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 19 June 2015
Accepted 23 August 2015
Available online xxxx
1. Introduction
of palladium and chiral phosphoric acid in asymmetric reactions
have been reported.9 We envisioned that we could harness the
Oxygen-containing heterocycles, particularly furans or hydrofu-
rans, can be found in a large number of active pharmaceutical
ingredients and natural products.1 Intramolecular hydroalkoxyla-
tion of alkenes, alkynes, and allenes represents an efficient strategy
for the construction of oxygen heterocycles.2 Among these
hydroalkoxylation protocols, asymmetric cycloisomerization reac-
tions of allenic alcohols can afford a series of optically active dihy-
drofuran structures which are often found in natural products.1h,3,4
Gold catalysts have shown high activity in metal-mediated
cycloisomerization of allenic alcohols and an asymmetric version
could be achieved efficiently with the assistance of chiral ligands
or chiral counterions (Scheme 1, 1a).3 On the other hand, silver salt
has also been successfully used in cycloisomerisation reactions of
allenic alcohols enantioselectively. Recently, Hong et al. reported
activity of the metal and asymmetric control ability of chiral
phosphoric acid to realize new transformations.
Enantioselective desymmetrization of meso/prochiral 1,3-diols
is a challenging task for organic chemists because of the remote
distance between the reaction site and the prochiral center of
molecules.10,11 For primary alcohols it is even more difficult due
to the high nucleophilicity of the hydroxyl group. Prochiral allenic
diol is a special type of 1,3-diol, and recently Deska et al.
reported the first enantioselective enzymatic desymmetrization
of prochiral allenic diols to afford optically active allenic alcohols
(Scheme 1, 1c).12 To the best of our knowledge, there is still no
non-enzymatic method to accomplish the desymmetrization of
prochiral allenic diols. Herein, we report for the first time an enan-
tioselective desymmetrization of prochiral allenic diols by cooper-
ative binary catalysis of Pd(OAc)2 and (R)-STRIP, which offered a
direct approach for the synthesis of optically active dihydrofurans.
a
novel chiral silver phosphate-catalyzed cycloisomerisation
kinetic resolution of a-allenic alcohols with excellent enantioselec-
tivity (Scheme 1, 1b).4 Although palladium has shown a great
ability for the activation of allenes,5 to the best of our knowledge,
the asymmetric palladium-catalyzed cycloisomerisation reactions
of allenic alcohols remain unexplored.
2. Results and discussion
Inspired by the elegant work of Hong et al.4 our investigation
began with allenic diol 1a in the presence of Ag2CO3 and chiral
phosphoric acid A1 in DCM at room temperature. The reaction
proceeded smoothly to afford the desired product 2a in 62% yield
but with poor enantiomeric excess (26% ee) after 12 h (Table 1,
entry 1). Next, we investigated other chiral phosphoric acid with
different substituents on the 3,30-position of the BINOL backbone
and found A5 to be the best catalyst, giving the product in 63%
yield and with 44% ee. Screening of solvents gave a slightly higher
ee of the product (50% ee in ethyl acetate). Further optimization
including reaction temperature, catalyst loading did not give better
results.
Chiral phosphoric acids have been demonstrated to be powerful
organocatalysts. However, the activation mode of chiral phospho-
ric acid remains limited.6 Recently, the cooperative binary catalysis
system with the combination of metal and chiral phosphoric acid
has become an interesting research field, which could make
diverse transformations due to the special activation ability of
the metal.7,8 Inspired by the power of palladium to activate allyl,
alkynyl, and allenyl systems, recent examples of the cooperation
⇑
Corresponding author. Fax: +86 025 83686085.
E-mail address: wzheng@nju.edu.cn (W.-H. Zheng).
http://dx.doi.org/10.1016/j.tetasy.2015.08.010
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cao, K.-S.; Zheng, W.-H. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.08.010

2
K.-S. Cao, W.-H. Zheng / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
(a) Asymmetric gold-catalyzed cycloisomerization of allenic alcohols
R3 R3
allenic diols. The optimization of the reaction conditions is
shown in Table 2. First, when the reaction was conducted with
Pd(OAc)2 and chiral phosphoric acid A1 in DCM at room
temperature, the desired product 2a was obtained in excellent
yield (95%) and with poor enantiomeric ratios (5%) after 4 h
(Table 2, entry 1). To improve the enantioselectivity of the
transformation, we then tested different BINOL-derived
phosphoric acids A2–A5 (Table 2, entries 2–5). All reactions
proceeded well and chiral phosphoric acid A4 was found to be
the best, giving the product with 41% ee (Table 2, entry 4). A
better enantioselectivity (53% ee) was observed with a lower
catalyst loading (Table 2, entry 6).
R1
R4
R4
O
OH
Au(I)/chiral ligands
*
R1
R2
R4 R4
or Au(I)/chiral anions
R3
R2
R3
excellent ee
(b) Asymmetric silver-catalyzed kinetic resolution of allenic alcohols
chiral silver
phosphate
O
OH
OH
R
+
R
R
high ee
high ee
To further improve the enantioselectivity, common solvents for
organic reactions were screened (Table 1, entries 7–11). When Et2O
was used as the solvent, 71% ee was achieved (Table 2, entry 11). In
addition, molecular sieves were also effective for the enantioselec-
tivity of the reaction and the ee was further improved to 76% when
4 Å MS was added (Table 2, entry 13). We also tested the reaction
at lower temperature but did not obtain better results because of
the poor solubility of catalyst in Et2O at a lower temperature
(Table 1, entry 15). Recently, novel phosphoric acids based on a
spirocyclic backbone have been shown to have better enantio-con-
trol in some reactions. We also studied spirocyclic TRIP-analog
(STRIP) as the catalyst. We found that the desired product 2a
was obtained in excellent yield (89%) and with high enantioselec-
tivity (85% ee) (Table 2, entry 16). Further screening of the loading
(c) Enzymatic desymmetrization of prochiral allenic diols
O
O
enzymatic
desymmetrization
R
R
OH
OH
OH
excellent yields and ee
(d) this work
R
Pd(OAc)2
OH
(R)-STRIP
OH
OH
cooperative binary catalysis
R
O
excellent yields
high enantioselectivity
desymmetrization of meso 1,3-diols
asymmetric palladium-catalyzed cycloisomerization of allenic alcohols
Table 2
Scheme 1. Non-enzymatic desymmetrization of prochiral allenic diols.
Screening of catalysts and optimization of the reaction conditionsa
OH
Pd(OAc)2
Recently, Bäckvall et al. developed a PdII/Brønsted acid cat-
OH
OH
BA (20 mol %)
alyzed enantioselective oxidative carbocyclization–borylation of
enallenes.9j Considering the powerful ability of palladium for the
activation of allenes, we envisioned that cooperative binary
catalysis of Pd(OAc)2 and chiral phosphoric acid might be
suitable for the enantioselective desymmetrization of prochiral
solvent,additive
rt
Ph
Ph
O
*
1a
2a
G
G
G
O
O
O
O
A1
A2
: G = 3,5-(CF3)2C6H3
: G = 1-naphthyl
O
O
(R)
P
P
OH
OH
Table 1
A3: G = SiPh3
Optimization of the reaction conditions catalyzed by chiral silver phosphatea
A4: G = 2,4,6-(iPr)3C6H2
: G = biphenyl
G
A5
A6: G = 2,4,6-(iPr)3C6H2
OH
(S)
Ag2CO3 (10 mol %)
OH
BA (20 mol %)
solvent, rt
Yieldb (%)
eec (%)
Ph
OH
Entry
Pd(OAc)2 (mol %)
BA
Additive
Solvent
*
Ph
O
1
2
3
4
5
6
7
8
20
20
20
20
20
10
10
10
10
10
10
10
10
10
10
10
10
10
A1
A2
A3
A4
A5
A4
A4
A4
A4
A4
A4
A4
A4
A4
A4
A6
A6
A6
—
—
—
—
—
—
—
—
—
—
—
3 Å MS
4 Å MS
5 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
DCM
DCM
DCM
DCM
DCM
DCM
EA
93
91
68
81
77
94
80
92
86
86
91
82
76
88
66
89
86
82
5
32
8
1a
2a
G
41
20
53
67
55
61
68
71
75
76
73
62
85
77
80
A1
: G = 3,5-(CF3)2C6H3
A2: G = 1-naphthyl
O
O
O
A3: G = SiPh3
P
i
A4
: G = 2,4,6-( Pr)3C6H2
OH
A5: G = biphenyl
Toluene
THF
9
G
10
11
12
13
14
15d
16
17e
18f
MTBE
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
(S)
Entry
Catalyst
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
A1
A2
A3
A4
A5
A5
A5
A5
DCM
DCM
DCM
DCM
DCM
toluene
Et2O
EA
62
63
n. r.
84
63
72
26
26
—
29
44
40
29
50
a
Reaction conditions: 1a (0.1 mmol), Pd(OAc)2 (x mol %), BA (20 mol %), additive
(80 mg), solvent (2 mL), rt, 4 h.
26
68
b
Isolated yields.
ee values were determined by chiral HPLC.
The reaction was performed at 0 °C.
10 mol % of A6 was used.
a
c
Reaction conditions: 1a (0.1 mmol), Ag2CO3 (10 mol %), BA (20 mol %), solvent
(1 mL), rt.
d
b
e
Isolated yields.
ee values were determined by chiral HPLC.
c
f
15 mol % of A6 was used.
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K.-S. Cao, W.-H. Zheng / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
Table 3
Substrate scopea
OH
Pd(OAc)2 (10 mol %)
A6
OH
OH
(20 mol %)
Et2O, 4Å MS
rt, 4h
R
R
O
1a
2a
OH
OH
OH
OH
OH
F3C
MeO
O
O
O
2c, 93%, 84% ee
2a
2b, 84%, 85% ee
, 89%, 85% ee
OH
OH
Me
Cl
O
O
O
Me
2d, 91%, 81% ee
2f, 92%, 79% ee
2e, 96%, 74% ee
OH
OH
OH
OH
Cl
F
O
O
O
Cl
2h, 90%, 80% ee
2i, 87%, 78% ee
2g, 88%, 75% ee
OH
Br
O
O
O
Ph
2j
, 90%, 78% ee
2k
, 98%, 80% ee
2l
, 93%, 80% ee
OH
O
2m
, 89%, 63% ee
a
Reaction conditions: 1a (0.1 mmol), Pd(OAc)2 (10 mol %), A6 (20 mol %), 4 Å
molecular sieve (80 mg), Et2O (2 mL), rt, 4 h. Yields were isolated yields purified by
column chromatography on silica gel. ee values were determined by chiral HPLC.
of A6 did not give better results (Table 2, entries 17 and 18). The
absolute configuration of 2a was determined to be (R).
Based on the results and previous work by other groups,9 we
have proposed a possible catalytic cycle (Scheme 2). First, the
ligand exchange between Pd(OAc)2 and (R)-STRIP and subsequent
With the optimal conditions in hand, we then turned our atten-
tion to the scope of substrates. First, we tested the substituents of
the benzene rings. Substrates bearing election-rich and electron-
withdrawing groups on benzene rings were all compatible with
high enantioselectivity, which showed that the electrical effect
had little influence on the enantioselectivity of the reaction
(Table 3, 2b–2e). Different halogen substituted benzene rings were
also well tolerated, and the desired product 2f, 2i, and 2j was
obtained in excellent yields with high enantioselectivities of 79%,
78%, and 78%, respectively (Table 3, 2f, 2i, 2j). Changing the posi-
tion of halogen on benzene rings seemed to have no obvious effect
on the ee with a slightly lower enantioselectivity (75%) obtained
for the 2-chlorophenyl substrate (Table 3, 2f, 2g, 2h). Furthermore,
excellent yield (98%) and excellent ee (80%) were achieved for 4-
biphenyl substrate 2k (Table 3). Given the general efficiency of
the diverse phenyl-substituted substrates, we next tested 2-naph-
thyl substituted substrate and the desired product 2l was obtained
with good enantioselectivity (Table 3). It should be noted that the
reaction with alkyl-substituted substrate could be converted into
the desired product 2m in excellent yield (89%) with a slightly
lower enantioselectivity (63% ee) (Table 3).
OH
(R)-STRIP
O
2a
Pd(OAc)2
HOAc
HOAc
OH
AcOPd
AcO Pd
O
O
O
*
P
O
O
B
OAc
Pd
1a
(R)-STRIP
OH
Ph
H
O
O
*
P
O
O
O
H
A
Scheme 2. Plausible catalytic cycle.
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4
K.-S. Cao, W.-H. Zheng / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
coordination of substrate 1a with Pd leads to transition state A. In
this cooperative binary catalysis system, the palladium activated
the allene part of 1a. At the same time, the P@O of the phosphate
serves as a base to enantioselectively deprotonate one alcohol.
Intermediate B was then formed and the desired product 2a was
subsequently achieved via protonation of carbon-palladium bond
of intermediate B and the palladium catalyst was released.
4.2.1. 2-(2-(3-Methoxyphenyl)vinylidene)propane-1,3-diol 1b
White solid. Analytical data for 1b: mp 103–104 °C. 1H NMR
(300 MHz, MeOD) d 7.21 (t, J = 7.8 Hz, 1H), 7.01–6.87 (m, 2H),
6.78 (ddd, J = 8.2, 2.5, 0.9 Hz, 1H), 6.35 (p, J = 2.2 Hz, 1H), 4.37–
4.20 (m, 4H), 3.80 (s, 3H). 13C NMR (101 MHz, MeOD) d 203.45,
161.43, 137.34, 130.49, 120.59, 113.78, 113.24, 110.07, 97.65,
61.46, 55.64. HRMS (ESI) m/z [M+Na]+: Calcd for C12H14O3Na:
229.0841. Found: 229.0839.
3. Conclusion
4.2.2. 2-(2-(3-(Trifluoromethyl)phenyl)vinylidene)propane-1,3-
diol 1c
In conclusion, we have reported for the first time a non-
enzymatic desymmetrization of prochiral allenic diols through
the combination of Pd and chiral phosphoric acid as catalyst. A
wide variety of optically active dihydrofurans were obtained in
excellent yields with high enantioselectivity. Further exploration
toward the applications of the method in total synthesis is
currently underway and will be reported in due course.
White solid. Analytical data for 1c: mp 76–77 °C. 1H NMR
(300 MHz, MeOD) d 7.69–7.56 (m, 2H), 7.53–7.48 (d, J = 5.3 Hz,
2H), 6.52–6.40 (m, 1H), 4.38–4.22 (m, 4H). 13C NMR (101 MHz,
MeOD) d 203.65, 137.46, 132.02 (q, JC–F = 124 Hz), 131.44, 130.34,
127.03, 124.51 (q, JC–F = 16.0 Hz), 124.34 (q, JC–F = 12.0 Hz),
111.21, 96.89, 61.24. HRMS (EI) m/z M+: Calcd for C12H11F3O2:
244.0711. Found: 244.0712.
4. Experimental
4.1. General
4.2.3. 2-(2-(3-chlorophenyl)vinylidene)propane-1,3-diol 1f
White solid. Analytical data for 1f: mp 104 °C. 1H NMR
(300 MHz, MeOD) d 7.39 (d, J = 1.0 Hz, 1H), 7.31–7.23 (m, 2H),
7.23–7.13 (m, 1H), 6.36 (p, J = 2.2 Hz, 1H), 4.35–4.21 (m, 4H). 13C
NMR (101 MHz, MeOD) d 203.59, 138.33, 135.58, 131.02, 127.95,
127.59, 126.36, 110.84, 96.79, 61.30. HRMS (ESI) m/z [M+Na]+:
Calcd for C11H11ClO2Na: 233.0345. Found: 233.0340.
Unless stated otherwise, all reactions were carried out in flame-
dried glassware under a dry argon atmosphere. All solvents were
purified and dried according to standard methods prior to use.
Melting points were measured on a SGW X-4. Melting points are
uncorrected. NMR spectras were recorded on Bruker ARX 300 spec-
trometer and Bruker ARX 400 spectrometer, which were recorded
in ppm (d) downfield of TMS (d = 0) in deuterated solvent. Signal
splitting patterns are described as singlet (s), doublet (d), triplet
(t), quartet (q), quintet (quint), or multiplet (m), with coupling
constants (J) in Hertz. Mass spectra were conducted at Micromass
Q-Tof instrument (ESI) and Agilent Technologies 5973 N (EI). HPLC
analyses were performed on Shimadzu SPD-20A using Daicel
Chiralpak AD-H, IB Column. Optical rotations were measured on
a Rudolph Automatic Polarimeter A21101 at the wavelength of
the sodium D-line (589 nm). Compounds 1a, 1d, 1e, 1h, 1l, and
1m are known compounds and were prepared according to the
literature.12a Compound 2a is a known compound.12a
4.2.4. 2-(2-(2-Chlorophenyl)vinylidene)propane-1,3-diol 1g
White solid. Analytical data for 1g: mp 126–128 °C. 1H NMR
(300 MHz, MeOD) d 7.57 (dd, J = 7.7, 1.8 Hz, 1H), 7.37 (dd, J = 7.8,
1.4 Hz, 1H), 7.29–7.14 (m, 2H), 6.81–6.71 (m, 1H), 4.37–4.22 (m,
4H). 13C NMR (101 MHz, MeOD) d 204.30, 133.54, 132.98, 130.63,
129.76, 129.38, 128.08, 110.63, 93.91, 61.30. HRMS (ESI) m/z [M
+Na]+: Calcd for C11H11ClO2Na: 233.0345. Found: 233.0340.
4.2.5. 2-(2-(3-Fluorophenyl)vinylidene)propane-1,3-diol 1i
White solid. Analytical data for 1i: mp 122–123 °C. 1H NMR
(300 MHz, MeOD)
d 7.31 (td, J = 7.9, 6.0 Hz, 1H), 7.20–7.05
(m, 2H), 6.98–6.87 (m, 1H), 6.42–6.31 (m, 1H), 4.36–4.20
(m, 4H). 13C NMR (101 MHz, MeOD) d 203.63, 164.60 (d, JC–F
= 968 Hz), 138.76 (d, JC–F = 32.0 Hz), 131.20 (d, JC–F = 36.0 Hz),
123.91 (d, JC–F = 8.0 Hz), 114.66 (d, JC–F = 88.0 Hz), 114.18 (d,
JC–F = 92.0 Hz), 110.72, 96.99 (d, JC–F = 8.0 Hz), 61.31. HRMS (ESI)
m/z [M+Na]+: Calcd for C11H11FO2Na: 217.0641. Found: 217.0634.
4.2. General procedure for the preparation of allendiols 1a–1l12a
At first, ZnBr2 (2.44 g, 4.4 mmol) was carefully dried with a
heatgun in vacuo until a fine powder formed. After cooling to room
temperature, under an argon atmosphere, Pd(PPh3)4 (20 mg,
0.06 mmol) was added. The catalyst and zinc salt were then
dissolved in dry THF (15 ml) and cooled to 0 °C. A solution of the
corresponding Grignard reagent (4 mmol, 0.5–1 M in THF) was
added dropwise and stirring at 0 °C was continued for 20 min
4.2.6. 2-(2-(3-Bromophenyl)vinylidene)propane-1,3-diol 1j
White solid. Analytical data for 1j: mp 86–88 °C. 1H NMR
(300 MHz, MeOD) d 7.54 (t, J = 1.6 Hz, 1H), 7.39–7.29 (m, 2H),
7.21 (t, J = 7.8 Hz, 1H), 6.40–6.30 (m, 1H), 4.35–4.22 (m, 4H). 13C
NMR (101 MHz, MeOD) d 203.56, 138.60, 131.29, 130.94, 130.56,
126.78, 123.68, 110.87, 96.72, 61.31. HRMS (ESI) m/z [M+Na]+:
Calcd for C11H11BrO2Na: 276.9840. Found: 276.9835.
where upon
a white precipitate formed. In a second flask,
5-acetoxy-2,2-dimethyl-5-ethynyl-1,3-dioxane (396 mg, 2.0 mmol)
was dissolved in dry THF (4 ml) and added to the solution of the
organozinc reagent at 0 °C. The reaction mixture was allowed to
warm to room temperature overnight. After the addition of saturated
NH4Cl (10 ml) and ethyl acetate (20 ml), the aqueous phase was
extracted with ethyl acetate (20 ml) and the combined organic layers
were dried over Na2SO4 and filtered through a small plug of silica. The
solvents were removed in vacuo, and the residue redissolved in
methanol (10 ml) and cooled to 0 °C. A drop of conc. sulfuric acid
was added and the reaction mixture was stirred for approx. 30 min
at 0 °C (TLC-control). Saturated NaHCO3 (5 ml) and ethyl acetate
(30 ml) were then added, the aqueous layer was extracted with ethyl
acetate (2 ꢀ 10 ml) and the combined organic layers were dried over
Na2SO4. After removal of the solvents in vacuo, column chromatogra-
phy (SiO2, cyclohexane/ethyl acetate 7/3 to 4/6) gave the pure allenic
diols (65–87% yields).
4.2.7. 2-(2-([1,10-Biphenyl]-4-yl)vinylidene)-propane-1,3-diol 1k
White solid. Analytical data for 1k: mp 135–136 °C. 1H NMR
(300 MHz, MeOD) d 7.59 (dd, J = 12.6, 7.8 Hz, 4H), 7.50–7.38 (m,
4H), 7.33 (t, J = 6.8 Hz, 1H), 6.42 (s, 1H), 4.39–4.20 (m, 4H). 13C
NMR (101 MHz, MeOD) d 203.66, 142.04, 141.12, 135.01, 129.88,
128.47, 128.31, 128.11, 127.77, 110.13, 97.32, 61.52. HRMS (ESI)
m/z [M+Na]+: Calcd for C17H16O2Na: 275.1048. Found: 275.1046.
4.3. General procedure for the enantioselective desymmetrization
of prochiral allenic diols
To
a flame-dried Schlenk tube were added substrate 1
(0.1 mmol), Pd(OAc)2 (10 mol %), A6 (20 mol %), 4 Å molecular
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K.-S. Cao, W.-H. Zheng / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
sieves (80 mg), and dry Et2O (2 mL). The mixture was stirred at rt
4.3.6. (R)-(5-(3-Chlorophenyl)-2,5-dihydrofuran-3-yl)methanol 2f
Colorless oil, 92%, 80% ee. Analytical data for 2f: [
20 = +143.8
until the starting material disappeared (monitored by TLC). The
solvent was removed under reduced pressure, and the residue
was purified by silica gel column chromatography (PE/EA = 2:1)
to afford product 2.
a]
D
(c 0.21, CHCl3), 1H NMR (300 MHz, CDCl3) d 7.35–7.26 (m, 3H),
7.24–7.17 (m, 1H), 5.87–5.75 (m, 2H), 4.93–4.75 (m, 2H), 4.37 (s,
2H). 13C NMR (101 MHz, CDCl3) d 144.02, 141.28, 134.46, 129.82,
127.95, 126.37, 124.39, 124.11, 87.53, 75.58, 58.65. HRMS (EI)
m/z M+: Calcd for C11H11ClO2: 210.0448. Found: 210.0443. The
enantiomeric ratio was determined by Daicel Chiralpak IC,
Hexanes/IPA = 90:10, 1.0 mL/min, k = 220 nm, tR (major) = 10.43
min, tR (minor) = 8.92 min.
4.3.1. (R)-(5-Phenyl-2,5-dihydrofuran-3-yl)methanol 2a12a
Colorless oil, 89%, 85% ee. Analytical data for 2a (known com-
pound): [a]
20 = +170.0 (c 0.40, CHCl3), 1H NMR (300 MHz, CDCl3):
D
d 7.28–7.41 (m, 5H), 5.80–5.89 (m, 1H), 5.79 (br s, 1H), 4.87 (dd,
J = 5.6, 12.3 Hz, 1H), 4.77 (d, J = 12.2 Hz, 1H), 4.34 (s, 2H), 1.80 (s,
1H). 13C NMR (75 MHz, CDCl3): d 141.82, 140.83, 128.51, 127.88,
126.17, 124.66, 88.22, 75.43, 58.71. HRMS (EI) m/z M+: Calcd for
C11H12O2: 176.0837. Found: 176.0834. The enantiomeric ratio
was determined by Daicel Chiralpak OJ-H, Hexanes/IPA = 90:10,
1.0 mL/min, k = 220 nm, tR (major) = 18.03 min, tR (minor)
= 20.90 min.
4.3.7. (R)-(5-(2-Chlorophenyl)-2,5-dihydrofuran-3-yl)methanol 2g
Colorless oil, 88%, 75% ee. Analytical data for 2g: [a]
20 = +164.8
D
(c 0.5, CHCl3), 1H NMR (300 MHz, CDCl3) d 7.46 (dd, J = 7.6, 1.8 Hz,
1H), 7.25 (dddd, J = 20.5, 14.9, 7.5, 1.6 Hz, 3H), 6.17 (ddd, J = 5.3,
3.6, 1.7 Hz, 1H), 5.97–5.86 (m, 1H), 4.95–4.74 (m, 2H), 4.29 (s,
2H). 13C NMR (101 MHz, CDCl3) d 140.77, 139.65, 131.45, 129.38,
128.68, 127.17, 127.16, 123.47, 85.20, 75.71, 58.73. HRMS (EI)
m/z M+: Calcd for C11H11ClO2: 210.0448. Found: 210.0447. The
enantiomeric ratio was determined by Daicel Chiralpak OJ-H,
4.3.2. (R)-(5-(3-Methoxyphenyl)-2,5-dihydrofuran-3-yl)-
methanol 2b
Colorless oil, 84%, 85% ee. Analytical data for 2b: [
a
]
20 = +125.0
Hexanes/IPA = 95:5,
0.4 mL/min,
k = 220 nm,
tR
(major)
D
(c 0.27, CHCl3), 1H NMR (300 MHz, CDCl3) d 7.29 (t, J = 7.8 Hz, 1H),
6.97–6.81 (m, 3H), 5.87–5.75 (m, 2H), 4.93–4.70 (m, 2H), 4.33 (s,
2H), 3.84 (s, 3H). 13C NMR (101 MHz, CDCl3) d 159.82, 143.59,
140.88, 129.60, 124.58, 118.51, 113.20, 111.81, 88.06, 75.49,
58.70, 55.27. HRMS (EI) m/z M+: Calcd for C12H14O3: 206.0943.
Found: 206.0941. The enantiomeric ratio was determined by Daicel
Chiralpak OJ-H, Hexanes/IPA = 90:10, 1.0 mL/min, k = 220 nm, tR
(major) = 25.18 min, tR (minor) = 28.78 min.
= 49.85 min, tR (minor) = 47.79 min.
4.3.8. (R)-(5-(4-Chlorophenyl)-2,5-dihydrofuran-3-yl)methanol
2h
Colorless oil, 90%, 80% ee. Analytical data for 2h: [a]
20 = +174.2
D
(c 0.38, CHCl3), 1H NMR (300 MHz, CDCl3) d 7.31 (dd, J = 23.1,
8.4 Hz, 4H), 5.87–5.73 (m, 2H), 4.85 (dt, J = 26.8, 8.6 Hz, 2H), 4.36
(s, 2H). 13C NMR (101 MHz, CDCl3) d 141.25, 140.46, 133.55,
128.66, 127.65, 124.32, 87.50, 75.49, 58.70. HRMS (EI) m/z
M+: Calcd for C11H11ClO2: 210.0448. Found: 210.0449. The
enantiomeric ratio was determined by Daicel Chiralpak OJ-H,
Hexanes/IPA = 90:10, 1.0 mL/min, k = 220 nm, tR (major)
= 12.75 min, tR (minor) = 15.41 min.
4.3.3. (R)-(5-(3-(Trifluoromethyl)phenyl)-2,5-dihydrofuran-3-
yl)methanol 2c
Colorless oil, 93%, 84% ee. Analytical data for 2c: [a]
20 = +97.9 (c
D
0.29, CHCl3), 1H NMR (300 MHz, CDCl3) d 7.59–7.39 (m, 4H), 5.86
(ddd, J = 5.4, 3.7, 1.7 Hz, 1H), 5.79–5.73 (m, 1H), 4.95–4.69 (m,
2H), 4.32 (s, 2H). 13C NMR (101 MHz, CDCl3) d 143.01, 141.57,
4.3.9. (R)-(5-(3-Fluorophenyl)-2,5-dihydrofuran-3-yl)methanol
131.87 (q, JC–F = 132 Hz), 129.61, 128.99, 124.12 (d, JC–F
1084 Hz), 124.63 (d, JC–F = 16.0 Hz), 123.92, 122.96 (d, JC–F
=
=
2i
Colorless oil, 87%, 78% ee. Analytical data for 2i: [a]
20 = +99.3
D
16.0 Hz), 87.56, 75.64, 58.61. HRMS (EI) m/z M+: Calcd for
(c 0.30, CHCl3), 1H NMR (400 MHz, CDCl3) d 7.26–7.17 (m, 1H),
7.00 (d, J = 7.7 Hz, 1H), 6.97–6.84 (m, 2H), 5.77–5.69 (m, 1H),
5.69–5.64 (m, 1H), 4.81–4.61 (m, 2H), 4.23 (s, 2H). 13C NMR
C12H11F3O2: 244.0711. Found: 244.0708. The enantiomeric ratio
was determined by Daicel Chiralpak OJ-H, Hexanes/IPA = 97:3,
0.5 mL/min, k = 220 nm, tR (major) = 34.61 min, tR (minor)
= 36.23 min.
(101 MHz, CDCl3)
d 163.05 (d, JC–F = 980 Hz), 144.66 (d, JC–F
= 28.0 Hz), 141.23, 130.05 (d, JC–F = 36.0 Hz), 124.16, 121.73 (d,
JC–F = 1.2 Hz), 114.67 (d, JC–F = 88.0 Hz), 113.07 (d, JC–F = 88.0 Hz),
87.54 (d, JC–F = 4.0 Hz), 75.57, 58.63. HRMS (EI) m/z M+: Calcd for
4.3.4. (R)-(5-(m-Tolyl)-2,5-dihydrofuran-3-yl)methanol 2d
Colorless oil, 91%, 81% ee. Analytical data for 2d: [a]
20 = +169.0
D
C11H11FO2: 194.0743. Found: 194.0740. The enantiomeric ratio
(c 0.2, CHCl3), 1H NMR (300 MHz, CDCl3) d 7.34–7.19 (m, 1H),
7.18–7.10 (m, 3H), 5.86–5.75 (m, 2H), 4.99–4.66 (m, 2H), 4.33 (s,
2H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) d 141.78, 140.77,
138.25, 128.66, 128.45, 126.94, 124.72, 123.37, 88.26, 75.43,
58.72, 21.45. HRMS (EI) m/z M+: Calcd for C12H14O2: 190.0994.
Found: 190.0990. The enantiomeric ratio was determined by Daicel
Chiralpak OJ-H, Hexanes/IPA = 96:4, 0.5 mL/min, k = 220 nm, tR
(major) = 73.33 min, tR (minor) = 77.15 min.
was determined by Daicel Chiralpak IC, Hexanes/IPA = 80:20,
1.0 mL/min, k = 220 nm, tR (major) = 6.22 min, tR (minor)
= 5.60 min.
4.3.10. (R)-(5-(3-Bromophenyl)-2,5-dihydrofuran-3-yl)-
methanol 2j
Colorless oil, 90%, 78% ee. Analytical data for 2j: [a]
20 = +97.3
D
(c 0.22, CHCl3), 1H NMR (300 MHz, CDCl3) d 7.51–7.32 (m, 2H),
7.28–7.19 (m, 2H), 5.89–5.72 (m, 2H), 4.96–4.71 (m, 2H), 4.35
(s, 2H). 13C NMR (101 MHz, CDCl3) d 144.31, 141.38, 130.88,
130.12, 129.28, 124.87, 124.07, 122.70, 87.48, 75.61, 58.66. HRMS
(EI) m/z M+: Calcd for C11H11BrO2: 253.9942. Found: 253.9946.
The enantiomeric ratio was determined by Daicel Chiralpak IC,
Hexanes/IPA = 90:10, 1.0 mL/min, k = 220 nm, tR (major) = 10.83 min,
tR (minor) = 9.29 min.
4.3.5. (R)-(5-(p-Tolyl)-2,5-dihydrofuran-3-yl)methanol 2e
Colorless oil, 96%, 74% ee. Analytical data for 2e: [a]
20 = +96.2 (c
D
0.53, CHCl3), 1H NMR (300 MHz, CDCl3) d 7.18 (q, J = 8.1 Hz, 4H),
5.84–5.71 (m, 2H), 4.96–4.68 (m, 2H), 4.30 (s, 2H), 2.34 (s, 3H).
13C NMR (101 MHz, CDCl3) d 140.82, 138.89, 137.62, 129.20,
126.30, 124.79, 88.08, 75.33, 58.72, 21.14. HRMS (EI) m/z M+: Calcd
for C12H14O2: 190.0994. Found: 190.0997. The enantiomeric ratio
was determined by Daicel Chiralpak OJ-H, Hexanes/IPA = 90:10,
1.0 mL/min, k = 220 nm, tR (major) = 18.80 min, tR (minor)
= 24.81 min.
4.3.11. (R)-(5-([1,10-Biphenyl]-4-yl)-2,5-dihydrofuran-3-yl)-
methanol 2k
Colorless oil, 98%, 80% ee. Analytical data for 2k: [
a]
20 = +145.0
D
(c 0.16, CHCl3), 1H NMR (300 MHz, CDCl3) d 7.58 (d, J = 7.7 Hz, 4H),
Please cite this article in press as: Cao, K.-S.; Zheng, W.-H. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.08.010

6
K.-S. Cao, W.-H. Zheng / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Nat. Prod. 1999, 62, 504–540; (e) Lorente, A.; Lamariano-Merketegi, J.;
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7.50–7.33 (m, 5H), 5.88 (br, 1H), 5.83 (s, 1H), 4.96–4.72 (m, 2H),
4.36 (s, 2H). 13C NMR (101 MHz, CDCl3) d 141.05, 140.94, 140.92,
140.89, 128.76, 127.35, 127.29, 127.14, 126.72, 124.65, 87.96,
75.49, 58.81. HRMS (EI) m/z M+: Calcd for C17H16O2: 252.1150.
Found: 252.1144. The enantiomeric ratio was determined by
Daicel Chiralpak OJ-H, Hexanes/IPA = 85:15, 2.0 mL/min,
k = 220 nm, tR (major) = 17.14 min, tR (minor) = 15.15 min.
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4.3.12. (R)-(5-(Naphthalen-2-yl)-2,5-dihydrofuran-3-yl)
methanol 2l
Colorless oil, 93%, 80% ee. Analytical data for 2l: [a]
20 = +143.2 (c
D
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0.25, CHCl3), 1H NMR (300 MHz, CDCl3) d 7.90–7.78 (m, 3H), 7.76
(s, 1H), 7.60–7.34 (m, 3H), 6.03–5.92 (m, 1H), 5.85–5.75 (m, 1H),
5.01–4.72 (m, 2H), 4.30 (s, 2H). 13C NMR (101 MHz, CDCl3) d
141.03, 139.26, 133.33, 133.16, 128.42, 128.00, 127.73, 126.20,
125.97, 125.01, 124.58, 124.34, 88.42, 75.61, 58.70. HRMS (EI)
m/z M+: Calcd for C15H14O2: 226.0994. Found: 226.0993. The
enantiomeric ratio was determined by Daicel Chiralpak OJ-H,
Hexanes/IPA = 80:20, 1.5 mL/min, k = 220 nm, tR (major) = 13.23 min,
tR (minor) = 17.77 min.
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4.3.13. (S)-(5-Cyclohexyl-2,5-dihydrofuran-3-yl)methanol 2m
Colorless oil, 89%, 63% ee. Analytical data for 2m: [a]
20 = +70.3
D
(c 0.33, CHCl3), 1H NMR (300 MHz, CDCl3) d 5.71–5.65 (m, 1H),
4.69–4.49 (m, 3H), 4.24 (d, J = 3.0 Hz, 2H), 2.06 (t, J = 4.8 Hz, 1H),
1.77–0.95 (m, 10H). 13C NMR (101 MHz, CDCl3) d 140.84, 122.88,
91.14, 74.90, 58.84, 43.51, 28.60, 28.50, 26.51, 26.10, 26.07. HRMS
(EI) m/z M+: Calcd for C11H18O2: 182.1307. Found: 182.1302.
The enantiomeric ratio was determined by Daicel Chiralpak IC,
Hexanes/IPA = 95:5, 0.5 mL/min, k = 220 nm, tR (major) = 38.09 min,
tR (minor) = 36.46 min.
Acknowledgments
Generous financial support from the National Natural Science
Foundation of China (21202081), the Natural Science Foundation
of Jiangsu Province (BK2012297), Research Fund for the Doctoral
Program of Higher Education of China (20120091120026) is
gratefully acknowledged.
References and notes
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Please cite this article in press as: Cao, K.-S.; Zheng, W.-H. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.08.010