One-pot asymmetric synthesis of substituted tetrahydrofurans via a multicatalytic benzoin/Michael/acetalization cascade

Article abstract of DOI:10.1002/adsc.201400172

A sequential benzoin/Michael/acetalization tandem reaction catalyzed by NHC and amine together has been developed to assemble aromatic aldehydes and enals into chiral tetrahydrofuran derivatives bearing multiple functional groups and stereogenic centers with high stereoselectivity of up to 95:5 dr and 96% ee. The high yield and stereocontrol of this process may be due to both acid-promoted symmetrization of racemic acyloins and iminium ion activation of enals.

Full text of DOI:10.1002/adsc.201400172

FULL PAPERS
DOI: 10.1002/adsc.201400172
One-Pot Asymmetric Synthesis of Substituted Tetrahydrofurans
via a Multicatalytic Benzoin/Michael/Acetalization Cascade
Gu He,a Fengbo Wu,a Wei Huang,a,b Rui Zhou,a Liang Ouyang,a and Bo Hana,b,*
a
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Peopleꢀs Republic of
China
b
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine
Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Peopleꢀs
Republic of China
Fax : (+86)-28-6180-0234; e-mail: phdhuangwei@sina.com or hanbo@cdutcm.edu.cn
Received: February 17, 2014; Revised: March 17, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400172.
Abstract: A sequential benzoin/Michael/acetalization this process may be due to both acid-promoted sym-
tandem reaction catalyzed by NHC and amine to- metrization of racemic acyloins and iminium ion acti-
gether has been developed to assemble aromatic al- vation of enals.
dehydes and enals into chiral tetrahydrofuran deriva-
tives bearing multiple functional groups and stereo- Keywords: asymmetric synthesis; domino reactions;
genic centers with high stereoselectivity of up to 95:5 heterocycles; multicomponent reactions; organoca-
dr and 96% ee. The high yield and stereocontrol of talysis
Introduction
The NHC-catalyzed benzoin condensation is an
atom-economical method of generating a-hydroxy ke-
Developing multicomponent cascade reactions in tones, which are highly valuable synthons that occur
which densely functionalized scaffolds are assembled naturally in various furan-based biologically active
in one pot has become an increasingly fruitful area of compounds (Figure 1).[9] Several groups have reported
research.[1] This approach can be particularly powerful the synthesis of racemic tetrahydrofuran derivatives
when two catalytic entities are combined,[2] since this via benzoin-triggered multicomponent tandem reac-
can enable transformations and stereocontrol that tions under alkaline conditions with low yield and no
would be impossible in the presence of either catalyst stereocontrol.[10] However, we are unaware of studies
on its own.
exploring whether an analogous approach based on
One efficient combination involves N-heterocyclic sequential NHC–amine catalysis could generate these
carbene (NHC) catalysis,[3] an elegant organocatalytic
method for forming new bonds through umpolung, in
concert with either sequential transition metal cataly-
sis[4] or cooperative Lewis acid catalysis.[5] This cata-
lytic combination should be used under carefully con-
trolled conditions to prevent self-quenching and
mutual interference between the two catalysts.[6] Very
recently, Rovis,[7a,b] Enders,[7c] Jørgensen,[7d,e] Cꢁrdo-
va,[7f] Xu[7g] and Melchiorre[7h] have taken advantage
of the inherent basicity and compatibility of chiral
amines and NHCs to develop a model of consecutive
amine–NHC catalysis to stereoselectively access com-
plex molecules.[7] Conversely, few studies have exam-
ined the reverse catalytic sequence of NHC followed
by amine for the asymmetric synthesis of enantioen-
riched architectures.[8]
Figure 1. Examples of natural products containing the acy-
loin moiety.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

FULL PAPERS
Gu He et al.
Scheme 1. Synthetic strategy.
polysubstituted oxa-cyclic compounds efficiently and catalyst Id and DBU in acetonitrile or THF at room
stereoselectively.
temperature.
With the racemate 2a in hand, we then explored
the feasibility of subsequent Michael/acetalization.
First we acidified the basic mixture and induced for-
mation of the symmetrical enediol nucleophile, after
Results and Discussion
Previous studies and our own preliminary experi- which we added the chiral secondary amine catalyst
ments suggested that this approach was vulnerable to II and enal 3. Using this approach, we obtained hemi-
a significant side reaction, even in an air atmosphere, acetal 4a in moderate yield from 2a and cinnamyl al-
in which oxidation of the base-promoted anion inter- dehyde 3a using the Jørgensen–Hayashi catalyst IIa
mediate afforded dicarbonyl co-products in high yield and acetic acid (Table 1, entry 1). Direct oxidation of
(Scheme 1, Path A).[10] To avoid this path, we envi- the hemiacetal with PCC gave the more stable corre-
sioned that adding an acid to the acyloin would sponding g-lactone 5a as a 85:15 mixture of diastereo-
induce the formation of stable and symmetrical ene- mers, with 86% ee for the major isomer. Interestingly,
diol intermediates, thereby assuring a steady supply of this facile conversion may provide an alternative
nucleophiles for the subsequent enantio- and diaste- strategy for generating chiral cyclic a-acyloxycarbonyl
reoselective domino reaction. We know that chiral compounds.[16]
secondary amines can catalyze the stereoselective
The reaction gave lower yields of the desired prod-
conjugate Michael addition of various nucleophiles to uct when we used other secondary amine catalysts
a,b-unsaturated aldehydes, and that this addition de- (IIb–IId; entries 2–4). Screening identified the addi-
pends on acid-promoted iminium ion activation.[11] tive 4-fluorobenzoic acid and the solvent THF as
Therefore we decided to investigate a benzoin/Mi- giving the highest yield and stereoselectivity (en-
chael/acetalization cascade catalyzed by NHC and tries 5–9). To our delight, increasing the reaction tem-
amine to asymmetrically generate pharmaceutically perature to 608C improved the diastereoselectivity to
important tetrahydrofuran derivatives bearing multi- 90:10, and significantly shortened the time required
ple stereocenters (Path B).[12] In this process, the acid for completion (entry 10). Apparently, hemiacetal for-
promoted both the symmetrization of racemic acy- mation is under thermodynamic control in these ex-
loins and the iminium ion activation of enals, which perimental conditions.
we predicted would lead to high yield and stereoselec-
Using the optimized reaction conditions, we pro-
tivity. If successful, this approach would allow the ceeded to investigate the substrate scope (Table 2).
enantioselective construction of chiral quaternary The process showed a broad scope, but efficiencies
centers,[13] provide a novel cascade for asymmetric and stereoselectivities varied with the electronic
synthesis, and broaden the useful scope of sequential nature of the aromatic aldehydes 1. Products were
dual catalysis.[14]
generated in higher yield and with greater enantiose-
We first tested our hypothesis using aromatic alde- lectivity from aromatic aldehydes 1 bearing electron-
hyde 1a and NHC precatalyst I (Table 1). Based on withdrawing groups (Table 2, entries 2–7) than from
reports of NHC-catalyzed intermolecular benzoin those with neutral or electron-donating groups (en-
condensation,[15] we tested imidazolium-, thiazolium- tries 1 and 8). Heteroaryl aldehydes participated effi-
and triazolium-based precatalysts Ia–Id. We screened ciently, giving even higher yields and diastereoselec-
numerous conditions, including base, temperature, tivities than aryl aldehydes (entries 9 and 10). To
time and concentrations; complete optimisation re- extend the scope of the reaction further, we explored
sults are presented in Table S1 (Supporting Informa- other enals 3. The position and electronic properties
tion). Acyloin was produced in good yield using pre- of substituents on the aromatic ring of aryl-substituted
2
asc.wiley-vch.de
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
One-Pot Asymmetric Synthesis of Substituted Tetrahydrofurans
Table 1. Optimization of reaction conditions.[a]
Entry
Cat. II
Solvent
Additive
Time [h]
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
IIa
IIb
IIc
IId
IIa
IIa
IIa
IIa
IIa
IIa
MeCN
MeCN
MeCN
MeCN
toluene
THF
THF
THF
THF
THF
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
BzOH
TFA
16
>24
>24
8
8
8
16
4
4
40
32
30
34
40
45
32
50
65
62
85:15
85:15
87:13
75:25
85:15
85:15
90:10
80:20
85:15
90:10
86
85
85
82
90
89
90
91
90
92
9
p-FBA
p-FBA
10[e]
2
[a]
Unless otherwise noted, reactions were performed with precatalyst I (0.1 mmol), DBU (0.1 mol) and 1a (1.6 mmol) in sol-
vent (2 mL) at room temperature, after which acidic additive (0.2 mmol), catalyst II (0.1 mmol) and 3a (0.4 mmol) were
added.
Yield of isolated 5a.
Calculated based on H NMR analysis of the crude reaction mixture.
Determined by HPLC using a chiral stationary phase.
[b]
[c]
[d]
[e]
1
Reaction performed at 608C.
a,b-unsaturated aldehydes did not appear to signifi- enediol and the Si face of the iminium ion to provide
cantly affect reaction efficiency (entries 11–14). Even the adduct and subsequent hemiacetal in the S,S con-
the less reactive acrolein and crotonaldehyde partici- figuration in high optical purity.
pated in the reaction, giving products with moderate
To illustrate the synthetic potential of our ap-
enantioselectivity (entries 15 and 16), albeit with proach, we smoothly converted the chiral hemiacetal
lower dr for 5p. Unfortunately, the reaction did not 4 into several versatile building blocks beside the g-
proceed with a-substituted or g-branched enals.[17] lactone (Scheme 3). The hemiaminal 4a was dehy-
When this catalytic cascade reaction was conducted droxylated by treatment with Et3SiH and BF3·Et2O in
on a larger scale, similar good results were observed CH2Cl2 as solvent at À208C, providing the chiral tet-
(Table 2, entry 17).
rahydrofuran 6. The hydroxy group of 4a was also
The absolute configuration of 5a was determined acetylated to give 7. Directly treating the tetrahydro-
by X-ray crystallographic analysis,[18] while that of pyranol 4a with allyltrimethylsilane or cyanotrime-
other products was tentatively assigned by analogy.
thylsilane in the presence of TiCl4 generated the cor-
We propose a transition-state model to explain the responding polysubstituted tetrahydrofurans 8 and 9
high diastereo- and enantioselectivity of the reaction with three stereogenic centers via SN1 reactions.
(Scheme 2). The symmetrical enediol approaches the
b-position of the chiral iminium ion intermediate,
while avoiding steric repulsion from the bulky diphe- Conclusions
nylsiloxymethyl group on the pyrrolidine ring and b-
substituent of the enal. As a result, a carbon-carbon In summary, we have developed an unprecedented se-
bond forms preferentially between the Re face of the quential organocatalytic reaction involving a benzoin/
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

FULL PAPERS
Gu He et al.
Table 2. Investigating the scope of the cascade reaction.[a]
Entry
R1
R2
Product
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5a
62
65
73
68
70
68
63
55
76
74
67
64
61
60
47
58[e]
58
90:10
92:8
84:16
93:7
90:10
90:10
95:5
94:6
95:5
95:5
82:18
90:10
92:8
87:13
–
92
91
90
96
93
95
92
90
86
87
90
92
91
88
61
75/71
90
2-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
4-FC6H4
2,4-Cl2C6H3
4-i-PrC6H4
2-furyl
2-thienyl
Ph
Ph
Ph
Ph
4-ClC6H4
Ph
9
Ph
Ph
10
11
12
13
14
15
16
17[f]
4-ClC6H4
4-BrC6H4
3-FC6H4
4-MeC6H4
H
CH3
Ph
52:48
90:10
Ph
[a]
See entry 10 and footnote[a] in Table 1.
Yield of isolated 5.
[b]
[c]
[d]
[e]
[f]
Based on chiral HPLC analysis.
1
Calculated from H NMR analysis of the crude reaction mixture.
Calculated from two isolated isomers.
The scaled-up reaction: 1a (8 mmol), 3a (2 mmol), Id (0.5 mmol), IIa (0.5 mmol).
Scheme 2. Proposed mechanism to explain the high stereoselectivity.
Scheme 3. Chemical transformations of 4a.
4
asc.wiley-vch.de
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
One-Pot Asymmetric Synthesis of Substituted Tetrahydrofurans
chromatography (petroleum ether/ethyl acetate=15:1) to
give g-lactone 5.
AHCTUNGTREG(NNUN 4S,5S)-5-Benzoyl-4,5-diphenyldihydrofuran-2(3H)-one
Michael/acetalization cascade for the asymmetric as-
sembly of aromatic aldehydes and enals into tetrahy-
drofuran derivatives bearing multiple functional
groups and stereogenic centers. The reaction proceeds
with high stereoselectivity of up to 95:5 dr and 96%
ee. The high yield and diastereomeric ratio may be
due to the fact that acid promotes not only the imini-
um ion activation of enals but also the symmetrization
of racemic acyloins. The mild reaction conditions,
short reaction times, and high tolerance for various
functional groups makes this strategy an attractive
method for the construction of enantioenriched heter-
ocyclic compounds. Our laboratory is conducting fur-
ther studies into asymmetric domino reactions involv-
ing sequential NHC-amine catalysis.
(5a): Obtained as a white solid; yield: 85 mg (62%) for two
steps after flash chromatography. The dr value was calculat-
1
ed to be 90:10 by H NMR analysis of the crude reaction
mixture and the enantiomeric excess was determined to be
92% by HPLC (AmyCoat column, 5% 2-propanol/n-
hexane, 1 mLminÀ1, UV 254 nm): tmajor =9.77 min, tminor
=
11.73 min; mp 138–1398C; [a]2D0: À138.9 (c 0.12 in EtOH);
1H NMR (400 MHz, CDCl3): d=7.90 (d, J=7.6 Hz, 2H),
7.46–7.43 (m, 1H), 7.32–7.26 (m, 2H), 7.11–7.07 (m, 8H),
6.94 (s, 2H), 4.88 (t, J=5.6 Hz, 1H), 3.03 (dd, J1 =18.0 Hz,
J2 =8.8 Hz, 1H), 2.88 (dd, J1 =18.0 Hz, J2 =3.2 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=195.29, 175.24, 137.31,
135.33, 133.59, 133.42, 130.95, 128.79, 128.45, 128.27, 128.19,
128.07, 127.26, 124.68, 95.07, 47.94, 35.53; ESI-HR-MS:
m/z=365.1152, calcd. for C23H18O3 +Na: 365.1154.
AHCTUNGERTG(NNUN 4S,5S)-5-(2-Chlorobenzoyl)-5-(2-chlorophenyl)-4-phenyl-
Experimental Section
dihydrofuran-2(3H)-one (5b): Obtained as a white solid;
yield: 107 mg (65%) for two steps after flash chromatogra-
phy. The dr value was calculated to be 92:8 by 1H NMR
analysis of the crude reaction mixture and the enantiomeric
excess was determined to be 91% by HPLC (Amycoat
column, 5% 2-propanol/n-hexane, 1 mLminÀ1, UV 220 nm):
1
NMR data was obtained for H at 400 MHz, and for 13C at
100 MHz. Chemical shifts were reported in ppm from tetra-
methylsilane with the solvent resonance as the internal stan-
dard in CDCl3 solution. ESI HR-MS was recorded on
a Waters SYNAPT G2. In each case, the enantiomeric ratio
was determined by HPLC analysis on a chiral column in
comparison with authentic racemates, using a Daicel Chiral-
pak AD-H Column (250ꢃ4.6 mm), Daicel Chiralpak OD-H
Column (250ꢃ4.6 mm), Daicel Chiralpak AS-H Column
(250ꢃ4.6 mm) or Kromasil AmyCoat Column (250ꢃ
4.6 mm). UV detection was monitored at 220 nm or 254 nm.
Optical rotation data were examined in EtOH solution at
208C. Column chromatography was performed on silica gel
(200–300 mesh) eluting with ethyl acetate and petroleum
ether. TLC was performed on glass-backed silica plates. UV
light and I2 were used to visualize products. Melting points
were determined on a Mel-Temp apparatus and are uncor-
rected. All chemicals were from Adamas-beta and were
used without purification unless otherwise noted.
t
major =9.97 min,
t
minor =11.09 min; mp 144–1458C; [a]2D0:
1
À156.3 (c 0.03 in EtOH); H NMR (400 MHz, CDCl3): d=
7.57 (d, J=7.2 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.26–7.21
(m, 1H), 7.12–6.93 (m, 10H), 5.05 (d, J=8.8 Hz, 1H), 3.62
(dd, J1 =18.0 Hz, J2 =9.2 Hz, 1H), 2.71 (d, J=18.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=193.46, 175.25, 139.28,
134.30, 134.02, 133.48, 131.81, 131.11, 130.70, 129.80, 129.70,
129.32, 128.21, 127.93, 127.38, 126.77, 125.48, 94.29, 45.32,
37.97; ESI-HR-MS: m/z=433.0371, calcd. for C23H16Cl2O3 +
Na: 433.0374.
AHCTUNGERTG(NNUN 4S,5S)-5-(4-Chlorobenzoyl)-5-(4-chlorophenyl)-4-phenyl-
dihydrofuran-2(3H)-one (5c): Obtained as a white solid;
yield: 120 mg (73%) for two steps after flash chromatogra-
1
phy. The dr value was calculated to be 84:16 by H NMR
analysis and the enantiomeric excess was determined to be
90% by HPLC (Chiralpak OD-H column, 5% 2-propanol/n-
hexane, 1 mLminÀ1, UV 254 nm): tmajor =17.29 min, tminor
=
20.24 min; mp 114–1158C; [a]2D0: À176.4 (c 0.1 in EtOH);
1H NMR (400 MHz, CDCl3): d=7.84 (d, J=8.4 Hz, 2H),
7.31–7.29 (m, 2H), 7.11–7.09 (m, 5H), 6.98–6.93 (m, 4H),
4.85 (dd, J1 =8.0 Hz, J2 =5.6 Hz, 1H), 3.03 (dd, J1 =18.0 Hz,
J2 =8.4 Hz, 1H), 2.87 (dd, J1 =18.0 Hz, J2 =5.6 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=193.84, 174.65, 140.29,
136.89, 134.49, 133.76, 132.27, 131.61, 128.79, 128.76, 128.63,
128.35, 127.62, 126.07, 94.48, 47.75, 35.38; ESI-HR-MS:
m/z=433.0378, calcd. for C23H16Cl2O3 +Na: 433.0374.
General Procedure for the Asymmetric Synthesis of
g-Lactone 5
The reaction was carried out with precatalyst Id (0.1 mmol),
DBU (0.1 mol) and 1 (1.6 mmol) in THF (2.0 mL) at room
temperature to afford the racemate acyloin 2, after which 4-
fluorobenzoic acid (0.2 mmol), diphenylprolinol TMS ether
IIa (0.1 mmol) and enal 3 (0.4 mmol) were added in one-
pot. The reaction mixture was stirred at 608C for a specified
reaction time (about 6–8 h) until the reaction was completed
(monitored by TLC). Then the reaction mixture was concen-
trated and the residue was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate=10:1) to give
hemiacetal 4.
Hemiacetal 4 was oxidized to the stable corresponding g-
lactone 5 as follows. To a solution of 4 in dichloromethane
(5 mL) was added PCC (107.8 mg, 0.5 mmol). The mixture
was stirred for 2 h at 508C. The solid was removed by filtra-
tion through celite. The filtrate was evaporated under re-
duced pressure and the residue was purified by column
AHCTUNGTREG(NNUN 4S,5S)-5-(3-Bromobenzoyl)-5-(3-bromophenyl)-4-phenyl-
dihydrofuran-2(3H)-one (5d): Obtained as a white solid;
yield: 136 mg (68%) for two steps after flash chromatogra-
phy. The dr value was calculated to be 93:7 by 1H NMR
analysis of the crude reaction mixture and the enantiomeric
excess was determined to be 96% by HPLC (Chiralpak OD-
H
column, 10% 2-propanol/n-hexane, 1 mLminÀ1, UV
220 nm): tminor =13.18 min, tmajor =15.51 min; mp 126–1278C;
[a]2D0: À175.0 (c=0.10 in EtOH); 1H NMR (400 MHz,
CDCl3): d=8.08 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.60–7.56
(m, 1H), 7.25–7.23 (m, 1H), 7.20–7.16 (m, 2H), 7.11 (m,
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

FULL PAPERS
Gu He et al.
3H), 7.00–6.91 (m, 4H), 4.84 (t, J=6.8 Hz, 1H), 3.03 (dd,
J1 =18.0 Hz, J2 =8.4 Hz, 1H), 2.88 (dd, J1 =18.0 Hz, J2 =
5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=193.60,
174.52, 137.25, 136.73, 136.55, 135.04, 133.47, 131.57, 130.07,
129.94, 129.60, 128.59, 128.32, 127.78, 127.70, 123.26, 122.92,
122.68, 94.20, 47.94, 35.24; ESI-HR-MS: m/z=520.9361,
calcd. for C23H16Br2O3 +Na: 520.9364.
solid; yield: 94 mg (55%) for two steps after flash chroma-
tography. The dr value was calculated to be 94:6 by
1H NMR analysis of the crude reaction mixture and the
enantiomeric excess was determined to be 90% by HPLC
(Amycoat column, 5% 2-propanol/n-hexane, 1 mLminÀ1,
UV 254 nm):
tmajor =6.43 min, tminor =7.74 min; mp 132–
1338C; [a]2D0: À130.2 (c 0.096 in EtOH); H NMR (400 MHz,
CDCl3): d=7.86 (d, J=8.4 Hz, 2H), 7.17–7.15 (m, 2H),
7.04–7.03 (m, 3H), 6.96–6.88 (m, 6H), 4.82 (dd, J1 =8.4 Hz,
J2 =6.4 Hz, 1H), 2.99 (dd, J1 =18.0 Hz, J2 =8.8 Hz, 1H),
2.90–2.83 (m, 2H), 2.77–2.71 (m, 1H), 1.20 (d, J=2.0 Hz,
3H), 1.18 (d, J=1.6 Hz, 3H), 1.11 (d, J=3.2 Hz, 3H), 1.10
(d, J=3.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=195.06,
175.47, 154.91, 148.99, 137.40, 132.71, 131.44, 131.32, 128.85,
127.86, 127.06, 126.39, 124.57, 95.20, 48.04, 35.40, 34.24,
33.60, 23.78, 23.77, 23.53, 23.47; ESI-HR-MS: m/z=
449.2090, calcd. for C29H30O3 +Na: 449.2093.
1
ACHTUNGTRENNUNG(4S,5S)-5-(4-Bromobenzoyl)-5-(4-bromophenyl)-4-phenyl-
dihydrofuran-2(3H)-one (5e): Obtained as a white solid;
yield: 140 mg (70%) for two steps after flash chromatogra-
1
phy. The dr value was calculated to be 90:10 by H NMR
analysis of the crude reaction mixture and the enantiomeric
excess was determined to be 93% by HPLC (Amycoat
column, 5% 2-propanol/n-hexane, 1 mLminÀ1, UV 220 nm):
t
major =10.94 min, tminor =13.64 min; mp 143–1448C; [a]2D0:
1
À188.5 (c 0.052 in EtOH); H NMR (400 MHz, CDCl3): d=
7.76 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.26–7.24
(m, 3H), 7.11 (s, 3H), 6.91–6.89 (m, 3H), 4.84 (t, J=6.4 Hz,
1H), 3.03 (dd, J1 =18.0 Hz, J2 =8.4 Hz, 1H), 2.87 (dd, J1 =
18.0 Hz, J2 =5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
193.85, 174.58, 136.83, 134.26, 132.31, 132.01, 131.78, 131.74,
129.19, 128.62, 128.36, 127.64, 126.34, 122.68, 94.50, 47.70,
AHCTUNGERTG(NNUN 4S,5S)-5-(Furan-2-carbonyl)-5-(furan-2-yl)-4-phenyldihy-
drofuran-2(3H)-one (5i): Obtained as a white solid; yield:
98 mg (76%) for two steps after flash chromatography. The
1
dr value was calculated to be 95:5 by H NMR analysis and
the enantiomeric excess was determined to be 86% by
35.37;
C23H16Br2O3 +Na: 520.9364.
(4S,5S)-5-(4-Fluorobenzoyl)-5-(4-fluorophenyl)-4-phenyl-
ESI
-HR-MS:
m/z=520.9362,
calcd.
for
HPLC (Chiralpak OD-H column, 20% 2-propanol/n-
hexane, 1 mLminÀ1, UV 220 nm), tmajor =22.59 min, tminor
=
G
28.17 min. m.p. 126–1278C; [a]2D0: À116.4 (c=0.12 in EtOH);
1H NMR (400 MHz, CDCl3): d=7.65 (s, 1H), 7.32 (br s,
1H), 7.18 (br s, 4H), 7.09 (br s, 2H), 6.49 (s, 1H), 6.15 (d,
J=8.8 Hz, 2H), 4.70 (t, J=8.4 Hz, 1H), 3.11–2.97 (m, 2H)
ppm; 13C NMR (100 MHz, CDCl3): d=181.03, 174.27,
149.14, 148.16, 147.95, 143.20, 136.25, 128.29, 128.24, 127.66,
123.13, 112.56, 110.58, 109.38, 89.67, 46.69, 34.42 ppm; ESI
HRMS: calcd. For C19H14O5 +Na 345.0739, found 345.0743.
dihydrofuran-2(3H)-one (5f): Obtained as a white solid;
yield: 103 mg (68%) for two steps after flash chromatogra-
1
phy. The dr value was calculated to be 90:10 by H NMR
analysis of the crude reaction mixture and the enantiomeric
excess was determined to be 95% by HPLC (Chiralpak OD-
H
column, 5% 2-propanol/n-hexane, 1 mLminÀ1, UV
254 nm): tminor =16.58 min, tmajor =25.25 min; mp 127–1288C;
1
[a]2D0: À102.4 (c 0.1 in EtOH); H NMR (400 MHz, CDCl3):
ACHTUNGTREN(NUNG 4S,5R)-4-Phenyl-5-(thiophen-2-yl)-5-(thiophene-2-car-
d=7.95 (s, 2H), 7.10 (br s, 3H), 7.01–7.00 (m, 4H), 6.92 (m,
2H), 6.83–6.79 (m, 2H), 4.86 (t, J=6.0 Hz, 1H), 3.03 (dd,
J1 =18.0 Hz, J2 =8.4 Hz, 1H), 2.88 (dd, J1 =18.0 Hz, J2 =
4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=193.59,
174.82, 165.77 (d, JC,F =255 Hz), 162.41 (d, JC,F =247 Hz),
137.10, 133.78 (d, JC,F =9 Hz), 131.14 (d, JC,F =4 Hz), 129.72
(d, JC,F =3 Hz), 128.65, 128.27, 127.50, 126.54 (d, JC,F =9 Hz),
115.72 (d, JC,F =3 Hz), 115.50 (d, JC,F =2 Hz), 94.57, 47.81,
35.38; ESI-HR-MS: m/z=401.0968, calcd. for C23H16F2O3 +
Na: 401.0965.
bonyl)dihydrofuran-2(3H)-one (5j): Obtained as a white
solid; yield: 105 mg (74%) for two steps after flash chroma-
tography. The dr value was calculated to be 95:5 by
1H NMR analysis of the crude reaction mixture and the
enantiomeric excess was determined to be 87% by HPLC
on Chiralpak OD-H column (10% 2-propanol/n-hexane,
1 mLminÀ1, UV 254 nm): tminor =18.83 min, tmajor =23.25 min;
mp 90–918C; [a]2D0: À90.8 (c 0.10 in EtOH); 1H NMR
(400 MHz, CDCl3): d=7.98 (d, J=3.6 Hz, 1H), 7.66 (d, J=
4.8 Hz, 1H), 7.16–7.05 (m, 7H), 6.75–6.72 (m, 1H), 6.60–
6.59 (m, 1H), 4.75 (t, J=7.2 Hz, 1H), 3.06–2.93 (m, 2H);
13C NMR (100 MHz, CDCl3): d=187.83, 174.24, 139.34,
138.10, 136.77, 136.63, 135.76, 128.70, 128.61, 128.18, 127.67,
127.10, 126.17, 126.09, 93.47, 48.18, 34.96; ESI-HR-MS:
m/z=377.0280, calcd. for C19H14O3S2 +Na: 377.0282.
ACHTUNGTRENNUNG(4S,5S)-5-(2,4-Dichlorobenzoyl)-5-(2,4-dichlorophenyl)-4-
phenyldihydrofuran-2(3H)-one (5g): Obtained as a white
solid; yield: 121 mg (63%) for two steps after flash chroma-
tography. The dr value was calculated to be 95:5 by
1H NMR analysis of the crude reaction mixture and the
enantiomeric excess was determined to be 92% by HPLC
(Amycoat column; 5% 2-propanol/n-hexane, 1 mLminÀ1,
AHCTUNGERTG(NNUN 4S,5S)-5-Benzoyl-4-(4-chlorophenyl)-5-phenyldihydrofur-
an-2(3H)-one (5k): Obtained as a white solid; yield: 101 mg
(67%) for two steps after flash chromatography. The dr
UV 254 nm):
tmajor =6.80 min, tminor =9.08 min; mp 148–
1498C; [a]2D0: À61.4 (c 0.12 in EtOH); H NMR (400 MHz,
CDCl3): d=7.49 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.19–7.17
(m, 1H), 7.07–6.97 (m, 8H), 4.98 (d, J=8.8 Hz, 1H), 3.61
(dd, J1 =18.0 Hz, J2 =9.2 Hz, 1H), 2.82 (d, J=18.4 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=192.09, 174.73, 138.86,
137.85, 135.08, 134.85, 132.83, 132.17, 131.36, 131.33, 130.30,
129.68, 128.73, 128.46, 127.75, 127.25, 126.03, 93.71, 45.39,
37.76; ESI-HR-MS: m/z=500.9593, calcd. for C23H14Cl4O3 +
Na: 500.9595.
value was calculated to be 82:18 by H NMR analysis of the
1
1
crude reaction mixture and the enantiomeric excess was de-
termined to be 90% by HPLC (Amycoat column, 5% 2-
propanol/n-hexane, 1 mLminÀ1, UV 254 nm): tmajor
=
12.18 min, tminor =16.32 min; mp 123–1248C; [a]2D0: À50 (c
1
0.10 in EtOH); H NMR (400 MHz, CDCl3): d=7.89 (d, J=
8.0 Hz, 2H), 7.47–7.43 (m, 1H), 7.32–7.29 (m, 2H), 7.15 (br
s, 3H), 7.06–7.04 (m, 4H), 6.86 (d, J=7.6 Hz, 2H), 4.85 (t,
J=7.6 Hz, 1H), 3.01 (dd, J1 =18.0 Hz, J2 =8.4 Hz, 1H), 2.82
(dd, J1 =18.0 Hz, J2 =6.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=194.03, 173.71, 134.67, 134.01, 132.50, 132.41,
ACHTUNGTRENNUNG
6
asc.wiley-vch.de
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
One-Pot Asymmetric Synthesis of Substituted Tetrahydrofurans
132.18, 129.91, 129.10, 127.65, 127.46, 127.26, 127.17, 123.58,
93.64, 46.37, 34.28; ESI-HR-MS: m/z=399.0766, calcd. for
C23H17ClO3 +Na: 399.0764.
ACHTUNGTRENNUNG(4S,5S)-5-Benzoyl-4-(4-bromophenyl)-5-phenyldihydrofur-
an-2(3H)-one (5l): Obtained as a white solid; yield: 108 mg
UV 254 nm): tmajor =18.24 min, tminor =20.52 min; [a]2D0: À83.3
1
(c 0.06 in EtOH); H NMR (400 MHz, CDCl3): d=7.89 (d,
J=8.4 Hz, 2H), 7.39 (br s, 4H), 7.32 (d, J=8.4 Hz, 2H),
3.46–3.39 (m, 1H), 2.61–2.56 (m, 2H), 2.32–2.25 (m, 1H);
13C NMR (100 MHz, CDCl3): d=193.72, 175.03, 140.33,
137.65, 134.88, 132.13, 131.52, 129.64, 128.80, 125.17, 91.49,
34.17, 27.88; ESI-HR-MS: m/z=357.0059, calcd. for
C17H12Cl2O3 +Na: 357.0061.
(64%) for two steps after flash chromatography. The dr
1
value was calculated to be 90:10 by H NMR analysis of the
crude reaction mixture and the enantiomeric excess was de-
termined to be 92% by HPLC (Amycoat column, 5% 2-
AHCTUNGTREG(NNUN 4R,5S)-5-Benzoyl-4-methyl-5-phenyldihydrofuran-2(3H)-
propanol/n-hexane, 1 mLminÀ1, UV 254 nm): tmajor
=
one (5p): Obtained as a white semisolid; yield: 34 mg (30%)
for two steps after flash chromatography. The enantiomeric
excess was determined to be 75% by HPLC (Chiralpak OD-
12.79 min, tminor =17.69 min; mp 149–1508C; [a]2D0: À89.3 (c
1
0.12 in EtOH); H NMR (400 MHz, CDCl3): d=7.89 (d, J=
H
column, 2% 2-propanol/n-hexane, 1 mLminÀ1, UV
8.0 Hz, 2H), 7.46–7.43 (m, 1H), 7.32–7.28 (m, 2H), 7.21–
7.15 (m, 5H), 7.04 (br s, 2H), 6.80 (d, J=8.0 Hz, 2H), 4.83
(t, J=7.6 Hz, 1H), 3.01 (dd, J1 =18.0 Hz, J2 =8.8 Hz, 1H),
2.81 (dd, J1 =18.0 Hz, J2 =6.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=195.04, 174.70, 136.23, 135.02, 133.53, 133.44,
131.16, 130.94, 130.49, 128.70, 128.52, 128.30, 124.62, 121.37,
94.59, 47.48, 35.26; ESI-HR-MS: m/z=399.0766, calcd. for
C123H17BrO3 +Na: 443.0259.
220 nm): tmajor =7.99 min, tminor =12.63 min; [a]2D0: À192.3 (c
1
0.05 in EtOH); H NMR (400 MHz, CDCl3): d=7.88 (d, J=
8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.40–7.36 (m, 4H),
7.26 (s, 2H), 3.09 (t, J=6.4 Hz, 1H), 2.57 (dd, J1 =17.2 Hz,
J2 =7.2 Hz, 1H), 2.26 (dd, J1 =17.2 Hz, J2 =9.2 Hz, 1H), 1.24
(d, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=196.01,
174.83, 140.07, 136.55, 135.20, 133.69, 131.31, 129.34, 128.73,
126.60, 94.11, 42.83, 36.01, 16.48; ESI-HR-MS: m/z=
303.0995, calcd. for C18H16O3 +Na: 303.0997.
ACHTUNGTRENNUNG(4S,5S)-5-Benzoyl-4-(3-fluorophenyl)-5-phenyldihydrofur-
an-2(3H)-one (5m): Obtained as a white solid; yield: 88 mg
(61%) for two steps after flash chromatography. The dr
AHCTUNGTREG(NNUN 4S,5S)-5-Benzoyl-4-methyl-5-phenyldihydrofuran-2(3H)-
1
one: The diastereomer of 5p was obtained as a white semi-
solid; yield: 31 mg (28%) for two steps after flash chroma-
tography. The enantiomeric excess was determined to be
71% by HPLC (Chiralpak AD-H column, 5% 2-propanol/n-
value was calculated to be 92:8 by H NMR analysis of the
crude reaction mixture and the enantiomeric excess was de-
termined to be 91% by HPLC (Amycoat column; 5% 2-
propanol/n-hexane, 1 mLminÀ1, UV 254 nm): tmajor
=
hexane, 1 mLminÀ1, UV 254 nm): tmajor =14.53 min, tminor
=
10.57 min, tminor =12.95 min; mp 129–1308C; [a]2D0: À97.7 (c
22.05 min; [a]2D0: +115.2 (c 0.06 in EtOH); 1H NMR
(400 MHz, CDCl3): d=7.83 (d, J=8.4 Hz, 2H), 7.40–7.27
(m, 8H), 3.63 (m, 1H), 2.75 (dd, J1 =17.6 Hz, J2 =8.0 Hz,
1H), 2.28 (dd, J1 =17.6 Hz, J2 =4.8 Hz, 1H), 0.77 (d, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=194.30,
174.58, 140.21, 134.93, 133.84, 132.17, 131.68, 129.50, 128.75,
125.90, 93.93, 36.81, 36.43, 16.52; ESI-HR-MS: m/z=
303.0995, calcd. for C18H16O3 +Na: 303.0997.
1
0.13 in EtOH); H NMR (400 MHz, CDCl3): d=7.90 (d, J=
8.0 Hz, 2H), 7.47–7.43 (m, 1H), 7.33–7.29 (m, 2H), 7.15–
7.14 (m, 3H), 7.07–7.02 (m, 3H), 6.79–6.73 (m, 2H), 6.65 (d,
J=10.0 Hz, 1H), 4.88 (t, J=7.2 Hz, 1H), 3.03 (dd, J1 =
18.0 Hz, J2 =8.8 Hz, 1H), 2.86 (dd, J1 =18.0 Hz, J2 =6.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=194.96, 174.70, 162.36
(d, JC,F =244 Hz), 139.85 (d, JC,F =7 Hz), 135.05, 133.53,
133.42, 130.97, 129.52, 128.62, 128.45, 128.30, 125.17, 124.57,
115.93 (d, JC,F =21 Hz), 114.25 (d, JC,F =21 Hz), 94.76, 47.59,
35.27; ESI-HR-MS: m/z=383.1057, calcd. for C23H17FO3 +
Na: 383.1059.
Synthetic Transformations to Access Diverse Building
Blocks
ACHTUNGTRENNUNG(4S,5S)-5-Benzoyl-5-phenyl-4-(para-tolyl)dihydrofuran-
2(3H)-one (5n): Obtained as a white solid; yield: 86 mg
(60%) for two steps after flash chromatography. The dr
value was calculated to be 87:13 by H NMR analysis of the
ACHUTNGREN[NUG (2S,3S)-2,3-Diphenyltetrahydrofuran-2-yl]ACHTUNTGREN(NUGN phenyl)meth-
anone (6): To a solution of 4a (68.9 mg, 0.2 mmol) and trie-
thylsilane (69.8 mg, 0.6 mmol) in DCM (5 mL) was added
BF3·Et2O (84 mL, 0.66 mmol). The mixture was stirred at
08C for 12 h. The reaction was quenched with aqueous
NaHCO3, extracted with CH2Cl2. The organic layer was
dried over Na2SO4 and concentrated. The residue was puri-
fied by flash chromatography on silica gel (petroleum ether/
ethyl acetate=40:1). The tetrahydrofuran derivative 6 was
obtained as a white semisolid; yield: 53 mg (80%) after
flash chromatography. The dr value was calculated to be
1
crude reaction mixture and the enantiomeric excess was de-
termined to be 88% by HPLC on Chiralpak AD-H column
(5% 2-propanol/n-hexane, 1 mLminÀ1, UV 254 nm): tmajor
=
11.13 min, tminor =12.73 min, mp 99–1008C; [a]2D0: À118.0 (c
1
0.10 in EtOH); H NMR (400 MHz, CDCl3): d=7.90 (d, J=
7.6 Hz, 2H), 7.45–7.41 (m, 1H), 7.31–7.27 (m, 2H), 7.12–
7.11 (m, 3H), 7.065–7.056 (m, 2H), 6.87 (d, J=8.0 Hz, 2H),
6.81 (d, J=8.0 Hz, 2H), 4.83 (t, J=7.2 Hz, 1H), 2.99 (dd,
J1 =17.6 Hz, J2 =8.4 Hz, 1H), 2.84 (dd, J1 =18.0 Hz, J2 =
6.0 Hz, 1H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
195.40, 175.32, 136.91, 135.38, 134.15, 133.78, 133.36, 130.92,
128.74, 128.66, 128.44, 128.25, 128.17, 124.76, 95.06, 47.68,
35.64, 20.96; ESI-HR-MS: m/z=379.1312, calcd. for
C24H20O3 +Na: 379.1310.
(S)-5-(4-Chlorobenzoyl)-5-(4-chlorophenyl)dihydrofuran-
2(3H)-one (5o): Obtained as a white semisolid; yield: 63 mg
(47%) for two steps after flash chromatography. The enan-
tiomeric excess was determined to be 61% by HPLC (Chir-
alpak AS-H column, 2% 2-propanol/n-hexane, 1 mLminÀ1,
1
95:5 by H NMR analysis and the enantiomeric excess was
determined to be 90% by HPLC (Chiralpak AD-H column,
5% 2-propanol/n-hexane, 1 mLminÀ1, UV 254 nm): tmajor
=
4.86 min, tminor =5.20 min; [a]2D0: À82.4 (c 0.21 in EtOH);
1H NMR (400 MHz, CDCl3): d=7.97 (d, J=7.6 Hz, 2H),
7.39–7.36 (m, 1H), 7.27–7.21 (m, 3H), 7.13–7.11 (m, 2H),
7.05–6.95 (m, 7H), 4.55 (t, J=7.2 Hz, 1H), 4.43 (dt, J1 =
8.4 Hz, J2 =4.4 Hz, 1H), 3.92 (dd, J1 =16.8 Hz, J2 =8.4 Hz,
1H), 2.43–2.24 (m, 2H); 13C NMR (100 MHz, CDCl3): d=
200.13, 140.62, 138.63, 134.83, 132.56, 130.66, 129.26, 127.93,
127.84, 127.59, 127.08, 126.12, 125.67, 95.26, 67.89, 50.94,
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

FULL PAPERS
Gu He et al.
32.95; ESI-HR-MS: m/z=351.1360, calcd. for C23H20O2 +
Na: 351.1361.
ACHTUNGTRENNUNG(2R,4S,5S)-5-Benzoyl-4,5-diphenyltetrahydrofuran-2-yl
rated aqueous NaHCO3 solution (2 mL) at À408C. The re-
sulting suspension was filtered through a celite pad. The
aqueous layer was extracted three times with EtOAc. The
combined organic layer was washed with H2O and saturated
aqueous NaCl, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by flash chroma-
tography on silica gel (petroleum ether/ethyl acetate=40:1).
The cyano-substituted tetrahydrofuran derivative 9 was ob-
tained as a white solid; yield: 41 mg (58%) after flash chro-
matography. The dr value was calculated to be 90:10 by
1H NMR analysis and the enantiomeric excess was deter-
mined to be 89% by HPLC (Chiralpak AD-H column, 5%
acetate (7): To a solution of 4a (68.9 mg, 0.2 mmol) in DCM
(4 mL) was added acetic anhydride (30.6 mg, 0.3 mmol) and
triethylamine (30.4 mg 0.3 mmol). The mixture was stirred
for 2 h at room temperature. When the reaction was com-
plete, the reaction mixture was concentrated and the residue
was purified by flash chromatography on silica gel (petrole-
um ether/ethyl acetate=30:1). The acetylated derivative 7
was obtained as a white solid; yield: 63 mg (82%) after flash
chromatography. The dr value was calculated to be 95:5 by
1H NMR analysis and the enantiomeric excess was deter-
mined to be 91% by HPLC (Chiralpak AD-H column, 5%
2-propanol/n-hexane, 1 mLminÀ1, UV 254 nm): tminor
=
5.03 min, tmajor =7.57 min; mp 148–1498C; [a]2D0: +118.9 (c
1
2-propanol/n-hexane, 1 mLminÀ1, UV 254 nm): tmajor
=
0.04 in EtOH); H NMR (400 MHz, CDCl3): d=7.88 (d, J=
6.12 min, tminor =6.48 min; mp 104–1058C; [a]2D0: À62.5 (c
7.2 Hz, 2H), 7.37–7.36 (m, 1H), 7.30–7.28 (m, 2H), 7.04–
7.00 (m, 5H), 6.95 (br s, 3H), 6.69 (br s, 2H), 5.30–5.29 (m,
1H), 4.59 (t, J=6.4 Hz, 1H), 1.75–1.70 (m, 1H), 1.61–1.58
(m, 1H); 13C NMR (100 MHz, CDCl3): d 199.53, 140.12,
137.52, 135.30, 132.16, 130.65, 129.04, 128.63, 127.89, 127.82,
127.46, 127.14, 126.00, 125.17, 100.63, 95.33, 50.08, 38.95;
ESI-HR-MS: m/z=376.1310, calcd. for C24H19NO2 +Na:
376.1313.
1
0.12 in EtOH); H NMR (400 MHz, CDCl3): d=7.96 (d, J=
7.6 Hz, 2H), 7.41–7.37 (m, 1H), 7.30–7.28 (m, 2H), 7.09–
7.02 (m, 8H), 6.95–6.93 (m, 2H), 6.82–6.81 (m, 1H), 4.86 (t,
J=7.6 Hz, 1H), 2.61–2.48 (m, 2H), 1.52 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=198.55, 170.29, 139.34, 136.86, 134.65,
132.52, 130.83, 129.79, 129.11, 127.99, 127.92, 127.73, 126.44,
125.27, 97.88, 96.39, 49.63, 38.84, 20.46; ESI-HR-MS: m/z=
393.1465, calcd. for C25H22O3 +Na: 393.1467.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Acknowledgements
trimethylsilane (79.5 mL, 0.5 mmol) were added to a solution
of 4a (68.9 mg, 0.2 mmol) in CH2Cl2 (5 mL) at À708C under
an argon atmosphere. The resulting mixture was slowly
warmed up to À408C and stirred for 5 h before being
quenched with Et3N (0.4 mL) followed by addition of satu-
rated aqueous NaHCO3 solution (2 mL) at À408C. The re-
sulting suspension was filtered through a celite pad. The
aqueous layer was extracted three times with EtOAc. The
combined organic layer was washed with H2O and saturated
aqueous NaCl, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by flash chroma-
tography on silica gel (petroleum ether/ethyl acetate=40:1).
The allyl-substituted tetrahydrofuran derivative 8 was ob-
tained as a white semisolid; yield: 48 mg (65%) after flash
chromatography. The dr value was calculated to be 94:6 by
1H NMR analysis and the enantiomeric excess was deter-
mined to be 90% by HPLC (Chiralpak AD-H column, 5%
We are grateful for financial support from the National Natu-
ral Science Foundation of China (21302016, 81303208 and
81273471) and the China Postdoctoral Science Foundation.
References
[1] For a discussion of the advantages of one-pot reactions,
see: a) L. F. Tietze, Chem. Rev. 1996, 96, 115–136;
b) J. M. Lee, Y. Na, H. Han, S. Chang, Chem. Soc. Rev.
2004, 33, 302–312; for recent reviews on cascade reac-
tion, see: c) H. Pellissier, Adv. Synth. Catal. 2012, 354,
237–294; d) H. Clavier, H. Pellissier, Adv. Synth. Catal.
2012, 354, 3347–3403; e) H. Pellissier, Chem. Rev. 2013,
113, 442–524.
[2] For recent reviews on dual catalysis in which transition
metal catalysis is combined with organocatalysis, see:
a) C. Zhong, X. Shi, Eur. J. Org. Chem. 2010, 2999–
3025; b) C. C. J. Loh, D. Enders, Chem. Eur. J. 2012, 18,
10212–10225; c) Z. Du, Z. Shao, Chem. Soc. Rev. 2013,
42, 1337–1378; d) M. Rueping, R. M. Koenigs, I. Ato-
diresei, Chem. Eur. J. 2010, 16, 9350–9365; for exam-
ples of dual catalysis in which photoredox catalysis is
combined with organocatalysis, see: e) D. A. Nicewicz,
D. W. C. MacMillan, Science 2008, 322, 77–80;
f) J. M. R. Narayanam, C. R. J. Stephenson, Chem. Soc.
Rev. 2011, 40, 102–113; for examples of dual catalysis
combining two organocatalytic systems, see: g) X. Yu,
W. Wang, Org. Biomol. Chem. 2008, 6, 2037–2046;
h) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010,
2, 167–178; i) Ł. Albrecht, H. Jiang, K. A. Jørgensen,
Angew. Chem. 2011, 123, 8642–8660; Angew. Chem.
Int. Ed. 2011, 50, 8492–8509; for recent reviews on mul-
ticatalysis, see: j) J. Zhou, Chem. Asian J. 2010, 5, 422–
434; k) S. Piovesana, D. M. Scarpino Schietroma, M.
2-propanol/n-hexane, 1 mLminÀ1, UV 254 nm): tmajor
=
4.33 min, tminor =4.56 min; [a]2D0: À65.8 (c 0.08 in EtOH);
1H NMR (400 MHz, CDCl3): d=7.99 (d, J=8.0 Hz, 2H),
7.38–7.35 (m, 1H), 7.27–7.23 (m, 2H), 7.13–7.12 (m, 2H),
7.05–6.97 (m, 8H), 5.67 (dt, J1 =17.2 Hz, J2 =7.2 Hz, 1H),
4.94 (d, J=10.0 Hz, 1H), 4.86 (d, J=17.2 Hz, 1H), 4.77 (t,
J=6.8 Hz, 1H), 4.67 (t, J=6.4 Hz, 1H), 2.42–2.36 (m, 1H),
2.27–2.07 (m, 3H); 13C NMR (100 MHz, CDCl3): d=199.91,
140.25, 139.07, 135.11, 134.59, 132.37, 131.04, 129.27, 127.83,
127.80, 127.63, 126.99, 126.12, 125.62, 117.27, 95.59, 80.67,
51.06, 41.65, 38.14; ESI-HR-MS: m/z=391.1073, calcd. for
C26H24O2 +Na: 391.1674.
ACHTUNGTRENNUNG(2S,4S,5S)-5-Benzoyl-4,5-diphenyltetrahydrofuran-2-car-
bonitrile (9): TiCl4 (55.0 mL, 0.5 mmol) and cyanotrimethyl-
silane (66.7 mL, 0.5 mmol) were added to a solution of 4a
(68.9 mg, 0.2 mmol) in CH2Cl2 (5 mL) at À708C under an
argon atmosphere. The resulting mixture was slowly
warmed up to À408C and stirred for 5 h before being
quenched with Et3N (0.4 mL) followed by addition of satu-
8
asc.wiley-vch.de
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
One-Pot Asymmetric Synthesis of Substituted Tetrahydrofurans
Bella, Angew. Chem. 2011, 123, 6340–6357; Angew.
Chem. Int. Ed. 2011, 50, 6216–6232; l) A. E. Allen,
D. W. C. MacMillan, Chem. Sci. 2012, 3, 633–658;
m) N. T. Patil, V. S. Shinde, B. Gajula, Org. Biomol.
Chem. 2012, 10, 211–224; n) H. Pellissier, Tetrahedron
2013, 69, 7171–7210.
[10] a) O. Winkelmann, C. Nꢆther, U. Lꢄning, Org. Biomol.
Chem. 2009, 7, 553–556; b) M. Yoshida, N. Terai, K.
Shishido, Tetrahedron 2010, 66, 8922–8927; c) W. Ye, G.
Cai, Z. Zhuang, X. Jia, H. Zhai, Org. Lett. 2005, 7,
3769–3771.
[11] For a recent review, see: A. Mielgo, C. Palomo, Chem.
Asian J. 2008, 3, 922–948.
[12] For recent examples of organocatalytic asymmetric syn-
thesis of functionalized tetrahydrofurans, see: a) D.
Enders, C. Wang, A. Greb, Adv. Synth. Catal. 2010,
352, 987–992; b) P. G. McGarraugh, R. C. Johnston, A.
Martꢇnez-MuÇoz, P. H. Cheong, S. E. Brenner-Moyer,
Chem. Eur. J. 2012, 18, 10742–10752; c) W. Wang, J.
Wang, S. Zhou, Q. Sun, Z. Ge, X. Wang, R. Li, Chem.
Commun. 2013, 49, 1333–1335; d) Z. Chen, J. Sun,
Angew. Chem. 2013, 125, 13838–13841; Angew. Chem.
Int. Ed. 2013, 52, 13593–13596.
[13] For recent reviews on the enantioselective formation of
quaternary stereogenic centers, see: a) M. Bella, T.
Gasperi, Synthesis 2009, 1583–1614; b) C. Hawner, A.
Alexakis, Chem. Commun. 2010, 46, 7295–7306; c) J.
Prakash Das, I. Marek, Chem. Commun. 2011, 47,
4593–4623.
[14] For selected examples of our groupꢀs work on stereose-
lectively assembling substrates into synthetically impor-
tant cyclic molecules via multicatalytic cascade reac-
tions, see: a) X. Xie, C. Peng, G. He, H.-J. Leng, B.
Wang, W. Huang, B. Han, Chem. Commun. 2012, 48,
10487–10489; b) X. Li, L. Yang, C. Peng, X. Xie, H.-J.
Leng, B. Wang, Z.-W. Tang, G. He, L. Ouyang, W.
Huang, B. Han, Chem. Commun. 2013, 49, 8692–8694.
[15] For selected examples, see: a) Y. Shimakawa, T. Mori-
kawa, S. Sakaguchi, Tetrahedron Lett. 2010, 51, 1786–
1789; b) D. Enders, A. Henseler, Adv. Synth. Catal.
2009, 351, 1749–1752.
[3] For recent reviews on NHC organocatalysis, see: a) D.
Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007,
107, 5606–5655; b) A. Grossmann, D. Enders, Angew.
Chem. 2012, 124, 320–332; Angew. Chem. Int. Ed. 2012,
51, 314–325; c) J. Izquierdo, G. E. Hutson, D. T. Cohen,
K. A. Scheidt, Angew. Chem. 2012, 124, 11854–11866;
Angew. Chem. Int. Ed. 2012, 51, 11686–11698; d) X.
Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511–
3522.
[4] a) K. Hirano, I. Piel, F. Glorius, Chem. Lett. 2011, 40,
786–791; b) N. T. Patil, Angew. Chem. 2011, 123, 1797–
1799; Angew. Chem. Int. Ed. 2011, 50, 1759–1761.
[5] D. T. Cohen, K. A. Scheidt, Chem. Sci. 2012, 3, 53–57.
[6] a) W. A. Herrmann, Angew. Chem. 2002, 114, 1342–
1363; Angew. Chem. Int. Ed. 2002, 41, 1290–1309; b) S.
Wꢄrtz, F. Glorius, Acc. Chem. Res. 2008, 41, 1523–1533.
[7] a) S. P. Lathrop, T. Rovis, J. Am. Chem. Soc. 2009, 131,
13628–13630; b) K. E. Ozboya, T. Rovis, Chem. Sci.
2011, 2, 1835–1838; c) D. Enders, A. Grossmann, H.
Huang, G. Raabe, Eur. J. Org. Chem. 2011, 4298–4301;
d) C. B. Jacobsen, K. L. Jensen, J. Udmark, K. A. Jør-
gensen, Org. Lett. 2011, 13, 4790–4793; e) C. B. Jacob-
sen, Ł. Albrecht, J. Udmark, K. A. Jørgensen, Org.
Lett. 2012, 14, 5526–5529; f) L. Deiana, P. Dziedzic, G.-
L. Zhao, J. Vesely, I. Ibrahem, R. Rios, J. Sun, A. Cꢁr-
dova, Chem. Eur. J. 2011, 17, 7904–7917; g) Y.-Z. Liu, J.
Zhang, P.-F. Xu, Y.-C. Luo, J. Org. Chem. 2011, 76,
7551–7555; h) Y. Liu, M. Nappi, E. C. Escudero-Adꢅn,
P. Melchiorre, Org. Lett. 2012, 14, 1310–1313.
[16] For the chiral hypervalent iodine catalytic approach,
see: a) T. Dohi, A. Maruyama, N. Takenaga, K.
Senami, Y. Minamitsuji, H. Fujioka, S. B. Caemmerer,
Y. Kita, Angew. Chem. 2008, 120, 3847–3850; Angew.
Chem. Int. Ed. 2008, 47, 3787–3790; b) T. Dohi, N. Tak-
enaga, T. Nakae, Y. Toyoda, M. Yamasaki, M. Shiro, H.
Fujioka, A. Maruyama, Y. Kita, J. Am. Chem. Soc.
2013, 135, 4558–4566; c) M. Uyanik, T. Yasui, K. Ishi-
hara, Angew. Chem. 2010, 122, 2221–2223; Angew.
Chem. Int. Ed. 2010, 49, 2175–2177; d) M. Uyanik, D.
Suzuki, T. Yasui, K. Ishihara, Angew. Chem. 2011, 123,
5443–5446; Angew. Chem. Int. Ed. 2011, 50, 5331–5334.
[17] We screened 4-methylpent-2-enal, 4-phenylpent-2-enal,
a-pentylcinnamaldehyde and a-bromocinnamaldehyde.
[18] CCDC 958885 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[8] Hongꢀs group pioneered an NHC-amine catalyzed Stet-
ter/Michael/aldol cascade reaction, see: a) B.-C. Hong,
N. S. Dange, C.-S. Hsu, J.-H. Liao, Org. Lett. 2010, 12,
4812–4815; b) B.-C. Hong, N. S. Dange, C.-S. Hsu, J.-H.
Liao, G.-H. Lee, Org. Lett. 2011, 13, 1338–1341. Here
we provide the first demonstration that NHC-catalyzed
benzoin condensation can also be integrated into a mul-
ticatalytic cascade.
[9] For selected examples of natural products containing
the acyloin and furan moieties, see: a) S. Adachi, K.
Watanabe, Y. Iwata, S. Kameda, Y. Miyaoka, M. Ono-
zuka, R. Mitsui, Y. Saikawa, M. Nakata, Angew. Chem.
2013, 125, 2141–2145; Angew. Chem. Int. Ed. 2013, 52,
2087–2091; b) F. Konno, T. Ishikawa, M. Kawahata, K.
Yamaguchi, J. Org. Chem. 2006, 71, 9818–9823; c) Y.-Q.
Shi, T. Fukai, H. Sakagami, W.-J. Chang, P.-Q. Yang, F.-
P. Wang, T. Nomura, J. Nat. Prod. 2001, 64, 181–188.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!

FULL PAPERS
10 One-Pot Asymmetric Synthesis of Substituted
Tetrahydrofurans via a Multicatalytic Benzoin/Michael/
Acetalization Cascade
Adv. Synth. Catal. 2014, 356, 1 – 10
Gu He, Fengbo Wu, Wei Huang, Rui Zhou, Liang Ouyang,
Bo Han*
10
asc.wiley-vch.de
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!