Enantioselective synthesis of tetrahydrofuran derivatives by sequential henry reaction and iodocyclization of γ,δ-unsaturated alcohols

Article abstract of DOI:10.1002/ejoc.201402396

A sequential one-pot Cu-catalyzed asymmetric Henry reaction and iodocyclization is disclosed. The transformation provides efficient access to biologically and synthetically useful 2,2,5-trisubstituted tetrahydrofuran derivatives. The combination of Cu(OAc)₂·H₂O with a novel chiral sulfoxide-Schiff base hybrid ligand under mild reaction conditions tolerates a wide range of 4-substituted γ,δ-unsaturated aldehydes, and the subsequent iodocyclization furnishes the corresponding products in generally high yields with excellent enantioselectivities. The products can be easily converted into amines with excellent diastereo- and enantioselectivities.

Full text of DOI:10.1002/ejoc.201402396

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402396
Enantioselective Synthesis of Tetrahydrofuran Derivatives by Sequential Henry
Reaction and Iodocyclization of γ,δ-Unsaturated Alcohols
Li-Yan Chen,[a,b] Jia-Rong Chen,*[a,b] Hong-Gang Cheng,[a,b] Liang-Qiu Lu,[a,b] and
Wen-Jing Xiao*[a,b]
Keywords: Halocyclization / Henry reaction / Domino reactions / Synthetic methods / Oxygen heterocycles
A sequential one-pot Cu-catalyzed asymmetric Henry reac-
tion and iodocyclization is disclosed. The transformation pro-
vides efficient access to biologically and synthetically useful
2,2,5-trisubstituted tetrahydrofuran derivatives. The combi-
nation of Cu(OAc)2·H2O with a novel chiral sulfoxide–Schiff
base hybrid ligand under mild reaction conditions tolerates
a wide range of 4-substituted γ,δ-unsaturated aldehydes, and
the subsequent iodocyclization furnishes the corresponding
products in generally high yields with excellent enantio-
selectivities. The products can be easily converted into
amines with excellent diastereo- and enantioselectivities.
prepare enantioenriched 2,2,5-trisubstituted tetrahydro-
furan derivatives are still highly desirable.
Introduction
2,2,5-Trisubstituted tetrahydrofurans (THF) represent a
class of privileged heterocyclic scaffolds that are found
in a plethora of important pharmaceuticals, biologically
active natural products, and versatile building blocks in or-
ganic synthesis.[1,2] Representative examples include oscilla-
riolide, amphidinolactone B, leiodelide B, and lituarine C
(Scheme 1).[1a,1c] Consequently, the development of efficient
methodologies for the construction of such an important
motif has attracted much research effort from synthetic
chemists.[3] The commonly used approaches to tetra-
hydrofurans have usually been based on the single or tan-
dem cyclization of 1,4-diols,[4] oxidative cyclization of alk-
enes or polyenes,[5] electrophilic cyclization of α,β-unsatu-
rated and β,γ-unsaturated alcohols,[6] ring-closing olefin
metathesis,[7] radical cyclization,[8] reductive cyclizations of
carbonyl compounds,[9] and [3+2] cycloadditions.[10]
Among these strategies, however, there are only a few exam-
ples of catalytic enantioselective variants for the formation
of stereocenters at the 2- and 5-positions of the tetra-
hydrofuran scaffolds. Therefore, new methods to efficiently
Scheme 1. Representative examples of natural products containing
2,2,5-trisubstituted tetrahydrofuran motifs.
[a] Key Laboratory of Pesticide & Chemical Biology Ministry of
Education
The strategy of merging electrophilic halogenation of ole-
fins with tandem intramolecular cyclization has been estab-
lished as one of the most powerful methods for the con-
struction of diversely functionalized complex carbocycles
and heterocycles.[11–14] In this context, stereoselective iodo-
etherification has attracted extensive interest and has en-
joyed remarkable advances owing to its practical aspects for
the synthesis of oxygen heterocycles and subsequent versa-
tile manipulations of the installed iodide handle. For exam-
ple, in 2003, Kang’s group developed an elegant example of
College of Chemistry, Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079, China
E-mail: chenjiarong@mail.ccnu.edu.cn
wxiao@mail.ccnu.edu.cn
http://chem-xiao.ccnu.edu.cn
[b] Collaborative Innovation Center of Chemical Science and
Engineering
92 Weijin Road, Tianjin 300072, China
E-mail: chenjiarong@mail.ccnu.edu.cn
wxiao@mail.ccnu.edu.cn
http://chem-xiao.ccnu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402396.
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Enantioselective Synthesis of Tetrahydrofuran Derivatives
catalytic asymmetric iodocyclization of (Z)-γ-hydroxyalk- terminal C=C bond of 3 would be further activated by the
enes promoted by a combination of an (R,R)-salen–CoII formation of the iodonium salt and then undergo subse-
complex and N-chlorosuccinimide to afford the corre- quent nucleophilic attack of the oxygen atom to give the
sponding 2-iodo-substituted tetrahydrofurans in excellent desired iodocyclization products. In contrast to our strat-
yields with high enantioselectivities of up to 90% ee.[14e] egy, the group of Gong recently developed an elegant CuII-
Recently, Fujioka and co-workers reported an interesting catalyzed asymmetric Henry reaction between 2H-
silylenol-promoted iodocyclization of γ,δ-unsaturated chromene-3-carbaldehydes and nitromethane, and success-
alcohols for the selective synthesis of cis-2,5-disubstituted fully applied the products to iodocyclization after the re-
THF stereoisomers through a one-pot procedure.[14a] De- duction of the nitro group and the protection of amines.[17]
spite these impressive contributions, it remains of great im- Herein, we wish to communicate the development of an ef-
portance to develop more efficient protocols for the con- ficient catalytic system (Scheme 3) for the designed reac-
struction of diversely functionalized 2,2,5-trisubstituted tion.
tetrahydrofuran derivatives in a highly enantioselective
fashion.
Recently, we developed a class of chiral sulfoxide–Schiff
Results and Discussion
base ligands and successfully applied these ligands to the
At the outset of our studies, we focused on the optimiza-
Cu-catalyzed asymmetric Henry reaction with excellent
tion of the conditions by screening various chiral sulfoxide–
Schiff base ligands for the Henry reaction between γ,δ-un-
saturated aldehyde 1a and nitromethane (2a; Table 1). To
our delight, the combination of Cu(OAc)2·H2O with ligand
L1 in tBuOH did indeed catalyze the designed reaction to
afford product 3a in 98% yield with 84%ee (Table 1, En-
try 1). Encouraged by this result, we continued to improve
the enantioselectivity by exploring chiral sulfoxide–Schiff
base ligands L2–L18, which could be easily prepared ac-
cording to our previous procedure.[15] First, we examined
the substituent effect of the Schiff base moiety on the reac-
tion by using L2–L6 (Table 1, Entries 2–6); only a slight
increase in the enantioselectivity was observed in the case
enantioselectivities.[15] To further explore the potential of
these ligands in asymmetric synthesis and as a part of our
ongoing program on heterocycle synthesis,[16] we envisioned
that a sequential Henry reaction and iodocyclization of γ,δ-
unsaturated alcohols would provide a new entry to chiral
2,2,5-trisubstituted tetrahydrofurans (Scheme 2). In this de-
sign, upon completion of the asymmetric Henry reaction
between γ,δ-unsaturated aldehydes 1 and nitromethane, the
Table 1. Ligand screening for the asymmetric Henry reaction of
γ,δ-unsaturated aldehyde 1a with nitromethane (2a).[a]
Scheme 2. Reaction design: sequential asymmetric Henry reaction
and iodocyclization of γ,δ-unsaturated aldehydes.
Entry
t [h]
Ligand
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
142
121
124
171
53
74
99
L1
L2
98
88
68
93
98
78
72
89
79
98
59
96
46
97
97
62
74
97
84
87
91
84
85
74
83
90
75
83
73
82
0
L3
L4
L5
L6
L7
68
L8
151
120
144
69
110
52
93
74
74
62
L9
L10
L11
L12
L13
L14
L15
L16
L17
L18
91
60
72
75
94
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.5 mL), Cu(OAc)2·
H2O (5 mol-%), ligand (5 mol-%), tBuOH (2.0 mL). [b] Yield of
isolated product. [c] Determined by HPLC analysis on a chiral sta-
tionary phase.
Scheme 3. Chiral sulfoxide–Schiff base ligands studied in this work.
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L.-Y. Chen, J.-R. Chen, H.-G. Cheng, L.-Q. Lu, W.-J. Xiao
SHORT COMMUNICATION
of ligand L3. Replacement of the phenyl group in the Schiff cemic Henry adduct 3a as the model substrate (Table 3).
base moiety with a naphthyl group (e.g., L7, L8) led to Inspired by the recent work on iodocyclization from the
some decrease in the yield or the enantioselectivity (Table 1, group of Gong,[17] we first tested iodine as the halogen
Entries 7 and 8). Then, we turned our attention toward ex- source in CH2Cl2, but the reaction only provided poor re-
ploring the effect of the sulfoxide moiety with different sub- sults (Table 3, Entries 1 and 2). Pleasingly, upon addition
stituents on the aromatic ring. Unfortunately, the reaction of K2CO3 (0.5 equiv.) as the base in CH3CN, the reaction
with ligands L9–L12 gave rise to inferior results, whereas furnished a 46% yield of the desired product 5a (Table 3,
the use of L13 led to no stereoinduction (Table 1, Entries 9– Entry 3). Notably, if the ratio of I2/3a was increased from
13). It was found that switching the phenyl group in the 2:1 to 4:1, the yield significantly improved to 92% (Table 3,
sulfoxide motif to a benzyl group (i.e., L14) resulted in the Entry 4). Under otherwise identical conditions, the use of
formation of product 3a in 97% yield with 91% ee (Table 1, N-iodosuccinimide (NIS) also afforded comparable results
Entry 14). Encouraged by this promising result, we con- (Table 3, Entry 5).
ducted a further study with respect to the structural modifi-
cation of both the Schiff base moiety and the sulfoxide scaf-
fold and identified ligand L18 as the best choice in terms
of yield and enantioselectivity (Table 1, Entry 18; 97% yield
and 94% ee).
Table 3. Optimization of the conditions for the iodocyclization of
3a.
With the best ligand L18 in hand, we briefly examined
some commonly used solvents, and it was found that the
solvent had a significant effect on the reaction efficiency
Entry
Solvent
4
Additive
t
[h]
T
[°C]
Yield[a]
[%]
(Table 2). For example, in the case of less polar solvents,
such as dichloromethane and tetrahydrofuran, only moder-
ate enantioselectivity was observed (Table 2, Entries 1 and
2). The reaction in aromatic solvents only afforded poor
yields with fair enantioselectivities (Table 2, Entries 3–5). In
accordance with our previous observation, a screening of
alcohol solvents showed that tBuOH gave superior results
to those obtained with MeOH, iPrOH, and EtOH
(Table 2, Entry 9 vs. entries 6–8). Finally, a combination of
Cu(OAc)2·H2O (5 mol-%) with ligand L18 (5 mol-%) in
tBuOH at 25 °C was determined to be the optimal system
for the asymmetric Henry reaction.
1[b]
2[b]
3[c]
4[d]
5[d]
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
I2
I2
I2
I2
NIS
–
–
48
48
48
25
3
–78
25
25
25
25
12
trace
46
92
89
K2CO3
K2CO3
K2CO3
[a] Yield of isolated product. [b] 3a (0.20 mmol), 4 (0.3 mmol),
(1.0 mmol), K2CO3
CH2Cl2 (5.0 mL). [c] 3a (0.50 mmol),
4
(0.25 mmol), CH3CN (5.0 mL). [d] 3a (2.0 mmol), 4 (8.0 mmol),
K2CO3 (1.0 mmol), CH3CN (8.0 mL).
Next, we attempted to conduct a sequential Cu-catalyzed
asymmetric Henry reaction and iodocyclization in a one-
pot fashion (Table 4). Fortunately, it was found that re-
placement of tBuOH with CH3CN as the reaction medium
after the Henry reaction, together with the addition of
K2CO3 and I2, allowed the subsequent iodocyclization to
proceed smoothly, and the desired product 5a was obtained
in 88% yield with 1:1.4 dr, 90% and 88% ee.
Table 2. Solvent optimization for the asymmetric Henry reaction
of γ,δ-unsaturated aldehyde 1a with nitromethane (2a).[a]
With the optimized conditions in hand, we then exam-
ined the substrate scope. It was found that a diverse set of
weakly electron-withdrawing (Br, F, Cl) and electron-donat-
ing groups (MeO, Me) were well tolerated at the aromatic
ring of the γ,δ-unsaturated aldehydes, and the correspond-
ing tetrahydrofuran derivatives 5b–f were obtained in good
to high yields (68–99%) with excellent enantioselectivities.
A naphthyl group could also be successfully incorporated
into the tetrahydrofuran scaffold (see 5g, 94% ee). Replace-
ment of the phenyl ring of the γ,δ-unsaturated aldehydes
with a heteroaromatic ring, such as furyl and thienyl
groups, also resulted in the formation of the corresponding
products 5h and 5i with excellent enantioselectivities and in
34% and 80% overall yields, respectively. γ,δ-Unsaturated
aldehydes 1j and 1k with aliphatic substituents (Me and Bn)
in the γ-position participated in the desired reaction ef-
ficiently to produce 5j and 5k in high yields with high enan-
Entry
t [h]
Solvent
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
48
91
40
147
144
36
146
82
CH2Cl2
THF
toluene
xylene
mesitylene
iPrOH
MeOH
EtOH
90
80
24
27
33
82
20
97
97
65
66
76
85
90
86
88
88
60
84
94
80
76
82
144
56
tBuOH
CH3CN
CH3NO2
10
11
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.5 mL), Cu(OAc)2·
H2O (5 mol-%), ligand L18 (5 mol-%), tBuOH (2.0 mL). [b] Yield
of isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase.
With the optimal conditions for the asymmetric Henry tiomeric excess. Notably, the γ,δ-unsaturated aldehyde with
reaction established, we then turned our attention to in- an ethyl group at the terminal C=C bond reacted well to
vestigating conditions for the iodocyclization step with ra- give a 80% yield of product 5m. However, substrate 1l bear-
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Enantioselective Synthesis of Tetrahydrofuran Derivatives
Table 4. Substrate scope of the one-pot sequential Cu-catalyzed established to be (2S,5R) by X-ray crystallographic analysis
asymmetric Henry reaction and iodocyclization.[a]
(Figure 1).[18] On the basis of the stereoinduction provided
by the sulfoxide–Schiff base ligand in the Cu-catalyzed
asymmetric Henry reaction, we established the absolute
configuration of diastereoisomer cis-5a as (2R,5R).
Figure 1. X-ray crystallographic structure of (2S,5R)-trans-5a [ther-
mal ellipsoids are set at 30% probability; Flack parameter: 0.01(2)].
A demonstration of the synthetic potential of this trans-
formation was performed. Products 5a and 5d were conve-
niently transformed into the corresponding amines 6a and
6d in high yields with excellent diastereo- and enantio-
selectivities through reduction of the nitro group and pro-
tection of the resulting amine group (Scheme 4). Given that
all attempts to obtain the X-ray crystallographic structure
of both 6a and 6d failed, we then performed extensive NOE
studies of the key intermediate 5aЈ, which was obtained in
good yield with excellent diastereoselectivity upon re-
duction of 5a. The NOE results together with the X-ray
crystallographic structure of tetrahydrofuran trans-5a fi-
nally confirmed both trans-6a and 6d to be (2S,5R).[19] The
significantly increased diastereoselectivity was presumably
due to reversible O-Michael reaction during the reduction
step.
[a] Reaction conditions: (1) 1 (0.20 mmol), 2 (0.5 mL), Cu(OAc)2·
H2O (5 mol-%), L18 (5 mol-%), tBuOH (2.0 mL), 25 °C, 1–3 d;
(2) I2 (0.8 mmol), K2CO3 (0.1 mmol), CH3CN (2.0 mL), 2–3 h.
[b] Yield of isolated diastereomeric mixture. [c] Determined by
1
HPLC analysis on a chiral stationary phase. [d] Determined by H
NMR spectroscopy.
Scheme 4. Synthetic applications. Ts = para-tolylsulfonyl.
ing a methyl group at the terminal C=C bond only gave
poor results. Finally, nitroethane and nitropropane were
also examined, and the corresponding products 5n and 5o
were both obtained in high yields with good enantio-
selectivities. Although the iodocyclization reaction pro-
ceeded with low diastereoselectivities at the current state,
Conclusions
We developed a sequential one-pot Cu-catalyzed asym-
the diastereoisomers of products 5a–o could be easily iso- metric Henry reaction and iodocyclization of γ,δ-unsatu-
lated by column chromatography, which further highlights rated alcohols. The reaction provided efficient access to a
the synthetic utility of this reaction.
range of biologically and synthetically important 2,5-poly-
The absolute configuration of tetrahydrofuran trans-5a substituted tetrahydrofuran derivatives in high yields with
(98% ee after single recrystallization) was unambiguously excellent enantioselectivities (up to 97% ee). Although the
Eur. J. Org. Chem. 2014, 4714–4719
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L.-Y. Chen, J.-R. Chen, H.-G. Cheng, L.-Q. Lu, W.-J. Xiao
SHORT COMMUNICATION
J. A. Marshall, R. K. Hann, J. Org. Chem. 2008, 73, 6753–
6757.
diastereoselectivity of the iodocyclization reaction awaits
further improvement, the diastereoisomers of all the prod-
ucts could be easily separated. Moreover, the products
could be transformed into the corresponding chiral amines
with excellent diastereo- and enantioselectivities. Further
application of these ligands to the Lewis acid catalyzed
asymmetric synthesis of other valuable heterocycles is on-
going in our laboratory.
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Experimental Section
Typical Procedure: Cu(OAc)2·H2O (2.0 mg, 0.01 mmol) and L18
(5.1 mg, 0.01 mmol) were dissolved in tBuOH (2.0 mL, 0.1 m), and
the mixture was stirred at 25 °C for 60 min. Then, γ,δ-unsaturated
aldehyde 1 (0.2 mmol) and nitroalkane 2 (0.5 mL) were added to
the mixture. The mixture was stirred at 25 °C until 1 had totally
disappeared, as monitored by TLC. Then, tBuOH was removed in
vacuo, and acetonitrile (2.0 mL, 0.1 m) was introduced into the
above mixture, followed by the addition of iodine (203.0 mg,
0.8 mmol) and K2CO3 (13.8 mg, 0.1 mmol). The resulting mixture
was then stirred at 25 °C for another 2–3 h. Upon completion of
the reaction, as detected by TLC, saturated sodium thiosulfate
(10 mL) was added to quench the reaction. The aqueous layer was
extracted with CH2Cl2 (2ϫ). The organic layers were combined
and dried with anhydrous Na2SO4. The filtrate was concentrated
and purified by flash column chromatography on silica gel (petro-
leum ether/ethyl acetate, 30:1 to 20:1) to afford product 5. The dia-
stereoselectivity was determined by analysis of the crude mixture
by 1H NMR spectroscopy, and the enantioselectivity was deter-
mined by HPLC analysis on a chiral stationary phase.
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (grant numbers 21272087, 21202053, and 21232003) and the
National Basic Research Program of China (973 program, grant
number 2011CB808603) for support of this research.
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Received: April 11, 2014
Published Online: June 26, 2014
Eur. J. Org. Chem. 2014, 4714–4719
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