Highly enantioselective synthesis of γ-substituted butenolides via the vinylogous Mukaiyama-Michael reaction catalyzed by a chiral scandium(III)-N,N′-dioxide complex

Article abstract of DOI:10.1039/c1ob05558e

A highly efficient catalytic asymmetric vinylogous Mukaiyama-Michael reaction of the 2-silyloxyfuran with chalcone derivatives, catalyzed by a chiral N,N′-dioxide-scandium(iii) complex, has been accomplished which tolerates a wide range of substrates. The reaction proceeds with complete regioselectivities, excellent diastereoselectivities (up to >99:1 dr) and good to excellent enantioselectivities (up to 94% ee) under mild conditions, delivering highly functionalized enantiomerically enriched anti-γ- substituted butenolides. The process is air-tolerant and easily manipulated with available reagents. In order to illustrate the synthetic potential of this reaction, the gram-scale synthesis and the elaboration of the butenolides have been explored. On the basis of the experimental results, a possible catalytic cycle and favorable stereorecognition model have been proposed.

Full text of DOI:10.1039/c1ob05558e

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PAPER
Highly enantioselective synthesis of c-substituted butenolides via the
vinylogous Mukaiyama–Michael reaction catalyzed by a chiral
scandium(III)–N,N¢-dioxide complex†
Qi Zhang, Xiao Xiao, Lili Lin, Xiaohua Liu and Xiaoming Feng*
Received 8th April 2011, Accepted 17th May 2011
DOI: 10.1039/c1ob05558e
A highly efficient catalytic asymmetric vinylogous Mukaiyama–Michael reaction of the 2-silyloxyfuran
with chalcone derivatives, catalyzed by a chiral N,N¢-dioxide–scandium(III) complex, has been
accomplished which tolerates a wide range of substrates. The reaction proceeds with complete
regioselectivities, excellent diastereoselectivities (up to >99 : 1 dr) and good to excellent enantio-
selectivities (up to 94% ee) under mild conditions, delivering highly functionalized enantiomerically
enriched anti-g-substituted butenolides. The process is air-tolerant and easily manipulated with
available reagents. In order to illustrate the synthetic potential of this reaction, the gram-scale synthesis
and the elaboration of the butenolides have been explored. On the basis of the experimental results, a
possible catalytic cycle and favorable stereorecognition model have been proposed.
nucleophilicity between the a and g positions of the dienolate
Introduction
to afford a- or g- addition products (Scheme 1).4d,9 Moreover,
the utilization of chalcones as Michael acceptors was disclosed
in only two reports about the direct Michael addition of 2-(5H)-
furanones,7b,7c in which syn-adducts were provided as the major
diastereomer with high enantioselectivities, but the reactivity and
diastereoselectivity were not well accomplished.
The butenolide skeleton ranks among one of the most ubiquitous
structural motifs found in naturally occurring products and
biologically active compounds.1 Owing to the prevalence of
butenolides, much effort has been directed towards exploiting
the efficient methodology for its synthesis and transformations.2
In recent years, the development of enantioselective protocols to
access g-substituted butenolide derivatives by utilizing the concept
of vinylogy, which usually involves the carbon–carbon formation
with an appropriate electrophile at the g-position of butenolide
to afford the corresponding g-substituted products, has triggered
increasing interest.3 As a variant of the vinylogous reactions,
with the dienolates derived from butenolides,4–6 the asymmetric
vinylogous Michael-type approach is more attractive,7,8 as it
provides highly functionalized chiral g-substituted butenolides
bearing a C4-substituent functionalized at its terminal group that
allows the further transformation.
Scheme 1 The regioselective Michael reaction of dienolate to afford a-
or g- addition product. EWG = electron-withdrawing groups.
Recently, direct Michael-type versions have been utilized as a
convenient strategy for the construction of the chiral butenolides,
where the dienolate anion is generated from 2-(5H)-furanone by
a Lewis acid or base in situ.7 However, this process generally
suffers from a regioselective problem that is due to the similar
An efficient alternative approach to circumvent the issues of
regioselectivity and reactivity is the use of 2-silyloxyfurans in
Lewis acid catalyzed vinylogous Mukaiyama–Michael reactions
(VMMR),8 in which regulating the electronic and steric effects of
both the 2-silyloxyfurans and catalyst complex is of paramount
importance for high stereoselectivity. Moreover, this methodol-
ogy has been used in diastereoselective synthesis of important
compounds such as ( ) mitomycins by Fukuyama and Yang.10
Nevertheless, the chiral Lewis acid catalyzed enantioselective 2-
silyloxyfuran variant with chalcones as the Michael acceptors has
never been reported on account of the weak chelating character of
chalcones. Thus searching for a suitable and efficient chiral Lewis
Key Laboratory of Green Chemistry & Technology, Ministry of Educa-
tion, College of Chemistry, Sichuan University, Chengdu, 610064, China.
E-mail: xmfeng@scu.edu.cn; Fax: (+86)28-8541-8249
† Electronic supplementary information (ESI) available: Experimental
procedures, analytical data (1H NMR, 13C NMR and HRMS) for all
new compounds and the ESIMS investigation of the reaction mechanism.
X-ray structure of the product 3j. CCDC reference number 808488. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05558e
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acid catalyst to afford chiral g-substituted butenolides with well-
defined regio-, diastereo- and enantioselectivities is still a high
priority.
In previous studies,11,12 the chiral N,N¢-dioxide–lanthanide
complexes have exhibited excellent abilities for the activation of
various electrophiles and strong asymmetry-inducing capability
for many reactions, especially in bromoamination,13 the inverse
electron-demand aza-Diels–Alder reaction14 and the Roskamp
reaction15 using N,N¢-dioxide–scandium(III) complexes. In light
of these successes, we envisioned that such a catalyst with an
electronic and steric tunable chiral environment might be effective
for asymmetric VMMR. Herein, we wish to describe our efforts
to address the enantioselective synthesis of a series of attractive
anti-g-substituted butenolides, where the regio-, diastereo- and
enantioselectivities were well accomplished simultaneously using
a chiral scandium(III)–N,N¢-dioxide complex.
Fig. 1 Ligands employed in this study.
excellent yields (Table 1, entry 5–7), meanwhile no side product
was detected. Furthermore, when R was replaced by aliphatic
amines, such as benzylamine and 1-adamantylamine, no better
results were obtained (Table 1, entries 8 and 9). Intensive studies
on the amino acid backbone showed that the N,N¢-dioxide L3,
which was based on L-proline, was superior to both L-pipecolic
acid derived N,N¢-dioxide L7 and L-ramipril derived N,N¢-dioxide
L8 (Table 1, entry 6 vs. entries 10 and 11), and afforded the anti-
g-substituted butenolide 3a in 99% yield with >99% dr and up to
82% ee.
To further improve the enantioselectivity of the reaction,
solvents of the reaction were intensely investigated and the results
are listed in Table 2. They indicated that the reaction solvent
played an important role in governing the enantioselectivity of the
reaction. Polar and coordinating solvents generally provided the
expected product 3a with higher enantioselectivities than nonpolar
solvents did (Table 2, entries 1–6). Compared with THF, ethyl
acetate was also found to be a suitable solvent for the reaction to
afford 3a in excellent yield with comparable ee value (up to 81%
ee) (Table 2, entry 6 vs. 1). Thus further optimization was aimed
at fully examining the solvents such as esters and alcohols. The
Results and discussion
Initially, chalcone 2a and 2-(tert-butyldimethylsilyloxy)furan (TB-
SOF) 1 derived from unmodified g-butenolide were chosen as
starting materials for optimizing the conditions. Prompted by the
great successes obtained in asymmetric reactions using chiral Ln
complexes,16 our preliminary study began with a systematic screen
of Ln complexes in the presence of the N,N¢-dioxide ligand L1.
As shown in Table 1, the investigation revealed that Sc(OTf)3 (Tf =
trifluoromethanesulfonyl) was superior at giving higher yields of
the g-substituted butenolide compared to other representative
metals of lanthanides which mainly gave side-products (Table 1,
entries 1–4). To obtain the most effective ligand structure, various
N,N¢-dioxides were complexed in situ with Sc(OTf)3 to catalyze the
Mukaiyama–Michael reaction (Fig. 1 and Table 1, entries 5–11).
The steric effect of the amide moiety played a crucial role on both
the enantioselectivity and the yield. It was shown that ligands with
bulky groups at the ortho position of the aniline regiospecifically
provided the g-adducts with satisfactory enantioselectivities and
Table 1 Effects of central metal and ligand on catalytic asymmetric VMMR of TBSOF 1 and chalcone 2aa
Entry
Ligand
Metal
Time (h)
Yield (%)b
Drc
Ee (%)d
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
Sc(OTf)3
Y(OTf)3
La(OTf)2
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
12
12
12
12
3
35
tracee
tracee
tracee
96
> 99 : 1
—
11
—
—
—
77
82
80
12
4
—
—
> 99 : 1
> 99 : 1
> 99 : 1
> 99 : 1
95 : 5
> 99 : 1
> 99 : 1
3
99
12
12
12
3
99
37e
9
10
11
99
99
99
72
59
12
a Unless otherwise noted, reactions were carried out with N,N¢-dioxide (10 mol%), Sc(OTf)3 (10 mol%), 1 (0.25 mmol), 2a (0.1 mmol) in THF (0.3 mL)
at 0 ◦C. b Isolated yield. c Determined by HPLC analysis and 1H NMR spectroscopy. d The ee value of the major diastereomer is given, determined by
HPLC using chiral OD–H column. e Side products were detected.
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Table 2 Screening of the solvents in catalytic asymmetric VMMR of
TBSOF 1 and chalcone 2aa,b
Table 3 Effects of temperature and catalyst loading on catalytic asym-
metric VMMR of TBSOF 1 and chalcone 2aa,b
Catalyst loading
Entry (x mol%)
Entry
Solvent
Time (h)
Yield (%)c
Ee (%)d
T (◦C) Time (h) Yield (%)c
Ee (%)d
1
2
3
4
5
6
7
8
THF
toluene
CH2Cl2
CHCl3
3
12
3
3
3
3
3
3
99
86
99
99
99
99
99
99
93
99
99
99
99
99
82
75
67
75
56
81
81
86
86
70
84
85
87
88
1
2
3
4
5
6
10
5
2
1
5
0
0
0
0
-20
rt
3
3
18
18
18
99
99
trace
n.r.e
99
88
90
89
—
89
84
Et2O
ethyl acetate
propyl acetate
ethyl propionate
ethyl benzoate
EtOH
i-PrOH
t-BuOH
t-BuOH/THF
t-BuOH/ethyl
propionate
5
< 3
99
a Unless otherwise noted, reactions were carried out with N,N¢-dioxide
L3 (10 mol%), Sc(OTf)3 (10 mol%), 1 (0.25 mmol), 2a (0.1 mmol) in
t-BuOH/ethyl propionate (0.3 mL, 1 : 1) at 0 ◦C. b The anti-product was
obtained as the major diastereomer and the anti: syn ratio was up to >99 : 1,
which was determined by HPLC analysis and 1H NMR spectroscopy.
c Isolated yield. d The ee value of the major diastereomer was given,
determined by HPLC using chiral OD–H column. e No reaction.
9
12
10
11
12e
13f
14f
<2
<2
15 min
3
3
a Unless otherwise noted, reactions were carried out with N,N¢-dioxide
L3 (10 mol%), Sc(OTf)3 (10 mol%), 1 (0.25 mmol), 2a (0.1 mmol) in
indicated solvent (0.3 mL) at 0 ◦C. b The anti-product was obtained as the
major diastereomer and the anti : syn ratio was up to >99 : 1, which was
determined by HPLC analysis and 1H NMR spectroscopy. c Isolated yield.
d The ee value of the major diastereomer was given, determined by HPLC
0
◦C. It should be noted that the process was air and moisture
tolerant.
With the optimized conditions in hand, the substrate scope of
◦
using chiral OD–H column. e The reaction temperature was 30 C. f The
the VMMR was explored.17 A series of functionalized chalcones
2 was investigated, and the corresponding enantioenriched g-
substituted butenolides 3 were obtained in excellent yields with
complete regioselectivities and excellent stereoselectivities. The
results of significant structural variations in chalcone derivatives
are collected in Table 4. It is notable that this catalyst system
exhibited a remarkably broad substrate scope under exclusive
diastereocontrol without any side product from a-addition.
Regardless of the electronic properties or steric hindrance of
the substituent at the b-phenyl group of the chalcones, excellent
enantioselectivities were observed (Table 4, entries 1–17). To our
delight, the catalyst was also applicable to heterocyclic systems,
which delivered the adducts with excellent ee values of 92% and
90%, respectively (Table 4, entries 18–19). Chalcone derivatives
containing an electron-donating group functionalized on a ben-
zoyl moiety reacted smoothly with TBSOF 1 to give the expected
products 3t–3w in good enantioselectivities (Table 4, entries 20–
23). Furthermore, exploring the effect of the substituents on both
aromatic rings Ar1 and Ar2 revealed chalcones such as 2x–2aa were
also suitable substrates for this reaction (Table 4, entries 24–27).
Particularly, with electron-withdrawing groups on the b-phenyl
moiety and electron-donating groups on the benzoyl moiety, the
variations proceeded in excellent ee values with a longer reaction
time.
volume ratio was 1 : 1.
investigation of esters revealed that the g-substituted butenolide
3a was isolated with better enantioselectivity and reactivity by
utilizing ethyl propionate as a solvent and up to 86% ee was
achieved (Table 2, entry 8 vs. 6–9). On the other hand, alcohols
benefited the activity greatly and complete transformation was
achieved within 2 h (Table 2, entries 10–12). In particular, in the
case of t-BuOH 3a was obtained with comparable ee value in
only 15 min at 30 ◦C (Table 2, entry 12). In order to observe
the performance of t-BuOH at lower temperature, the strategy
of adding a cosolvent was adopted. To our delight, a mixture of
ethyl propionate and t-BuOH (1 : 1) provided the adduct with best
results (>99% yield, >99 : 1 dr and 88% ee) (Table 2, entry 13 vs.
14).
Subsequently, the effects of the catalyst loading and reaction
temperature were examined and the results are presented in Table
3. Reducing the loading from 10 mol% to 5 mol% caused a
slight increase in the enantioselectivity without deterioration of
reactivity, affording the adduct 3a with 90% ee, >99 : 1 dr and
99% yield in 3 h (Table 3, entry 2 vs. 1). However, when using
2 mol% catalyst, only trace amounts of product was obtained with
maintained enantioselectivity in 18 h (Table 3, entry 3). Further
reducing the loading of the catalyst to 1 mol% resulted in no
product (Table 3, entry 4). Then the reaction temperature was
evaluated. It revealed that the reaction rate decreased dramatically
at -20 ◦C, whereas increasing the temperature to rt led to a slight
decrease in the enantioselectivity (Table 3, entries 5–6). Extensive
screening showed that the optimal conditions were as follows:
5 mol% L3–Sc(OTf)3 complex (1 : 1), 0.2 mmol TBSOF 1 and
0.1 mmol chalcone in 0.3 mL t-BuOH/ethyl propionate (1 : 1) at
The absolute configuration of the adduct 3j was determined to
be (1S, 2S) by a single crystal X-ray structural analysis (Fig. 2).18
Different from the previous reports about 2-(5H)-furanones,7b,7c
the major adduct of vinylogous Mukaiyama–Michael variant
catalyzed by the chiral N,N¢-dioxide–Sc(III) complex is anti.
In addition, for some solid products, enantiopure samples (up
to >99% ee) were obtained upon a single recrystallization.
Undoubtedly, the good substrate generality combined with the
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Table 4 Substrate scope of catalytic asymmetric VMMR of TBSOF 1 and chalcone 2 under the optimal conditionsa,b
Entry
Ar1
Ar2
Time (h)
Yield (%)c
Ee (%)d
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
3
3
2.5
6
3
3
3
8
48
15
8
18
5
99 (3a)
99 (3b)
97 (3c)
99 (3d)
98 (3e)
99 (3f)
98 (3g)
92 (3h)
95 (3i)
99 (3j)
99 (3k)
96 (3l)
99 (3m)
98 (3n)
99 (3o)
90 (>99)e
87 (93)e
90
90
90
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
3-MeOC6H4
4-FC6H4
4-ClC6H4
3-ClC6H4
3,4-Cl2C6H3
4-BrC6H4
3-BrC6H4
4-CNC6H4
3-CF3C6H4
91
90 (>99)e
90 (>99)e
92
9
10
11
12
13
14
15
92 (>99)e
91 (>99)e
92
92 (>99)e
94 (>99)e
91
18
16
17
18
19
20
21
22
23
3-PhOC6H4
4-PhC6H4
2-thienyl
3-thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
24
3
16
3
5
99 (3p)
94 (3q)
99 (3r)
99 (3s)
99 (3t)
96 (3u)
99 (3v)
99 (3w)
91
91 (>99)e
92 (>99)e
90
4-MeC6H4
3-MeC6H4
4-MeOC6H4
88 (>99)e
84 (93)e
83 (>99)e
83
24
36
Ph
24
25
26
27
4-MeOC6H4
4-BrC6H4
3-BrC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
36
18
18
48
92 (3x)
92 (3y)
99 (3z)
99 (3aa)
82
88
91
89
3-CF3C6H4
a Unless otherwise noted, reactions were carried out with N,N¢-dioxide L3 (5 mol%), Sc(OTf)3 (5 mol%), 1 (0.25 mmol), 2 (0.1 mmol) in t-BuOH/ethyl
propionate (0.3 mL, 1 : 1) at 0 ◦C. b The anti-product was obtained as the major diastereomer and anti : syn ratio was up to >99 : 1, which was determined
by HPLC analysis and 1H NMR spectroscopy. c Isolated yield. d The ee value of the major diastereomer was given, determined by HPLC using commercial
chiral columns. e After a single recrystallization in ethyl acetate/petroleum ether.
Scheme 2 Gram-scale version of catalytic asymmetric VMMR of TBSOF
1 and chalcone 2a.
Fig. 2 X-ray structure of product 3j.
treatment of 5 mmol of chalcone 2a, the vinylogous Michael
product 3a was produced in 99% yield without any loss of
simplicity of the experimental procedure for the reaction made it
very attractive from a synthetic point of view.
stereoselectivity. After a single recrystallization, only one single
isomer of 3a (up to 99% ee and >99 : 1 dr) was obtained in 77%
yield.
The VMMR products 3 were versatile building blocks, as
they allowed for further elaboration at the terminal carbon of
the butenolide side chain. Compound 3a served as a model to
straightforwardly illustrate this synthetic potential. As shown in
The mild reaction conditions, the inexpensive starting materials
and the catalyst for this vinylogous Mukaiyama–Michael reaction
offered a practical use of the present approach, so a gram-scale
synthesis of the chiral g-substituted butenolide was performed
under the optimized conditions. As shown in Scheme 2, upon
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Table 5 Control experiments for mechanistic studies of catalytic asym-
metric VMMR of TBSOF 1 and chalcone 2aa
Sc(OTf)3
Entry (x mol%)
L3 (y mol%)
Yield (%)b
Drc
Ee (%)d
1e
2
none
5
none
5
none
none
5
trace
99
4 : 1
19 : 1
—
0
0
—
86
Scheme 3 Elaboration of a vinylogous Michael adduct. Reagents and
conditions: a) 20% Pd/C, 1 atm H2, MeOH, rt, 12 h, 95% yield; b)
m-CPBA, KH2PO4, CH2Cl CH2Cl, 60 ◦C, 5 h, 65% yield; c) NH2OH·HCl,
pyridine, EtOH, 5 h, 90% yield; d) PCl5, toluene, 3 h, 70% yield.
3
n.r.g
99
4f
5
>99 : 1
a Unless otherwise noted, reactions were carried out with N,N¢-dioxide
L3, Sc(OTf)3, 1 (0.25 mmol), 2a (0.1 mmol) in ethyl propionate (0.3 mL)
Scheme 3, the Michael adduct 3a was readily converted to g-
lactone 4 in 95% yield after reduction of the olefinic double bond
of the butenolide moiety. Baeyer–Villiger oxidation of 4 proceeded
with m-CPBA to afford lactone 5 in 65% yield with >99 : 1 dr
and up to 98% ee. In addition, considering that the butenolide
moiety was also synthetically useful, the product 3a could be
easily transformed into oxime 6 by treatment with NH2OH·HCl.
Beckmann rearrangement of 6 afforded butenolide 7 bearing an
amide group on the side chain in 70% yield with >99 : 1 dr and
98% ee.
To gain insight into the reaction mechanism, the relationship
between the enantiomeric excess of the product 3a and N,N¢-
dioxide L3 complex showed that the ee correlated linearly to
each other (Fig. 3).19 This suggested that dimeric species of L3–
Sc(OTf)3 complex did not participate in this reaction and all the
events occurred in a monomeric species of L3–Sc(OTf)3 complex.
Moreover, on the HRMS spectrum of the sample only one MS
peak at 907.2258 assigned to the monomeric scandium species
[L3–Sc(OTf)2]+ (HR-ESIMS: m/z calcd: 907.2259) was obtained
and no oligomeric species of L3–Sc(OTf)3 complex was detected.
at 0 ◦C for 3 h. b Isolated yield. c Determined by HPLC analysis and H
1
NMR spectroscopy. d The ee value of the major anti-diastereomer is given,
determined by HPLC using chiral OD–H column. e The reaction time was
12 h. f The reaction time was 5 h. g No reaction.
revealed that both of the substrates were securely fixed at a
specific location by the chelation of Sc(OTf)3, which has been
mentioned in previous studies.5e,6o,7a The coordination of the two
reactants to the central metal was confirmed directly by the HRMS
experiment. On the spectrum of the sample an acquired ion at
m/z 1115.4252 (HR-ESIMS: m/z calcd for [(L3–Sc(OTf)2)+2a]+:
1115.3147) was revealed, which corresponded to the species of L3–
Sc(III) complex coordinating with one molecule chalcone 2a. And
characteristic signal of [(L3–ScIII)+2a+1-2H+]+ (HR-ESIMS: m/z
calcd: 1013.5026) at m/z 1013.5045 were observed. These results
suggested that the central metal conducted the two substrates into
the highly organized chiral environment in sequence by a manner
of dual control.
Based on the X-ray structure of N,N¢-dioxide–scandium
complex12f and the experimental results, as well as the absolute
configuration of the product, a concerted stereorecognition model
was proposed (Fig. 4). The favourable anti-diastereoselectivity
was rationalized through the Newman projection. To avoid steric
repulsion between the TBS group and the phenyl group, the
nucleophilic addition proceeded via projection II preferentially to
afford anti-product. A possible stereorecognition model is given
in Fig. 4 to explain the enantioselectivity. In this model, the N-
oxide and amide oxygen atoms of L3 coordinated to scandium in
a tetradentate manner to form two six-membered chelate rings,
and the chalcone was attached to scandium at the favourable
equatorial position. The Re face of the chalcone was shielded
Fig. 3 Nonlinear effects observed in the L3–Sc(OTf)3-catalyzed VMMR
of TBSOF 1 and chalcone 2a.
Control experiments (Table 5) and HRMS analysis (see support-
ing information †) were carried out to investigate the coordination
states of the reactants. Initially, only trace amounts of product
3a were obtained without Sc(OTf)3 and N,N¢-dioxide L3 with
poor diastereoselectivity (4 : 1 dr) (Table 5, entry 1). In contrast,
5 mol% Sc(OTf)3 as Lewis acid was effective enough to complete
the reaction and provided 3a with 19 : 1 dr in 99% yield (Table
5, entry 2). The distinct consequence of the diastereoselectivity
Fig. 4 Stereorecognition models for catalytic VMMR.
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by the neighboring 2,6-diethylphenyl group of the ligand, and the
nucleophile, TBSOF 1, attacked from the Si face to give the (S,S)-
product.
was added at 0 ◦C. The reaction was stirred at 0 ◦C and monitored
by TLC. After complete consumption of the starting material 2a,
the mixture was direct purified by column chromatography on
silica gel (ethyl acetate/petroleum ether 1 : 5 to 1 : 3) to afford the
white solid 3a in 99% yield, as a mixture of diastereomers (90% ee,
>99 : 1 dr; >99% ee was obtained after a single recrystallization
in ethyl acetate/petroleum ether). The ee and diastereoselectivity
were determined by HPLC analysis [Chiralpak OD–H, 80 : 20 n-
hexane/iPrOH, 1.0 mL min-1; tr (major) = 16.495 min, tr (minor) =
Conclusions
We have developed a highly efficient catalytic asymmetric viny-
logous Mukaiyama–Michael reaction of 2-silyloxyfuran with
chalcone derivatives using a chiral N,N¢-dioxide–scandium com-
plex. This contribution provides a practical synthetic strategy
for the formation of highly functionalized chiral g-substituted
butenolides with broad substrate scope. In the presence of 5 mol%
N,N¢-dioxide–Sc(III) complex, complete regioselectivities, exclu-
sive diastereoselectivities and good to excellent enantioselectivities
(up to 94% ee) have been achieved under mild conditions. The
synthetic potential of this methodology was also demonstrated
by the excellent results obtained on a gram scale. And the
elaboration of the product has also been explored to illustrate
the synthetic versatility of g-substituted butenolides. Moreover,
the pathway is air-tolerant and easily manipulated, and reagents
are readily available. On the basis of the experimental results, a
possible catalytic cycle and favorable stereorecognition model have
been proposed to probe the reaction mechanism and explain the
origin of the asymmetric induction. Application of N,N¢-dioxide–
metal complexes to other reactions involving 2-silyloxyfurans as
nucleophiles is ongoing in our laboratory.
◦
1
18.822 min] and H NMR spectroscopy. M.p. 99–102 C. [a]D25
-75.5 (c 0.58 in CH2Cl2). 1H NMR (400 MHz, CDCl3) d = 7.88 (d,
J = 7.5, 2H), 7.55 (t, J = 7.4, 1H), 7.43 (t, J = 7.7, 2H), 7.36–7.25
(m, 6H), 5.27 (dd, J = 7.3, 1.4, 1H), 3.70 (td, J = 7.7, 5.0, 1H), 3.58
(dd, J = 17.7, 5.0, 1H), 3.48 (dd, J = 17.7, 8.2, 1H) ppm.
Acknowledgements
We appreciate the National Natural Science Foundation of China
(Nos. 20732003 and 21021001) and the National Basic Research
Program of China (973 Program: No. 2011CB808600) for financial
support. We also thank Sichuan University Analytical & Testing
Center for NMR analysis and the State Key Laboratory of
Biotherapy for HRMS analysis.
Notes and references
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Experimental section
General methods and materials
1H NMR spectra were recorded on commercial instruments
(400 MHz or 600 MHz). Chemical shifts are reported in ppm
from tetramethylsilane with the solvent resonance as the internal
standard (CDCl3, d = 7.26). Spectra are reported as follows:
chemical shift (d (ppm)), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet), coupling constants (Hz),
integration, and assignment. 13C NMR spectra were collected on
commercial instruments (100 MHz or 150 MHz) with complete
proton decoupling. Chemical shifts are reported in ppm from the
tetramethylsilane with the solvent resonance as internal standard
(CDCl3, d = 77.0). The enantiomeric excess was determined by
HPLC analysis on commercial chiral columns. Optical rotations
were measured on a commercial polarimeter and reported as
follows: [a]TD (c = g/100 mL, solvent). HR-ESIMS spectra
were recorded using a commercial apparatus and methanol or
acetonitrile was used to dissolve the sample. Unless otherwise
indicated, reagents obtained from commercial sources were used
without further purification. Solvents were dried and distilled
prior to use according to the standard methods. The N,N¢-dioxide
ligands were prepared according to previous reports.12b,12c TBSOF
1, 2-(tert-butyldimethylsilyloxy)furan, was prepared according to
reported procedures4a,20 and immediately used due to its instability.
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N,N¢-Dioxide L3 (0.005 mmol, 2.9 mg), Sc(OTf)3 (0.005 mmol, 2.5
mg), chalcone 2a (0.1 mmol, 20.8 mg), t-BuOH (0.15 mL) and ethyl
propionate (0.15 mL) were stirred in a dry reaction tube under air
◦
at 30 C for 0.5 h. Subsequently, TBSOF 1 (0.25 mmol, 60 mL)
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was replaced by methyl or tertiary butyl group (Ar2 = Ph) only the
side products were obtained. Moreover the reaction of cinnamone
and TBSOF 1 did not occur at all. The distinct performance of the
aromatic and aliphatic enones suggested that a p–p interaction might
exist between the aromatic enones and the aromatic ring of the catalyst,
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5754 | Org. Biomol. Chem., 2011, 9, 5748–5754
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