Asymmetric intramolecular oxa-Michael reactions to tetrahydrofurans/2H- pyrans catalyzed by primary-secondary diamines

Article abstract of DOI:10.1021/cs4002332

The asymmetric intramolecular oxa-Michael reactions of α,β- unsaturated ketones have been achieved by using readily accessible primary-secondary diamines as the organocatalysts, giving the synthetically useful tetrahydrofurans/2H-pyrans in good yields and

Full text of DOI:10.1021/cs4002332

Letter
pubs.acs.org/acscatalysis
Asymmetric Intramolecular Oxa-Michael Reactions to
Tetrahydrofurans/2H‑Pyrans Catalyzed by Primary−Secondary
Diamines
Yingpeng Lu,†,‡ Gang Zou,*,† and Gang Zhao*,‡
†Laboratory of Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong
Road, Shanghai 200237, People’s Republic of China
‡Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: The asymmetric intramolecular oxa-Michael
reactions of α,β-unsaturated ketones have been achieved by
using readily accessible primary−secondary diamines as the
organocatalysts, giving the synthetically useful tetrahydrofur-
ans/2H-pyrans in good yields and with high enantioselectiv-
ities (up to 90% ee).
KEYWORDS: oxa-Michael reaction, organocatalysis, asymmetric catalysis, diamine catalyst, tetrahydrofurans
he oxa-Michael reaction has been widely used in organic
Tsynthesis as a powerful tool to construct carbon−oxygen
bond.1,2 Compared with the amino group,3,4 the lower
nucleophilicity of the hydroxyl group makes it more challenging
as a Michael donor in Michael additions, and a strong base is
usually required to promote the reaction, which usually caused
difficulty in achieving a compatible chiral environment in
catalysis. Solutions to this problem include using more-active
phenols,5−9 oximes10−13 or hydrogen peroxide14,15 with
improved nucleophilic oxygen atom or using more-reactive
conjugate acceptors,16−21 such as conjugated enals or nitro-
styrene, and the design of intramolecular processes.22−30 Over
recent decades, with the rapid development of organocatalysis,
organocatalytic enantioselective oxa-Michael additions have
also achieved impressive progress, providing efficient access to
Figure 1. Structures of typical THF/THP containing macrolides.
various oxygen-containing heterocycles31−33 such as tetrahy-
drofurans (THF), tetrahydropyrans (THP), chromenes, or
xanthones, which could be found in numerous natural products
challenging intramolecular oxa-Michael reactions of enones.
Herein, we describe the development of a new primary−
secondary diamine catalyst derived from L-tert-leucine, which
efficiently catalyzed the asymmetric intramolecular oxa-Michael
reactions of conjugate enones to give the synthetically useful
chiral tetrahydrofurans/2H-pyrans.
Initially, (E)-8-hydroxy-1-phenyloct-4-en-3-one 1a was syn-
thesized, and the model reaction with 1a was carried out in the
presence of 10 mol % of catalyst and 10 mol % of TFA as an
additive in CHCl3 under room temperature (Table 1). The
primary−tertiary diamines, primary−secondary diamines, and
primary−primary diamines listed in Figure 2 were prepared and
with important biological activities34−42 (Figure 1).
However, to our knowledge, only a few reports have been
focused on the intramolecular oxa-Michael reactions of
unsaturated ketones with alcohol nucleophiles which used
chiral Brønsted acid26 or bifunctional chiral thiourea27 as the
catalysts. Very recently, Ye’s group has reported that the
desymmetrization of cyclohexadienones could be achieved via
an asymmetric intramolecular oxa-Michael reaction using
primary amine catalysts.30
Our group has great interest in the development of amino
acid-derived catalysts, and we have first developed from amino
acids a variety of primary amine catalysts43−55 that have showed
excellent catalytic reactivity in Michael additions and
epoxidation of enones. Inspired by these results, we then
became interested in the application of these catalysts to the
Received: March 28, 2013
Revised: May 12, 2013
© XXXX American Chemical Society
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dx.doi.org/10.1021/cs4002332 | ACS Catal. 2013, 3, 1356−1359

ACS Catalysis
Letter
a
the ring closure product with 88% yield and 72% ee value
(Table 1, entry 13). In our previous and other related works,
acid additives have been found to play an important role in the
catalytic efficiency of these amino acid-derived diamine
catalysts. Similarly, in the absence of an acid, this reaction
gave the product with only 50% yield and 7% ee (Table 1, entry
15). A screen of several acids was then performed to improve
the enantioselectivity with catalyst 3m. L-camphorsulfonic acid
((L)-CSA) gave the best result of 96% yield and 85% ee (Table
1, entry 23). Notably, a proper match of the chirality of the
diamine catalyst and the chiral acid additive is necessary
because the use of (D)-CSA affords only moderate
enantioselectivity (Table 1, entry 24). A control experiment
with the acid alone gave the racemic product in the same
excellent yield (Table 1, entry 25), indicating that cooperative
catalysis of the diamine catalyst and the acid additive was crucial
to achieve good enantioselectivity in this reaction system.
With the catalyst combination of 3m/(L)-CSA, other
reaction parameters, such as the solvent effect, temperature
and the loading of the catalyst, were also examined (for details,
see the Supporting Information, Table S1). In general,
nonprotic solvents, such as toluene, dichloromethane, and
chloroform, bearing no coordinative atoms are superior to
protic solvents. Decreasing the temperature or reducing the
catalyst/acid loading caused obviously decreases in reactivity
and enantioselectivity. Thus, the best reaction conditions are a
combination of 3m/(L)-CSA (1:1) in chloroform at 25 °C,
providing the product with 96% yield and 85% ee.
With the optimized reaction conditions in hand, the scope of
the oxa-Michael reaction was investigated, and the results are
summarized in Table 2. In general, the 2-substituted
tetrahydrofuran or tetrahydropyran products were exclusively
formed in high yields with good ee values. Substrates with both
electron-donating and -withdrawing groups on the phenyl
group worked well under the catalysis (Table 2, 2a−2c).
Aliphatic enones as well as enones bearing ether or amide
functional groups also performed well to give the products with
good yields and high stereoselectivity, except for substrate 2d,
the low yield of which might be due in part to the high volatility
of the product (Table 2, 2d−2f). Enones with bulky
substituents on the side of the ketone moiety gave both
significantly lower yield and enantioselectivity (Table 2, 2g).
Secondary alcohol in the substrate also worked well to afford
2,5-substituted tetrahydrofuran with high yields and good
enantioselectivities, albeit with a poor diastereoselectivity
(Table 2, 2h). The more sterically demanding tertiary alcohol
gave unsatisfactory results, with a sharp drop in the ee value
(Table 2, 2i). Less reactive enones with an additional methyl
group on the alkene double bond were also evaluated; however,
using (E)- or (Z)-1j as a substrate, both the conversion and the
ee value were low, and the absolute configuration of the
corresponding product was reversed (Table 2, 2j). Pleasingly,
this catalyst system could also be applied to the synthesis of the
six-membered tetrahydropyran products with good to excellent
yields, ee values, and similar functional group tolerance (Table
2, 2k−2m).
Table 1. Screening the Catalysts and Acid Additives
b
c
entry
cat. 3
acid additive
yield (%)
ee (%)
1
2
3a
TFA
85
80
85
92
90
86
90
76
80
74
72
76
88
91
52
76
82
89
36
88
77
80
96
92
96
26
32
26
57
52
61
68
12
56
66
40
30
72
5
3b
TFA
3
3c
TFA
4
3d
3e
TFA
5
TFA
6
3f
TFA
7
3g
TFA
8
3h
3i
TFA
9
TFA
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3j
TFA
3k
TFA
3l
TFA
3m
3n
3m
3m
3m
3m
3m
3m
3m
3m
3m
3m
none
TFA
TFA
none
7
PhCOOH
p-NBA
TsOH
CCl3COOH
TfOH
L-Boc-Ph-OH
D-Boc-Ph-OH
L-CSA
D-CSA
L-CSA
45
40
63
41
65
60
72
85
51
0
a
Unless otherwise specified, the reaction was carried out with 1a (0.1
mmol), 3 (10 mol %), and acid additive (10 mol %) in CHCl3 (1.0
mL) at room temperature for 48 h. Isolated yields. Determined by
chiral HPLC analysis. The absolute configuration was determined by
comparison of the specific optical rotation value with the literature
data.27
b
c
Figure 2. Structures of the catalysts studied.
evaluated in the reaction. Cinchona alkaloid-derived primary
amine catalyst, which usually worked well in Michael addition
and epoxidation, was examined but gave only the product 2a
with 26% ee (Table 1, entry 1). Primary−tertiary diamine
catalysts or primary−primary diamine catalyst generally
provided inferior stereocontrol in this reaction.
The examination of different amino acids skeletons and
substituents of the secondary amine moiety revealed that the
catalyst 3m derived from L-tert-leucine bearing a sterically
hindered adamantanyl group was the optimal catalyst, affording
A bifunctional iminium mechanism similar to those
previously proposed for the primary amine catalysts in the
iminium catalysis of enone may be invoked to explain the
observed stereochemical results (Figure 3). The primary amine
moiety of the catalyst 3m was presumed to activate enone 1 via
the formation of an iminium ion, whereas the secondary amine
activates the nucleophilic hydroxyl group. The si-face of the
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a
To gain some insight into the catalytic mechanism of the
catalyst system, an ESI-MS analysis was taken for the
combination of catalyst and substrate 1b (Figure 4). A signal
matching the key iminium ion could be explicitly observed,
which may be supportive of our proposed transition state I for
the reaction.
Table 2. Substrate Scope of the Oxa-Michael Reaction
Figure 4. Mass spectrum of the combination of 1b with catalyst 3m..
In summary, a novel primary−secondary diamine catalyst has
been developed and applied in the intramolecular oxa-Michael
addition of α,β-unsaturated ketones. This new system features
easily accessible modular catalysts and simple operation,
enabling the synthesis of 2-substituded tetrahydrofurans or
tetrahydropyrans under mild conditions with good yields and
high enantioselectivities. Efforts are being focused on further
application of this catalyst system to other related reactions as
well as a more detailed mechanistic understanding of this
reaction.
ASSOCIATED CONTENT
* Supporting Information
Details of condition optimization, experimental procedures, and
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.”
■
S
a
Unless otherwise specified, the reaction was carried out with 1 (0.1
mmol), 3m (10 mol %), and (L)-CSA (10 mol %) in chloroform (1.0
b
c
mL) at room temperature for 48 h. Isolated yields. Determined by
chiral HPLC analysis. The absolute configuration was determined by
comparison of the specific optical rotation value with the literature
AUTHOR INFORMATION
Corresponding Author
*(Gang Zou) Fax: (+86)-21-6425-3881. E-mail: zougang@
ecust.edu.cn. (Gang Zhao) Fax: (+86)-21-6416-6128; e-mail:
zhaog@mail.sioc.ac.cn.
■
d
data.27 dr. = 1:1, ee value of the two diastereomer were 89% and 80%,
e
respectively (see the Supporting Information for details). (Z)-1j was
studied under optimized conditions.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research support from National Basic Research Program of
China (973 Program, 2010CB833300), the National Natural
Science Foundation of China (Nos. 21032006, 203900502,
20532040, 21290180), the Science and Technology Commis-
sion of Shanghai Municipality (11XD1406400), and the
Excellent Young Scholars Foundation of the National Natural
Science Foundation of China (20525208) is gratefully
acknowledged.
Figure 3. Possible transition state of the reaction.
enone in this transition state assembly I is shielded by the bulky
groups of both sides of the catalyst, driving the alcohol oxygen
atom to attack the re-face of the enone 1. The acid additive may
facilitate the formation of the iminium ion and promote the
intramolecular nucleophilic ring closure by generating a suitable
leaving group through protonation of the catalyst amine.
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