Asymmetric diels-alder reaction of 3-olefinic benzofuran-2-ones and polyenals: Construction of chiral spirocyclic benzofuran-2-ones

Article abstract of DOI:10.1021/ol403094a

A highly enantioselective Diels-Alder reaction of 3-olefinic benzofuran-2-ones with polyenals catalyzed by diphenylprolinolsilyl ether through a trienamine activation strategy was developed.

Full text of DOI:10.1021/ol403094a

Letter
pubs.acs.org/OrgLett
Asymmetric Diels−Alder Reaction of 3‑Olefinic Benzofuran-2-ones
and Polyenals: Construction of Chiral Spirocyclic Benzofuran-2-ones
Xin Li,* Mao-Hui Lin, Yu Han, Feng Wang, and Jin-Pei Cheng*
State Key Laboratory of Elemento-Organic Chemistry, Department of Chemistry, Nankai University, and Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A highly enantioselective Diels−Alder reaction
of 3-olefinic benzofuran-2-ones with polyenals catalyzed by
diphenylprolinolsilyl ether through a trienamine activation
strategy was developed.
symmetric aminocatalysis1 has constituted a perfect
scenario for activating carbonyl compounds, which
for efficient methods for the construction of these compounds
is therefore interesting in organic synthesis. Stereoselective
construction of spiro[cyclohexanone-benzofuran-2-one] deriv-
atives from benzofuran-2(3H)-ones and enals was accom-
plished by the group of Rios by using a chiral secondary amine
(Scheme 2).10a An asymmetric cascade reactions leading to
A
facilitated a range of chiral transformations. The widely
known enamine activation2 and iminium ion activation3
modes have provided a reliable synthetic platform for
generating stereogenic centers at the α and β positions of
unmodified carbonyls. Recently, the interest of chemists has
shifted toward the stereocontrolled generation of stereocenters
of a carbonyl substrate requiring the propagation of the
electronic effects inherent to enamine and iminium ion
activations through the conjugated π-system of poly unsatu-
rated carbonyls, which is called the “aminocatalytic remote
functionalization strategy”.4 Complying with this trend, a new
type of catalytic strategy, named “trienamine activation”, was
jointly developed by Chen and Jørgensen (Scheme 1).5,6 Their
Scheme 2. General Strategy for the Construction of Chiral
Spirocyclic Hexanones of Benzofuran-2-ones
Scheme 1. Trienamine Activation Strategy
work found that trienamine intermediates were produced in
situ through the propagated HOMO-raising electronic effect, in
which Diels−Alder reaction were easily occur in the further
process. Such a catalytic tool allows the rapid construction of
stereochemically dense cyclohexenyl rings adorned with a
broad spectrum of functional groups and with high stereo-
control. A number of highly functionalized chiral cyclohexene
derivatives,7 especially spirocycles,8 were synthesized with
excellent stereoselectivities.
enantiomerically pure spiro[cyclohexone-benzofuran-2-one]
derivatives with 3-olefinic benzofuran-2-ones and enones was
reported by Melchiorre and co-workers by using chiral primary-
amine catalyst (Scheme 2).10b We realized the highly
enantioselective double Michael addition reaction of sub-
stituted benzofuran-2-ones to divinyl ketones by a simple
Cinchona alkaloid type tertiary amine thiourea catalyst, in
Spirocyclic benzofuran-2-one units are privileged structural
motifs found in natural and unnatural compounds with diverse
and important biological activities.9 Consequently, the search
Received: October 28, 2013
Published: December 2, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
which functionalized chiral spirocyclic benzofuran-2-ones were
obtained (Scheme 2).11 In addition, there are only a few
examples of the synthesis of chiral 3,3′-substituted benzofuran-
2-ones by asymmetric catalysis.12 Given that a different class of
spirocycle ring system may show promise in medicinally
relevant compounds in drug development and biological
phenomena studies, continued development of more creative
methods for the synthesis of structurally diverse spirocyclic
benzofuran-2-ones in an enantiopure form is significantly
desired. We report herein a transformation of benzo-lactone
type activated olefin by trienamine activation.13 An asymmetric
Diels−Alder reaction of 3-olefinic benzofuran-2-ones with
polyenals was achieved, thus generating enantiomeric enriched
spirocyclic benzofuran-2-ones derivatives with chiral all-carbon
quaternary centers (Scheme 2).
retentive enantioselectivity (entry 4 in Table 1). A less
favorable result was obtained when more acidic p-NO2 benzoic
acid (PNBA) was selected as additive (entry 5 in Table 1),
while a further increase in the acidity of the additive led to a
significant drop in reactivity (entry 6 in Table 1). With the
optimal combination of 4b and OFBA, we then screened
solvents. As illustrated in Table 1, initial used CHCl3 gave the
best result among a range of screened solvents (entries 2 and
7−13 in Table 1). Collectively, the best result with respect to
yield and stereoselectivity was obtained by performing the
reaction at room temperature in CHCl3 with 20 mol % of 4b
and 20 mol % of OFBA. Under these conditions, the reaction
provided the desired product with 90% yield in 91:9 dr and
95% ee (entry 2 in Table 1).
After the reaction conditions were optimized, scope was
explored. As shown in Table 2, the reaction proceeded
We initiated our investigations using 3-olefinic benzofuran-2-
one (1a) and 2,4-hexadienal (2a) in the presence of 20 mol %
of chiral secondary amine α,α-diphenylprolinolsilyl ether 4a
and o-F benzoic acid (OFBA) in CHCl3 at room temperature
(Table 1). To our delight, 4a exhibited high catalytic activity,
a
Table 2. Scope of the Diels−Alder Reaction
a
Table 1. Screening of Conditions.
b
d
time
(h)
yield
ee
c
entry
R1
R2
R3
(%)
dr
(%)
1
2
3
4
5
6
1a: H
1b: H
1c: H
1d: H
1e: H
1f: H
CO2Et
CO2tBu
CO2Bn
COMe
COPh
2a: H
2a: H
2a: H
2a: H
2a: H
18
24
24
7
3a: 90
3b: 90
3c: 86
3d: 80
3e: 81
3f: 81
91:9
95
96
95
92
93
94
91:9
90:10
86:14
85:15
86:14
5
CO(4-Br) 2a: H
Ph
5
b
d
time yield
ee
c
entry cat
acid
solvent
CHCl3
(h)
(%)
dr
(%)
7
8
1g: H
CO(4-
MeO)Ph
2a: H
2a: H
2a: H
4
5
3g: 85
3h: 70
89:11
80:20
93
83
1
4a
4b
4c
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
OFBA
OFBA
OFBA
BA
18
18
18
18
18
18
18
18
18
18
18
18
18
86
88:12
86
95
2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
ClCH2CH2Cl
CCl4
90
91:9
1h: 5,7- COPh
t-Bu
e
e
3
trace
81
nd
nd
9
1i: H
1a: H
CN
24
48
3i: 78
3j: 72
82:18
80:20
89
93
4
88:12
95
93
10
CO2Et
2b: n-
C3H7
5
PNBA
TFA
87
89:11
e
e
6
15
nd
nd
11
12
13
1a: H
1a: H
1a: H
CO2Et
CO2Et
CO2Et
2c: n-
C4H9
48
48
48
3k:75
3l:79
82:18
81:19
80:20
91
91
91
7
OFBA
OFBA
OFBA
OFBA
OFBA
OFBA
OFBA
86
89:11
89:11
71:29
80:20
87:13
76:24
75:25
93
93
94
93
94
8
88
2d: n-
C5H11
9
29
2e: n-
C6H13
3m:74
10
11
12
13
Toluene
THF
32
47
a
e
The reactions were conducted with 0.1 mmol of 1, 0.15 mmol of 2,
20 mol % of 4b, and 20 mol % of OFBA as cocatalyst in 1 mL of
CHCl3 at room temperature. Yield of the isolated major
diastereoisomer of product 3 after chromatographic purification on
silica gel. Determined by H NMR of crude products. Measured by
chiral HPLC analysis.
Et2O
trace
47
nd
1,4-dioxane
94
b
a
The reactions were conducted with 0.1 mmol of 1a, 0.15 mmol of 2a,
20 mol % of catalyst, and acids (20 mol %) as co-catalyst in 1 mL
solvent at room temperature. Yield of the isolated major
diastereoisomer of product 3a after chromatographic purification on
c
d
1
b
c
d
1
silica gel. Determined by H NMR of crude product. Measured by
e
smoothly to give the desired products in high yields with
very good enantioselectivity for different ester substituted
dienophiles (1a−c, entries 1−3, in Table 2). Moreover, the
reactions were shown to work well with a range of acyl-group
substituted benzofuran-2-one alkenes bearing either electron-
withdrawing or electron-donating groups (1d−h, entries 4−8,
in Table 2) to give the desired products 3d−h with very good
yields (up to 85%), moderate diastereoselectivities (up to 89:11
dr), and good enantioselectivities (83−94% ee). A more
accurate analysis of these results showed that the enantiose-
lectivity of the reaction is sensitive to the steric effect of
benzofuranone. Lower ee value was obtained when 1h was
applied as the dienophile. Remarkably, the chemistry can be
chiral HPLC analysis. Not determined.
and the Diels−Alder product was isolated with good yield and
very good stereoselectivity (88:12 dr and 86% ee) (entry 1 in
Table 1). Improvements could be achieved by employing the
more sterically demanding O-triethylsilyl (O-TES) ether
analogue 4b (entry 2 in Table 1). When electron-withdrawing
substituted secondary amine 4c was used as the catalyst, only a
trace of the desired product was isolated (entry 3 in Table 1).
Furthermore, acid additives proved to have decisive effects on
the reactivity. The weaker acid benzoic acid (BA) decreased the
reaction rate and resulted in lower isolated yield with the
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Organic Letters
Letter
successfully extended to a cyanogroup substituent in 1, thus
maintaining good enantioselectivity (entry 9 in Table 2).
In order to further extend the substrate scope, other
trienamine precursors 2b−e were also examined. As revealed
in Table 2 (entries 10−13), the reactions were shown to work
well with a range of polyconjugated enals bearing different alkyl
substituted groups to give the desired products with good yields
(up to 79%), moderate diastereoselectivities (up to >82:18 dr)
and good enantioselectivities (91−93% ee).
Scheme 4. Transformations of the Products
The absolute configuration of product 3a was determined by
X-ray analysis (Figure 1).14 And the configurations of other
gave product 5a with almost retentive enantioselectivity.
Reduction of 3a by NaBH4 led to the formation of a novel
ester ring-opening rearrangement product 5b.
In summary, we have presented the chiral secondary amine
promoted highly enantioselective Diels−Alder reaction with 3-
olefinic benzofuran-2-ones and polyenals by a triamine−
activation strategy. The reaction scope is substantial, and a
number of substituted benzofuran-2-ones and polyenals could
be successfully applied to give multifunctional chiral benzofur-
an-2-one derivatives bearing spirocyclic hexanes at the 3-
position with moderate diastereoselectivities and good
enantioselectivities.
Figure 1. X-ray crystal structure of 3a.
products were tentatively assigned by referring to that of 3a. A
catalytic mode in accordance with previous studies5 was
proposed to account for the observed stereoselectivities
(Scheme 3).
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 3. Rationalization for Generating the Consecutive
Chiral Centers
Experimental details, analytic data for all new compounds, and
X-ray crystallographic data of 3a and 5b (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xin_li@nankai.edu.cn.
Notes
Finally, application of this methodology to the synthesis of
chiral 2-spirocyclohexane benzofuran-3-ones has been envi-
sioned due to the widespread 2-spirocyclic benzofuran-3-one
framework in natural products and biologically active
derivatives.15 From the results in Figure 2, we can see that
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Most (2010CB833300, 2012CB821600), NSFC
(21390400, 21172112 and 21172118), the Program for New
Century Excellent Talents in University (NCET-12-0279), and
the State Key Laboratory on Elemento-organic Chemistry for
financial support.
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