Highly diastereo- and enantioselective [3+2] annulation of isatin-derived Morita-Baylis-Hillman carbonates with trifluoropyruvate catalyzed by tertiary amines

Article abstract of DOI:10.1039/c3cc46490c

An enantioselective [3+2] annulation of Morita-Baylis-Hillman carbonates with trifluoropyruvate catalyzed by modified cinchona alkaloids was developed in good to excellent yields with excellent diastereo- and enantioselectivities.

Full text of DOI:10.1039/c3cc46490c

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Highly diastereo- and enantioselective [3+2]
annulation of isatin-derived Morita–Baylis–Hillman
carbonates with trifluoropyruvate catalyzed by
tertiary amines†
Cite this: Chem. Commun., 2013,
49, 11071
Received 29th August 2013,
Accepted 5th October 2013
Neng-Jun Zhong,ab Feng Wei,ab Qing-Qing Xuan,ab Li Liu,*a Dong Wanga and
Yong-Jun Chena
DOI: 10.1039/c3cc46490c
www.rsc.org/chemcomm
An enantioselective [3+2] annulation of Morita–Baylis–Hillman the phosphonium allylic ylide, phosphorus could stabilize the
carbonates with trifluoropyruvate catalyzed by modified cinchona ylide, which led to the Wittig olefination product rather than
alkaloids was developed in good to excellent yields with excellent the [3+2] cycloaddition product.10 Recently, Me2S was reported
diastereo- and enantioselectivities.
to catalyze the [3+2] annulation of MBH bromide with carbonyl
compounds in a racemic manner.11 Although various Lewis bases
Oxa-spirooxindoles are important moieties in many natural products such as P, N or S-derivatives could be used as catalysts in the
and pharmaceutical molecules.1–3 For example, 3-oxa-spirooxindoles generation of allylic ylides derived from MBH adducts, the asym-
have been used as antagonists of progesterone receptors (I),3b metric [3+2] annulation of MBH adducts with carbonyl compounds
antihypertension agents of mammals (II)3c and biological mole- has never been reported. Unlike phosphorus, the nitrogen atom in
cules to treat cancers (III) (Fig. 1).3d
allylic N-ylides could not bond with the oxygen atom in carbonyl
On the other hand, Mortia–Baylis–Hillman (MBH) adducts have compounds, so we envisioned that a tertiary amine catalyst could
been proven to be useful precursors for the synthesis of many bioactive be used in the [3+2] annulation of allylic ylides with carbonyl
molecules and natural products owing to their dense functionalities.4 compounds in order to avoid the Wittig-type olefination.12 Herein,
Since Lu and co-workers reported the first phosphine-catalyzed [3+2] we would like to report an enantioselective [3+2] annulation of isatin-
annulation reaction of MBH derivatives with electron-deficient alkenes derived MBH carbonates with activated ketones catalyzed by a
via allylic P-ylide intermediates,5 MBH adducts have been successfully modified cinchona alkaloid to afford chiral 2H-spiro[furan-3,30-
used in annulation with electron-deficient olefins,6 imines7 or diazo8 indolin]-20-ones bearing two contiguous quaternary centers, in
for the construction of various five-membered rings. However it should good yields with excellent diastereo- and enantioselectivities.
be noted that the reaction of aldehydes or ketones with allylic
Initially, the reaction of isatin-derived MBH carbonate 1d
ylides generated from MBH derivatives in the catalysis of with ethyl fluoropyruvate (2a) was carried out in the presence of
phosphine provided only olefination products.9 In the case of PPh3 (1.2 equiv.) in THF at room temperature. The reaction
proceeded smoothly to generate the olefination product 3 in
79% yield (Fig. 2). However, when DABCO was used as the
catalyst (20 mol%) in the same reaction of 1a with 2a, the [3+2]
cycloaddition product 4a was isolated in 40% yield.
To realize the [3+2] annulation of MBH carbonates with 2a
asymmetrically, various chiral catalysts 5a–f (Fig. 3) derived from
cinchona alkaloids13 were employed in the reaction of 1a with 2a.
Fig. 1 Oxa-spirooxindole.
For catalyst 5a, the annulation product was not detected (Table 1,
entry 1). When b-isocupreidine (b-ICD, 5b) was used as the catalyst,14
the annulation product 4a was obtained in 54% yield with 2 : 1 dr
a Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory
of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy
of Sciences, Beijing 100190, China. E-mail: lliu@iccas.ac.cn;
Fax: +86 10 62554449; Tel: +86 10 62554614
b University of Chinese Academy of Sciences, Beijing 100049, China
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, and chiral chromatographic analysis of all new
compounds. CCDC 934201. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3cc46490c
Fig. 2 Wittig-type reaction and [3+2] cycloaddition.
Chem. Commun., 2013, 49, 11071--11073 11071
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Table 2 The reaction of isatin-derived MBH carbonates (1a–l) and 2a
Entry
1 (R1, R2)
Product 4
drb
19 : 1
14 : 1
12 : 1
17 : 1
>20 : 1
17 : 1
14 : 1
9 : 1
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
1a (H, H)
1b (F, H)
1c (Cl, H)
1d (Br, H)
1e (I, H)
1f (Me, H)
1g (MeO, H)
1h (CF3O, H)
1i (NO2, H)
1j (Me, Me)
1k (H, F)
4a
4b
4c
4d
4e
4f
4g
4h
4i
94
93
91
86
95
85
81
89
90
95
76
89
97
96
93
95
97
94
97
96
97
96
98
99
Fig. 3 Modified cinchona alkaloid catalysts.
Table 1 Enantioselective reaction of 1a with 2aa
9
17 : 1
>20 : 1
>20 : 1
>20 : 1
10
11
12
4j
4k
4l
1l (H, Br)
Entry
Cat.
Solvent
drb
—
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5f
5f
5f
5f
5f
THF
THF
THF
THF
THF
THF
DCM
Toluene
EtOAc
EtOAc
EtOAc
n.r.g
54
75
70
85
93
40
85
94
83
82
—
50
83
91
96
96
97
96
97
96
92
2 : 1
10 : 1
5 : 1
7 : 1
15 : 1
—
6 : 1
19 : 1
16 : 1
6 : 1
9
10e
11f
a
b
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol). Determined by
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), solvent (1 mL).
1H NMR. Isolated yield of major diastereoisomer. The ee of the
major diastereoisomer was determined by chiral HPLC.
c
d
Catalyst loading: 20 mol%, at ꢀ40 1C. Determined by 1H NMR.
b
c
d
Isolated yield of the major diastereoisomer. Major diastereoisomer’s
e
f
ee determined by chiral HPLC. Reaction temperature of ꢀ50 1C. Catalyst
g
loading: 10 mol%. No reaction.
Excellent results were obtained also with MBH substrate 1j,
bearing two methyl groups at C5 and C7 positions of the indole
moiety, and MBH carbonates 1k and 1l, bearing a F or a Br atom at
the C7 position of the indole moiety (entries 11 and 12). In addition
the reaction of N-methyl-MBH carbonate 1m could give the annula-
tion product 4m in good yield with 10 : 1 dr and 98% ee. The reaction
of other activated keto-dipoles 2b and 2c also provided the annulation
products 4n and 4o in good to excellent yields (85% and 99%) and
enantioselectivities (95% and 94% ee).
On the basis of the above observations, a possible catalytic cycle
was proposed in Fig. 4. The tertiary amine unit of cinchona
alkaloid derivatives attacked the MBH carbonate to generate an
N-allylic ylide intermediate A. Ethyl 3,3,3-trifluoropyruvate reacted
with intermediate A to give intermediate B, which was a key step for
and 50% ee (entry 2). Considering that the phenolic hydroxyl
group of 5b may not be favorable to the formation of the allylic
N-ylide, in replace of 5b with 5d, the yield, diastereoselectivity and
enantioselectivity were all increased greatly (70%, 5 : 1 dr and 91%
ee, respectively) (entry 4). When catalyst 5c derived from cinchonine
was used, the enantioselectivity of 4a decreased to 83% ee (entry 3).
Obviously, the substituent at the C-60 position of the catalyst has a
great influence on the stereoselectivity. When catalysts 5f and 5e,
both bearing an aryl group at the C-60 position, were used,15 an
excellent enantioselectivity (96% ee) was obtained with the latter
providing both a slightly better yield (93% vs. 85%) and diastereo-
selectivity (15 : 1 vs. 7 : 1) than the former, which suggested that the
catalyst 5f bearing a more sterically hindered 1-naphthyl group at
the C-60 position is better than 5e (entry 5 vs. 6). After screening
other reaction conditions, the best results were obtained in EtOAc
at ꢀ40 1C with 20% loading of catalyst 5f (Table 1, entry 9).
Under the optimal reaction conditions, the substrate scope was
examined and the results are summarized in Table 2. For MBH
carbonates 1a–g with different substituents (R1) at the C5 position of
the indole moiety, both electron-withdrawing and electron-donating
groups gave good to excellent yields (81–94%), excellent diastereo-
selectivities (up to >20 : 1 dr) and enantioselectivities (93–97% ee)
(entries 1–7). The MBH carbonates bearing a trifluoromethoxyl 1h or
a nitro 1i group also gave the 3-oxa-spirooxindole products 4h and 4i
in good yields (80% and 90%), diastereoselectivities (9 : 1 and
17 : 1) and enantioselectivities (96% and 97% ee) (entries 8 and 9).
Fig. 4 Plausible mechanism of annulation reaction.
c
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Fig. 6 Reduction of 4a by LiBH4 and EtOH.
controlling the stereoselectivity during the [3+2] annulation process.
Then, B may undergo an intramolecular oxo-Michael addition to give
the ring-closed zwitterion C. Elimination of the catalyst unit from C
afforded the chiral 2H-spiro[furan-3,30-indolin]-20-one product.
A stereochemistry of the transition state has been proposed in
Fig. 5. The N-allylic ylide intermediate is stabilized by the electron-
withdrawing cyano group. The Si-face of the 1,3-dipole is blocked
by the quinoline moiety and the naphthalene ring of the catalysts,
which favors the approach of trifluoropyruvate to the N-allylic ylide
from the Re-face. Thus, the group at C-60 plays an important role in
diastereo- and enantioselectivities (see ESI†).16
The annulation product 4 could be readily transformed further.
When 4a was treated under reductive conditions of LiBH4 and
EtOH, product 5 was obtained in 45% yield with high diastereo-
selectivity (>20 : 1) and nearly without any loss of enantiomeric
excess (96% ee) (Fig. 6).
In conclusion, an organocatalytic and enantioselective [3+2]
annulation of isatin-derived MBH carbonates with activated ketones
was developed in good to excellent yields with high diastereo- and
enantioselectivities. The protocol provided an efficient and convenient
method for the synthesis of chiral 2H-spiro[furan-3,30-indolin]-20-one.
We thank the National Natural Science Foundation of China,
Ministry of Science and Technology (2010CB833300) and the
Chinese Academy of Sciences for the financial support.
Notes and references
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c
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Chem. Commun., 2013, 49, 11071--11073 11073