Phosphine-catalyzed asymmetric [4+1] annulation of activated α,β-unsaturated ketones with Morita-Baylis-Hillman carbonates: Enantioselective synthesis of spirooxindoles containing two adjacent quaternary stereocenters

Article abstract of DOI:10.1039/c4cc03479a

The asymmetric [4+1] annulation of activated α,β-unsaturated ketones with MBH carbonates catalyzed by bifunctional thiourea-phosphine catalysts derived from an axially chiral binaphthyl scaffold has been developed, giving spirooxindoles with two adjacent

Full text of DOI:10.1039/c4cc03479a

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Phosphine-catalyzed asymmetric [4+1] annulation
of activated a,b-unsaturated ketones with Morita–
Baylis–Hillman carbonates: enantioselective
synthesis of spirooxindoles containing two
adjacent quaternary stereocenters†
Cite this: Chem. Commun., 2014,
50, 8912
Received 8th May 2014,
Accepted 17th June 2014
DOI: 10.1039/c4cc03479a
Fang-Le Hu, Yin Wei and Min Shi*
www.rsc.org/chemcomm
The asymmetric [4+1] annulation of activated a,b-unsaturated ketones dicyano-2-methylenebut-3-enoates and MBH carbonates catalyzed
with MBH carbonates catalyzed by bifunctional thiourea–phosphine by chiral bifunctional phosphine, providing an efficient synthesis
catalysts derived from an axially chiral binaphthyl scaffold has been of highly functionalized cyclopentenes bearing one all-carbon
developed, giving spirooxindoles with two adjacent quaternary stereo- quaternary stereogenic center.8a To the best of our knowledge, no
centers in good yields with high enantioselectivities and moderate asymmetric [4+1] annulation of activated alkenes with MBH carbo-
diastereoselectivities under mild conditions.
nates has been further disclosed after our previous report.8b
The spirooxindole backbones are commonly present in a number
Nucleophilic phosphines are widely used as Lewis base catalysts in of biologically active compounds as well as natural products.9 They
organic reactions. On the basis of phosphine catalysis, a variety of have recently become one of the most attractive synthetic targets and
unique carbo- and heterocyclic frameworks, some of which are many kinds of elegant synthetic approaches have been developed for
commonly present in bioactive natural products and medicinally their syntheses.10 In continuation of our efforts to seek efficient
important compounds, can be easily acquired.1 It has grown approaches toward the construction of the spirooxindole motif,11 we
significantly over the past decade and now it is an active area of wish to report chiral phosphine catalyzed asymmetric [4+1] annu-
organocatalysis.2 Recently, Morita–Baylis–Hillman (MBH) adducts lation of MBH carbonates with activated a,b-unsaturated ketones,
have aroused organic chemists’ interest after Lu’s pioneering work effectively providing 2H-spiro[furan-3,30-indolin]-20-one derivatives
on the intra- and intermolecular [3+n] annulations (n = 2, 3, 4, and 6) with two adjacent quaternary stereocenters.
using MBH carbonates as 1,3-dipoles with various activated
Initially, we examined the reaction of activated a,b-unsaturated
alkenes catalyzed by a trivalent phosphine,3 affording the corre- ketone 1a (0.1 mmol) with MBH carbonate 2a (0.11 mmol,
sponding cycloadducts in good yields and high regioselectivities 1.1 equiv.) catalyzed by a bifunctional chiral phosphine catalyst
under mild conditions.4 Furthermore, recently some examples of TP1 derived from a natural amino acid in toluene (2 mL) at room
asymmetric [3+2] annulation of MBH carbonates with activated temperature. The desired [4+1] cycloadduct 3a was obtained in
alkenes have also been disclosed.5 More recently, Zhang, Huang, 92% total yield along with 1 : 2 dr within 12 h, the ee value of the
He and Shi as well as their co-workers have also developed [4+1] major product is 11%, however, the minor product’s ee value is
annulations utilizing MBH carbonates as 1,1-dipoles to obtain the 86% (Table 1, entry 1). In order to improve the ee values, multi-
heterocyclic products in high yields, respectively.6 In this aspect, we functional thiourea–phosphines with more sterically hindered
have further developed a series of bifunctional thiourea–phosphine substituents TP2, TP3 and TP4 were further tested in this reaction,
catalysts derived from natural amino acids and applied them in providing the spirooxindole 3a containing two adjacent quaternary
asymmetric [3+2] annulations of MBH carbonates with electron- stereocenters in good yields along with moderate stereochemical
deficient alkenes, furnishing the corresponding highly functiona- outcomes (up to 3 : 1 dr and up to 69% ee) (Table 1, entries 2–4).
lized cyclopentenes in good yields and ee values.7 We have also We next utilized bifunctional chiral phosphines derived from an
reported the first highly enantioselective [4+1] annulations between axially chiral binaphthyl scaffold TP5–TP7 as catalysts for this
reaction. TP6 is the best catalyst in terms of enantioselectivity,
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
P. R. China. E-mail: mshi@mail.sioc.ac.cn
affording 3a in 97% total yield along with 3 : 1 dr, and the major
product’s ee value is 96% (Table 1, entries 5–7). During the
investigation of the nucleophilic phosphine catalysis, we have
noticed that substituents in the phosphorus center of chiral
phosphine catalysts could remarkably influence the diastereoselec-
tivities,11j,12 TP8–TP10 were therefore synthesized and subjected to
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data for new compounds. CCDC 991742 and 990849.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4cc03479a
8912 | Chem. Commun., 2014, 50, 8912--8914
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Table Optimization of reaction conditions for the asymmetric
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1
Table 2 Substrate scope of the asymmetric [4+1] annulation of 1 with 2
[4+1] annulation
Yieldb eec drc
Yieldb ee (anti : dr (anti :
(%)
Entrya R1
R2
Ar1
R3
(%)
(%) (%)
Entrya Catalyst Solvent
syn)c (%) syn)c (%)
1
2
1b, H
1c, H
Me
C6H5
2a, 4-NO2 3b, 97 98 2/1
2a, 4-NO2 3c, 92 98 2/1
2a, 4-NO2 3d, 99 98 3/1
2a, 4-NO2 3e, 90 97 2/1
2a, 4-NO2 3f, 65 95 3/1d
2a, 4-NO2 3g, 61 95 3/1d
2a, 4-NO2 3h, 58 90 3/1d
2a, 4-NO2 3i, 62 96 3/1d
1
TP1
TP2
TP3
TP4
TP5
TP6
TP7
TP8
TP9
TP10
TP6
TP6
TP6
TP6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
92
95
87
86
82
97
94
87
82
96
92
93
86/11
69/2
50/30
59/17
73/58
96/7
89/55
87/10
73/60
75/95
96/10
64/97
56/85
65/99
1/2
1/2
1/2
1/3
7/1
3/1
2/1
2/1
6/1
6/1
2/1
10/1
7/1
7/1
MOM C6H5
2
3
4
5
6
7
8
9
3
4
1d, H
1e, H
Allyl
Ph
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
5
6
7
8
1f, H f
1g, 5-Me f
1h, 5-F f
1i, 7-Br f
1j, H f
1k, H f
1a, H f
1a, H f
1a, He
1f, H f
1f, H
9
3-MeC6H4 2a, 4-NO2 3j, 75
96 4/1d
10
11
12
13
14
15
4-ClC6H4 2a, 4-NO2 3k, 51 90 3/1d
10
11
12
13
14
C6H5
C6H5
C6H5
C6H5
C6H5
2b, 4-Cl2
2b, 4-CN
3l, 90
97 3/1
3m, 98 98 3/1
Fluorobenzene
2d, 3,4-Cl2 3n, 85 81 1/1
2e, 3,5-Cl2 3o, 89 96 2/1
(Trifluoromethyl)benzene 90
p-Xylene 87
2f, 4-Me
NR
a
1 (0.01 mmol), 1 (0.11 mmol) and TP6 (0.02 mmol) were stirred in
2 mL of toluene within 12 h. b Isolated yield. Determined by chiral HPLC.
c
d Determined by 1H NMR analysis. The reaction mixtures were stirred for
e
f
4 days. The reaction mixtures were stirred for 48 h.
moderate de and high ee values (up to 3 : 1 dr, 97–98% ee)
(Table 2, entries 1–4). To our delight, as for the N-unprotected
a,b-unsaturated ketone 1f, the corresponding [4+1] annulation
product 3f was obtained in 65% yield along with 95% ee and 3 : 1
dr, although the reactivity of 3f was reduced and the reaction was
conducted for 48 h (Table 2, entry 5). When other N-unprotected
a,b-unsaturated ketones were used in this reaction, the corre-
sponding products were acquired in moderate yields (up to 62%
yield) along with excellent enantioselectivities (90–96% ee) and
moderate dr values (up to 3 : 1 dr), respectively (Table 2, entries
6–8). When substituents were introduced on the Ar1 group, the
a
The reaction carried out using 1a (0.1 mmol), 2a (0.2 mmol) and
b
c
catalyst (0.02 mmol) in solvent (2.0 mL). Isolated yield. Determined
by chiral HPLC analysis.
this reaction. It was found that the bifunctional chiral phosphine reaction could also proceed smoothly to give the desired products in
catalysts TP8 and TP9, having the methyl groups on the 3,5- up to 75% yield and up to 4 : 1 dr (96% ee, respectively) (Table 2,
positions of the benzene ring, showed poor performance in entries 9 and 10). Finally, substrates with electron-withdrawing
terms of enantioselectivity (Table 1, entries 8 and 9). Increasing substituents on the aromatic ring of MBH carbonates were also
the steric hindrance of the thiourea moiety did not further tested in this reaction, giving the desired products in good yields
increase the enantioselectivity, affording 3a in total 96% yield along with moderate de values and high ee values (Table 2, entries
along with 6 : 1 dr, 75% and 95% ee, respectively (Table 1, entry 11–14). Only in the case of MBH carbonate 2e, the corresponding
10). Finally, the solvent effects have also been examined using adduct 3o was obtained in a relatively low ee value (81% ee),
TP6 as the catalyst. In dichloromethane (DCM), similar results presumably due to the influence of steric hindrance (Table 2,
were obtained, but in fluorobenzene, benzotrifluoride or entry 13). Unfortunately, when the methyl group was introduced into
p-xylene, the ee values of 3a (major diastereomer) decreased the aromatic ring of MBH carbonate, the reactivity of 2f decreased
remarkably (Table 1, entries 11–14). Therefore, the best reaction remarkably with no desired product being formed (Table 2, entry 15).
conditions have been determined to be TP6 (20 mol%) in toluene
It should be pointed out that the two diastereoisomers 3f–3k
at room temperature within 12 hours.
can be isolated by column chromatography and the structures
With the optimized reaction conditions in hand, we next of minor diastereomers 3f0–3k0 have also been determined by
turned our attention to the scope and limitations of this reaction 1H and 13C NMR spectroscopy, MS and HRMS analyses. The
using a variety of activated a,b-unsaturated ketones 1 with structure of 1c has been determined by X-ray diffraction to be Z
MBH carbonates 2. It was found that a variety of N-protected configuration and the absolute configuration of 3i has also
a,b-unsaturated ketones were suitable for this reaction, producing been unambiguously determined by X-ray diffraction. Their
the desired products 3b, 3c, 3d and 3e in high yields along with CIF data are presented in the ESI.†
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The plausible mechanism of these [4+1] annulations is
proposed in Scheme S1 in the ESI† on the basis of previous
literature,3a,d,6,8,13 and the plausible transition state has also
been presented in Fig. S1 in the ESI.†
In conclusion, the asymmetric [4+1] annulation of activated
a,b-unsaturated ketones derived from isatin with MBH carbo-
nates catalyzed by chiral bifunctional phosphine has been
developed for the first time, which provides highly efficient
and enantioselective synthesis of spirooxindoles containing
two adjacent quaternary stereocenters. Further efforts are in
progress to develop the use of this reaction in organic synthesis.
We thank the Shanghai Municipal Committee of Science
and Technology (11JC1402600), the National Basic Research
Program of China (973)-2010CB833302, and the National
Natural Science Foundation of China (20472096, 21372241,
21361140350, 20672127, 21102166, 21121062, 21302203 and
20732008).
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8914 | Chem. Commun., 2014, 50, 8912--8914
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