Highly enantioselective [3+2] annulation of Morita-Baylis-Hillman adducts mediated by L-threonine-derived phosphines: Synthesis of 3-spirocyclopentene-2- oxindoles having two contiguous quaternary centers

Article abstract of DOI:10.1002/anie.201102094

Spiral bound: The Morita-Baylis-Hillman adducts were employed as C ₃ synthons in the asymmetric [3+2] annulation with malonitrile substrates using L-threonine-derived 1 as the catalyst (see scheme). The reaction is highly regioselective and ste

Full text of DOI:10.1002/anie.201102094

DOI: 10.1002/anie.201102094
Asymmetric Synthesis
Highly Enantioselective [3+2] Annulation of Morita–Baylis–Hillman
Adducts Mediated by l-Threonine-Derived Phosphines: Synthesis of 3-
Spirocyclopentene-2-oxindoles having Two Contiguous Quaternary
Centers**
Fangrui Zhong, Xiaoyu Han, Youqing Wang, and Yixin Lu*
Spirocyclic oxindoles[1] are the structural motifs frequently
found in many natural products and biologically active
molecules.[2] Among many spirooxindole cores, the 3,3’-
pyrrolidinyl spirooxindole units are well known for their
strong bioactivity profiles, thus synthetic studies toward this
fused heterocyclic system have been pursued intensively.
Oxindoles having spiral carbocyclic rings are also important
substructures that are widely present in numerous bioactive
natural products. In this context, 3-spirocyclopentane-2-
oxindoles containing two adjacent quaternary centers are
particularly striking structural motifs[3] (Scheme 1), and their
efficient asymmetric constructions are formidable synthetic
tasks.[4] To the best of our knowledge, there were only two
catalytic asymmetric syntheses in the literature dealing with
similar structural scaffolds. Trost and co-workers reported an
enantioselective construction of spirocyclic oxindolic cyclo-
pentanes by using a palladium-catalyzed [3+2] cycloaddition
of trimethylenemethane.[5] Very recently, Marinetti et al.
disclosed an organocatalytic asymmetric [3+2] cyclization
between 3-alkylideneindolin-2-ones and allenes for the syn-
thesis of spirooxindoles.[6]
Nucleophilic catalysis employing chiral phosphines is an
intensively explored research area in asymmetric catalysis.[7]
For the construction of five-membered ring systems, phos-
phine-mediated [3+2] annulations represents one of the most
efficient approaches.[8] As part of our research program
toward the development of asymmetric synthetic methods
catalyzed by amino-acid-based organocatalysts,[9] we recently
focused on the development of novel chiral phosphines from
amino acids. We showed that dipeptide-derived novel phos-
phines were powerful catalysts for the enantioselective
allene–acrylate [3+2] cycloadditions.[8n] More recently, we
also derived a series of phosphine sulfonamide bifunctional
catalysts and demonstrated their effectiveness in the enantio-
selective aza-Morita–Baylis–Hillman (aza-MBH) reac-
tions.[10] We envisioned that phosphine-mediated [3+2] cy-
clizations may be utilized to construct spirooxindole cores
(Scheme 2). The electron-deficient alkene components nec-
essary for the annulation reactions can be conveniently
derived from isatins. Notably, such tetrasubstituted activated
alkenes are unexplored substrates in the asymmetric [3+2]
cyclization processes, and their successful elaboration in the
cycloaddition reaction may create two contiguous quaternary
centers. Allenes and alkynes are commonly employed as
C3 synthons in the annulation reactions, and in this context,
employment of more readily available and versatile
C3 synthons in the annulations is certainly ideal. The MBH
reaction is one of the most atom-economic reactions for the
construction of densely functionalized products,[11] and the
Scheme 1. Spirocyclicpentane oxindole structures having two contigu-
ous quaternary centers.
[*] F. Zhong, X. Han, Prof. Dr. Y. Lu
Department of Chemistry & Medicinal Chemistry Program
Life Sciences Institute, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: chmlyx@nus.edu.sg
Prof. Dr. Y. Wang
Provincial Key Laboratory of Natural Medicine and Immuno-
Engineering, Henan University, Jinming Campus
Kaifeng, Henan, 475004 (China)
[**] We thank the National University of Singapore and the Ministry of
Education (MOE) of Singapore (R-143-000-362-112) for generous
financial support.
Scheme 2. Construction of 3-spirocyclopentene-2-oxindoles through
phosphine-catalyzed [3+2] cycloadditions of MBH adducts. EWG=
electron-withdrawing group.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102094.
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Table 1: Asymmetric [3+2] annulations of MBH adducts with isatin-
MBH adducts are tremendously useful intermediates in
derived activated alkenes.[a]
organic synthesis. In the past few years, Lu and co-workers
pioneered the use of the MBH adducts in [3+2] cyclizations
and various cycloadditions.[12] However, an asymmetric cyclo-
addition employing the MBH adducts is yet to be devel-
oped.[13] Compared with allenes and alkynes, the MBH
adducts are much more challenging substrates for such
annulations; their lower reactivity makes the development
of an asymmetric catalytic annulation process particularly
difficult. Given the high nucleophilicity observed for our
amino-acid-derived chiral phosphines,[8n,10] we reasoned that
our catalysts may be suitable for such an activation. Herein,
we document the first highly enantioselective [3+2] cyclo-
addition between the MBH carbonates and isatin-derived
tetrasubstituted activated alkenes, thereby creating 3-spiro-
cyclopentene-2-oxindoles containing two contiguous quater-
nary centers.
The [3+2] cycloaddition between isatin-derived a,a-
dicyanoalkene[14] 7 and the MBH carbonate 8 was selected
as a model reaction, and the catalytic effects of various amino-
acid-derived phosphines were examined (Table 1). To induce
effective stereochemical control, potential interactions of the
catalyst with the hydrogen-bond acceptor groups in the isatin
derivatives seem to be important, thus, a number of amino-
acid-based phosphines having various Brønsted acid moieties
were prepared. l-Valine-derived phosphine sulfonamide 1
showed poor catalytic activity (entry 1). In the presence of
valine-derived amide 2 or carbamate 3, the reaction pro-
ceeded smoothly, thus affording the desired cyclization
product in excellent yield, albeit with low stereoselectivity
(entries 2 and 3). Valine-derived phosphine thiourea 4
displayed much-improved catalytic effects, and the products
were obtained in excellent yield and with moderate enantio-
selectivity. However, the ratio of the a to g regioisomer
remained very poor (entry 4). With our previous success in
threonine-based catalytic systems,[9] we then focused on
threonine-derived phosphine thiourea catalysts. To our
delight, the enantioselectivity was significantly improved
when the threonine core was introduced, and only one
diastereomer was observed. Common sterically hindered
silyloxy groups[15] all proved to be effective, and the catalyst
5d having a TIPS group gave slightly better results (entries 5–
8). Replacement of the thiourea moiety in the catalyst with a
urea resulted in a faster reaction, but with slightly decreased
enantioselectivity (entry 9). Notably, the thiourea catalyst
containing a 3,5-di-trifluoromethylphenyl group was not more
effective than 4-fluorophenyl-derived thiourea, and the latter
was thus chosen as it is more economical (entry 5 versus 10).
To improve the regioselectivity of the reaction, we next
employed oxindoles with different N-alkyl groups. Gratify-
ingly, the introduction of a benzyl group on the oxindole
nitrogen atom led to substantially enhanced regioselectivity
(entry 11). When the N-para-methoxybenzyl (PMB) was
employed, the cyclization products were formed with an g
to a ratio of 14:1 (entry 12). The utilization of N-trityl
substrate 7d, however, resulted in very poor conversion,
probably as a result of the steric hindrance introduced by the
trityl group (entry 13). Variation of the ester groups in the
MBH adducts led to further improvement; ethyl ester proved
Entry Cat.
7
8
Solvent
t
Yield
g/a[c]
ee
[h] [%][b]
[%][d]
1
1
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
8a THF
8a THF
8a THF
8a THF
8a THF
8a THF
8a THF
8a THF
8a THF
8a THF
12
12
12
12
12
12
12
12
6
12
18
18
48
18
48
48
18
18
18
18
48
18
<30
90
92
94
93
89
83
93
92
89
86
84
<30
83
90
n.r.
92
89
70
–
–
2
2
1.5:1 10
3
3
1.5:1 16
1.5:1 35
2:1 71
2:1 70
2:1 69
2:1 74
2:1 68
2:1 70
13:1 75
14:1 77
4
4
5
6
7
8
5a
5b
5c
5d
5e
6
5d
5d
5d
5d
5d
5d
5d
5d
5d
5d
5d
5d
5d
5d
9
10
11
12
13
14
15
16
17[e]
18[e]
19[e]
20[e]
21[e]
22[e]
23[e]
24[e]
7b 8a THF
7c 8a THF
7d 8a THF
–
–
7c
7c
7c
7c
7c
7c
7c
7c
7c
7c
7c
8b THF
8c THF
8d THF
8c THF
8c
8c
8c
8c
8c
8c
8c
14:1 80
13:1 85
–
14:1 86
7:1 88
2:1 63
–
CH2Cl2
CH3CN
toluene
DMF
Et2O
CH3OH 48
CHCl3 18
90
trace
91
trace
93
>20:1 90
–
–
>20:1 85
–
–
13:1 96
[a] Reactions conditions: 7 (0.05 mmol), 8 (0.075 mmol), catalyst
(0.005 mmol), and solvent (0.5 mL) under Ar. [b] Yield of the isolated
product. [c] The g/a ratios were determined by H NMR analysis of the
crude products. [d] The ee value of the major regioisomer was deter-
mined by HPLC analysis using a chiral stationary phase. [e] 3 ꢀ molecular
sieves (30 mg) were added. Boc=tert-butoxycarbonyl, DMF=N,N’-
dimethylformamide, n.r.=no reaction, TBDPS=tert-butyldiphenylsilyl,
TBS=tert-butyldimethylsilyl, TDS=thexyldimethylsilyl, THF=tetrahy-
drofuran, TIPS=triisopropylsilyl, Trt=trityl.
1
to be superior to the methyl ester (entry 14), and the
utilization of the MBH adduct with the tert-butyl ester further
increased the ee value of the cyclization product to 85%
(entry 15). The carbonate group in the MBH adducts is
important for the observed reactivity, since the corresponding
MBH acetate was found to be inactive in the cycloaddition
(entry 16). The addition of 3 ꢀ molecular sieves to the
7838
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Table 2: Substrate scope.[a]
naphthyl-, 3-furyl-, and 2-thiophenyl-containing MBH carbo-
nates (entries 14–16). When the MBH adduct with a vinylic
substituent was used, good enantioselectivity could be
obtained (entry 17).[16] The MBH carbonate bearing an alkyl
group could also be employed, although the ee value was only
modest (entry 18). It should be noted the alkyl-substituted
MBH adducts are intrinsically difficult C3 synthons for the
asymmetric [3+2] annulation,[12c] and our results represent
one of the only two successful examples reported in the
literature.[13] Moreover, the reaction worked well for different
isatin-derived a,a-dicyanoalkenes, and both good regioselec-
tivities and enantioselectivities were observed (entries 20–
23). The absolute configurations of the cycloaddition products
were determined based on X-ray crystal structural analysis of
an amide derivative of 9d (see the Supporting Information for
details).[17]
The 2-(2-oxoindolin-3-ylidene)malononitriles utilized in
this study were prepared from isatins and malononitrile 11. To
make our method more synthetically appealing, the feasibility
of carrying out the reaction in one pot was examined. The
one-pot protocol proved to be equally effective; simply
mixing isatin 10, malononitrile 11, and the MBH carbonate 8c
in the presence of 5d resulted in a smooth annulation
reaction, thus delivering the spirooxindole 9a in 89% yield
and with 96% ee (Scheme 3).
Entry
R’, R (9)
Yield
[%][b]
g/a[c]
ee
[%][d]
1
Ph, H (9a)
93
92
96
96
90
92
94
95
91
92
93
89
78
94
91
91
94
83
92
89
86
82
85
13:1
17:1
21:1
23:1
16:1
14:1
12:1
13:1
12:1
15:1
15:1
4:1
14:1
16:1
4:1
1:1
25:1
1:2
96
94
94
94
93
93
94
95
94
95
92
87
91
94
87
90
75
65
96
99
96
91
94
2
3
4
5
6
7
8
9
10
11
12
13[e]
14
15
16[f]
17[g]
18[h]
19[i]
20
21
22
23
4-FC6H4, H (9b)
4-ClC6H4, H (9c)
4-BrC6H4, H (9d)
4-CF3C6H4, H (9e)
4-CNC6H4, H (9 f)
4-MeC6H4, H (9g)
3-ClC6H4, H (9h)
3-BrC6H4, H (9i)
3-MeC6H4, H (9j)
3-CNC6H4, H (9k)
2-FC6H4, H (9l)
3,5-(CF3)2-C6H3, H (9m)
2-naphthyl, H (9n)
3-furyl, H (9o)
2-thiophenyl, H (9p)
=
(E)-PhCH CH, H (9q)
PhCH2CH2, H (9r)
CO2Et, H (9s)
Ph, 5-Me (9t)
Ph, 5,7-Me (9u)
Ph, 7-Cl (9v)
1:1
12:1
10:1
7:1
Ph, 7-F (9w)
7:1
[a] Reactions conditions: 7 (0.05 mmol), 8 (0.075 mmol), 5d
(0.005 mmol), and 3 ꢀ molecular sieves (30 mg) in CHCl3 (0.5 mL)
under Ar. [b] Yield of the isolated product. [c] The g/a ratios were
1
determined by H NMR analysis of the crude products, and the two
isomers could be easily separated. [d] The ee value of g-regioisomer was
determined by HPLC analysis using a chiral stationary phase. [e] The
reaction time was 36 h. [f] The ee value of the a isomer was 53%. [g] The
reaction was performed with 10 mol% of 5e in toluene (1.0 mL) at 808C
for 10 min. [h] The reaction was performed with 20 mol% of 5e at 08C
for 48 h and the ee value of the a isomer was 67%. [i] The reaction was
performed at 08C for 1 h and the ee value of the a isomer was 54%.
M.S.=molecular sieves.
Scheme 3. One-pot construction of a 3-spirocyclopentene-2-oxindole.
A plausible reaction mechanism is proposed in Scheme 4.
The reaction is initiated by the nucleophilic attack of the
phosphine on the MBH carbonate 8c to yield the phospho-
nium salt A. The in situ generated tert-butoxide anion
deprotonates A to give the ylide B, which then undergoes
g addition to alkene 7c to give the intermediate C. Subse-
quent intramolecular cyclization then delivers D, and the
reaction mixture was beneficial, as the reaction rate was
significantly enhanced and a better enantioselectivity
was attainable (entry 17). A solvent screening was
subsequently performed, and chloroform was identified
to be the best solvent for the reaction (entries 18–24).
Under the optimized conditions, the diastereomerically
pure spirooxindole 9 was regioselectively formed in 93%
yield and with 96% ee.
The scope of 5d-mediated [3+2] annulations
between a variety of 2-(2-oxoindolin-3-ylidene)malono-
nitriles 7 and different MBH carbonates 8 was evaluated,
and the results are summarized in Table 2. In general,
excellent yields and selectivities were attainable for all
the examples examined. The reaction tolerated different
aromatic moieties in the MBH carbonates 8. Notably, the
presence of ortho-substituted aryls in 8 resulted in
reduced
regioselectivity
and
enantioselectivity
(entry 12). The reaction also worked well for the 2- Scheme 4. Proposed mechanism.
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3003; f) F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352,
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elimination of the phosphine moiety then regenerates the
catalyst and affords the final cycloaddition product. The
in situ generated tert-butoxide anion is crucial for the
reaction, as the cyclization did not occur when the MBH
acetate was employed (Table 1, entry 16). The observed
g selectivity may be attributed to the steric hindrance induced
by the N-PMB group of 7 in the key cycloaddition step, and
the potential aromatic interactions cannot be excluded at this
stage. We believe the hydrogen-bonding interactions between
the thiourea moiety of the catalyst and the isatins play a
crucial role in asymmetric induction. Such an assumption has
been supported experimentally; the methylated phosphine
thiourea[18] 12 was able to catalyze the [3+2] annulation
between 7c and 8c, however, an g to a ratio of 2:1 and 11% ee
(for the g isomer of 9a) were obtained. In comparison a 12:1
regioselectivity and 83% ee were observed when 4 was used
under otherwise identical conditions (Scheme 5).
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In conclusion, we have utilized the MBH carbonates as
C3 synthons in asymmetric [3+2] annulation reactions for the
first time. These MBH carbonates, compared to allenes and
alkynes, are more readily available and versatile, thus they are
expected to have applications in asymmetric synthesis. We
have also developed a threonine-derived phosphine thiourea
catalyst for the promotion of the stereoselective [3+2]
cycloaddition process between the MBH carbonates and
isatin-derived tetrasubstituted alkenes. This strategy allows
facile enantioselective preparation of biologically important
3-spirocyclopentene-2-oxindoles with two contiguous quater-
nary centers. Biological evaluations of our synthetic spiroox-
indoles, further applications of the MBH adducts in other
asymmetric organic reactions, and mechanistic investigations
of this novel [3+2] annulation are underway in our laboratory.
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Received: March 24, 2011
Revised: May 16, 2011
Published online: July 4, 2011
Keywords: amino acids · asymmetric synthesis · cycloaddition ·
.
phosphines · spiro compounds
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[17] CCDC 830830 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif
[18] The corresponding bis(methylated) thiourea phosphine could
not be prepared; see the Supporting Information for details.
Angew. Chem. Int. Ed. 2011, 50, 7837 –7841
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7841