Organocatalytic michael-alkylation cascade: The enantioselective nitrocyclopropanation of oxindoles

Article abstract of DOI:10.1002/chem.201003423

The spiro saga goes on! The title reaction sequence provides the first enantioselective synthesis of spiro nitrocyclopropyl oxindoles. The method provides easy access to these new, biologically inspired compounds from readily available starting materials

Full text of DOI:10.1002/chem.201003423

DOI: 10.1002/chem.201003423
Organocatalytic Michael–Alkylation Cascade: The Enantioselective
Nitrocyclopropanation of Oxindoles
Fabio Pesciaioli, Paolo Righi, Andrea Mazzanti, Giuseppe Bartoli,* and
Giorgio Bencivenni*[a]
Oxindoles containing
a
spiro quaternary stereogenic
egy for the one-step synthesis of enantioenriched spiro cy-
clopropyl oxindoles with three adjacent stereogenic centers
(Scheme 1).
center as part of a pyrrolidinyl[1] or cyclohexyl[2] ring, are a
privileged structural core of natural and synthetic alkaloids,
which exhibit important biological and medicinal activity.
For this reason, this family of alkaloids has been deeply ex-
amined.[3,1c,f–g] Moreover, the construction of highly strained
spirocyclic structures[4,1h] and the generation of all-carbon
quaternary stereogenic centers[5] remains a challenging issue
for asymmetric catalysis. Recently, spiro 3,3’-cyclopropyl ox-
indole scaffolds have been intensively studied because of
their biological activity as powerful inhibitors of HIV-1 non-
nucleoside reverse transcriptase (NNRTIs).[6] However, a
direct enantioselective route to this complex molecule has
never been attempted.[6,7]
Scheme 1. Synthetic strategy: the enantioselective nitrocyclopropanation
of N-Boc-protected 3-alkylidene oxindoles.
The use of a bifunctional catalyst capable of simultane-
ously activating the oxindole and halonitroalkane was fun-
damental; it is well established that thioureas are excellent
activators of the imide moiety through hydrogen bonds,[11]
whereas tertiary amines efficiently promote the conjugate
addition of bromonitroalkanes to suitable Michael accept-
ors.[9b,12] Therefore, we focused our attention on catalysts
1a–1d, which incorporate these functionalities within their
structures.
With the aim of expanding our previous studies on the
enantioselective synthesis of spiro compounds with an oxin-
dole as a core feature,[4a] we decided to investigate the un-
precedented enantioselective nitrocyclopropanation[8,9] of
oxindoles through the direct reaction of bromonitroalkyl de-
rivatives and N-tert-butoxycarbonyl (Boc)-protected 3-alky-
lidene oxindoles. Organocatalytic cascade reactions[10] are
well recognized as one of the most powerful methods to syn-
thesize useful chiral compounds with high optical purity and
structural complexity. For this reason, we envisaged that a
chiral base-catalyzed reaction based on a tandem Michael
addition–alkylation sequence,[9d] might be an effective strat-
An intense study of the catalyst activity[13] led us to identi-
fy 1c as the most powerful and efficient catalyst (Table 1).
In the presence of 9-epi-9-thiourea-9-deoxydihydroquini-
dine[14] 1c (10 mol%) and NaHCO3 (1 equiv),[15] the reaction
of (E)-tert-butyl 3-(2-ethoxy-2-oxoethylidene)-2-oxoindo-
line-1-carboxylate (2a) with bromonitromethane (3) provid-
ed the desired spiro nitrocyclopropyl oxindole 4a in a con-
version of 63%, with a diastereomeric ratio (d.r.) of 18:1
and 98% enantiomeric excess (ee, Table 1, entry 1).
[a] F. Pesciaioli, Prof. Dr. P. Righi, Prof. Dr. A. Mazzanti,
Prof. G. Bartoli, Dr. G. Bencivenni
Dipartimento di Chimica Organica “A. Mangini”
Alma Mater Studiorum, Universitꢀ di Bologna
Viale Risorgimento 4, 40136 Bologna (Italy)
Fax : (+39)051-209-3654
E-mail: giorgio.bencivenni2@unibo.it
Encouraged by this important result, different solvents
and additives were screened (Table 1). The polarity of the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003423.
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Chem. Eur. J. 2011, 17, 2842 – 2845

COMMUNICATION
Table 1. Optimization studies for the enantioselective nitrocyclopropana-
tion of oxindoles.[a]
Table 2. Synthesis of spiro nitrocyclopropyl oxindoles with two adjacent
tertiary stereogenic centers.[a]
Entry
4
R
R1
T [8C]/
t [h]
Yield
[%][b]
d.r.[c]
19:1
9:1
>19:1
3:1
4:1
7.7:1.6:1
3:1
ee
[%][d]
Entry Base
Solvent t [h] Conversion [%][b] d.r.[b] ee [%][c]
1
2
a
b
b
c
c
d
e
f
H
H
H
H
H
H
H
5-Br
5-Br
5-Cl
6-Cl
5-Me
H
COOEt
COPh
COPh
n-butyl
n-butyl
Ph
2-MePh
COOEt
COOEt
Ph
0/48
0/72
77
52
82
60
75
83
80
76
74
84
65
60
99
98
90
98
93
92
90
90
87
93
90
89
91
97
1
2
3
4
NaHCO3 Toluene 65
NaHCO3 CH2Cl2 24
NaHCO3 CH3CN 24
63
57
40
67
76
47
48
70
100
18:1 98
9.8:1 96
9.4:1 82
9.4:1 97
16:1 98
16:1 98
5.3:1 93
16:1 98
19:1 98
3[e]
4
RT/72
RT/72
RT/72
RT/72
RT/48
RT/24
0/72
RT/48
RT/48
RT/72
RT/72
NaHCO3 THF
NaHCO3 MTBE
NaHCO3 MTBE
24
24
24
24
24
48
5[f]
6[e]
7[e]
8
5
7[d]
8[d]
9[d]
Et3N
Na2CO3
MTBE
MTBE
MTBE
9:1
9[e]
10[e]
11[e]
12[g]
13[h]
f
>19:1
8.6:1.3:1
12:2:1
7:1
10[d,e] Na2CO3
g
h
i
Ph
Ph
COOEt
[a] Unless otherwise specified, the reactions were performed at room
temperature on a 0.1 mmol scale with 1c (10 mol%), 3 (1.5 equiv), base
a
11:1
1
(1 equiv), and 2a (0.2m) [b] Determined by H NMR spectroscopic analy-
sis of the crude mixture. [c] Determined by HPLC analysis on a chiral
stationary phase. [d] Reaction performed with 5 mol% of 1c. [e] Re-
action performed at 08C.
[a] Unless otherwise specified, the reactions were performed on a
0.2 mmol scale with 1c (5 mol%), 3 (1.5 equiv), Na2CO3 (1 equiv), and
1
2a (0.2m). [b] Sum of diastereoisomers. [c] Determined by H NMR spec-
troscopic analysis of the crude mixture. [d] Determined by HPLC analy-
sis on a chiral stationary phase. [e] Reaction performed with 5 mol% of
1d. [f] Reaction performed with 10 mol% of 1d. [g] 99% ee after a single
crystallization. [h] Reaction performed with 2 mol% of 1d.
reaction solvent dramatically affected the conversion, d.r.,
and ee values (Table 1, entries 2–4), with the exception of
methyl tert-butyl ether (MTBE), which gave similar results
to toluene, but with a faster rate of reaction (Table 1,
entry 5). When an organic base stronger than NaHCO3 was
used, the reaction did not proceed efficiently and 4a was
isolated with a lower ee value, probably because of a com-
petitive background reaction (Table 1, entry 8).[9a] Converse-
ly, the addition of one equivalent of Na2CO3 provided the
same level of enantiocontrol with an increase in conversion
and diastereoselectivity (Table 1, entries 9 and 10). The reac-
tion proceeded smoothly with 1c (5 mol%) at 08C for 48 h
to give 4a in 77% yield, with an ee value of 98% and a d.r.
of 19:1.
The optimized reaction conditions were then used to in-
vestigate the synthesis of different spiro nitrocyclopropane
oxindoles and to explore the accessibility of both enantio-
mers (Table 2). Indeed, the use of catalyst 1d (the pseudo-
enantiomeric form of catalyst 1c), allowed access to the op-
posite enantiomers of the spirooxindoles, with an improve-
ment of both the diastereo- and enantiocontrol (Table 2, en-
tries 3, 5 and 9). Activated double bonds with ester and
ketone substituents gave the corresponding cyclopropane as
We believe that the high diastereo- and enantioselectivity
observed in the course of the reaction, is mainly due to the
ability of the bifunctional catalyst to activate the Michael
donor and the electrophilic oxindole simultaneously. This
hypothesis led us to propose a reaction mechanism in which
À
a hydrogen-bond interaction between the N H bonds of the
thiourea moiety and the imidic carbonyl groups[11a–b] of the
oxindole, plays a crucial role in the stereochemical outcome
of the reaction.[16] By placing the oxindole in the correct po-
sition for the oncoming nucleophile on the Si face of the
double bond, the reaction follows the alkylation pathway
shown in Scheme 2.
a
single diastereoisomer with high enantioselectivity
(Table 2, entries 1, 3 and 9). Similarly, the reaction proceed-
ed smoothly when alkyl and aryl substituents were used
(Table 2, entries 4–7 and 10–12). The presence of electron-
withdrawing or donating substituents on the aromatic ring
of the oxindole did not interfere with the general trend of
the results (Table 2, entries 8–12). Remarkably, the use of
2 mol% of 1d gave 4a in quantitative yield, with higher
enantiocontrol, albeit with a lower d.r. value (Table 2,
entry 13).
Scheme 2. Proposed activation mode of the bifunctional catalyst 1c.
The interesting results obtained so far prompted us to
face the synthetic problem associated with the construction
of two adjacent quaternary stereocenters. For this purpose
we tested the reaction of 1-bromo-1-nitroethane (5) with
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G. Bencivenni, G. Bartoli et al.
under vacuum and the nitrocyclopropane adduct 4a was isolated by flash
column chromatography (with hexane/diethyl ether 85:15 as the eluent)
in 77% yield and with 98% ee.
Acknowledgements
This work was supported by Bologna University and by the MIUR Na-
tional Project “Stereoselezione in Sintesi Organica: Metodologie e Appli-
cazioni”.
Keywords: asymmetric catalysis
·
cyclopropanation
·
Michael addition
compounds
·
quaternary stereocenters
·
spiro
[1] a) C. V. Galliford, K. A. Scheidt, Angew. Chem. 2007, 119, 8902;
Angew. Chem. Int. Ed. 2007, 46, 8748; b) C. Marti, E. M. Carreira,
Eur. J. Org. Chem. 2003, 2209; c) C. Marti, E. M. Carreira, J. Am.
Chem. Soc. 2005, 127, 11505; d) K. Ding, J. Am. Chem. Soc. 2005,
127, 10130; e) K. Ding, J. Med. Chem. 2006, 49, 3432; f) S. Shangary,
Proc. Natl. Acad. Sci. USA 2008, 105, 3933; g) X. H. Chen, Q. Wei,
S. W. Luo, H. Xiao, L. Z. Gong, J. Am. Chem. Soc. 2009, 131, 13819;
h) A. P. Antonchick, C. Gerding-Reimers, M. Catarinella, M. Schur-
mann, H. Preut, S. Ziegler, D. Raush, H. Waldmann, Nat. Chem.
2010, 2, 735.
Scheme 3. Synthesis of nitrocyclopropyl spirooxindoles with two adjacent
quaternary stereocenters. Unless otherwise specified, the reactions were
performed on a 0.2 mmol scale with 1d (5 mol%), 5 (1.5 equiv), Na2CO3
(1 equiv), and 2a (0.2m). [a] Reaction performed with 20 mol% of 1d.
[b] Reaction performed with 5 mol% of 1d. [c] Reaction performed with
10 mol% of 1c. [d] Sum of the diastereoisomers. [e] Determined by
1H NMR spectroscopic analysis of the crude mixture. [f] Determined by
HPLC analysis on a chiral stationary phase.
[2] a) M. Rottmann, Science 2010, 329, 1175; b) H. Lin, S. J. Danishef-
sky, Angew. Chem. 2003, 115, 38; Angew. Chem. Int. Ed. 2003, 42,
36; c) A. Ashimori, L. A. Overman, J. Org. Chem. 1992, 57, 4571;
d) J.-J. Liu, Z. Zhang (Hoffman-La Roche AG), PCT Int. Appl. WO
2008/055812, 2008.
[3] a) B. M. Trost, M. K. Brennan, Synthesis 2009, 3003; b) S. Edmond-
son, S. J. Danishefsky, L. Sepp-Lorenzino, N. Rosen, J. Am. Chem.
Soc. 1999, 121, 2147; c) B. M. Trost, N. Cramer, S. M. Silverman, J.
Am. Chem. Soc. 2007, 129, 12396; d) B. M. Trost, N. Cramer, H.
Bernsmann, J. Am. Chem. Soc. 2007, 129, 3086; e) P. R. Sebahar,
R. M. Williams, J. Am. Chem. Soc. 2000, 122, 5666; f) A. K. Franz,
P. D. Dreyfuss, S. L. Schreiber, J. Am. Chem. Soc. 2007, 129, 1020.
[4] a) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli,
M.-P. Song, G. Bartoli, P. Melchiorre, Angew. Chem. 2009, 121,
7336; Angew. Chem. Int. Ed. 2009, 48, 7200; b) F.-L. Zhang, A.-W.
Xu, Y.-F. Gong, M.-H. Wei, X.-L. Yang, Chem. Eur. J. 2009, 15,
6815.
[5] a) Quaternary Stereocenters. Challenges and Solutions in Organic
Synthesis (Eds.: J. Christoffers, A. Baro), Wiley-VCH, Weinheim,
2006; b) M. Bella, T. Gasperi, Synthesis 2009, 1583; c) F. Pesciaioli,
X. Tian, G. Bencivenni, G. Bartoli, P. Melchiorre, Synlett 2010, 1704;
c) P. Galzerano, G. Bencivenni, F. Pesciaioli, A. Mazzanti, B. Gianni-
chi, L. Sambri, G. Bartoli, P. Melchiorre, Chem. Eur. J. 2009, 15,
7846; e) T. Bui, S. Syed, C. F. Barbas III, J. Am. Chem. Soc. 2009,
131, 8758; f) X. Tian, K. Jiang, J. Peng, W. Du, Y.-C. Chen, Org.
Lett. 2010, 10, 3583; g) S. Ogawa, N. Shibata, J. Inagaki, S. Naka-
mura, T. Toru, M. Shiro Angew. Chem. 2007, 119, 8820; Angew.
Chem. Int. Ed. 2007, 46, 8666; Angew. Chem. Int. Ed. 2007, 46, 8666;
h) C. J. Douglas, L. E. Overman, Proc. Natl. Acad. Sci. USA 2004,
101, 5363; i) B. M. Trost, J. Chunhui, Synthesis 2006, 369.
various oxindoles. As depicted in Scheme 3, a series of
highly substituted spiro cyclopropyl oxindoles with two qua-
ternary stereogenic centers could be synthesized in an
almost enantiomerically pure form (with ee values ranging
from 92 to >99%) in high yields, with good diastereocon-
trol. The relative and absolute configurations of 4a and 6a
were assigned by NOE and NMR spectroscopic analyses,
and time dependent (TD) DFT calculations of the electronic
circular dichroism (ECD) spectra (see the Supporting Infor-
mation for details).
In conclusion, we have developed the unprecedented or-
ganocatalyzed asymmetric synthesis of biologically inspired
spiro 3,3’-cyclopropyl oxindoles from readily available and
simple starting materials. Our approach allows the highly
enantioselective construction of complex molecular architec-
tures with multiple stereogenic centers, in one step with a
low catalyst loading. Our results support the capability of
these organocascade reactions to provide a useful synthetic
approach for the development of potential medicinal agents
and biologically active compounds.
Experimental Section
[6] a) Y. He, T. Jiang, K. L. Kuhen, D. A. Ellis, B. Wu, T. Y.-H. Wu, B.
Bursulaya, PCT Int. Appl. WO 2004/037247, 2004; b) T. Jiang,
Bioorg. Med. Chem. Lett. 2006, 16, 2105.
[7] a) S. R. Yong, A. T. Ung, S. G. Pyne, B. W. Skelton, A. H. White,
Tetrahedron 2007, 63, 1191; b) H. Yu, Y. Liu, H. Zhang, J. Chen, H.
Deng, M. Shao, Z. Ren, W. Cao, Tetrahedron 2010, 66, 2598; c) S.
Muthusamy, C. Gunanathan, Synlett 2003, 1599.
[8] For interesting reviews on cyclopropanation reactions, see: a) S. R.
Goudreau, A. B. Charette, Angew. Chem. 2010, 122, 496; Angew.
Chem. Int. Ed. 2010, 49, 486; b) H. Pellissier, Tetrahedron 2008, 64,
All the reactions were carried out in undistilled MTBE. Bromonitrome-
thane 3 (0.3 mmol, 22.4 mL, 1.5 equiv) was added to 1c (0.01 mmol,
5.98 mg, 5 mol%) in MTBE (1 mL) in a vial equipped with a Teflon-
coated stirrer bar. After 5 min, N-Boc-protected oxindole 2a (0.2 mmol,
1.0 equiv) and Na2CO3 (0.2 mmol, 1 equiv) were added and the resulting
solution was stirred at 08C for 48 h. The crude mixture was diluted with
CH2Cl2 and flushed through a short plug of silica (with dichloromethane/
ethyl acetate 1:1 as the eluent (100 mL)). The solvent was removed
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Enantioselective Synthesis of Spiro Nitrocyclopropyl Oxindoles
COMMUNICATION
7041; c) H. Lebel, J. F. Marcoux, C. Molinaro, A. B. Charette, Chem.
Rev. 2003, 103, 977; d) K.-S. Yeung, I. Paterson, Chem. Rev. 2005,
105, 4237; e) J. Pietruszka, Chem. Rev. 2003, 103, 1051; f) W. A. Do-
naldson, Tetrahedron 2001, 57, 8589; g) R. Faust, Angew. Chem.
2001, 113, 2312; Angew. Chem. Int. Ed. 2001, 40, 2251; h) Y. Nishii,
N. Maruyama, K. Waskasugi, Y. Tanabe, Bioorg. Med. Chem. 2001,
9, 33; i) F. Brackmann, A. de Meijere, Chem. Rev. 2007, 107, 4493;
j) C. A. Carson, M. A. Kerr, Chem. Soc. Rev. 2009, 38, 3051; k) F.
Gnad, O. Reiser, Chem. Rev. 2003, 103, 1603.
Angew. Chem. 2007, 119, 1590; Angew. Chem. Int. Ed. 2007, 46,
1570; c) A. M. Walji, D. W. C. MacMillan, Synlett 2007, 1477;
d) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006,
118, 7292; Angew. Chem. Int. Ed. 2006, 45, 7134.
[11] a) T. Inokuma, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2006,
128, 9413; b) P. R. Schreiner, A. Wittkopp, Org. Lett. 2002, 4, 217;
c) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713.
[12] a) R. Ballini, A. Rinaldi, Tetrahedron Lett. 1994, 35, 9247; b) R. Bal-
lini, G. Bosica, Tetrahedron 1995, 51, 4213; c) R. Ballini, G. Bosica,
D. Fiorini, M. Gil, M. Petrini, Org. Lett. 2001, 3, 1265.
[9] For selected examples of enantioselective organocatalytic cyclopro-
panation reactions, see: a) V. Terrasson, A. van der Lee, R. M. de Fi-
gueiredo, J. M. Campagne, Chem. Eur. J. 2010, 16, 7875; b) T. Inoku-
ma, S. Sakamoto, Y. Takemoto, Synlett 2009, 1627; c) R. Rios, H.
Sundꢂn, J. Veseley, G.-L. Zhao, P. Dziedzic, A. Cordova, Adv. Synth.
Catal. 2007, 349, 1028; d) H. Xie, L. Zu, H. Li, J. Wang, W. Wang, J.
Am. Chem. Soc. 2007, 129, 10886; e) H.-M. Hansen, D.-A. Logbot-
tom, S.-V. Ley, Chem. Commun. 2006, 4838; f) C. C. C. Johansson,
N. Bremeyer, S. V. Ley, D. R. Owen, S. C. Smith, M. J. Gaunt,
Angew. Chem. 2006, 118, 6170; Angew. Chem. Int. Ed. 2006, 45,
6024; g) R. K. Kunz, D. W. C. MacMillan, J. Am. Chem. Soc. 2005,
127, 3240; h) N. Bremeyer, S. C. Smith, S. V. Ley, M. J. Gaunt,
Angew. Chem. 2004, 116, 2735; Angew. Chem. Int. Ed. 2004, 43,
2681; i) C. D. Papageorgiou, M. A. Cubillo de Dios, S. V. Ley, M. J.
Gaunt, Angew. Chem. 2004, 116, 4741; Angew. Chem. Int. Ed. 2004,
43, 4641; j) C. D. Papageorgiou, S. V. Ley, M. J. Gaunt, Angew.
Chem. 2003, 115, 852; Angew. Chem. Int. Ed. 2003, 42, 828; k) S. H.
McCooey, T. McCabe, S. J. Connon, J. Org. Chem. 2006, 71, 7494;
l) Y.-N. Xuan, S.-Z. Nie, L.-T. Dong, J.-M. Zhang, M. Yan, Org. Lett.
2009, 11, 1583; m) R. Fan, Y. Ye, W. Li, L. Wang, Adv. Synth. Catal.
2008, 350, 2488; n) S. L. Riches, C. Saha, N. Fontaꢃn Filgueira, E.
Grange, E. M. McGarrigle, V. K. Aggarwal, J. Am. Chem. Soc. 2010,
132, 7626 and references therein.
[13] For a detailed screening of the reaction conditions, including those
of unprotected oxindoles with catalysts 1a–1c, see the Supporting
Information.
[14] a) B. Vakulya, S. Varga, A. Csampai, T. Soꢅs, Org. Lett. 2005, 7,
1967; b) B. Vakulya, S. Varga, T. Soꢅs, J. Org. Chem. 2008, 73, 3475;
for a comprehensive review on the cinchona alkaloids as organoca-
talysts, see: c) T. Marcelli, H. Hiemstra, Synthesis 2010, 1229.
[15] We reasoned that the use of NaHCO3 as a scavenger of HBr gener-
ated during the ring-closing step, was fundamental to avoid catalyst
deactivation thus accelerating the reaction rate, as well as improving
the yield. For previous work that employs an inorganic base as an
acidic scavenger in aziridination reactions, see: a) F. Pesciaioli, F. De
Vincentiis, P. Galzerano, G. Bencivenni, G. Bartoli, A. Mazzanti, P.
Melchiorre, Angew. Chem. 2008, 120, 8831; Angew. Chem. Int. Ed.
2008, 47, 8703; b) F. De Vincentiis, G. Bencivenni, F. Pesciaioli, A.
Mazzanti, G. Bartoli, P. Galzerano, P. Melchiorre, Chem. Asian J.
2010, 5, 1652.
[16] The reaction performed with catalyst 1c and an oxindole with a free
NH group in toluene after 65 h gave a dramatic decrease in the ee,
d.r., and conversion values: 81% conversion, 8.8:1 d.r., and 79% ee,
compared with that obtained with N-Boc oxindole (Table 1,
entry 1).
[10] For recent reviews, see: a) C. Grondal, M. Jeanty, D. Enders, Nat.
Chem., 2010, 2, 167; b) D. Enders, C. Grondal, M. R. M. Hꢄttl,
Received: November 26, 2010
Published online: February 9, 2011
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