Noncovalent organocatalysis: A powerful tool for the nucleophilic epoxidation of α-ylideneoxindoles

Article abstract of DOI:10.1021/ol202646w

A novel asymmetric nucleophilic epoxidation for α-ylideneoxindole esters has been successfully devised, resulting in enantioenriched spiro compounds with two new contiguous stereocenters. The employed (S)-α,α-diphenylprolinol functions as a bifunctional c

Full text of DOI:10.1021/ol202646w

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6248–6251
Noncovalent Organocatalysis: A Powerful
Tool for the Nucleophilic Epoxidation of r-
Ylideneoxindoles
Chiara Palumbo,‡ Giuseppe Mazzeo,§ Andrea Mazziotta,‡ Augusto Gambacorta,†
M. Antonietta Loreto,‡ Antonella Migliorini,‡ Stefano Superchi,§ Daniela Tofani,† and
Tecla Gasperi*,†
ꢀ
Department of Mechanical and Industrial Engineering and the CISDiC, Universita
“Roma Tre”, via della Vasca Navale 79, I-00146 Roma, Italy, Department of Chemistry,
ꢀ
“Sapienza” Universita di Roma, p.le Aldo Moro 5, I-00185 Roma, Italy, and Department
of Chemistry “A.M. Tamburro”, Universita della Basilicata, via dell’Ateneo Lucano 10,
ꢀ
I-85000 Potenza, Italy
*tgasperi@uniroma3.it
Received October 10, 2011
ABSTRACT
A novel asymmetric nucleophilic epoxidation for R-ylideneoxindole esters has been successfully devised, resulting in enantioenriched spiro
compounds with two new contiguous stereocenters. The employed (S)-R,R-diphenylprolinol functions as a bifunctional catalyst, creating a
complex H-bond network in conjunction with a substrate and an oxidant.
As a consequence of their functional group diversity and
complex architectural platforms, synthetic and natural
oxindole products have drawn the attention of an increasing
number of chemists.1 Their wide range of biocidal prop-
erties have also piqued curiosity in medical fields.2 Specifi-
cally, spiro-epoxyoxindoles and their closest derivatives,
3-substituted 3-hydroxyoxindoles, have been found to pos-
sess remarkable medicinal effectiveness and serve a unique
role in direct access to highly valuable bioactive molecules.3
Noteworthy examples are some benzoyl-substituted oxi-
ranes, which have been tested as antitubercular agents,4
†
ꢀ
Universita “Roma Tre”.
‡
§
ꢀ
“Sapienza” Universita di Roma.
ꢀ
Universita della Basilicata.
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r
10.1021/ol202646w
Published on Web 11/04/2011
2011 American Chemical Society

and convolutamydines AꢀE, which are potent inhibitors of
the differentiation of promyelocytic leukemia cells.5
Although several elegant strategies have been reported for
3-hydroxyoxindoles,6 the current synthetic repertoire to a
spiro[oxirane-oxindole] framework still suffers from poor
stereocontrol, employs metal catalysis, and displays a poor
substrate scope.7
Table 1. Effects of the Organocatalyst and Solvent during
Epoxidation Reactionsa
Encouraged by the previously observed high reactivity
of 3-(oxyphosphonylmethylene)oxindoles with nucleophi-
lic oxidants,8 we devised the possibility of synthesizing
optically active spiro-epoxyoxindole esters by exploiting
an asymmetric catalytic modification of the WeitzꢀScheffer
epoxidation9 of electron-poor R-ylideneoxindoles (1).
10
ꢁ
Aside from the well-established JuliaꢀColonna reaction
and the phase transfer catalysis approach,11 efficient sys-
tems have been devised for the asymmetric epoxidation of
R,β-unsaturated aldehydes and ketones. Among the former
class of substrates, excellent results have been obtained by
employing diarylprolinol silyl ethers,12 chiral phospho-
ric amine salts,13 and diphenylfluoromethylpyrrolidine as
highly effective catalysts.14 Diphenylprolinol15 as well as
guanidine16 and amino alcohol based17 catalysts are more
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a Unless otherwise stated, the reaction conditions were as follows: N-
methyl-R-ylideneoxindole 1a (0.5 mmol), TBHP (0.6 mmol), catalyst
(0.15 mmol), and solvent at rt. b The yields of the isolated products are
expressed as the sum of the diastereomers. c Determined by 1H NMR of
the crude reaction mixture. d Determined by chiral-phase HPLC analy-
sis. e H2O2 (30% in water, 0.15 mmol) was employed as the oxidant.
f Cumene hydroperoxide (CHP, 0.15 mmol) was employed as the
oxidant. g The reaction was performed at 4 °C.
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efficiently involved in the asymmetric epoxidation of
R,β-unsaturated ketones.
Conversely, the application of such organocatalytic
strategies to R,β-unsaturated carboxylic acid derivatives
is still a mostly unexplored field18 and remains a challeng-
ing endeavor of great interest.
ꢁ
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By taking advantage of the impressive progress with
carbonyl derivatives, we pursued our research by investi-
gating the organocatalytic epoxidation of R-ylideneoxin-
doles (1), which are electron-poor olefins bearing two
electron-withdrawing groups on the opposite sides of the
double bond. Here, we report the initial successful asym-
metric oxidation to form the spiro[oxirane-oxindole] deri-
vatives 2 and 3 promoted by R,R-diaryl-prolinol deriv-
atives as bifunctional catalysts (Table 1).
Because a number of chiral secondary amines exhibit
different outcomes when employed as catalysts, the en-
antiopure prolinol derivatives AꢀE (Figure 1) were initi-
ally used as organocatalysts (30 mol %) to promote the
asymmetric epoxidation of a model electron-poor olefin,
N-methyl-R-ylideneoxindole 1a (Table 1).
ꢁ
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Zhao, G.-L.; Ibrahem, I.; Suden, H.; Cordova, A. Adv. Synth. Catal.
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Org. Lett., Vol. 13, No. 23, 2011
6249

(2aand 3a) was used to simulate the optical rotation dispersion
(ORD).20 This calculation was performed using an arbitrarily
fixed absolute configuration (20R,30R) for the major enantio-
mer of trans-2a. Because the sign, order of magnitude, and
uniform trend of the experimental ORD were correctly
reproduced by the calculations, (20R,30R)-2a was strongly
supported as the absolute configuration. The (20S,30R) con-
figuration was assigned to the major enantiomer of cis-3a by
applying the same quantum mechanical approach.
The developed conditions were evaluated using the
analogous R-ylideneoxindoles 1bꢀm, which were var-
iously substituted on both nitrogen (R1) and the aromatic
ring (R2 and R3). These results are summarized in Table 2.
The presence of a halide in position 5 (1b, 1c) or 7 (1eꢀg)
induced a surprising inversion in dr with respect to the
model reaction, whereas the enantioselectivity was almost
the same or even better with bromine in position 7 (88% ee,
trans-2g). Similar stereoselectivity was observed when the
substrate bearing the CF3O group was employed (1d).
Conversely, the initial dr (in favor of trans diastereomers)
was slowly restored by removing the decoration on the
fused aromatic ring and diversifying the substituent on the
nitrogen atom (1h, 1i, 1m). However, a decrease in the
enantioselectivity was observed. Additional structural and
electronic modifications on both aromatic moieties (1jꢀl)
resulted in the optimal diastereomeric excess without im-
proving the enantioselectivity.
Figure 1. Organocatalysts examined in this study.
We selected tert-butylhydroperoxide (TBHP) as the
oxidant and hexane as the solvent, even though both the
substrate and products were barely soluble in such a
medium. Despite the substrate having the E configuration,
both spiro-oxirane-2-carboxylates (trans-2a and cis-3a)
were always obtained, with the former as the major
diastereoisomer.19 The initial hypothesis of a fast inter-
conversionbetween the two observedproductswasquickly
excluded because independent experiments, performed by
treating the trans-2a spiro-epoxide with the same catalyst/
oxidant system, provided none of the corresponding cis-3a
diastereomer.
Of the employed catalysts, the simplest R,R-diphenyl-
prolinol (S)-A provided the trans-2a spiro-epoxide with
good enantioselectivity (70% ee, entry 1), while either the
O-methylated (S)-B (entry 2) or the more hindered O-
trimethylsilylated (S)-C (entry 3) provided decreased en-
antiomeric excess and an inverted diastereomeric ratio.
Such results strongly suggested the key role of the free OH
group in the catalyst as establishing an H-bond network
with both the substrate and reagent. Despite this evidence,
the introduction of EWGs on both catalyst aromatic rings
[Ar = 3,5-(CF3)2-C6H3, (S)-D], which should have pro-
moted H-bond formation, only protracted the reaction
time without increasing the overall enantioselectivity
(entry 4). However, similar steric hindrance on the aryl
groups [Ar = 3,5-(CH3)2-C6H3, (S)-E] led to analogous
yield and stereoselectivity results (entry 5) with the first
employed catalyst (S)-A. On the basis of these preliminary
trials, subsequent reaction optimization was performed
with the less expensive R,R-diphenylprolinol (S)-A, which,
surprisingly, provided the optimal enantioselectivity when
more hexane was added (entry 11). Additional screening of
oxidizing agents (H2O2 in entry 6 and CHP in entry 7),
temperature (entry 12), and solvents (entries 14ꢀ19) failed
to improve either the yield or the stereoselectivity and
resulted in a longer reaction time and poorer substrate
conversion.
Table 2. Substrate Scope of the Asymmetric Epoxidation
Reactions of the 3-Ylideneoxindoles 1aꢀma
The given stereochemical assignments are based on a
thorough comparison of the reported experiments, analy-
tical data, and a quantum mechanical ab initio calculation
of chiroptical properties.19 Indeed, once it is unambiguously
determined via 1H NMR and NOESY experiments,15 the
trans/cis configuration of the obtained diastereomers
a Reaction conditions: R-ylideneoxindole 1 (0.5 mmol), catalyst A
(0.15 mmol), TBHP (0.6 mmol) and HPLC-grade hexane (2.7 mL) at rt.
b The yields of the isolated products are expressed as the sum of the
diastereomers. c Determined by 1H NMR of the crude reaction mixture.
d Determined by chiral-phase HPLC analysis.
(19) Spectroscopic analyses of 2a and 3a, ORD values, and the
complete calculated/experimental data discussion are reported in the
Supporting Information.
The experimental evidence and the obtained configura-
tion(20R,30R) ofthemajor stereoisomer could be explained
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Org. Lett., Vol. 13, No. 23, 2011

byassumingthe catalytic cycle depicted in Scheme 1, which
fully agrees with the recent statements regarding the
asymmetric epoxidation of R,β-unsaturated ketones.15b
According to this hypothesis, we propose the following:
(i) the interaction between TBHP and the catalyst activates
the oxidizing agent, leading to the tight ion pair 4a; (ii) the
first regiospecific attack of 4a at the Cβ carbon21 of the
substrate is promoted by both the intermediate aromatiza-
tion and formation of a stabilizing H-bond between the
OH catalyst and the partial negative charge on the lactam
carbonyl moiety; (iii) thus, the reagent approach is prefer-
entially driven toward the less-hindered Re-face of the
double bond, resulting in the aromatic and long-living 6a
intermediate; and (iv) two alternative evolutions of 6a may
result in either the oxirane (20R,30R)-2a (via irreversible
direct ring closure) or the diastereomer (20S,30R)-3a (via
intramolecular H-bond breaking and the rapid subsequent
rotation around the CRꢀCβ σ-bond to produce the 7a
intermediate).
of halides on the fused aromatic ring facilitates the forma-
tion of an additional stabilizing H-bond between the
substrate and OH catalyst (Figure 2).
The successful achievement of the desired spiro com-
pounds provides a novel, nucleophilic approach to the
organocatalytic epoxidation of R,β-unsaturated carboxylic
acid derivatives. This route offers a valuable alternative to
the electrophilic procedure developed by Shi.22 Addition-
ally, it confirmed the action of noncovalent catalysis that
relies on a hydrogen bond network between the substrate
and the bifunctional catalyst/oxidant system.
Scheme 1. Postulated Reaction Mechanism
Figure 2. Interconversion between the 6eꢀg and 7eꢀg inter-
mediates (X = F, Cl, or Br).
Detailed studies to elucidate the mechanism and broad-
en the substrate scope are ongoing in our laboratories and
willbereportedindue course. Finally, these results provide
straightforward access to new spirocyclic oxindolic oxi-
ranes, which are extremely attractive building blocks and
intermediates due to the presence of additional moieties
that are capable of additional chemical elaboration.
Acknowledgment. We thank Dr. Giovanna Mancini
ꢀ
(CNR, “Sapienza” Universita di Roma) for the NOESY
experiments and Dr. Paolo Lupattelli (Universita della
ꢀ
Basilicata) for the ORD measurements.
Supporting Information Available. Detailed experimen-
tal procedures and a full characterization and copies of
the 1H, 13C NMR spectra, HPLC, and ORD calculations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) For general discussion of ab initio calculation of chiroptical
properties, see: (a) Polavarapu, P. L. Chirality 2002, 14, 768.
(b) Stephens, P. J. Computational Medicinal Chemistry for Drug
Discovery; Bultnick, P., de Winter, H., Langenaecker, W., Tollenaere, J.,
Eds.; Dekker: New York, NY, 2003. (c) Pecul, M.; Ruud, K. Adv.
Quantum Chem. 2005, 50, 185. (d) Crawford, T. D. Chem. Acc.
2006, 115, 227. (e) Autscbach, J.; Nitsch-Velasquez, L.; Rudolph,
M. Top. Curr. Chem. 2011, 298, 1.
(21) R- and β-positions are refferred to the lactamic carbonyl group.
For other examples of Michael addition, see: (a) Savitha, G.; Niveditha,
S. K.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2007, 48,
2943. (b) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem.;
Eur. J. 2010, 16, 2852.
This catalytic pathway also accounts for the poor en-
antioselectivity observed for the cis-2a diastereomer
(Table 1), which is a consequence of both the less-favored
Si-face attack and the continuous interconversion between
the aromatic intermediates (6a and 7a). Such an equili-
brium is shifted toward intermediate 7 when the presence
(22) (a) Wang, Z. X.; Tu, Y.; Frohn, M.; Zhang, J. R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224. (b) Shi, Y. Acc. Chem. Res. 2004, 37, 488.
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