Enantioselective synthesis of spirooxindole α-exo-methylene-γ- butyrolactones from 3-OBoc-oxindoles

Article abstract of DOI:10.1002/ejoc.201301684

Chiral Lewis bases facilitated the synthesis of highly functionalized spirooxindoles containing α-exo-methylene-γ-butyrolactones in high yields (76-92 %) and excellent enantioselectivities (up to 98 % ee) at ambient temperature.

Full text of DOI:10.1002/ejoc.201301684

FULL PAPER
DOI: 10.1002/ejoc.201301684
Enantioselective Synthesis of Spirooxindole α-exo-Methylene-γ-butyrolactones
from 3-OBoc-Oxindoles
Samydurai Jayakumar,[a] Subramaniam Muthusamy,[a] Muthuraj Prakash,[a] and
Venkitasamy Kesavan*[a]
Keywords: Organocatalysis / Lewis bases / Asymmetric catalysis / Spiro compounds / Allylic alkylation
Chiral Lewis bases facilitated the synthesis of highly func-
butyrolactones in high yields (76–92%) and excellent
tionalized spirooxindoles containing α-exo-methylene-γ-
enantioselectivities (up to 98% ee) at ambient temperature.
highly functionalized spirooxindoles.[1] The ever-increasing
number of publications on the enantioselective synthesis of
Introduction
The presence of spirooxindoles in various pharmacologi- these scaffolds highlight their importance. Spirooxindoles
cally active compounds stimulates interest of organic chem- bearing γ-butyrolactones (I; Figure 1) are formidable syn-
ists in developing new methodologies for the synthesis of thesis targets, as only a few protocols are available to pre-
Figure 1. Strategies to create spirooxindoles bearing γ-butyrolactone.
pare them in a stereoselective manner.[2] Bergonzini et al.
[a] Chemical Biology Laboratory, Department of Biotechnology,
Bhupat and Jyothi Metha School of Bioscience Building, Indian
accomplished the enantioselective synthesis of spiroox-
Institute of Technology Madras,
indole γ-butyrolactones by an enamine strategy with 3-hy-
droxyoxindole as a nucleophile (Figure 1; Route A).[2a] Ra-
cemic spirocyclic γ-butyrolactones I were generated by N-
heterocyclic carbene (NHC) catalysis in 2006.[2b] Sun et
Chennai 600036, India
E-mail: vkesan@iitm.ac.in
http://www.biotech.iitm.ac.in/faculty/kesavan/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301684.
Eur. J. Org. Chem. 2014, 1893–1898
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1893

S. Jayakumar, S. Muthusamy, M. Prakash, V. Kesavan
FULL PAPER
al.[2c] and Dugal-Tessier et al.[2d] developed an NHC-cata- alkylation of MBH carbonate 1a with 3-OBoc-oxindole 2a.
lyzed enantioselective version that involves annulation of We performed the model alkylation reaction in the presence
1,2-dicarbonyl compounds to construct oxindole spirolact- of a tertiary amine catalyst (10 mol-%), and the results are
ones I (Figure 1; Route B). Trost et al. employed an umpo- presented in Table 1.
lung strategy in a spiroannulation reaction to synthesis ox-
It is evident from Table 1 that quinine derivatives 5a–5d
indole-containing spiro-γ-butyrolactones
I
(Figure 1; failed to catalyze the alkylation reaction of MBH carbon-
Route C).[2e] Despite these developments, it is necessary to ates efficiently. Only moderate yields and enantioselecti-
expand the diversity of the oxindole skeleton to improve vities were obtained (Table 1, Entries 1–4). Among the cin-
their pharmacological properties.
chonine derivatives, quinidine (6b) afforded the expected
α-exo-Methylene-γ-butyrolactone is a privileged scaffold product 3 in fair yield with very good enantioselectivity,
that displays a wide range of biological activities[3] and is and the diastereomeric ratio (dr) was 9.5:1 (Table 1, En-
an important constituent of various natural products.[4] It try 6). Efforts to increase the enantioselectivity further by
is noteworthy that this scaffold can form covalent bonds using (QN)2PHAL (7a) and (QD)2PHAL (7b) did not pro-
with cysteine residues and thereby inhibit the function of duce the desired results (Table 1, Entries 10 and 11). Fur-
proteins.[5] Among the various electrophiles that have been ther attempts to enhance the enantioselectivity by using cat-
employed to impair the function of proteins,[6] inhibitors alysts 8 (β-ICN) and 9 (β-IQD) were not fruitful. In those
appended with Michael acceptors are quite common and experiments – although good yields were obtained – only
well explored.[7]
moderate to fair enantioselectivity was observed (Table 1,
Apart from increasing the diversity in the oxindole skel- Entries 12 and 13). The alkylation proceeded with very
eton, the fusion of α-exo-methylene-γ-butyrolactone to ox- good enantioselectivity and yield, but the diastereoselec-
indole may pave the way to the generation of more promis- tivity was lower when β-ICD (10) was employed as the cata-
ing covalent inhibitors. Despite various efforts to construct lyst (Table 1, Entry 14). Both 6b and 10 were chosen as cat-
spirooxindole γ-butyrolactones, there has been little effort alysts for other experimental optimization studies. As the
to obtain enantioenriched spirooxindoles bearing α-exo- one-pot cyclization of the alkylated products (3 and 4) to
methylene-γ-butyrolactone (II) scaffolds. Hence, the devel- yield α-exo-methylene-substituted spiro-γ-butyrolactones II
opment of an efficient methodology to synthesize this valu- under acidic conditions in toluene was sluggish, the identifi-
able scaffold is very much needed. To the best of our knowl- cation of a suitable reaction medium was undertaken by
edge, there was no literature precedent when we commenced using 6b as the catalyst. The choice of solvent had a pro-
the enantioselective synthesis of spirooxindoles containing found effect on both the stereoselectivity and the yield, and
α-exo-methylene-γ-butyrolactones. While we were complet- the results are summarized in Table 2. The use of chlorin-
ing our experiments, Wang et al. described the enantioselec- ated solvents lowered both the yield and the enantio-
tive synthesis of identical compounds in moderate yields selectivity (Table 2, Entries 1 and 2). Neither the enantio-
(Figure 1; Route D).[8] The low yield of this methodology selectivity nor the diastereoselectivity improved when eth-
can be attributed to the dimerization of 3-hydroxyoxindole ereal solvents such as methyl tert-butyl ether (MTBE),
under basic conditions[2a] and the possibility of competitive tetrahydrofuran (THF), and dioxane were used (Table 2,
C,O-alkylation. Furthermore, the addition of 3 equiv. of Entries 3–5). It is evident that increasing the number of
Morita–Baylis–Hillman (MBH) carbonate is required to af- methyl substituents on the benzene ring affected both the
ford the corresponding lactone in moderate yield. To over- enantioselectivity and the diastereoselectivity in the desired
come all these shortcomings, we describe herein a simple manner (Table 2, Entries 6–10). Thus, we have identified
protocol to synthesize optically enriched spirooxindole scaf- mesitylene as the most suitable reaction medium in which
folds containing α-exo-methylene-γ-butyrolactone (II) in excellent yield (88%) and diastereoselectivity (20:1) in ad-
very good yield by using 3-OBoc-oxindoles 2 as nucleo- dition to admirable enantioselectivity were obtained for the
philes.
expected product 3 (Table 2, Entries 10 and 11). Although
very good diastereo- and enantioselectivity were obtained
in mesitylene, the one-pot cyclization of the alkylated prod-
uct did not proceed as expected. Hence, the diastereomeric
Results and Discussion
The combination of a chiral tertiary amine catalyst and mixture 3/4 was isolated by flash column chromatography
MBH carbonates 1 has been well exploited to create struc- and subjected to cyclization in dichloromethane under
turally diverse compounds.[9] The asymmetric allylic alkyl- acidic conditions to quantitatively afford the corresponding
ation of 3-aryloxindole with MBH carbonates[10] led us to lactone of the major diastereomer with no loss of enantio-
apply an umpolung strategy to achieve the target spirolact- purity. Thus, we have identified a suitable tertiary amine
ones II in two steps. The 3-OBoc-protected N-methyloxin- catalyst and reaction medium to accomplish the enantiose-
dole 2a was chosen as a nucleophile, because the resulting lective synthesis of α-exo-methylene-γ-butyrolactones II in
alkylated product 3 can be cyclized under trifluoroacetic good yield in two steps.
acid conditions with ease.[11] The OBoc protection of 3-
We were also curious to check whether the ester group
hydroxyoxindole may avoid both dimerization and competi- of the MBH carbonate and the N-substitution of 3-OBoc-
tive O-alkylation. Our efforts were dedicated to the identifi- oxindole may influence the enantioselectivity (Table 3). Ini-
cation of suitable tertiary amines to catalyze the asymmetric tially, we studied the steric effect of the ester functional
1894
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1893–1898

Spirooxindole α-exo-Methylene-γ-butyrolactones
Table 1. Ligand optimization.[a]
Entry
Catalyst
Yield [%][b]
dr (3/4)[c]
ee (3) [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5a
5b
5c
5d
6a
6b
6c
6d
6e
7a
7b
8
64
45
trace
63
60
71
54
52
trace
trace
trace
81
6.2:1
5.2:1
n.d.
6.1:1
8.1:1
9.5:1
5:1
1.8:1
n.d.
n.d.
–2
–50
n.d.
–40
70
84
36
39
n.d.
n.d.
n.d.
50
72
86
n.d.
6.5:1
8.6:1
6:1
9
77
87
10
[a] Unless otherwise indicated, the reaction was performed with 1a (0.18 mmol), 2a (0.15 mmol), and 10 mol-% catalyst in toluene (1 mL).
1
[b] Isolated yields of diastereomers 3 and 4. [c] Determined by H NMR spectroscopy. [d] Enantiomeric excess of major diastereomer
determined by chiral HPLC.
Table 2. Influence of solvents.[a]
group of the MBH carbonates 1a–1c in the presence of
Entry Catalyst
Solvent
Yield [%][b] dr (3/4)[c] ee (3) [%][d]
either 6b or 10. Methyl ester 1a and ethyl ester 1b were well
tolerated when 6b was used (Table 2, Entries 1 and 3), but
the tert-butyl ester led to decreased enantioselectivity
(Table 3, Entry 5). β-ICD (10) performed better than quin-
idine (6b) irrespective of ester substituents. Excellent dia-
stereo- and enantioselectivity were observed in the presence
of the tert-butyl ester of the MBH carbonate 1c when 10
was employed (Table 3, Entry 6).
Having established the optimal structural requirements
of the MBH carbonate and chiral catalyst, we next focused
on the synthesis of spiro-α-exo-methylene-γ-butyrolactones
from oxindoles with varying N-protecting groups. As un-
protected oxindoles may exhibit better pharmacological ac-
tivities than their protected counterparts, it is imperative to
generate spirooxindole α-exo-methylene-γ-butyrolactones in
1
2
3
4
5
6
7
8
9
6b
6b
6b
6b
6b
6b
6b
6b
10
6b
10
ClCH2CH2Cl
CH2Cl2
MTBE
40
53
61
40
86
80
71
92
92
95
95
19:1
8.2:1
8:1
16.5:1
6:1
2.3:1
9.5:1
15.2:1
15:1
21.5:1
20:1
46
53
40
56
74
64
84
84
82
86
88
THF
dioxane
benzene
toluene
xylene
xylene
10
11
mesitylene
mesitylene
[a] Unless otherwise indicated, the reaction was performed with 1a
(0.18 mmol), 2a (0.15 mmol), and 10 mol-% catalyst in the appro-
priate solvent (1 mL). [b] Isolated yields of diastereomers 3 and 4.
1
[c] Determined by H NMR spectroscopy. [d] Enantiomeric excess
of major diastereomer determined by chiral HPLC.
Eur. J. Org. Chem. 2014, 1893–1898
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1895

S. Jayakumar, S. Muthusamy, M. Prakash, V. Kesavan
FULL PAPER
Table 3. Substrate optimization study.[a]
negative influence, and 15e was isolated in very good yield
(81%) and high stereoselectivity (dr 17:1, 84% ee). Almost
similar enantioselectivity (82% ee) with a significant change
in the diastereoselectivity (dr 4:1) was noticed with an elec-
tron-withdrawing para-NO2 group (15f).
The presence of a chloro substituent at the meta position
(1i) is well accommodated, unlike a para substituent (1e),
and the resulting cyclized product 15g was isolated in good
yield and with excellent enantioselectivity (94% ee). Inter-
estingly, even the presence of an ortho-chloro substituent in
the 2,4-dichloro-substituted MBH carbonate 1j did not
pose any negative impact on the enantioselectivity (98%
ee), and the corresponding butyrolactone 15h was isolated
Entry Catalyst
1
2
Yield [%][b]
dr[c]
ee [%][d]
1
2
6b
10
6b
10
6b
10
10
10
10
10
a
a
b
b
c
c
c
c
c
c
a
a
a
a
a
a
b
c
90
91
84
86
71
92
81
86
82
92
21:1
20:1
17:1
12:1
12:1
20:1
14:1
12:1
11:1
20:1
86
88
80
88
70
92
88
80
92
95
3
4
5
6
Table 4. Substrate scope.[a]
7
8
9
10
d
e
[a] Unless otherwise indicated, the reaction was performed with
1a–1c (0.18 mmol), 2a–2e (0.15 mmol), and 10 mol-% catalyst in
mesitylene (1 mL). [b] Isolated yields of mixture of diastereomers.
1
[c] Determined by H NMR spectroscopy. [d] Enantiomeric excess
of major diastereomer determined by chiral HPLC.
which facile deprotection of N-1 can be accomplished with
ease. 3-OBoc-Oxindoles with different protecting groups,
such as benzyl (2b), allyl (2c), and methyl acetate (2d), ren-
dered the cyclized products 12a–14a with slightly decreased
enantioselectivities (Table 3, Entries 7–9) in the presence of
10. We were delighted to observe that the N-propargyl-pro-
tected oxindole derivative 2e afforded the desired lactone
15a in high selectivity (dr 20:1, 95% ee) and yield (92%;
Table 3, Entry 10). It is easier to deprotect N-propargyl
groups than to deprotect N-methyl groups.[12] N-Propargyl
protection can also be utilized for activity-based proteome
profiling (ABPP) in addition to target identification by pull-
down assay.[13] These experiments led to the identification
of the optimal substituents on the oxindole moiety as well
as on the MBH carbonates. In all of these reactions, 10 was
a superior catalyst over 6b (Table 3, Entries 1–10).
Having identified the suitable protecting group on the
oxindole moiety and the substituent effects on the MBH
carbonates, the investigation of the substrate scope of the
MBH carbonates and oxindoles was undertaken (Table 4).
Under the established catalytic conditions, nucleophile 2e
was treated with various MBH carbonates 1c–1j with
10 mol-% of 10. Halogen substituents at the para position
(1d–1f) of the MBH carbonates did not hamper the effi-
ciency of 10 in inducing very good enantioselectivity. The
para-halogen-substituted spirooxindole lactones 15b–15d
were obtained in very good yields (84–87%), although
stereoselectivity varied a little (80–90% ee) when the corre-
sponding MBH carbonates 1d–1f were employed. The re-
placement of the halogen substituent with a phenyl ring at
[a] Unless otherwise indicated, the reaction was performed with 1c–
1j (0.18 mmol), 2e–2i (0.15 mmol), and 10 mol-% 10 in mesitylene
the para position of MBH carbonate 1g did not exert any (1 mL).
1896
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1893–1898

Spirooxindole α-exo-Methylene-γ-butyrolactones
ethyl acetate, 9:1) to afford the corresponding spirooxindole-bear-
ing α-exo-methylene-γ-butyrolactone in very good yield.
in 79% yield. We would like to highlight that the presence
of two chlorine atoms on the phenyl ring of MBH carbon-
ate 1j decreased the diastereoselectivity despite excellent Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all compounds and HPLC data
enantioselectivity for the respective diastereomer.
for all substrates.
After we examined the substituent effects on various
MBH carbonates, we also studied the impact of different
groups at the 5-position of the oxindole moiety. β-ICD can
endure the presence of different substituents such as F, Cl,
Acknowledgments
This work was supported by the Department of Science & Technol-
ogy, Government of India, New Delhi (Grant No. SR/S1/OC-60/
2006). We thank the Department of Biotechnology IIT, Madras
for the infrastructure and the Sophisticated Analytical Instrument
Facility (SAIF) IIT, Madras for spectroscopy data.
Br, and OMe at the 5-position of the oxindole 2f–2i. In
all these cases, cyclized products were isolated with similar
enantioselectivities (15i–15l). The 5-chloro- and 5-bromo-
substituted oxindoles 2g and 2h rendered the corresponding
spirooxindole α-exo-methylene-γ-butyrolactones 15j and
15k with exquisite diastereoselectivity (dr 20:1). To study
the effect of 5-fluoro and 5-methoxy substituents on the
diastereoselectivity, oxindoles were treated with MBH
carbonate 1j under the established reaction conditions. It is
apparent that dihalo substitution lowered the diastereo-
selectivity as in the case of product 15h. The corresponding
butyrolactones 15m and 15n were isolated with diminished
diastereoselectivity. Although we obtained very good
enantioselectivity for dihalo-substituted MBH carbonate 1j
with oxindole 2e, decreased enantioselectivity was noticed
for substrates 2f and 2i in combination with MBH carbon-
ate 1j.
[1] For selected publications, see: a) A. P. Antonchick, C. Gerding-
Reimers, M. Catarinella, M. Schürmann, H. Preut, S. Ziegler,
D. Rauh, H. Waldmann, Nat. Chem. 2010, 2, 735–740; b) J. J.
Badillo, N. V. Hanhan, A. K. Franz, Curr. Opin. Drug Discov.
Devel. 2010, 13, 758–786; c) B. K. S. Yeung, B. Zou, M.
Rottmann, S. B. Lakshminarayana, S. H. Ang, S. Y. Leong, J.
Tan, J. Wong, S. Keller-Maerki, C. Fischli, A. Goh, E. K.
Schmitt, P. Krastel, E. Francotte, K. Kuhen, D. Plouffe, K.
Henson, T. Wagner, E. A. Winzeler, F. Petersen, R. Brun, V.
Dartois, T. T. Diagana, T. H. Keller, J. Med. Chem. 2010, 53,
5155–5164; d) V. V. Vintonyak, K. Warburg, H. Kruse, S.
Grimme, K. Hübel, D. Rauh, H. Waldmann, Angew. Chem.
2010, 122, 6038; Angew. Chem. Int. Ed. 2010, 49, 5902–5905;
e) F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352,
1381–1407; f) S. M. Rajesh, S. Perumal, J. C. Menendez, P.
Yogeeswari, D. Sriram, Med. Chem. Commun. 2011, 2, 626–
630; g) J. Schönhaber, T. J. J. Müller, Org. Biomol. Chem. 2011,
9, 6196–6199. For selected reviews, see: h) C. Marti, E. M. Car-
reira, Eur. J. Org. Chem. 2003, 2209–2219; i) C. V. Galliford,
K. A. Scheidt, Angew. Chem. 2007, 119, 8902; Angew. Chem.
Int. Ed. 2007, 46, 8748–8758; j) G. S. Singh, Z. Y. Desta, Chem.
Rev. 2012, 112, 6104–6155; k) L. Hong, R. Wang, Adv. Synth.
Catal. 2013, 355, 1023–1052.
Conclusions
We have established a simple and high-yielding protocol
to access spirooxindoles comprising α-exo-methylene-γ-
butyrolactones with excellent diastereo- and enantio-
selectivities (dr up to 20:1, 98% ee) at ambient temperature.
By using the modified cinchona alkaloid β-ICD (10) as a
catalyst, we created highly functionalized spirolactones in
very good yields of 76–92% under the optimized condi-
tions. Newly synthesized spirolactones are currently being
evaluated against various cancer cell lines, and the results
will be reported in due course. We expect that these com-
pounds may act as covalent inhibitors owing to the presence
of α-exo-methylene-γ-butyrolactones, and the N-propargyl
handle may pave a way to identify biological targets.
[2] a) G. Bergonzini, P. Melchiorre, Angew. Chem. 2012, 124, 995;
Angew. Chem. Int. Ed. 2012, 51, 971–974; b) V. Nair, S. Vellalth,
M. Poonoth, R. Mohan, E. Suresh, Org. Lett. 2006, 8, 507–
509; c) L.-H. Sun, L.-T. Shen, S. Ye, Chem. Commun. 2011,
47, 10136–10138; d) J. Dugal-Tessier, E. A. O’Bryan, T. B. H.
Schroeder, D. T. Cohen, K. A. Scheidt, Angew. Chem. 2012,
124, 5047; Angew. Chem. Int. Ed. 2012, 51, 4963–4967; e) B. M.
Trost, K. Hirano, Org. Lett. 2012, 14, 2446–2449.
[3] For selected examples of biological activities, see: a) T. Janecki,
E. Błaszczyk, K. Studzian, A. Janecka, U. Krajewska, M.
Rózalski, J. Med. Chem. 2005, 48, 3516–3521; b) L. Albrecht,
˙
J. Wojciechowski, A. Albrecht, W. M. Wolf, A. Janecka, K.
Studzian, U. Krajewska, M. Rózalski, T. Janecki, H. Kraw-
˙
czyk, Eur. J. Med. Chem. 2010, 45, 710–718; c) P. V. Ramachan-
dran, D. Pratihar, H. N. G. Nair, M. Walters, S. Smith, M. T.
Yip-Schneider, H. Wu, C. M. Schmidt, Bioorg. Med. Chem.
Experimental Section
Lett. 2010, 20, 6620–6623; d) A. Janecka, A. Wyrebska, K.
˛
General Experimental Procedure for Catalytic Reactions: A flame-
dried reaction vial was charged with N-protected 3-OBoc-oxindole
2a–2i (0.15 mmol), MBH carbonate 1a–1j (0.l8 mmol), and 10
(10 mol-%) in mesitylene (1 mL). The reaction mixture was stirred
under argon at ambient temperature (25 °C). The completion of
the conversion (24–48 h) was ascertained by TLC, and the alkylated
product was isolated by filtration column chromatography (petro-
leum ether/ethyl acetate, 95:5). The isolated diastereomeric mixture
was treated with TFA (0.1 ml) in dry DCM (2 mL) at 0 °C. The
reaction mixture was warmed to room temperature and stirred fur-
ther for 3–4 h. After the completion of the reaction, the solvent
was evaporated, and the crude product was purified by column
chromatography with silica gel 230–400 mesh (petroleum ether/
Gach, J. Fichna, T. Janecki, Drug Discovery Today 2012, 17,
561–572; e) J.-T. Feng, D.-L. Wang, Y.-L. Wu, Y. He, Z. Xing,
Bioorg. Med. Chem. Lett. 2013, 23, 4393–4397.
[4] a) R. R. A. Kitson, A. Millemaggi, R. J. K. Taylor, Angew.
Chem. 2009, 121, 9590; Angew. Chem. Int. Ed. 2009, 48, 9426–
9451; b) T. G. Elford, D. G. Hall, Synthesis 2010, 6, 893–907;
c) T. Naito, Y. Honda, O. Miyata, I. Ninomiya, Chem. Pharm.
Bull. 1993, 41, 217–219.
[5] For selected examples of covalent inhibition, see: a) P. A. Bae-
uerle, D. Baltimore, Cell 1988, 53, 211–217; b) S. M. Ruben,
P. J. Dillon, R. Schreck, T. Henkel, C. H. Chen, Science 1991,
251, 1490–1493; c) M. L. Schmitz, P. A. Baeuerle, EMBO J.
1991, 10, 3805–3817; M. I. Konaklieva, B. J. Plotkin, Mini-Rev.
Med. Chem. 2005, 5, 73–95.
Eur. J. Org. Chem. 2014, 1893–1898
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1897

S. Jayakumar, S. Muthusamy, M. Prakash, V. Kesavan
FULL PAPER
[6] For selected references, see: a) T. Schirmeister, J. Med. Chem.
1999, 42, 560–572; b) J. C. Powers, J. L. Asgian, O. D. Ekici,
K. E. James, Chem. Rev. 2002, 102, 4639–4750; c) J. G. Robert-
son, Biochemistry 2005, 44, 5561–5571; d) M. S. Cohen, C.
Zhang, K. M. Shokat, J. Taunton, Science 2005, 308, 1318–
1321; e) A. Poliakov, A. Sandström, E. Åkerblom, U. H. Dan-
ielson, J. Enzyme Inhib. Med. Chem. 2007, 22, 191–199; f) A.
Watzke, G. Kosec, M. Kindermann, V. Jeske, H.-P. Nestler, V.
Turk, B. Turk, K. U. Wendt, Angew. Chem. 2008, 120, 412;
Angew. Chem. Int. Ed. 2008, 47, 406–409; g) H. A. Lim, J. Joy,
J. Hill, C. S. B. Chia, Eur. J. Med. Chem. 2011, 46, 3130–3134.
[7] a) O. D. Ekici, Z. Z. Li, A. J. Campbell, K. E. James, J. L. Asg-
ian, J. Mikolajczyk, G. S. Salvesen, R. Ganesan, S. Jelakovic,
M. G. Grütter, J. C. Powers, J. Med. Chem. 2006, 49, 5728–
5749; b) W. Chu, J. Rothfuss, A. D’Avignon, C. Zeng, D. Zhou,
R. S. Hotchkiss, R. H. Mach, J. Med. Chem. 2007, 50, 3751–
3755; c) M. M. M. Santos, R. Moreira, Mini-Rev. Med. Chem.
2007, 7, 1040–1050; d) W. Chu, J. Rothfuss, Y. Chu, D. Zhou,
R. H. Mach, J. Med. Chem. 2009, 52, 2188–2191; e) A. Ovat,
F. Muindi, C. Fagan, M. Brouner, E. Hansell, J. Dvorˇák, D.
Sojka, P. Kopácˇek, J. H. McKerrow, C. R. Caffrey, J. C. Pow-
ers, J. Med. Chem. 2009, 52, 7192–7210; f) A. Breuning, B.
Degel, F. Schulz, C. Büchold, M. Stempka, U. Machon, S.
Heppner, C. Gelhaus, M. Leippe, M. Leyh, C. Kisker, J. Rath,
A. Stich, J. Gut, P. J. Rosenthal, C. Schmuck, T. Schirmeister,
J. Med. Chem. 2010, 53, 1951–1963; g) d. L. W. A. van, P. P.
Geurink, C. Oskam, d. M. G. A. van, B. I. Florea, H. S. Overk-
leeft, Org. Biomol. Chem. 2010, 8, 1885–1893; h) d. W. R. van,
E. Strauss, J. Am. Chem. Soc. 2010, 132, 12853–12855; i)
P. M. C. Glória, I. Coutinho, L. M. Gonçalves, C. Baptista, J.
Soares, A. S. Newton, R. Moreira, L. Saraiva, M. M. M. San-
tos, Eur. J. Med. Chem. 2011, 46, 2141–2146; j) J. Xu, A. Chen,
J. Joy, V. J. Xavier, E. H. Q. Ong, J. Hill, C. L. L. Chai, Chem-
MedChem 2013, 8, 1483–1494.
[9]
For selected recent publications, see: a) F. Zhong, X. Han, Y.
Wang, Y. Lu, Angew. Chem. 2011, 123, 7983; Angew. Chem.
Int. Ed. 2011, 50, 7837–7841; b) L. Jiang, Q. Lei, X. Huang,
H.-L. Cui, X. Zhou, Y.-C. Chen, Chem. Eur. J. 2011, 17, 9489–
9493; c) C. Liu, B.-X. Tan, J.-L. Jin, Y.-Y. Zhang, N. Dong, X.
Li, J.-P. Cheng, J. Org. Chem. 2011, 76, 5838–5845; d) F.
Zhong, J. Lou, G.-Y. Chen, X. Dou, Y. Lu, J. Am. Chem. Soc.
2012, 134, 10222–10227; e) G.-Y. Chen, F. Zhong, Y. Lu, Org.
Lett. 2012, 14, 3955–3957; f) D. Wang, Y.-L. Yang, J.-J. Jiang,
M. Shi, Org. Biomol. Chem. 2012, 10, 7158–7166; g) G. Tong,
B. Zhu, R. Lee, W. Yang, D. Tan, C. Yang, Z. Han, L. Yan,
K.-W. Huang, Z. Jiang, J. Org. Chem. 2013, 78, 5067–5072; h)
Q.-G. Wang, Q.-Q. Zhou, J.-G. Deng, Y.-C. Chen, Org. Lett.
2013, 15, 4786–4789.
[10]
[11]
K. Jiang, J. Peng, H.-L. Cui, Y.-C. Chen, Chem. Commun.
2009, 3955–3957.
X. Companyó, A. Mazzanti, A. Moyano, A. Janecka, R. Rios,
Chem. Commun. 2013, 49, 1184–1186.
[12] M. Pal, K. Parasuraman, K. R. Yeleswarapu, Org. Lett. 2003,
5, 349–352.
[13] a) A. E. Speers, G. C. Adam, B. F. Cravatt, J. Am. Chem. Soc.
2003, 125, 4686–4687; b) A. E. Speers, B. F. Cravatt, Chem.
Biol. 2004, 11, 535–546; c) M. Tantama, W.-C. Lin, S. Licht, J.
Am. Chem. Soc. 2008, 130, 15766–15767; d) P.-Y. Yang, K. Liu,
M. H. Ngai, M. J. Lear, M. R. Wenk, S. Q. Yao, J. Am. Chem.
Soc. 2010, 132, 656–666; e) P.-Y. Yang, K. Liu, C. Zhang,
G. Y. J. Chen, Y. Shen, M. H. Ngai, M. J. Lear, S. Q. Yao,
Chem. Asian J. 2011, 6, 2762–2775; f) J. L. Slack, C. P. Causey,
Y. Luo, P. R. Thompson, ACS Chem. Biol. 2011, 6, 466–476;
g) E. Tashiro, M. Imoto, Bioorg. Med. Chem. 2012, 20, 1910–
1921; h) Q. Miao, C.-C. Zhang, J. Kast, Expert Rev. Proteomics
2012, 9, 281–291.
Received: November 10, 2013
Published Online: January 15, 2014
[8] Q.-L. Wang, L. Peng, F.-Y. Wang, M.-L. Zhang, L.-N. Jia, F.
Tian, X.-Y. Xu, L.-X. Wang, Chem. Commun. 2013, 49, 9422–
9424.
1898
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1893–1898