Asymmetric Ugi 3CR on isatin-derived ketimine: Synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

Article abstract of DOI:10.3762/bjoc.10.141

An efficient Ugi three-component reaction of a preformed chiral ketimine derived from isatin with various isonitrile and acid components has been developed. The reactions proceeded smoothly and in a stereocontrolled manner with regard to the new center of the Ugi products due to the stereoinduction of the amine chiral residue. A wide variety of novel chiral 3,3-disubstituted 3-aminooxindoles were obtained, a selection of which were subjected to post-Ugi transformations, paving the way to application as peptidomimetics. 2014 Lesma et al;.

Full text of DOI:10.3762/bjoc.10.141

Asymmetric Ugi 3CR on isatin-derived ketimine:
synthesis of chiral 3,3-disubstituted
3-aminooxindole derivatives
Giordano Lesma1, Fiorella Meneghetti2, Alessandro Sacchetti3,
Mattia Stucchi1 and Alessandra Silvani*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1383–1389.
1Dipartimento di Chimica, Università degli Studi di Milano, via C.
Golgi, 19, 20133 Milano (Italy), 2Dipartimento di Scienze
Farmaceutiche, Università degli Studi di Milano, via L. Mangiagalli 25,
20133 Milano, Italy and 3Dipartimento di Chimica, Materiali e
Ingegneria Chimica ‘Giulio Natta’, Politecnico di Milano, p.zza
Leonardo da Vinci 32, 20133 Milano, Italy
doi:10.3762/bjoc.10.141
Received: 11 February 2014
Accepted: 19 May 2014
Published: 18 June 2014
Associate Editor: J. A. Porco Jr.
Email:
Alessandra Silvani* - alessandra.silvani@unimi.it
© 2014 Lesma et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
isatin; multicomponent; oxindole; peptidomimetics; Ugi
Abstract
An efficient Ugi three-component reaction of a preformed chiral ketimine derived from isatin with various isonitrile and acid
components has been developed. The reactions proceeded smoothly and in a stereocontrolled manner with regard to the new center
of the Ugi products due to the stereoinduction of the amine chiral residue. A wide variety of novel chiral 3,3-disubstituted
3-aminooxindoles were obtained, a selection of which were subjected to post-Ugi transformations, paving the way to application as
peptidomimetics.
Introduction
Isatin and its derivatives have drawn considerable and renewed tions or spiroannulation [2,3]. Oxindoles represent a common
interest due to their peculiar chemistry and wide range of bioac- structural element in various natural products and biologically
tivities. This led to the development of stereoselective method- active compounds. Diverse oxindole derivatives act as non-
ologies and the synthesis of compounds with various biological peptide scaffolds [4] in peptidomimetic chemistry, either as
properties [1]. In particular, the high reactivity of the C-3 enzyme inhibitors or as ligands of G-protein-coupled receptors
prochiral carbonyl group allows the easy transformation of [5]. In particular, 3,3-disubstituted 3-amino-2-oxindoles are
isatin into 2-oxindole derivatives, mostly by nucleophilic addi- present in several drug candidates. They exhibit various types of
1383

Beilstein J. Org. Chem. 2014, 10, 1383–1389.
bioactivity, such as the potent gastrin/CCK-B receptor antago- (S)-phenyl ethylamine in the presence of MgSO4 [16]. The
nist I [6], the vasopressin VIb receptor antagonist II [7,8], the results of this initial study are reported in Table 1.
CRTH2 (DP2) receptor antagonist spirohydantoin III [9], and
the new antimalarial lead IV [10,11] (Figure 1).
Running the reaction in 2,2,2-trifluoroethanol for 4 days
produced only a complex mixture (Table 1, entry 1), while the
Giving the importance of this structural motif, the development use of dichloromethane as a solvent allowed us to obtain the
of rapid synthetic methods for oxindoles bearing a nitrogen desired Ugi product 4 under various reagents ratio albeit in
atom at the C3-stereogenic center is highly required [12-15]. In moderate yields and low dr (Table 1, entries 2–5). A change of
the course of our studies on new methodologies to access chiral the solvent to methanol resulted in a pronounced improvement
3,3-disubstituted 3-aminooxindoles [16-19], we looked at of the reaction. The reaction of imine 1 with 2 equiv of both
isocyanide-based multicomponent reactions as a possible effi- isocyanide and TFA in methanol (Table 1, entry 7) afforded the
cient tool to quickly prepare oxindole-based peptidomimetic product 4 in 77% yield and 89:11 dr after 48 hours at room
compounds [20-22]. Despite the synthetic efficiency of the Ugi temperature. A variation of the concentration of 1 in the range
reaction and its wide application in combinatorial and medic- from 0.05 M to 0.2 M did not entail any modification, neither in
inal chemistry [23-28], to the best of our knowledge a synthesis terms of yield nor dr. The remaining imine and a small amount
of 3,3-disubstituted 3-aminooxindoles which relies on of isatin could be detected from a 1H NMR analysis of the
isocyanide-based multicomponent reactions has not been unex- crude. The presence of either excess of 3a (Table 1, entry 6) or
plored yet.
additives (Table 1, entry 8 and entry 9) did not affect the results
significantly. Surprisingly, the yield decreased upon adding
Although in this kind of reaction a new stereogenic center is MgBr2, even though this promoter was shown to perform well
created, the stereoselectivity remains a difficult task. Waiting in other reactions on ketimine 1. Evidently, in this case, the
for enantioselective versions of the Ugi reaction [29-31], the effective protonation of the nitrogen would be required in order
diastereoselective approach by using chiral material is a to efficiently carry out the attack of the moderately nucle-
possible solution. In particular, amines have shown to be ophilic isonitrile. An increase of the reaction temperature (Ta-
promising as chiral auxiliaries, even though only a few exam- ble 1, entry 10) facilitated a slightly shorter reaction time. Based
ples with satisfactory selectivity were achieved to date [32-36]. on this result, we decided to investigate the use of microwave
irradiation, with the aim of further increasing the speed of the
Results and Discussion
reaction. Running the reaction in methanol under microwave ir-
Relying on our previous experience, we selected chiral ketimine radiation (300 W) at 65 °C afforded the product after 3 min,
1 as a suitable substrate and started to investigate the Ugi three- with a yield and a dr almost comparable to that obtained under
component reaction (3CR) with tert-butyl isocyanide (2a) and conventional heating conditions (Table 1, entry 11). An increase
trifluoroacetic acid (TFA, 3a) under various reaction conditions. of the temperature to 100 °C (Table 1, entry 12) or carrying out
Compound 1 was easily prepared by treatment of isatin with the reaction in the absence of a solvent (Table 1, entry 13) led to
Figure 1: Biologically active agents containing a 3-substituted-3-aminooxindole core.
1384

Beilstein J. Org. Chem. 2014, 10, 1383–1389.
Table 1: Optimization of reaction conditions for the U-3CR of 1 with tert-butyl isocyanide and TFA.
entry
solvent
time
1 (0.1 M):2a:3a
temp.
yielda
dr (a:b)b
1
2
TFE
4 d
4 d
1:2:2
1:2:2
1:2:3
1:3:3
1:2:3
1:2:3
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
rt
complex mixture
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
neat
rt
29
38
32
50
65
77c
73
53c
67
69
67
37
54
57:43
62:38
60:40
60:40
85:15
89:11c
81:19
90:10c
85:15
87:13
71:29
60:40
89:11
3
4 d
rt
4
4 d
rt
5
6 d
rt
rt
6
4 d
7
48 h
48 h
48 h
36 h
3 min
3 min
3 min
6 h
rt
8d
9e
10
11f
12f
13f
14g
rt
rt
65 °C
65 °C
100 °C
65 °C
rt
MeOH
aIsolated yield (%) after chromatographic purification (sum of the two diastereoisomers a (major) and b (minor)). bdr as determined by 1H NMR
analysis of the crude. cAverage value resulting from two runs. dLiCl (1 equiv) was added. eMgBr2 (1 equiv) was added. fUnder microwave irradiation
(300 W). gUnder sonication.
a reduction of both the yield and the reaction rate. The applica- scheme used (Figure 2). The stereochemical assignment S was
tion of sonication to shorten the reaction times was also useful, attributed on the basis of the known (S)-configuration of the
since compound 4 was obtained after 6 hours with the same dr, phenyl ethylamine residue.
although in a lower yield (Table 1, entry 14).
To exploit the potential of the Ugi reaction to introduce molec-
ular diversity by a one-pot operation, we attempted to realize a
four-component (4CR) version. An equimolar mixture of isatin
and (S)-phenyl ethylamine was reacted with 2a (2 equiv) and 3a
(2 equiv) in methanol in the presence of MgSO4 as a dehy-
drating agent to promote the formation of the ketimine. Unfor-
tunately, after 4 days, the Ugi product was only afforded in very
low yield.
In order to explain the observed diastereoselectivity, the major
diastereoisomer 4a, easily separated from the minor diastereo-
isomers 4b by column chromatography, was crystallized from a
1:1 acetone/water solution.
Figure 2: ORTEP [37] view of one of the two independent molecules
The X-ray diffraction of the obtained crystal established the
absolute configuration S at the tetrasubstituted stereocenter C3,
which corresponds to C7a of the arbitrary atom-numbering
of 4a present in the asymmetric unit, showing the arbitrary atom-
labelling scheme. Atomic displacement parameters for non-H atoms
are at a probability level of 50%.
1385

Beilstein J. Org. Chem. 2014, 10, 1383–1389.
Figure 3: Proposed explanation of the stereochemical outcome of the Ugi 3CR.
This outcome corroborated our previous achievements on add- Aimed to investigate the synthetic scope and limitations of our
ition reactions to ketimine 1. Figure 3 shows a working model approach, we finally choose the reaction conditions reported in
able to explain the observed diastereoselectivity (R1 = t-Bu, R2 Table 1, entry 7 as the most convenient ones. Thus, imine 1 was
= CF3). The stereochemical outcome can be justified by the reacted with different isocyanide (2a–d) and acid (3a–g)
presence of the 1,3-allylic strain, which favors the con- components (Table 2). The dr of the products (4–15) was deter-
formation on the right side of Figure 3. The major diastereoiso- mined by a 1H NMR analysis of the crude mixture. However, in
mer originates from the prevailing delivery of the nucleophile most cases chromatographic purification allowed the separation
from the less hindered re face of the imine double bond.
of the two diastereoisomers, the major a and the minor b.
Table 2: Reaction of imine 1 with different isocyanide and acid components.a
entry
2 (R1)
3 (R2CO2H)
yieldb
dr (a:b)c
compd
1
2
2a (t-Bu)
3a (TFA)
77
89:11
63:37
88:12
70:30
65:35
64:36
69:31
62:38
77:23
96:4
4a,b
5a,b
2a (t-Bu)
3b (HCO2H)
62
3
2b (CH2CO2Me)
2b (CH2CO2Me)
2c (Bn)
3a (TFA)
70
6a,b
4
3b (HCO2H)
66
7a,b
5
3a (TFA)
66
8a,b
6
2c (Bn)
3b (HCO2H)
70
9a,b
7
2d [C(CH3)2CH2(CH3)3]
2a (t-Bu)
3b (HCO2H)
48
10a,b
11a,b
12a,b
13a,b
8
3c (N-Boc-L-Ala-OH)
3d (N-Boc-L-Pro-OH)
3e (N-Boc-D-Pro-OH)
3f (N-Ac-Gly-OH)
3g (mono-ethyl fumarate)
3g (mono-ethyl fumarate)
51
9
2a (t-Bu)
31
10
11
12
13
2a (t-Bu)
18
2a (t-Bu)
complex mixt.
–
2a (t-Bu)
74
47
62:38
59:41
14a,b
15a,b
2c (Bn)
aReaction conditions: 1 (0.1 M), 2 (2 equiv), 3 (2 equiv), MeOH, rt, 48 h. bIsolated yield (%) after chromatographic purification (sum of the two dia-
stereoisomers a (major) and b (minor)). cdr as determined by 1H NMR analysis of the crude.
1386

Beilstein J. Org. Chem. 2014, 10, 1383–1389.
Most of the products were obtained in acceptable yields, while matching/mismatching effect between the chirality of ketimine
the dr proved to be more dependent on varying the different 1 and that of the D-Pro or L-Pro reagent, respectively. Satisfac-
components of the reaction. An exchange of the acid TFA with tory yields were also achieved with mono-ethyl fumarate as the
formic acid (Table 2, entries 2, 4, 6 and 7) resulted in a decrease acid component (Table 2, entry 12 and entry 13). The obtained
of the dr. This may be caused by a minor stereofacial differenti- products 14 and 15 can be further elaborated to yield more com-
ation of the intermediate carboxylate iminium ion during the plex structures (vide infra).
nucleophilic addition of the isocyanide. Isocyanide 2b (Table 2,
entry 3 and entry 4), formally derived from glycine, afforded Next, selected post-Ugi transformations were investigated in
satisfactory results, thus letting us foresee the application of this order to better evaluate the synthetic versatility of the Ugi
approach to isocyanides prepared from natural amino acids. If adducts. Compound 10a was easily converted to the primary
compared with tert-butylisocyanide (2a), benzylisocyanide (2c) amide 16 and then to the known amino amide 17 [16], thus
(Table 2, entries 5, 6 and 13) seems to be less effective in terms establishing the possible subsequent functionalization of both
of an acceptable dr, while the yields were still good. Of interest the primary amine and the isonitrile-derived primary carbox-
was also the product 10, derived from a reaction of isocyanide amide functional groups (Scheme 1). Also, this chemical corre-
2d (Table 2, entry 7), since it can be easily converted into the lation of the major diastereoisomer 10a allowed us to further
correspondent primary amide derivative (vide infra).
confirm the prevailing S-configuration at the tetrasubstituted
stereocenter C3 of the Ugi products.
To explore potential applications of the Ugi reaction products in
the field of peptidomimetics, we also tested the reaction of Compound 15a was submitted to a post-Ugi cyclization, namely
ketimine 1 in the presence of different N-Boc-protected amino an intramolecular aza-Michael [24] reaction, which afforded
acids as acid components. The use of L-amino acids 3c and 3d compound 18 bearing the privileged spiro-diketopiperazine
(Table 2, entry 8 and entry 9) afforded the desired products with scaffold (Scheme 2). Spiro-diketopiperazines are present in
moderate yields. The best result in terms of de (54%) was many natural products [38-40] and have recently received much
achieved with the more hindered proline. The reaction of the attention as pharmacologically active peptidomimetics [41-43].
glycine derivative 3f produced a complex inseparable mixture
of products (Table 2, entry 11). When N-Boc-D-Pro was used as The reaction proceeded smoothly in methanol under reflux in
the acid component (Table 2, entry 10) a high 96:4 dr was the presence of excess TEA to give the product 18 by a regiose-
measured despite a low yield (18%). This outcome suggests a lective six-exo-trig cyclization.
Scheme 1: Post-Ugi transformation on compound 10a.
Scheme 2: Post-Ugi cyclization on compound 15a.
1387

Beilstein J. Org. Chem. 2014, 10, 1383–1389.
9. Crosignani, S.; Jorand-Lebrun, C.; Page, P.; Campbell, G.;
Conclusion
Colovray, V.; Missotten, M.; Humbert, Y.; Cleva, C.; Arrighi, J.-F.;
Gaudet, M.; Johnson, Z.; Ferro, P.; Chollet, A. ACS Med. Chem. Lett.
2011, 2, 644–649. doi:10.1021/ml2001196
We have developed a novel approach to the synthesis of opti-
cally active 3,3-disubstituted 3-aminooxindoles by means of a
three-component Ugi reaction. A number of compounds could
be smoothly obtained in satisfactory yields (up to 77%) with
various levels of diastereoselectivity (up to 96:4 dr). The syn-
thetic versatility of the Ugi adducts was demonstrated by appli-
cations of post-Ugi transformations. Importantly, this repre-
sents the first example where an isocyanide-based multicompo-
nent reaction has been applied to an isatin-derived ketimine,
thus highlighting the promising reactivity of this derivative as a
precursor of chiral 3,3-disubstituted 3-aminooxindoles.
10.Yeung, B. K. S.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.;
Ang, S. H.; Leong, S. Y.; Tan, J.; Wong, J.; Keller-Maerki, S.;
Fischli, C.; Goh, A.; Schmitt, E. K.; Krastel, P.; Francotte, E.; Kuhen, K.;
Plouffe, D.; Henson, K.; Wagner, T.; Winzeler, E. A.; Petersen, F.;
Brun, R.; Dartois, V.; Diagana, T. T.; Keller, T. H. J. Med. Chem. 2010,
53, 5155–5164. doi:10.1021/jm100410f
11.Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.; Zhou, B.;
Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.;
Cohen, S. B.; Spencer, K. R.; Gonzalez-Paez, G. E.;
Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.;
Schmitt, E. K.; Beck, H.-P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.;
Keller, T. H.; Fidock, D. A.; Winzeler, E. A.; Diagana, T. T. Science
2010, 329, 1175–1180. doi:10.1126/science.1193225
12.Zhang, H.; Zhang, S.-J.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C.
Beilstein J. Org. Chem. 2012, 8, 1241–1245. doi:10.3762/bjoc.8.139
13.Yan, W.; Wang, D.; Feng, J.; Li, P.; Zhao, D.; Wang, R. Org. Lett. 2012,
14, 2512–2513. doi:10.1021/ol3007953
Supporting Information
Supporting information features the experimental section,
crystallographic data, general methods and copies of NMR
spectra (1H and 13C) for all new compounds.
14.Zhang, T.; Cheng, L.; Liu, L.; Wang, D.; Chen, Y.-J.
Tetrahedron: Asymmetry 2010, 21, 2800–2806.
Supporting Information File 1
doi:10.1016/j.tetasy.2010.11.002
Experimental section and crystallographic data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-141-S1.pdf]
15.Qian, Z.-Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.; Ding, M.; Zhao, X.-L.;
Zhou, J. Chem. Commun. 2009, 6753–6755. doi:10.1039/b915257a
16.Sacchetti, A.; Silvani, A.; Gatti, F. G.; Lesma, G.; Pilati, T.; Trucchi, B.
Org. Biomol. Chem. 2011, 9, 5515–5522. doi:10.1039/c1ob05532a
17.Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A.
J. Org. Chem. 2009, 74, 4537–4541. doi:10.1021/jo900623c
18.Lesma, G.; Landoni, N.; Sacchetti, A.; Silvani, A. Tetrahedron 2010,
66, 4474–4478. doi:10.1016/j.tet.2010.04.077
Supporting Information File 2
General methods and copies of NMR spectra for all new
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-141-S2.pdf]
19.Baroni, M.; Lesma, G.; Puleio, L.; Sacchetti, A.; Silvani, A.; Zanchet, M.
Synthesis 2010, 4075–4081. doi:10.1055/s-0030-1258289
20.van Berkel, S. S.; Bögels, B. G. M.; Wijdeven, M. A.; Westermann, B.;
Rutjes, F. P. J. T. Eur. J. Org. Chem. 2012, 3543–3559.
doi:10.1002/ejoc.201200030
References
1. Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104–6155.
21.Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083–3135.
doi:10.1021/cr100233r
doi:10.1021/cr300135y
22.Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
doi:10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO
;2-U
2. Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.; Franz, A. K.
Angew. Chem., Int. Ed. 2010, 49, 744–747.
doi:10.1002/anie.200904393
23.Zou, Y.; Hu, Y.; Liu, H.; Shi, D. ACS Comb. Sci. 2012, 14, 38–43.
doi:10.1021/co200128k
3. Thakur, P. B.; Sirisha, K.; Sarma, A. V. S.; Meshram, H. M.
Tetrahedron Lett. 2014, 55, 2459–2462.
24.Santra, S.; Andreana, P. R. J. Org. Chem. 2011, 76, 2261–2264.
doi:10.1021/jo102305q
doi:10.1016/j.tetlet.2014.03.008
4. Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.;
Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.;
Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127,
10130–10131. doi:10.1021/ja051147z
25.Nunez-Villanueva, D.; Angeles Bonache, M.; Infantes, L.;
Garcia-Lopez, M. T.; Martin-Martinez, M.; Gonzalez-Muniz, R.
J. Org. Chem. 2011, 76, 6592–6603. doi:10.1021/jo200894d
26.Zhu, D.; Chen, R.; Liang, H.; Li, S.; Pan, L.; Chen, X. Synlett 2010,
897–900. doi:10.1055/s-0029-1219533
5. Blakeney, J. S.; Reid, R. C.; Le, G. T.; Fairlie, D. P. Chem. Rev. 2007,
107, 2960–3041. doi:10.1021/cr050984g
27.Gulevich, A. V.; Shevchenko, N. E.; Balenkova, E. S.;
Röschenthaler, G.-V.; Nenajdenko, V. G. Tetrahedron 2008, 64,
11706–11712. doi:10.1016/j.tet.2008.10.004
6. Sato, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y. J. Org. Chem. 2009, 74,
7522–7524. doi:10.1021/jo901352u
7. Decaux, G.; Soupart, A.; Vassart, G. Lancet 2008, 371, 1624–1632.
doi:10.1016/S0140-6736(08)60695-9
28.Nenajdenko, V. G.; Gulevich, A. V.; Balenkova, E. S. Tetrahedron
2006, 62, 5922–5930. doi:10.1016/j.tet.2006.04.021
8. Shimazaki, T.; Iijima, M.; Chaki, S. Eur. J. Pharmacol. 2006, 543,
63–67. doi:10.1016/j.ejphar.2006.06.032
29.Hashimoto, T.; Kimura, H.; Kawamata, Y.; Maruoka, K.
Angew. Chem., Int. Ed. 2012, 51, 7279–7281.
doi:10.1002/anie.201201905
1388

Beilstein J. Org. Chem. 2014, 10, 1383–1389.
30.Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J.
Angew. Chem., Int. Ed. 2009, 48, 6717–6721.
doi:10.1002/anie.200902385
31.Ram, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
doi:10.1002/anie.200460548
32.Zou, D.; Xia, L.; Pan, L.; Li, S.; Chen, R.; Mou, Y.; Chen, X.
J. Org. Chem. 2012, 77, 1386–1395. doi:10.1021/jo2021967
33.Basso, A.; Banfi, L.; Riva, R.; Guanti, G. J. Org. Chem. 2005, 70,
575–579. doi:10.1021/jo048389m
34.Dyker, G.; Breitenstein, K.; Henkel, G. Tetrahedron: Asymmetry 2002,
13, 1929–1936. doi:10.1016/S0957-4166(02)00530-X
35.Oertel, K.; Zech, G.; Kunz, H. Angew. Chem., Int. Ed. 2000, 39,
1431–1433.
doi:10.1002/(SICI)1521-3773(20000417)39:8<1431::AID-ANIE1431>3.
0.CO;2-N
36.Ross, G. F.; Herdtweck, E.; Ugi, I. Tetrahedron 2002, 58, 6127–6133.
doi:10.1016/S0040-4020(02)00484-2
37.ORTEP-3 for Windows; Farrugia, L. J.: University of Glasgow,
Scotland, 1997.
38.Afiyatullov, S. S.; Zhuravleva, O. I.; Chaikina, E. L.; Anisimov, M. M.
Chem. Nat. Compd. 2012, 48, 95–98. doi:10.1007/s10600-012-0166-8
39.Gao, H.; Liu, W.; Zhu, T.; Mo, X.; Mándi, A.; Kurtán, T.; Li, J.; Ai, J.;
Gu, Q.; Li, D. Org. Biomol. Chem. 2012, 10, 9501–9506.
doi:10.1039/c2ob26757h
40.Wang, F.; Fang, Y.; Zhu, T.; Zhang, M.; Lin, A.; Gu, Q.; Zhu, W.
Tetrahedron 2008, 64, 7986–7991. doi:10.1016/j.tet.2008.06.013
41.Fytas, C.; Zoidis, G.; Tzoutzas, N.; Taylor, M. C.; Fytas, G.; Kelly, J. M.
J. Med. Chem. 2011, 54, 5250–5254. doi:10.1021/jm200217m
42.Watts, K. R.; Ratnam, J.; Ang, K.-H.; Tenney, K.; Compton, J. E.;
McKerrow, J.; Crews, P. Bioorg. Med. Chem. 2010, 18, 2566–2574.
doi:10.1016/j.bmc.2010.02.034
43.Gomez-Monterrey, I.; Campiglia, P.; Carotenuto, A.; Stiuso, P.;
Bertamino, A.; Sala, M.; Aquino, C.; Grieco, P.; Morello, S.; Pinto, A.;
Ianelli, P.; Novellino, E. J. Med. Chem. 2008, 51, 2924–2932.
doi:10.1021/jm7013056
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.10.141
1389