Novel tetracyclic structures from the synthesis of thiolactone-isatin hybrids

Article abstract of DOI:10.3762/bjoc.6.78

A simple and straightforward synthetic approach to potential anti-infective thiolactone-isatin hybrids led to the discovery of novel tetracyclic compounds which bear a macrocylic motif containing an unusual bridged amide bond.

Full text of DOI:10.3762/bjoc.6.78

Novel tetracyclic structures from the synthesis
of thiolactone-isatin hybrids
Renate Hazel Hans1, Hong Su2 and Kelly Chibale*2,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, No. 78. doi:10.3762/bjoc.6.78
1Department of Chemistry and Biochemistry, University of Namibia,
Windhoek, Namibia, 2Department of Chemistry, University of Cape
Town, Rondebosch 7701, South Africa and 3Institute of Infectious
Disease and Molecular Medicine, University of Cape Town,
Rondebosch 7701, South Africa
Received: 06 April 2010
Accepted: 02 July 2010
Published: 19 July 2010
Associate Editor: J. Aubé
Email:
Renate Hazel Hans - rhans@unam.na; Hong Su -
Hong.Su@uct.ac.za; Kelly Chibale* - Kelly.Chibale@uct.ac.za
© 2010 Hans et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
bridged amides; hybrids; isatin; tetracycles; thiolactomycin;
thiolactone
Abstract
A simple and straightforward synthetic approach to potential anti-infective thiolactone-isatin hybrids led to the discovery of novel
tetracyclic compounds which bear a macrocylic motif containing an unusual bridged amide bond.
Introduction
Hybrid structures have been found in nature and their synthesis (Figure 2). The former is a thiolactone antibiotic known for its
has become a useful drug discovery strategy for new anti- remarkable selectivity against the condensing enzymes of type
infective agents [1]. Improved pharmacokinetics, therapeutic II fatty acid synthesis which operate in a number of pathogenic
and toxicity profiles have been reported for natural and natural organisms [6-8]. Synthetic methodologies for 1 and a series of
product-like hybrid constructs such as the artemisinin-quinine racemic and enantiopure thiolactomycin-based analogues have
[2], nostocarboline-ciprofloxacin [3] and isatin-lamuvidine [4] been reported [9-16]. Of particular interest to this project are the
(Figure 1). Interest in exploring this approach also derives from structure-activity relationships delineated from O-4 modified
the pharmacophore-rich compound library it offers. This analogues which reportedly display enhanced antimalarial and
precludes the need for large libraries and concomitantly promising antitubercular activity [15,16]. The other component
shortens the time needed to identify potential leads [5]. The of the envisaged hybrid, isatin (2) is an intriguing and syntheti-
focus of this study is on the synthesis of hybrids with monomers cally versatile scaffold. Moreover, its presence in a number of
derived from natural products thiolactomycin (1) and isatin (2) proprietary molecules and synthetic drugs is noteworthy [17].
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Beilstein J. Org. Chem. 2010, 6, No. 78.
Figure 1: Natural product and natural product-like hybrids.
Figure 2, are modeled on 1 but devoid of the hydrophobic side
chain represented by the isoprenoid moiety at C-5.
Results and Discussion
The key intermediate, thiolactone 5 (Scheme 1), was syn-
thesized using a four-step reaction developed by Wang and
Salvino [20]. The N-alkylated 5-substituted isatin/isatin inter-
mediates 6 were obtained in a one-step reaction in good to
excellent yields by the reported procedure [21]. Thus, with 5
and 6 in hand, synthesis of the desired hybrids 3 was
subsequently undertaken.
For our synthesis we explored the use of bases of varying
strengths, starting with NaH. Although NaH afforded the
desired hybrids 3 and traces of the tetracycle 4, the obtained
yields were very poor. Next, the use of the weaker base,
K2CO3, was attempted. Refluxing 5 and 6 in acetone in the
presence of 4 equiv of K2CO3 did not produce 3. Instead, an
unidentified product was isolated from the product mixture,
Figure 2: Structures of thiolactomycin (1), isatin (2), the desired hybrid
3 and tetracycle 4.
Alkylation of 5, as shown in Scheme 1, is a common route whose 1H and 13C NMR suggested that it is possibly an aldol
towards diverse thiolactomycin analogues. A literature review product. All efforts were then directed towards a method which
revealed that γ-thiolactones are prone to undergo ring-opening utilizes the potassium salt of 5. The salt was obtained in quanti-
polymerization under the basic conditions required to effect tative yield from the reaction of 5 with an equimolar amount of
alkylation [18] and this has been cited as a likely contributor to aqueous potassium hydroxide in MeOH at room temperature.
the low yields reported in thiolactomycin analogue synthesis. Although no reaction between the potassium salt of 5 and 1.5
For example, Takabe and co-workers [19] attempted O-alkyl- equiv of 6 in anhydrous DMF was observed at room tempera-
ation of 5 using NaH and CH3I at room temperature. Although ture, when the temperature was increased to 60 °C, TLC
the reaction proceeded regioselectively, only 9% of the desired confirmed the consumption of the starting material after stir-
C-4 O-alkylated product was obtained after a reaction time of ring at this temperature for 48 h (see Supporting Information
144 h.
File 1 for full experimental data). The difficulties in purifica-
tion of the crude reaction mixtures may have contributed unfa-
We herein report the synthesis of a novel series of thiolactone- vourably towards the yields obtained for hybrids 3 (Table 1).
isatin hybrids. The envisaged target compounds 3, as shown in These yields, although disappointingly low, are in agreement
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Beilstein J. Org. Chem. 2010, 6, No. 78.
Scheme 1: Reagents and conditions: (a) KOH, MeOH, 25 °C, 95–100% (b) 6, DMF, 60 °C, 9–36%.
with published reports on thiolactomycin analogues synthesis bridged amide bond. Essentially, the amide functionality adopts
[15,18,20,22,23]. Of particular interest, however, was the a planar conformation in normal amides with stability being
formation of by-products (tetracycles) observed in the reaction conferred by the delocalization of the nitrogen lone pair into the
of 5 with the N-alkylated isatin intermediates 6 bearing the C=O bond [25]. The amides in bicyclic bridgehead lactams are
n = 3–5 linkers (Table 1). The tetracycle 4 had a slightly lower distorted from planarity and this severely affects their reactivity
Rf than the desired hybrid 3 and was colorless or light yellow and stability [26-31]. Furthermore, the use of bridged amides as
compared to the orange-colored hybrid 3. We initially suspected scaffolds in medicinal chemistry has been explored [32-37].
it to be a regioisomer of 3, that is, the C-3-alkylated or C-2 Indeed, the enhanced electrophilicity or acylating ability of
O-alkylated product consistent with the resonance contributors β-lactams is partially attributed to the distortion from planarity
of the anion of 5. Lack of regioselectivity in the alkylation reac- of the amide bond [28,38]. Also present in the structure of the
tions of thiolactomycin and its analogues is a common synthetic tetracycles 4 is the 3-substituted 3-hydroxyindolin-2-one moiety
problem [22-24].
which features prominently in a number of biologically active
natural products [39-41].
Table 1: Synthesis of thiolactone-isatin hybrids 3 and tetracycles 4.
The mechanism proposed for the formation of 4 as outlined in
Scheme 2, involves an in situ deprotonation at C-5 of the
thiolactone ring system by the relatively basic potassium salt of
5. This is followed by the regioselective, intramolecular addi-
tion of the nucleophile to the ketonic carbonyl facilitated by (i)
the strong electrophilicity of the α-keto amide group of the
isatin scaffold, (ii) the flexible alkane tether (n = 3–5) which
allows for the proper alignment of the orbitals of the reacting
groups and (iii) the rigidity [42] of the isatin and thiolactone
ring systems. In the absence of supporting information we spec-
ulate that the observed regioselectivity may be due to the ther-
modynamically more stable product 4α arising from reaction at
the α-position due to a more extended conjugated system
relative to the product 4γ (Scheme 2) that would result from
reaction at the γ-position. Scheme 2 also indicates that only one
diastereomer of tetracycle 4 is formed as indicated by X-ray
Compd
R
n
(3:4)a
Yield (%)
3a
Br
Cl
F
1
1
1
1
1
1
2
3
4
5
100:0
100:0
100:0
100:0
100:0
100:0
100:0
22:78
84:16
71:29
9
3b
13
3c
14
3d
I
10
3e
CH3
H
26
3f
36
3g
H
18
3h, 4a
3i, 4b
3j, 4c
H
45b
31b
21b
H
H
aDetermined from isolated yields;
bCombined isolated yields of 3 and 4.
Interest in the tetracycles 4 was further sparked by the ease and crystallographic data. The absence of the other diastereomer
simplicity of their preparation, and the novelty of their architec- may be due to destabilizing steric interactions with the carbonyl
ture as revealed by single X-ray crystal structure analysis. group of the amide and the oxygen of the vinyl ether. Similar
Attractive structural features of 4 include two vicinal quaternary cyclizations leading to bridged lactams have been reported
stereocenters and a complex, bicyclic ring system containing a [43,44].
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Beilstein J. Org. Chem. 2010, 6, No. 78.
Scheme 2: Proposed mechanism for the formation of tetracycles 4.
Synthesis of tetracycles 4 was therefore expanded to obtain a
small library for biological testing. Although a model study
revealed that prolonged reaction times (120 h) resulted in an
increase in tetracycle 4 formation, we were unable to signifi-
cantly increase the yields of the bridged products despite much
longer reaction times (Table 2).
Table 2: Synthesis of thiolactone-isatin hybrids 3 and tetracycles 4.
Compd
R
n
(3:4)a
Yield (%)c
4d
4e
4f
Br
I
3
3
3
3
3
4
4
4
5
5
5
5
11:89
10:90
19:81
15:85
30:70
63:37b
67:33b
60:40b
80:20
69:31
73:27
70:30
14
15
10
14
8
F
4g
4h
4i
Cl
NO2
Cl
Br
I
It is noteworthy that 4 did not form with the n = 1–2 linked
hybrids 3a–g (Table 1). This is most likely due to strain in the
transition state. Also notable is the decrease in yield with
increasing linker length as evidenced by the differences
observed for the n = 3–5 linked tetracycles/5′-substituted tetra-
cycles (Table 1 and Table 2). This drawback can most likely be
ascribed to entropy factors and stereoelectronic effects [45-48].
5
4j
7
4k
4l
4
Cl
F
6
4m
4n
4o
7
Br
I
6
7
aDetermined from isolated yields;
bRatio determined from crude reaction mixture using 1H NMR;
cIsolated yields of 4.
The structures of the tetracycles 4 were unambiguously
assigned by single crystal X-ray crystallographic analysis.
Single crystals for 4a–c were obtained from MeOH at room
temperature and subjected to crystallographic analysis (see
Supporting Information File 2 for crystallographic data). revealed the presence of two crystallographic independent
Figure 3 shows the molecular structure and atom labeling for molecules in the unit cell differentiated with the labels A and B
4a. The crystals are triclinic with space group P−1 and contains in the atom numbering scheme (Figure 3b). Because of similar
four molecules per unit cell. The crystal structure furthermore trends observed in the bond angles and lengths, we have limited
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Beilstein J. Org. Chem. 2010, 6, No. 78.
Figure 3: (a) Molecular structure of the tetracycle 4a. (b) Structure of the dimer of 4a showing the atomic numbering scheme. Displacement ellipsoids
are drawn at 40% probability level for non-hydrogen atoms. All hydrogen atoms are omitted except the hydroxyl hydrogens.
our discussion to molecule A. In this structure (Figure 3b) the Figure 4 shows the molecular structure atom labeling for 4b–c.
indole ring is almost planar with C7A and C8A showing devi- Both compounds crystallized in the centrosymmetric mono-
ations of −0.0918(10) and +0.0902(11), respectively from the clinic space group P21/n with 4 molecules in the unit cell.
least square plane. The syn relationship between the methyl at Similar to 4a, the indole moiety is nearly planar with the
C5A and the hydroxyl group at C7A was evident from the maximum deviation from the least-squares plane for all the nine
torsion angle of −65.81° (14) for O4A-C7A-C5A-C6A. Also atoms in the ring at +0.045(1) and +0.0412(15) for C8, in 4b
noted are the dihedral angles 106.80° (11) and 113.29° (11) for and 4c, respectively.
O4A-C7A-C5A and C6A-C5A-C7A, respectively, which shows
a distortion from the ideal value (109.47°) for a tetrahedral sp3 In recognition of the potential contribution of distorted bridged
carbon. Speculatively, this distortion coupled with the elon- amides to biological activity as alluded to earlier, the calcula-
gated C7A-C5A [1.5783(19) Å] bond indicates a repulsive tion of the Dunitz–Winkler distortion parameters (τ, χC, χN)
steric interaction between the relatively bulky hydroxyl group at [25,49,50] for the tetracycles 4a–c was undertaken (Table 3).
C7A and the adjacent methyl group at C5A.
Compared to planar formamide whose distortion parameters are
Figure 4: Molecular structure of (a) 4b and (b) 4c, with ellipsoidal model of probability level = 35%.
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Beilstein J. Org. Chem. 2010, 6, No. 78.
all 0° [53] compound 4a with a twist angle τ of 10.4° (Table 3),
show a slight distortion from planarity, whereas the amide dis-
tortion parameters for 4b–c indicate that the amide bond is close
to being planar. It is also known that twisted amides contain
pyramidal nitrogen atoms, which makes it a potential site for
reaction with protons and electrophiles [25,31]. However, for
4a–c the carbon and nitrogen pyramidality (χC and χN) and the
Supporting Information File 2
X-ray crystallography data for tetracycles 4a–c
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-78-S2.cif]
N-C(=O) and C=O bond lengths (Table 3) all indicate that the Acknowledgements
bridge amide bond is essentially relaxed.
We are grateful to the University of Cape Town, the African-
American Institute (RHH), the South African Research Chairs
Initiative of the Department of Science and Technology and the
National Research Foundation (KC) for financial support.
Table 3: Calculated Dunitz-Winkler distortion parameters and amide
bond lengths of planar formamide and 4a–c.
Formamide
(planar)b
Parametera
4ac
4b
4c
References
1. Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew. Chem., Int. Ed.
2003, 42, 3996–4028. doi:10.1002/anie.200200553
2. Walsh, J. J.; Coughlan, D.; Heneghan, N.; Gaynor, C.; Bell, A.
Bioorg. Med. Chem. Lett. 2007, 17, 3599–3602.
τ/°
0.0
0.0
0.0
10.4
0.7
5.3
3.0
1.1
0.6
4.5
8.9
χC/°
χN/°
5.1
doi:10.1016/j.bmcl.2007.04.054
Bond
length/Å
C=O
3. Gademann, K. Chimia 2006, 60, 841–845.
1.193
1.349
1.227(17) 1.223(16) 1.223(2)
1.357(18) 1.355(18) 1.361(3)
doi:10.2533/chimia.2006.841
4. Sriram, D.; Yogeeswari, P.; Gopal, G. Eur. J. Med. Chem. 2005, 40,
1373–1376. doi:10.1016/j.ejmech.2005.07.006
Bond
length/Å
N-C(=O)
5. Biot, C.; Chibale, K. Infect. Disord.: Drug Targets 2006, 6, 173–204.
doi:10.2174/187152606784112155
a[25,49,50];
b[51-53];
cFor molecule A.
6. Waller, R. F.; Keeling, P. J.; Donald, R. G. K.; Striepen, B.;
Handman, E.; Lang-Unnasch, N.; Cowman, A. F.; Besra, G. S.;
Roos, D. S.; McFadden, G. I. Proc. Natl. Acad. Sci. U. S. A. 1998, 95,
12352–12357. doi:10.1073/pnas.95.21.12352
7. Kremer, L.; Douglas, J. D.; Baulard, A. R.; Morehouse, C.; Guy, M. R.;
Alland, D.; Dover, L. G.; Lakey, J. H.; Jacobs, W. R., Jr..;
Brennan, P. J.; Minnikin, D. E.; Besra, G. S. J. Biol. Chem. 2000, 275,
16857–16864. doi:10.1073/pnas.95.21.12352
In summary we have described the straightforward synthesis of
novel compounds 3 and 4. The latter bears quaternary stereo-
genic centers and a macrocylic motif containing an unusual
bridged amide bond. The poor yields obtained are a concern and
require further optimization of reaction conditions. A study of
the biological activity of the novel structures (3 and 4) is
currently underway.
8. Oishi, H.; Noto, T.; Sasaki, H.; Suzuki, K.; Hayashi, T.; Okazaki, H.;
Ando, K.; Sawada, M. J. Antibiot. 1982, 35, 391–395.
9. Ohata, K.; Terashima, S. Tetrahedron Lett. 2006, 47, 2787–2791.
doi:10.1016/j.tetlet.2006.02.058
10.McFadden, J. M.; Frehywot, G. L.; Townsend, C. A. Org. Lett. 2002, 4,
3859–3862. doi:10.1021/ol026685k
11.Toyama, K.-i.; Tauchi, T.; Mase, N.; Yoda, H.; Takabe, K.
Tetrahedron Lett. 2006, 47, 7163–7166.
Supporting Information
doi:10.1016/j.tetlet.2006.07.152
Supporting information contains full experimental and
spectral data for thiolactone 5, the desired hybrids 3,
tetracycles 4 and the general procedure for the synthesis of
the N-alkylated 5-substituted isatin/isatin intermediates 6.
The 1H NMR and 13C NMR spectra for compounds 3 and 4
are also included.
12.Dormann, K. L.; Brückner, R. Angew. Chem., Int. Ed. 2007, 46,
1160–1163. doi:10.1002/anie.200603562
13.Kim, P.; Zhang, Y.-M.; Shenoy, G.; Nguyen, Q.-A.; Boshoff, H. I.;
Manjunatha, U. H.; Goodwin, M. B.; Lonsdale, J.; Price, A. C.;
Miller, D. J.; Duncan, K.; White, S. W.; Rock, C. O.; Barry, C. E., III;
Dowd, C. S. J. Med. Chem. 2006, 49, 159–171.
doi:10.1021/jm050825p
14.McFadden, J. M.; Medghalchi, S. M.; Thupari, J. N.; Pinn, M. L.;
Vadlamudi, A.; Miller, K. I.; Kuhajda, F. P.; Townsend, C. A.
J. Med. Chem. 2005, 48, 946–961. doi:10.1021/jm049389h
15.Jones, S. M.; Urch, J. E.; Kaiser, M.; Brun, R.; Harwood, J. L.;
Berry, C.; Gilbert, I. H. J. Med. Chem. 2005, 48, 5932–5941.
doi:10.1021/jm049067d
Supporting Information File 1
Experimental procedures and spectral data for compounds
3–6
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-78-S1.pdf]
Page 6 of 7
(page number not for citation purposes)

Beilstein J. Org. Chem. 2010, 6, No. 78.
16.Kamal, A.; Shaik, A. A.; Sinha, R.; Yadav, J. S.; Arora, S. K.
Bioorg. Med. Chem. Lett. 2005, 15, 1927–1929.
41.Da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001,
12, 273–286.
doi:10.1016/j.bmcl.2005.01.084
42.Illuminati, G.; Mandolini, L.; Masci, B. J. Am. Chem. Soc. 1974, 96,
1422–1427. doi:10.1021/ja00812a027
17.Lee, D.; Long, S. A.; Murray, J. H.; Adams, J. L.; Nuttall, M. E.;
Nadeau, D. P.; Kikly, K.; Winkler, J. D.; Sung, C.-M.; Ryan, M. D.;
Keller, P. M.; Levy, M. A.; DeWolf, W. E., Jr.. J. Med. Chem. 2001, 44,
2015–2026. doi:10.1021/jm0100537
43.Arata, Y.; Tanaka, K. I.; Yoshifuji, S.; Kanatoma, S. Chem. Pharm. Bull.
1979, 27, 981–983.
44.Waly, M. A.; Kodier, M. N.; Hossini, M. S.
18.Lin’kova, M. G.; Kuleshova, N. D.; Knunyants, I. L. Russ. Chem. Rev.
1964, 33, 493–507. doi:10.1070/RC1964v033n10ABEH001473
19.Toyama, K.; Tauchi, T.; Mase, N.; Yoda, H.; Takabe, K.
Tetrahedron Lett. 2006, 47, 7163–7166.
Chin. Pharm. J. (Taipei, Taiwan) 1994, 46, 135–144.
45.Knops, P.; Sendhoff, N.; Mekelburger, H.-B.; Vögtle, F.
Top. Curr. Chem. 1991, 161, 1–36.
46.Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95–102.
doi:10.1021/ar00064a001
doi:10.1016/j.tetlet.2006.07.152
20.Wang, C.-L. J.; Salvino, J. M. Tetrahedron Lett. 1984, 25, 5246.
21.Chu, W.; Rothfuss, J.; Chu, Y.; Zhou, D.; Mach, R. H. J. Med. Chem.
2009, 52, 2188–2191. doi:10.1021/jm900135r
47.Smith, M. B.; March, J. Advanced Organic Chemistry: Reactions,
Mechanisms and Structure, 6th ed.; John Wiley & Sons, Inc.: New
York, 2007.
22.Douglas, J. D.; Senior, S. J.; Morehouse, C.; Phetsukuri, B.;
Campbell, I. B.; Besra, G. S.; Minnikin, D. E.
48.Ruzicka, L. Chem. Ind. (London) 1935, 54, 2–8.
doi:10.1002/jctb.5000540102
Microbiology (Reading, U. K.) 2002, 148, 3101–3109.
23.Sakya, S. M.; Suarez-Contreras, M.; Dirlam, J. P.; O’Connell, T. N.;
Hayashi, S. F.; Santoro, S. L.; Kamicker, B. J.; George, D. M.;
Ziegler, C. B. Bioorg. Med. Chem. Lett. 2001, 11, 2751–2754.
doi:10.1016/S0960-894X(01)00567-4
49.Winkler, F. K.; Dunitz, J. D. J. Mol. Biol. 1971, 59, 169–182.
doi:10.1016/0022-2836(71)90419-0
50.Gillson, A.-M. E.; Glover, S. A.; Tucker, D. J.; Turner, P.
Org. Biomol. Chem. 2003, 1, 3430–3437. doi:10.1039/b306098p
51.Greenberg, A.; Moore, D. T.; DuBois, T. D. J. Am. Chem. Soc. 1996,
118, 8658–8668. doi:10.1021/ja960294h
24.McFadden, J. M.; Medghalchi, S. M.; Thupari, J. N.; Pinn, M. L.;
Vadlamudi, A.; Miller, K. I.; Kuhajda, F. P.; Townsend, C. A.
J. Med. Chem. 2005, 48, 946–961. doi:10.1021/jm049389h
25.Greenberg, A.; Brenemann, C. M.; Liebmann, J. F., Eds. The Amide
Linkage: Structural Significance in Chemistry, Biochemistry and
Materials Science; Wiley: New York, 2000.
52.Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc. 1993, 115,
6951–6957. doi:10.1021/ja00068a064
53.Wiberg, K. B.; Laidig, K. E. J. Am. Chem. Soc. 1987, 109, 5935–5943.
doi:10.1021/ja00254a006
26.Clayden, J.; Moran, W. J. Angew. Chem., Int. Ed. 2006, 45,
7118–7120. doi:10.1002/anie.200603016
License and Terms
27.Kirby, A. J.; Komarov, I. V.; Feeder, N. J. Chem. Soc., Perkin Trans. 2
2001, 522–529. doi:10.1039/b008270h
This is an Open Access article under the terms of the
Creative Commons Attribution License
28.Tani, K.; Stoltz, B. M. Nature 2006, 441, 731–734.
doi:10.1038/nature04842
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
29.Lei, Y.; Wrobleski, A. D.; Golden, J. E.; Powell, D. R.; Aubé, J.
J. Am. Chem. Soc. 2005, 127, 4552–4553. doi:10.1021/ja050214m
30.Szostak, M.; Aubé, J. Org. Lett. 2009, 11, 3878–3881.
doi:10.1021/ol901449y
31.Szostak, M.; Yao, L.; Aubé, J. J. Org. Chem. 2009, 74, 1869–1875.
doi:10.1021/jo802192v
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
32.Smissman, E. E.; Wirth, P. J.; Glynn, D. R. J. Org. Chem. 1975, 40,
281–283. doi:10.1021/jo00891a003
(http://www.beilstein-journals.org/bjoc)
33.Brouilliette, W. J.; Einspahr, H. M. J. Org. Chem. 1984, 49, 5113–5116.
doi:10.1021/jo00200a020
The definitive version of this article is the electronic one
which can be found at:
34.Brouilliete, W. J.; Jestkov, V. P.; Brown, M. L.; Akhtar, M. S.;
DeLorey, T. M.; Brown, G. B. J. Med. Chem. 1994, 37, 3289–3293.
doi:10.1021/jm00046a013
doi:10.3762/bjoc.6.78
35.Williams, R. M.; Lee, B. H.; Miller, M. M.; Anderson, O. P.
J. Am. Chem. Soc. 1989, 111, 1073–1081. doi:10.1021/ja00185a043
36.Aszodi, J.; Rowlands, D. A.; Mauvais, P.; Collette, P.; Bonnefoy, A.;
Lampilas, M. Bioorg. Med. Chem. Lett. 2004, 14, 2489–2492.
37.Urbach, A.; Dive, G.; Marchand-Brynaert, J. Eur. J. Org. Chem. 2009,
1757–1770. doi:10.1002/ejoc.200801193
38.Page, M. I. In The Chemistry of b-Lactams; Page, M. I., Ed.; Blackie:
Glasgow, 1992; pp 79–100.
39.Guo, X.; Huang, H.; Yang, L.; Hu, W. Org. Lett. 2007, 9, 4721–4723.
doi:10.1021/ol7019857
40.Chen, J.-R.; Liu, X.-P.; Zhu, X.-Y.; Li, L.; Qiao, Y.-F.; Zhang, J.-M.;
Xiao, W.-J. Tetrahedron 2007, 63, 10437–10444.
doi:10.1016/j.tet.2007.08.003
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