Rapid access to multiple classes of peptidomimetics from common γ-AApeptide building blocks

Article abstract of DOI:10.1002/ejoc.201301841

Herein we report a highly efficient new method for preparing γ-AApeptides capable of theoretically containing any functionality; the method uses a few common N-alloc γ-AApeptide building blocks. More importantly, using the same approach, new classes of peptidomimetics bearing novel backbone scaffolds can also be readily generated. Our results not only demonstrate the versatility of this new synthetic method, but also highlight the possibility that the resulting novel peptidomimetics may find discrete biomedical/biomaterial applications in the future. Copyright

Full text of DOI:10.1002/ejoc.201301841

FULL PAPER
DOI: 10.1002/ejoc.201301841
Rapid Access to Multiple Classes of Peptidomimetics from Common
γ-AApeptide Building Blocks
Haifan Wu,[a] Peng Teng,[a] and Jianfeng Cai*[a]
Keywords: Solid-phase synthesis / Acylation / Peptidomimetics / γ-AApeptides
Herein we report a highly efficient new method for preparing
γ-AApeptides capable of theoretically containing any func-
bone scaffolds can also be readily generated. Our results not
only demonstrate the versatility of this new synthetic
tionality; the method uses a few common N-alloc γ-AApep- method, but also highlight the possibility that the resulting
tide building blocks. More importantly, using the same ap-
proach, new classes of peptidomimetics bearing novel back-
novel peptidomimetics may find discrete biomedical/bioma-
terial applications in the future.
for generating γ-AApeptides with chemically diverse func-
tional groups is limitless. Furthermore, half of the side
chains of γ-AApeptides remain chiral, possibly imposing
conformational biases that are reflected in peptide/peptido-
mimetic secondary structure. Similar to other classes of
known peptidomimetics, γ-AApeptides are highly resistant
to proteolytic degradation,[5,7] making them promising can-
didates for modulation and perturbation of biological pro-
cesses. For instance, some γ-AApeptides can permeate
mammalian cell membranes,[8] bind to HIV-1 RNA with
affinity and specificity akin to Tat peptide,[9] modulate p53/
MDM2 protein-protein interactions,[5] and selectively dis-
rupt bacterial membranes by mimicking natural host-de-
fense peptides.[10] Furthermore, γ-AApeptides can even
form novel nanostructures,[11] suggesting their potential ap-
plications in the arena of biomaterials science. To further
expand the versatility of γ-AApeptides in biomedical and
materials applications, we report herein a method to pre-
pare γ-AApeptides with high efficiency. More importantly,
using the same synthetic approach, a few new classes of
peptidomimetics with novel backbones, including oligocar-
bamates, oligosulfonamides, and oligoureas, can be conve-
niently generated. These peptidomimetics are different from
classic oligocarbamates, oligosulfonamides and oligou-
reas,[12] and thus, may find novel functions and applications
in biomedical and materials sciences in the future.
Introduction
Peptides are involved in virtually all aspects of life pro-
cesses and display a remarkable repertoire of biological ac-
tivities.[1] However, they also have a few intrinsic drawbacks
for biological applications. Principal among these draw-
backs are their susceptibility to proteolytic degradation. Al-
ternatively, the development of peptidomimetics has been a
vibrant research area in the past two decades, since such
mimetics are designed to emulate the structures and func-
tions of peptides yet possess enhanced stability and enable
access to broadened structural diversity.[2] Peptidomimetics
have been used to study protein surface recognition pro-
cesses, disruption of protein–protein interactions and other
important biological functions.[3] However, as peptides and
proteins display an endless diversity of structures and func-
tions,[2] development of new classes of peptidomimetics
with novel backbones remains a highly significant pursuit.[4]
In pursuing the development of new peptidomimetics
and related enabling synthetic technologies, we recently de-
signed a new class of peptide mimics termed “γ-AApep-
tides” (Figure 1).[5] γ-AApeptides contain N-acylated N-
aminoethyl amino acid units (Figure 1) derived from γ-
PNAs.[6] In each unit (building block), the chiral side chain
is derived from an α-amino acid, whereas the other side
chain is introduced through acylation of the backbone ni-
trogen with assorted carboxylic acids or acyl chlorides. Ac-
cordingly, each monomeric unit of γ-AApeptides is struc-
turally, and possibly functionally, comparable to two mono-
meric residues in α-peptides. That is to say, γ-AApeptides
essentially project an identical number of functional groups
as α-peptides of the same length. Additionally, the potential
[a] Department of Chemistry, University of South Florida,
4202 E. Fowler Ave, Tampa, FL 33620, USA
E-mail: jianfengcai@usf.edu;
http://jianfengcai.myweb.usf.edu/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301841
Figure 1. General structure of α-peptide and γ-AApeptide back-
bone scaffolds.
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Peptidomimetics from Common γ-AApeptide Building Blocks
Route 2 has to be adopted to remove the benzyl group prior
to alloc N-protection. It is notable that 1% AcOH is critical
Results and Discussion
The synthesis of γ-AApeptides was originally carried out during debenzylation in order to protonate the secondary
on solid phase resin using the building-block approach.[10b] amine, which otherwise always leads to Fmoc group re-
Although this approach is well established and reliably pro- moval.
vides products in good yields, this strategy is not ideal for
The key step of this solid phase synthesis is the removal
quickly generating derivatives with diverse groups since of the alloc protecting group. Briefly, on the solid phase,
each building block has to be prepared separately prior to the alloc protecting group is removed by 10 mol-% equiv.
solid phase synthesis. We recently developed a submono- Pd(PPh3)4 and 6 equiv. Me2NH·BH3 in DCM.[14] This reac-
meric approach for the synthesis of γ-AApeptides that cir- tion is extremely efficient and only takes 10 min to give the
cumvents the need to generate γ-AApeptide building desired product with quantitative conversion. Following re-
blocks.[13] However, the basic units, Fmoc-amino aldehydes, moval of the alloc group, a variety of carboxylic acids or
are not stable at room temperature, and thus need to be acyl chlorides can then be used to acylate the backbone
used immediately following their preparation. Moreover, nitrogen of the γ-AApeptide. To test the efficiency of this
the synthetic procedure is tedious requiring several steps for methodology, we synthesized a tetra-block sequence γ-AA1
each cycle of monomer addition; this can significantly at- and a penta-block sequence γ-AA2 (Figure 3). As shown in
tenuate the overall yields when preparing longer sequences Figure 3, panel c, using just one N-alloc γ-AApeptide build-
of peptidomimetics. Consequently, solid phase synthesis as ing block, γ-AA2 was synthesized. Importantly, γ-AA2, de-
it is most commonly practiced, is impractical for preparing spite requiring only one monomer for construction, bears
γ-AApeptide libraries with large structural diversity.
diverse N-tethered side chains, the result of different acylat-
To overcome this obstacle, we report herein a new ing agents employed. Using multiple N-alloc γ-AApeptide
method that combines both building-block and submonom- building blocks and different acylating agents, peptidomi-
eric approaches. In this approach, only a few N-alloc γ- metic γ-AA1 containing a wide variety of random side
AApeptide building blocks need to be synthesized by either chains was prepared (Figure 3, panel b). The purity of the
Route 1 or Route 2 (Figure 2, panel a),[5,10b,10c] in order to crude preparations for both γ-AA1 and γ-AA2 exceeds 80%
prepare γ-AApeptides containing virtually limitless func- (Figure 3, b and 3c), thus demonstrating the feasibility of
tional diversity. When the stereoisomerically projected R this approach for efficient preparation of γ-AApeptides
group contains acid-labile protecting groups such as Boc, with structurally diverse side chains. Compared to previous
Figure 2. Synthesis of γ-AApeptides by a combined building-block and monomeric approach. a, synthesis of N-alloc γ-AApeptide building
blocks. b, synthesis of γ-AApeptide sequences; Alloc = allyloxycarbonyl.
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H. Wu, P. Teng, J. Cai
FULL PAPER
approaches, this new strategy significantly reduces the than Fmoc-amino aldehydes, the basic units historically
number of steps, shortens the time required for synthesis, used in the synthesis of γ-AApeptides by the submonomeric
and greatly improves the yield and purity of γ-AApeptides. approach.[13] As a result N-alloc-protected monomers can
Furthermore, N-alloc building blocks are much more stable be prepared in large batches and used for a long period of
Figure 3. a. N-Alloc γ-AApeptide building blocks 1–5 and acylating agents used for the synthesis of the sequences. b. The structure of γ-
AA1, and its crude and purified analytical HPLC traces. c. The structure of γ-AA2, and its crude and purified analytical HPLC traces.
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Peptidomimetics from Common γ-AApeptide Building Blocks
time, in stark contrast to Fmoc-amino aldehydes. This fea- ties using one N-alloc γ-AApeptide building block on solid
ture adds another dimension of versatility to the new syn- phase (Figures 4 and 5). These syntheses were accomplished
thetic method.
by acylating the backbone nitrogens with a variety of com-
It is known that peptidomimetics such as oligocarb- mercially available sulfonyl chlorides, chloroformates, and
amates, oligosulfonamides, and oligoureas have important isocyanates (Figure 4, panel a). HPLC chromatograms for
biological applications,[12] implying what could be the great both crude and purified peptidomimetics demonstrate the
promise of new peptidomimetics with novel functional efficiency of the executed syntheses (Figure S3). It should
backbones. However, the synthesis of these classes of pepti- be noted that these new peptidomimetics differ from classic
domimetics is not trivial, as reflected by the scarcity of re- oligocarbamates, oligosulfonamides and oligoureas[12] in
ports of their biological applications. Indeed, many more that they are based on the γ-AApeptide backbone and may
reports, both synthetically- and functionally-oriented, are therefore have discrete structures and functions. Our results
known for β-peptides and peptoids. We envisioned that, vividly demonstrate that, with common γ-AApeptide build-
using these same N-alloc γ-AApeptide building blocks, new ing blocks, different classes of peptidomimetics can be read-
peptidomimetic classes with novel backbones could be ily obtained.
readily accessed.
To test our hypothesis, we synthesized oligosulfonamide
γ-AA3, oligocarbamate γ-AA4, oligourea γ-AA5, and the
sequence γ-AA6 containing assorted backbone functionali-
Figure 5. The sequences of oligosulfonamide (γ-AA3), oligourea (γ-
AA4), oligocarbamate (γ-AA5), and the sequence containing all
possible backbone functionalities (γ-AA6).
Conclusions
In summary, we have developed a modified method for
efficient preparation of γ-AApeptides and a few new classes
of peptidomimetics such as oligosulfonamides, oligoureas
and oligocarbamates, using common N-alloc γ-AApeptide
building blocks. Generation of chemically diverse libraries
of γ-AApeptides with virtually limitless potential is now
feasible. We demonstrate here the versatility of this new syn-
thetic approach which is, in part, highlighted by the cre-
ation of new families of unprecedented peptidomimetics
bearing diverse functional backbones and side chains. Fur-
ther development of these novel peptidomimetics may
reveal that they have important biological applications in
the future. As such, the potential scope of research on γ-
AApeptides will be significantly expanded.
Figure 4. a. The N-alloc γ-AApeptide building block, sulfonyl
Experimental Section
1. General Experimental Methods: All Fmoc-protected α-amino
chlorides, chloroformates, and isocyanates used to prepare new
classes of peptidomimetics. b. Solid-phase synthesis of peptidomi-
metic backbone sequence with different N-tethered functionalities.
acids and Rink amide resins (0.7 mmol/g, 200–400 mesh, 1% DVB)
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were purchased from Chem-Impex International, Inc. (Wood Dale,
IL, USA). All other solvents and reagents were purchased from
assorted vendors and used without further purification. NMR
spectroscopic data for building blocks was obtained with a
400 MHz NMR spectrometer. High resolution masses of building
blocks were determined with a Liquid Chromatography/Quadru-
pole Time-of Flight mass spectrometer. Masses of peptidomimetics
were obtained using a Proteomics Analyzer. Solid-phase synthesis
was conducted in peptide synthesis vessels on a shaker. Oligomers
were analyzed and purified with an HPLC system, and then lyophi-
lized.
4.52 (m, 2 H), 4.37–3.92 (m, 5 H), 3.92–3.21 (m, 3 H), 3.06–3.02
(m, 2 H), 1.42–1.26 (m, 15 H) ppm. 13C NMR (100 MHz CDCl3)
(two rotamers): δ = 172.8, 156.9, 156.7, 156.4, 156.3, 143.9, 143.8,
141.3, 132.4, 125.0, 119.9, 117.3, 79.3, 76.8, 66.7, 66.6, 52.1, 50.5,
49.8, 49.1, 47.2, 40.2, 32.1, 29.3, 28.4, 22.8 ppm. HR-ESI: [M +
Na]+ calc: 618.2786, found 618.2810.
Compound 4: Yield 80% (from intermediate 6b). 1H NMR
(400 MHz, CDCl3) (two rotamers): δ = 9.08 (s, 1 H), 8.11 (d, J =
8 Hz, 1 H), 7.70 (d, J = 8 Hz, 2 H), 7.62–7.21 (m, 10 H), 5.84–5.61
(m, 1 H), 5.21–5.07 (m, 2 H), 4.55–4.50 (m, 2 H), 4.35–4.15 (m, 3
H), 4.02–3.71 (m, 3 H), 3.48–2.60 (m, 3 H), 1.61 (s, 9 H) ppm. 13C
NMR (100 MHz CDCl3) (two rotamers): δ = 173.5, 157.0, 156.6,
156.4, 156.2, 149.6, 143.8, 141.2, 135.4, 132.2, 132.1, 127.6, 127.0,
125.2, 125.0, 124.5, 124.0, 123.8, 122.7, 119.9, 118.9, 118.3, 117.6,
116.1, 115.3, 83.7, 83.6, 67.0, 66.8, 51.7, 51.3, 50.6, 50.5, 49.9, 49.1,
47.1, 28.1 ppm. HR-ESI: [M + H]+ calc: 654.2810, found 654.2826.
2. Preparation of γ-AApeptide Building Blocks: N-Alloc γ-AApep-
tide building blocks 1, 2, 5 were synthesized using Route 1 in Fig-
ure 2 by following previously reported methods.[5,15] Building
blocks 3 and 4 were synthesized by Route 2 in Figure 2 and the
procedure for preparation of 3 is briefly shown as follows. To
benzyl ester[5,15] (2 g, 1.66 mmol) in methanol (50 mL) containing
1% acetic acid was added Pd/C (0.2 g, 10wt.-%). Hydrogenation
was conducted at atmospheric pressure and room temperature for
2 h. After filtration and evaporation, the remaining solid was sus-
pended in CH2Cl2 (50 mL) and N,N-diisopropylethylamine
(434 μL, 2.49 mmol, 1.5 equiv.) was added. The reaction mixture
was cooled to 0 °C, then a solution of allyl chloroformate (176 μL,
1.66 mmol, 1 equiv.) in CH2Cl2 was slowly added over 1 h. The
mixture was allowed to stir at room temperature for another 2 h,
and then washed with saturated citric acid (30 mL ϫ3) and brine
solution, dried with Na2SO4, and concentrated under vacuum. The
pure building block 3 was obtained as a white foam solid after flash
chromatography with 10% MeOH/CH2Cl2 (1.68 g, 85% yield).
1
Compound 5: Yield 75%. H NMR (400 MHz, CDCl3) (two rota-
mers): δ = 7.73 (d, J = 8 Hz, 2 H), 7.55 (t, J = 8 Hz, 2 H), 7.37 (t,
J = 8 Hz, 2 H), 7.29 (t, J = 8 Hz, 2 H), 5.85–5.76 (m, 1 H), 5.29–
5.09 (m, 2 H), 4.55–4.54 (m, 2 H), 4.36–4.15 (m, 3 H), 4.04–3.89
(m, 2 H), 3.64–3.58 (m, 1 H), 3.43–3.13 (m, 2 H), 1.16–0.99 (m, 3
H) ppm. 13C NMR (100 MHz CDCl3) (two rotamers): δ = 173.1,
157.0, 156.5, 143.8, 141.3, 132.3, 124.9, 119.9, 117.5, 66.9, 66.7,
53.2, 52.9, 49.8, 49.0, 47.2, 46.4, 18.4 ppm. HR-ESI: [M + H]+ calc:
439.1864, found 439.1872.
3. Solid Phase Synthesis of γ-AApeptides and Other Classes of Pep-
tidomimetics: Solid phase synthesis was conducted in peptide syn-
thesis vessels on a Burrell Wrist-Action shaker. 100 mg of Rink
amide resin (0.07 mmol) was treated with 20% Piperidine/DMF
solution (3 mL) for 15 min (ϫ2) to remove the Fmoc protecting
group. The solution was drained and beads were washed with
DCM (3ϫ 3 mL) and DMF (3ϫ 3 mL). A solution of N-alloc γ-
AApeptide building block (2 equiv.), HOBt (38 mg, 0.28 mmol),
and DIC (44 μL, 0.28 mmol) in DMF (3 mL) was agitated for
5 min, and then added to the resin. The mixture was allowed to
react at room temperature for 6 h and drained. The beads were
washed with DCM (3ϫ 3 mL) and DMF (3ϫ 3 mL), followed by
a capping reaction with acetic anhydride (500 μL in 3 mL pyridine).
After washing with DMF (3ϫ 3 mL) and DCM (3ϫ 3 mL), to the
beads were added Pd(PPh3)4 (8 mg, 0.007 mmol) and Me2NH·BH3
(25 mg, 0.42 mmol) in DCM (3 mL).[14] The alloc deprotection re-
action was agitated for 10 min and repeated one more time. The
beads were washed with DCM and DMF, followed by the reaction
with acylating agents (4 equiv.) and DIPEA (6 equiv.) in 3 mL of
DCM for 30 min (ϫ2) or with carboxylic acid (4 equiv.), HOBt
(8 equiv.), and DIC (8 equiv.) for 4 h (ϫ2). The previous steps were
repeated until the desired sequences were obtained. After that, the
resin were washed with DCM and dried in vacuo. Peptide cleavage
1
Compound 1: Yield 65%. H NMR (400 MHz, CDCl3) (two rota-
mers): δ = 7.74 (d, J = 8 Hz, 2 H), 7.56 (t, J = 8 Hz, 2 H), 7.38 (t,
J = 8 Hz, 2 H), 7.29 (t, J = 8 Hz, 2 H), 5.92–5.73 (m, 1 H), 5.29–
5.06 (m, 2 H), 4.57–4.28 (m, 5 H), 4.17–3.83 (m, 3 H), 3.60–3.15
(m, 2 H), 1.69–1.23 (m, 3 H), 0.93–0.87 (m, 6 H) ppm. 13C NMR
(100 MHz CDCl3) (two rotamers): δ = 173.6, 173.2, 157.8, 156.8,
156.7, 156.6, 156.2, 143.8, 141.3, 132.3, 124.5, 119.9, 118.2, 117.4,
66.8, 66.6, 52.3, 49.8, 48.7, 47.2, 41.7, 24.8, 23.2, 22.0, 21.8, 21.7,
14.2 ppm. HR-ESI: [M + H]+ calc: 481.2333, found 481.2352.
1
Compound 2: Yield 61%. H NMR (400 MHz, CDCl3) (two rota-
mers): δ = 8.74 (s, 1 H), 7.73 (d, J = 8 Hz, 2 H), 7.50–7.47 (m, 2
H), 7.36 (t, J = 8 Hz, 2 H), 7.28–7.18 (m, 7 H), 5.82–5.74 (m, 1
H), 5.21–5.07 (m, 2 H), 4.53–4.43 (m, 2 H), 4.34–4.25 (m, 2 H),
4.11–3.21 (m, 6 H), 2.82 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3) (two rotamers): δ = 173.5, 157.5, 156.9, 156.5, 156.1, 143.8,
143.7, 141.3, 137.2, 132.2, 129.2, 129.1, 128.6, 127.7, 127.0, 126.7,
125.2, 119.9, 117.6, 66.9, 60.5, 51.7, 49.8, 49.0, 47.1, 38.8, 21.0,
14.2 ppm. HR-ESI: [M + H]+ calc: 515.2177, found 515.2196.
Compound 3: Yield 85% (from intermediate 6a). 1H NMR
(400 MHz, CDCl3) (two rotamers): δ = 8.74 (s, 1 H), 7.73 (d, J = was done in a 4 mL vial by treating resin with TFA/H2O/TIS
8 Hz, 2 H), 7.57 (d, J = 8 Hz, 2 H), 7.37 (t, J = 8 Hz, 2 H), 7.28 (95:2.5:2.5) for 2 h. The solvent was evaporated and the crude reac-
(t, J = 8 Hz, 2 H), 5.91–5.79 (m, 1 H), 5.28–5.07 (m, 2 H), 4.55–
tion was analyzed and purified on an analytical (1 mL/min) and
Table 1. Purity, yield and MALDI-TOF analysis of γ-AApeptides.
γ-AApeptide
Purity (based on crude
HPLC trace)
Yield [%] (based on
loading of the resin)
Exact mass
(theoretical)
Mass ([M + H]+ as determined by
MALDI-TOF)
γ-AA1
γ-AA2
γ-AA3
γ-AA4
γ-AA5
γ-AA6
82%
86%
80%
50%
55%
60%
15
18
17
15
12
11
1159.7522
1045.6324
1129.3735
1159.7190
1055.5288
1144.5045
1160.8005
1046.5728
1130.4100
1160.6294
1056.5046
1145.5491
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Peptidomimetics from Common γ-AApeptide Building Blocks
6010; i) F. Bouillere, S. Thetiot-Laurent, C. Kouklovsky, V.
Alezra, Amino Acids 2011, 41, 687–707; j) J. Aguilera, J. A.
Cobos, R. Gutiérrez-Abad, C. Acosta, P. Nolis, O. Illa, R. M.
Ortuño, Eur. J. Org. Chem. 2013, 3494–3503.
preparative (20 mL/min) HPLC columns, respectively using a
Waters HPLC. The HPLC gradient system employed a program of
5% to 100% linear gradient of solvent B (0.1% TFA in acetonitrile)
in A (0.1% TFA in water) over the duration of 40 min. HPLC
detection wavelength was set to 215 nm and products identified
were confirmed by MALDI-TOF (Table 1).
[4] C. M. Goodman, S. Choi, S. Shandler, W. F. DeGrado, Nat.
Chem. Biol. 2007, 3, 252–262.
[5] Y. Niu, Y. Hu, X. Li, J. Chen, J. Cai, New J. Chem. 2011, 35,
542–545.
[6] S. Rapireddy, G. He, S. Roy, B. A. Armitage, D. H. Ly, J. Am.
Chem. Soc. 2007, 129, 15596–15600.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra, HPLC traces.
[7] Y. Yang, Y. Niu, H. Hong, H. Wu, Y. Zhang, J. Engle, T.
Barnhart, J. Cai, W. Cai, Chem. Commun. 2012, 48, 7850–7852.
[8] Y. Niu, G. Bai, H. Wu, R. E. Wang, Q. Qiao, S. Padhee, R.
Buzzeo, C. Cao, J. Cai, Mol. Pharm. 2012, 9, 1529–1534.
[9] Y. Niu, A. J. Jones, H. Wu, G. Varani, J. Cai, Org. Biomol.
Chem. 2011, 9, 6604–6609.
[10] a) Y. Niu, S. Padhee, H. Wu, G. Bai, L. Harrington, W. N.
Burda, L. N. Shaw, C. Cao, J. Cai, Chem. Commun. 2011, 47,
12197–12199; b) H. Wu, Y. Niu, S. Padhee, R. E. Wang, Y. Li,
Q. Qiao, B. Ge, C. Cao, J. Cai, Chem. Sci. 2012, 3, 2570–2575;
c) Y. Niu, S. Padhee, H. Wu, G. Bai, Q. Qiao, Y. Hu, L. Har-
rington, W. N. Burda, L. N. Shaw, C. Cao, J. Cai, J. Med.
Chem. 2012, 55, 4003–4009.
Acknowledgments
This work was partially supported by the Elsa U. Pardee Founda-
tion (USF start-up fund) and by the Florida Bankhead-Coley Can-
cer Research Program.
[1] S. Gellman, Biopolymers 2009, 92, 293–293.
[2] Y. D. Wu, S. Gellman, Acc. Chem. Res. 2008, 41, 1231–1232.
[3] a) M. L. Huang, S. B. Shin, M. A. Benson, V. J. Torres, K. Kir-
shenbaum, ChemMedChem 2012, 7, 114–122; b) P. N. Cheng,
R. Spencer, R. J. Woods, C. G. Glabe, J. S. Nowick, J. Am.
Chem. Soc. 2012, 134, 14179–14184; c) N. Srinivas, P. Jetter,
B. J. Ueberbacher, M. Werneburg, K. Zerbe, J. Steinmann, B.
Van der Meijden, F. Bernardini, A. Lederer, R. L. Dias, P. E.
Misson, H. Henze, J. Zumbrunn, F. O. Gombert, D. Obrecht,
P. Hunziker, S. Schauer, U. Ziegler, A. Kach, L. Eberl, K. Rie-
del, S. J. DeMarco, J. A. Robinson, Science 2010, 327, 1010–
1013; d) H. S. Haase, K. J. Peterson-Kaufman, S. K. Lan Lev-
engood, J. W. Checco, W. L. Murphy, S. H. Gellman, J. Am.
Chem. Soc. 2012, 134, 7652–7655; e) E. A. Harker, D. S. Dan-
iels, D. A. Guarracino, A. Schepartz, Bioorg. Med. Chem. 2009,
[11] Y. Niu, H. Wu, R. Huang, Q. Qiao, F. Constanza, X. Wang,
Y. Hu, M. N. Amin, A. Naguyen, J. Zhang, E. Haller, S. Ma,
X. Li, J. Cai, Macromolecules 2012, 45, 7350–7355.
[12] a) N. Tamilarasu, I. Huq, T. M. Rana, Bioorg. Med. Chem.
Lett. 2001, 11, 505–507; b) Y. H. Liu, R. H. E. Hudson, Synlett
2001, 1626–1628; c) C. Gennari, C. Longari, S. Ressel, B. Sa-
lom, U. Piarulli, S. Ceccarelli, A. Mielgo, Eur. J. Org. Chem.
1998, 2437–2449; d) J. M. Kim, Y. Z. Bi, S. J. Paikoff, P. G.
Schultz, Tetrahedron Lett. 1996, 37, 5305–5308; e) C. Gennari,
H. P. Nestler, B. Salom, W. C. Still, Angew. Chem. 1995, 107,
1892; Angew. Chem. Int. Ed. Engl. 1995, 34, 1763–1765.
17, 2038–2046; f) R. Kapoor, M. W. Wadman, M. T. Dohm, [13] H. Wu, M. N. Amin, Y. Niu, Q. Qiao, N. Harfouch, A. Nimer,
A. M. Czyzewski, A. M. Spormann, A. E. Barron, Antimicrob.
Agents Chemother. 2011, 55, 3054–3057; g) C. Y. Cho, E. J. Mo-
ran, S. R. Cherry, J. C. Stephans, S. P. Fodor, C. L. Adams, A.
Sundaram, J. W. Jacobs, P. G. Schultz, Science 1993, 261, 1303–
1305; h) L. Mathieu, B. Legrand, C. Deng, L. Vezenkov, E.
Wenger, C. Didierjean, M. Amblard, M.-C. Averlant-Petit, N.
Masurier, V. Lisowski, J. Martinez, L. T. Maillard, Angew.
Chem. 2013, 125, 6122; Angew. Chem. Int. Ed. 2013, 52, 6006–
J. Cai, Org. Lett. 2012, 14, 3446–3449.
[14] P. Gomez-Martinez, M. Dessolin, F. Guibe, F. Albericio, J.
Chem. Soc. Perkin Trans. 1 1999, 2871–2874.
[15] a) Y. H. Niu, Y. G. Hu, X. L. Li, J. D. Chen, J. F. Cai, New J.
Chem. 2011, 35, 542–545; b) Y. H. Niu, A. Jones, H. F. Wu, G.
Varani, J. F. Cai, Org. Biomol. Chem. 2011, 9, 6604–6609.
Received: December 10, 2013
Published Online: January 14, 2014
Eur. J. Org. Chem. 2014, 1760–1765
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