Cydative cleavage through dipolar cycloaddition: Polymer-bound azidopeptidylphosphoranes deliver locked cis-triazolylcyclopeptides as privileged protein binders

Article abstract of DOI:10.1002/anie.200904980

Support and guidance: Azidopeptidyl phosphoranes on a solid support react very efficiently through cyclative cleavage to yield cyclopeptides with an incorporated triazole ring. The solid support is advantageous as cyclization is favored strongly over oligomerization reactions and thus only cyclized products are released. "Chemical equation presented".

Full text of DOI:10.1002/anie.200904980

Communications
DOI: 10.1002/anie.200904980
Cyclopeptide Synthesis
Cyclative Cleavage through Dipolar Cycloaddition: Polymer-Bound
Azidopeptidylphosphoranes Deliver Locked cis-Triazolylcyclopeptides
as Privileged Protein Binders**
Ahsanullah and Jꢀrg Rademann*
Dedicated to Professor Rolf Huisgen on the occasion of his 90th birthday
Cyclic peptides are important natural products displaying a
broad range of biological effects including immunosuppres-
sion, antibacterial properties, and anticancer activity.[1] Many
cyclopeptides act as potent inhibitors of protein–protein
interactions and enzymatic activities as they display partially
rigidified conformations and thus provide improved protein
target recognition together with favorable pharmacokinetic
properties and metabolic stability.[2] As a result several
cyclopeptides have been used successfully as clinically
approved drugs for decades, and cyclopeptides and pseudo-
cyclopeptides continue to supply the pharmaceutical industry
with novel drug candidates.[3,4]
Triazolylcyclopeptides have been introduced as pseudo-
cyclopeptides with decreased flexibility as one peptide bond is
replaced with the heterocycle locking it either in trans-
peptide or in cis-peptide geometry.[5] For several biological
targets, cis-locked cyclopeptides containing 1,5-disubstituted
triazoles display significantly increased binding affinity and
biological activity relative to the 1,4-disubstituted derivatives
and native cyclopeptides.[5] Based on these observations
triazolylcyclopeptides are considered as privileged protein
binders.
reaction competes with an intramolecular reaction path.[6]
Attachment to a solid support can reduce oligomer formation
considerably since the reaction sites are spatially separated
(pseudo-dilution principle).[7] Nevertheless, intersite reactions
are possible on highly swellable polymers, such as low-cross-
linked polystyrene, and depend critically on the length and
flexibility of the attached molecules.[8] If, however, cyclization
and cleavage proceed in the same chemical reaction (referred
to as cyclative cleavage), open-chain oligomeric by-products
remain attached to the solid support and are easily removed
by washing the resin, whereas cyclic monomers and cyclic
oligomers are released in solution (Scheme 1).[9] Moreover,
both the flexibility of the polymer support and the level of
resin loading are parameters that can be exploited to favor
intrasite versus intersite reactions.
In the light of these considerations, preparation of
triazolylcyclopeptides employing cyclative cleavage appeared
Despite their broad biological significance, the synthesis
of triazolylcyclopeptides and wild-type cyclopeptides still
presents a major challenge and requires improved synthetic
methods. Cyclization reactions in solution often deliver low
yields and furnish mixtures of monomeric, oligomeric,
cyclized, and open-chain products, when the intermolecular
[*] Prof. Dr. J. Rademann
Medicinal Chemistry, Institute of Pharmacy, Leipzig University
Brꢀderstrasse 34, 04103 Leipzig (Germany)
Fax: (+49)341-97378
E-mail: rademann@uni-leipzig.de
Ahsanullah, Prof. Dr. J. Rademann
Leibniz Institute of Molecular Pharmacology (FMP)
Robert-Rꢁssle-Strasse 10, 13125 Berlin (Germany)
Ahsanullah
Institute for Chemistry and Biochemistry, Free University Berlin
Takustrasse 3, 14195 Berlin (Germany)
[**] We gratefully acknowledge the Higher Education Commission
(HEC) of Pakistan and the Deutsche Akademische Austauschdienst
(DAAD) for a stipend granted to A. and the DFG (RA895/2, FOR
806, and SFB 765). J.R. thanks the Fonds der Chemischen Industrie
for continuous support.
Scheme 1. In cyclizations on solid supports intrasite reactions (A)
compete with intersite reactions (B). In the special case of cyclative
cleavage, path A yielding cyclic monomer competes with path B,
providing the open-chain dimer still attached to the polymer. The latter
can react either following path C to give the cyclic dimer (intrasite) or
by path D leading to the attached open oligomer in an intersite
reaction.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904980.
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to be an attractive enterprise. Though 1,3-dipolar cyclo-
additions of azides and alkynes under CuI or RuII catalysis can
be used to incorporate 1,4- and 1,5-disubstituted triazoles in
peptides,[10] the efficacy of the CuI-catalyzed, 1,4-selective
reactions dropped significantly for cyclizations[11] and the
yields were even more disappointing on solid support.[12]
Therefore, in most of these cases the 1,4-disubstituted triazole
was introduced into cyclic peptides through the reaction of
peptides with terminal azide and alkyne units in solution.[11–13]
Alternatively, the 1,4-disubstituted triazole was prepared first
in the linear peptide sequence and the cyclopeptide was
obtained after a final lactamization step.[14]
Unfortunately, the synthesis of the biologically privileged
1,5-disubstituted triazolylcyclopeptides has proved to be
especially difficult. No cyclizations of azidoalkynyl peptides
to give 1,5-disubstituted triazoles either in solution or on solid
support have been reported yet. As the ruthenium-catalyzed
cycloaddition must be performed at high concentration (0.5–
1.0m), the reaction was not suitable at the higher dilutions
required to reduce oligomer formation.[19] The only reported
synthesis of 1,5-disubstituted triazolylcyclopeptides pro-
ceeded through a final lactamization reaction.[5a]
Recently, we have developed the synthesis of 1,5-pepti-
dyltriazolyl peptides through metal-free, regioselective 1,3-
dipolar cycloaddition reactions.[15] The method enabled
preparation of triazolyl peptides starting from commercially
available amino acid building blocks and yielded the products
in high purity; a dipolar cycloaddition served as the cleavage
reaction. As demonstrated by ROESY NMR analysis and a
simulated annealing protocol, the obtained 1,5-disubstituted
triazole acting as a cis-peptide-bond mimetic induces turn
structures even in short peptide stretches. Moreover, using
azidopeptidylphosphorane resins for cyclative cleavage
should lead to the selective and exclusive formation of
cyclized products as all open-chain monomers and oligomers
are expected to remain attached to the polymer support
(Scheme 1).
Scheme 2. Preparation of azidopeptidylphosphoranes 5a–i on polystyr-
ene support. Reaction conditions: a) Fmoc-AA-OH and BTFFH, DIPEA,
DMF, 14 h; b) 20% piperidine/DMF; c) Fmoc-AA-OH, DIC, HOBt,
DMF, 2 h; d) steps (b) and (c) are repeated n times; e) 20%
piperidine/DMF; f) 2-azido acid (6 or 7), DIC, HOBt, DMF, 2 h;
g) TFA/CH2Cl2 (95% v:v), 5 h followed by treatment with Et3N.
BTFFH=bis (tetramethylene)fluoroformamidinium hexafluorophos-
phate, DIPEA=N,N-diisopropylethylamine, DIC=diisopropylcarbodi-
imide, HOBt=1-hydroxybenzotriazole, TFA=trifluoroacetic acid.
instantaneous decarboxylation of the phosphoranylidene
acetate, yielding azidopeptidylphosphoranes 5a–j.
To test this hypothesis we prepared N-terminal azidopep-
tidylphosphoranes on a solid support (Scheme 2).[16] Starting
from tert-butylphosphoranylidene acetate (1), amino acyl
phosphorane 2 was obtained from a nonracemizing C-
acylation employing an Fmoc-protected amino acid and
BTFFH for activation; the products were obtained in 76–
82% yield depending on the amino acid used in this step:
glycine, leucine, phenylalanine, or tert-butylserine. Intermedi-
ate 2 was extended with further amino acids by employing
standard couplings of Fmoc-protected amino acids (activation
with diisopropylcarbodiimide/1-hydroxybenzotriazole) to fur-
nish resin 3. For the elongation steps various amino acids with
and without side-chain protection were used including Pro,
Leu, Val, Trp, Ser, Thr, Met, and Tyr. Following removal of
the Fmoc groups from 3, the resulting free amines were
acylated with one of the 2-azido acids 6 or 7, which were
obtained by nucleophilic substitution of bromoacetic acid
with sodium azide and by diazo transfer from freshly prepared
triflyl azide, respectively.[17] The reaction furnished the
azidopeptidylphosphoranylidene acetate 4, which was treated
with trifluoroacetic acid to remove all side-chain protecting
groups. Cleavage of the C-terminal acetate ester led to
Cyclizations of 5a–j were investigated with peptide chains
of different lengths as well as varying amino acid sequences
(Scheme 3, Table 1). A reaction temperature of 60–808C and
polar solvents were sufficient for cyclative cleavage of
azidopeptidylphosphoranes. DMF was the preferred solvent
as it assured good solubility of those products which were only
partially soluble in other polar solvents used to swell the
polystyrene support. When the longer azidopenta-, and
azidooctapeptidylphosphoranes 5i,j (n = 3, 6) were heated
in DMF exclusively the expected monomeric triazolyl cyclo-
peptides 15 and 16, respectively, were formed. These results
indicate that the solid support exerts a considerable degree of
site separation.
When, however, the azidodipeptidylphosphoranes 5a,b
(n = 0) were treated under identical conditions, exclusively
the dimeric bistriazolylcyclotetrapeptides 8 and 9 formed
from intersite reactions (see Scheme 1). Azidotripeptidyl-
phosphoranes 5c (n = 1) delivered a 3:2 mixture of the
monomeric triazolyl cyclotripeptide with the respective
dimeric product. Azidotetrapeptidylphosphoranes 5e–h (n =
2) were cyclized under identical conditions and provided the
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Table 1: Formation of monomeric and dimeric products by cyclative
cleavage of phosphoranes 5a–j.[a]
Phos-
phorane sequence
Peptide
n
Prod. Ring
Monomer Dimer
(chain
length)
size[b] [%][c]
[%][c]
5a,b
AG, Fa
0 (dipep-
tide)
1 (tri-)
1 (tri-
1 (tri-)
8,9
12
0
100[b]
[d]
[d]
5c
5c
5d
5d
5e
5 f
5g
5h
5i
LPG
LPG
LSG
LSG
LaFG
GvaG
SMYG
lWMa
SMYTG
9
9
9
9
12
12
12
12
15
24
60
40
20[c]
88
25[c]
20
15
0
0
0
0
80[c]
12
10
10
11
12
13
14
1 (tri-)
75[c]
80
2 (tetra-)
2 (tetra-)
2 (tetra-)
2 (tetra-)
3 (penta-) 15
16
85
100
100
100
100
5j
LSASMYTG 6 (octa-)
[a] Peptide sequences are assigned with the one-letter code using capital
letters for l-amino acids and small letters for d-amino acids. [b] Number
of atoms in the ring. [c] The ratio of monomeric to dimeric products was
determined based on the UV absorption signal at 220 nm in the LCMS
chromatogram. If not noted specifically, the cleavage reactions were
conducted from low-cross-linked microporous polystyrene (2% divinyl-
benzene, 1.6 mmolgÀ1). [d] Product ratio for cleavage from low-cross-
linked, microporous triphenylphosphane polystyrene (2% divinylben-
zene, 1.6 mmolgÀ1) and from highly cross-linked, macroporous poly-
styrene (>20% divinylbenzene, 1.62 mmolgÀ1). [e] Product ratio for
cleavage from highly cross-linked, macroporous triphenylphosphane
polystyrene (>20% divinylbenzene, 1.62 mmolgÀ1). [f] Not isolated;
products precipitate during purification on column.
carrier, it should be enhanced in more rigid supports such as
macroreticular (macroporous) polystyrene. Use of macro-
reticular polystyrene is supposed to affect the cyclization
reaction and favor monomeric over dimeric cyclic products.
To test this assumption, azidopeptidylphosphoranes 5a,c,d
were prepared using macroporous resin with > 20% divinyl-
benzene (DVB) cross-linking, considerably more than the
standard low-cross-linked, microporous polystyrene resins
with only 2% DVB cross-linker. Both resins had an initial
loading of approximately 1.6 mmol of triphenylphosphane
per g. Cyclization of azidotripeptidylphosphorane 5c on
macroporous resin yielded the monomeric product in 80%
yield, indicating a significant shift towards the intrasite
reaction pathway. Unfortunately, the cyclization products
derived from 5c precipitated during purification and thus
could not be isolated. Therefore, the tripeptide precursor 5d,
in which the proline residue of 5c is replaced by serine to
improve the product solubility, was synthesized both on
micro- and macroporous resins. In this case, cyclization on the
microporous resin delivered products in a 12:88 ratio in favor
of the dimeric (intersite) cyclization product. Again the
synthesis on the macroporous support yielded the monomeric
(intrasite) reaction product 10 in excess (75:25); 10 was
isolated and characterized spectroscopically. On the other
hand, when the azidodipeptidylphosphorane 5a on macro-
porous resin was heated in DMF, the dimeric product 8 was
still delivered exclusively, albeit in significantly reduced yield
(46% instead of 78%). Obviously, the intersite cyclization
pathway is favored strongly in these cases so that formation of
Scheme 3. Products formed by cyclative cleavage of azidopeptidylphos-
phoranes 5a–j. Yields and purities for 8, 9, 11, 12, and 14 are given for
the crude products, data for compounds 10, 13, 15, and 16 are
reported after HPLC purification.
respective triazolyl cyclotetrapeptides as the major products.
While azidotetrapeptidylphosphoranes 5g,h furnished exclu-
sively the cyclic monomers 13 and 14, reactions of 5e and 5 f
yielded the monomeric triazolyl cyclopeptides 11 and 12
together with the corresponding dimeric products in minor
amounts according to LC–MS analysis.
The formation of dimeric products indicates a significant
degree of site interaction within the polymer support. As site
separation depends strongly on the flexibility of the polymer
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the monomeric product was not detected even on the more
rigid polymer.
Keywords: 1,3-dipolar cycloaddition · biocompatible ligation ·
cyclopeptides · peptidomimetics · triazoles
.
These results are surprising at first glance if one considers
a concerted mechanism of the dipolar cycloaddition reaction.
Both experimental findings and calculations indicate, how-
ever, a stepwise reaction mechanism in the case of electron-
rich dipolarophiles.[18] Considering phosphorus ylides as
electron-rich dipolarophiles we can postulate a stepwise
mechanism for their cycloadditions with azides as well. This
stepwise mechanism, however, requires the attack of the ylide
carbon at the terminal azide nitrogen (as depicted in
Scheme 3) and thus must strongly disfavor intrasite reactions
of shorter azidopeptidylphosphoranes over the concerted
mechanism leading to the dimeric products 8 and 9.
In summary, we have described the cyclative cleavage of
azidopeptidylphosphoranes. Depending on the length of the
starting material, the building block sequence, and the
polymer rigidity the method delivered either monomeric or
dimeric products. Pure dimers were obtained from azidodi-
peptidylphosphoranes (n = 0). Tripeptidylphosphoranes (n =
1) yielded mixtures of products, whereas longer starting
materials provided monomeric products, either entirely pure
(n > 3) or with small dimeric impurities (n = 3). The products
of intrasite reactions were significantly favored by the use of a
more rigid, highly cross-linked polymer support. All products
were isolated in good to excellent yields which greatly
exceeded previous results for comparable cyclizations in
solution phase.[5a,19] The solubility of the products was critical
for the yields obtained and for the feasibility of chromato-
graphic purification. The NMR signals of all isolated products
8–16 were fully assigned in one- and two-dimensional 1H and
13C NMR spectra and the products were characterized by
HRMS. The method completely avoids formation of soluble,
noncyclized, oligomeric by-products and is therefore superior
to solution protocols with respect to synthetic efficiency,
yields, and purity.[19] This approach to cis-locked triazolyl
cyclopeptides should considerably facilitate the systematic
investigation of the structural and biological properties of
these compounds, which are already known to have biological
significance.
[1] a) H. Kessler, Angew. Chem. 1982, 94, 509 – 520; Angew. Chem.
Int. Ed. Engl. 1982, 21, 512 – 523; b) R. M. Wenger, Angew.
Chem. 1985, 97, 88 – 96; Angew. Chem. Int. Ed. Engl. 1985, 24,
77 – 85; c) K. Maria, T. Theodore, D. Spyros, D. George, M.
Minos-Timotheos, L. Eliada, M. John, A. Vasso, Curr. Med.
Chem. 2006, 13, 2221 – 2232; d) Y. Hamada, T. Shioiri, Chem.
Rev. 2005, 105, 4441 – 4482.
[2] a) S. W. Millward, S. Fiacco, R. J. Austin, R. W. Roberts, ACS
Chem. Biol. 2007, 2, 625 – 634; b) A. Tavassoli, Q. Lu, J. Gam, H.
Pan, S. J. Benkovic, S. N. Cohen, ACS Chem. Biol. 2008, 3, 757 –
764; c) S. Bonetto, L. Spadola, A. G. Buchanan, L. Jermutus, J.
Lund, FASEB J. 2009, 23, 575 – 585.
[3] http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?mode =
&term = Cyclic + Peptides#TreeD12.644.641.
[4] a) R. Haubner, R. Gratias, B. Diefenbach, S. L. Goodman, A.
Jonczyk, H. Kessler, J. Am. Chem. Soc. 1996, 118, 7461 – 7472;
b) A. Montero, J. M. Beierle, C. A. Olsen, M. R. Ghadiri, J. Am.
Chem. Soc. 2009, 131, 3033 – 3041.
[5] a) W. S. Horne, C. A. Olsen, J. M. Beierle, A. Montero, M. R.
Ghadiri, Angew. Chem. 2009, 121, 4812 – 4818; Angew. Chem.
Int. Ed. 2009, 48, 4718 – 4724; b) J. M. Beierle, W. S. Horne, J. H.
van Maarseveen, B. Waser, J. C. Reubi, M. R. Ghadiri, Angew.
Chem. 2009, 121, 4819 – 4823; Angew. Chem. Int. Ed. 2009, 48,
4725 – 4729.
[6] a) P. Wipf, Chem. Rev. 1995, 95, 2115 – 2134; b) J. S. Davies, J.
Pept. Sci. 2003, 9, 471 – 501; c) U. Schmidt, U. Beutler, A.
Lieberknecht, Angew. Chem. 1989, 101, 344 – 346; Angew. Chem.
Int. Ed. Engl. 1989, 28, 333 – 334.
[7] a) M. C. Alcaro, G. Sabatino, J. Uziel, M. Chelli, M. Ginanne-
schi, P. Rovero, A. M. Papini, J. Pept. Sci. 2004, 10, 218 – 228;
b) M. Gonꢁalves, K. Estieu-Gionnet, G. Laffln, M. Bayle, N. Betz,
G. DØlØris, Tetrahedron 2005, 61, 7789 – 7795; c) J. Tulla-Puche,
G. Barany, J. Org. Chem. 2004, 69, 4101 – 4107.
[8] a) S. Punna, J. Kuzelka, Q. Wang, M. G. Finn, Angew. Chem.
2005, 117, 2255 – 2260; Angew. Chem. Int. Ed. 2005, 44, 2215 –
2220; b) R. Jagasia, J. M. Holub, M. Bollinger, K. Kirshenbaum,
M. G. Finn, J. Org. Chem. 2009, 74, 2964 – 2974; c) R. A. Turner,
A. G. Oliver, R. S. Lokey, Org. Lett. 2007, 9, 5011 – 5014; d) J. M.
Holub, H. Jang, K. Kirshenbaum, Org. Lett. 2007, 9, 3275 – 3278.
[9] For reviews on cyclative cleavage reactions see: a) P. Blaney, R.
Grigg, V. Sridharan, Chem. Rev. 2002, 102, 2607 – 2624; b) M.
Jung, M. Wiehn, S. Bräse, Top. Curr. Chem. 2007, 278, 1 – 88;
c) J. H. van Maarseveen, Comb. Chem. High Throughput
Screening 1998, 1, 185 – 214; d) A. Ganesan in Methods in
Enzymology: Combinatorial Chemistry, Vol. 369 (Eds.: G.
Morales, B. A. Bunin), Academic Press, San Diego, 2003,
pp. 415 – 434; e) R. Shi, F. Wang, B. Yan, Int. J. Pept. Res. Ther.
2007, 13, 213 – 219.
Experimental Section
Synthetic procedures and analytical data (HRMS, 1H NMR,
13C NMR) of all novel compounds are provided in the Supporting
Information.
General synthesis of cis-triazolyl cyclopeptides 8–16: Azidopep-
tidylphosphorane 5 (300 mg, 0.315 mmol) was swollen in anhydrous
DMF (4 mL) and heated in a sealed glass vial at 808C for 14 h. After
cooling to room temperature, the support was filtered off and washed
with DMF (5 ꢀ 2 mL) with shaking. All the washing fractions were
combined, and the solvent was removed under reduced pressure
leaving the solid products. Compounds 8, 9, 11, 12, and 14 were pure
enough in crude form to be characterized by NMR spectroscopy,
while 10, 13, 15, and 16 were purified by reversed-phase preparative
HPLC prior to NMR analysis.
[10] a) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002,
67, 3057 – 3064; b) V. V. Rostovtsev, L. G. Green, V. V. Fokin,
K. B. Sharpless, Angew. Chem. 2002, 114, 2708 – 2711; Angew.
Chem. Int. Ed. 2002, 41, 2596 – 2599; c) L. Zhang, X. Chen, P.
Xue, H. H. Y. Sun, I. D. Williams, K. B. Sharpless, V. V. Fokin, G.
Jia, J. Am. Chem. Soc. 2005, 127, 15998 – 15999.
[11] Y. Liu, L. Zhang, J. Wan, Y. Li, Y. Xu, Y. Pan, Tetrahedron 2008,
64, 10728 – 10734.
[12] a) S. Cantel, A. Le Chevalier-Isaad, M. Scrima, J. J. Levy, R. D.
DiMarchi, P. Rovero, J. A. Halperin, A. M. DꢂUrsi, A. M.
Papini, M. Chorev, J. Org. Chem. 2008, 73, 5663 – 5674; b) J.
Springer, K. R. de Cuba, S. Calvet-Vitale, J. A. J. Geenevasen,
P. H. H. Hermkens, H. Hiemstra, J. H. van Maarseveen, Eur. J.
Org. Chem. 2008, 2592 – 2600; c) V. Goncalves, B. Gautier, A.
Received: September 4, 2009
Revised: March 22, 2010
Published online: June 25, 2010
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Regazzetti, P. Coric, S. Bouaziz, C. Garbay, M. Vidal, N.
[17] J. T. Lundquist IV, J. C. Pelletier, Org. Lett. 2001, 3, 781 – 783.
[18] a) G. O. Jones, K. N. Houk, J. Org. Chem. 2008, 73, 1333 – 1342;
b) C. Di Valentin, M. Freccero, R. Gandolfi, A. Rastelli, J. Org.
Chem. 2000, 65, 6112 – 6120; c) L. R. Domingo, M. T. Picher,
Tetrahedron 2004, 60, 5053 – 5058; d) L. R. Domingo, M. T.
Picher, P. Arroyo, J. A. Sàez, J. Org. Chem. 2006, 71, 9319 – 9330.
[19] The difficulties in preparing this class of compounds through
RuII catalysis were discussed in a recent PhD thesis: J. Springer,
University of Amsterdam, 2008, chap. 4, pp. 106–126, (http://
dare.uva.nl/document/116338). To compare the efficiency of our
new approach for the synthesis of cis-triazolyl cyclopeptides with
the existing methods, compound 14 was prepared analogously to
one example reported in reference [5a]. The yield of the
cyclative cleavage was 64%, while the yield of the lactamization
procedure was 9%.
Inguimbert, Bioorg. Med. Chem. Lett. 2007, 17, 5590 – 5594.
[13] a) Y. Angell, K. Burgess, J. Org. Chem. 2005, 70, 9595 – 9598;
b) V. D. Bock, R. Perciaccante, T. P. Jansen, H. Hiemstra, J. H.
van Maarseveen, Org. Lett. 2006, 8, 919 – 922; c) V. D. Bock, D.
Speijer, H. Hiemstra, J. H. van Maarseveen, Org. Biomol. Chem.
2007, 5, 971 – 975.
[14] a) W. S. Horne, C. D. Stout, M. R. Ghadiri, J. Am. Chem. Soc.
2003, 125, 9372 – 9376; b) J. H. van Marseveen, W. S. Horne,
M. R. Ghadiri, Org. Lett. 2005, 7, 4503 – 4506.
[15] Ahsanullah, P. Schmieder, R. Kühne, J. Rademann, Angew.
Chem. 2009, 121, 5143 – 5147; Angew. Chem. Int. Ed. 2009, 48,
5042 – 5045.
[16] a) S. Weik, J. Rademann, Angew. Chem. 2003, 115, 2595 – 2598;
Angew. Chem. Int. Ed. 2003, 42, 2491 – 2494; b) A. El-Dahshan,
S. Weik, J. Rademann, Org. Lett. 2007, 9, 949 – 952.
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