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Date: 24-03-14 18:19:35
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Stereoselective Synthesis of Proline-Derived Dipeptide Scaffolds
triazol-1-yloxy)tripyrrolidinophosphonium
hexafluoro- Conclusions
phosphate (PyBop) in the presence of Hünig’s base in aceto-
nitrile, the dipeptide product was obtained in good yield as
a mixture of inseparable diastereomers (mainly 10 and dia-
Following a straightforward metathesis-based strategy,
the diastereomeric scaffolds ProM-3 and ProM-7 were
stereoselectively synthesized (as Fmoc derivatives), and
their configuration was unambiguously proven by means of
X-ray crystallography, which confirmed the expected PPII
helix-type conformation. We expect that these compounds,
in combination with other ProMs, will contribute to the
development of new proteomimetics that can selectively
bind to protein domains specialized in the recognition of
ligands adopting a PPII helix secondary structure.[
10). However, after ring-closing metathesis the isomers
could be easily separated by column chromatography, and
desired product 11 was obtained in 83% yield alongside dia-
11, which was obtained in 1% yield.
The conversion of 11 into target compound 1a was
achieved in 58% yield by applying our established one-pot
deprotection/Fmoc protection protocol.[
10,11]
The stereo-
18]
chemical assignments were secured by X-ray crystallogra-
phy of both diastereomers, that is, 11 and dia-11 (Figure 3).
Supporting Information (see footnote on the first page of this arti-
1
13
The molecular structure of 11 displays the expected confor- cle): Experimental details and copies of the H NMR and
mational features of a PPII helix (φ = –68° and ψ = NMR spectra of all relevant compounds.
C
[
17]
+
169°).
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
DFG) within the project Interfering with intracellular protein–pro-
tein interactions: Probing protein function with small molecules (FG
06).
(
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[
[
[
1] For selected recent reviews, see: a) M. J. Pérez de Vega, M.
Martín-Martínez, R. González-Muñiz, Curr. Top. Med. Chem.
2
007, 7, 33–62; b) J. Vagner, H. Qu, V. J. Hruby, Curr. Opin.
Chem. Biol. 2008, 12, 292–296; c) A. Grauer, B. König, Eur. J.
Org. Chem. 2009, 5099–5111; d) J. M. Mason, Future Med.
Chem. 2010, 2, 1813–1822; e) W. R. J. D. Galloway, D. R.
Spring, Divers. Orient. Synth. 2012, 21–28.
Figure 3. Structures of 11 (left) and dia-11 (right) in the crystalline
2] For selected reviews, see: a) O. Keskin, A. Gursoy, B. Ma, R.
Nussinov, Chem. Rev. 2008, 108, 1225–1244; b) D. González-
Ruiz, H. Gohlke, Curr. Med. Chem. 2006, 13, 2607–2625; c) Y.
Pommier, J. Cherfils, Trends Pharmacol. Sci. 2005, 26, 138–145;
d) A. Reayi, P. Arya, Curr. Opin. Chem. Biol. 2005, 9, 240–247;
e) T. Berg, Angew. Chem. Int. Ed. 2003, 42, 2462–2481; Angew.
Chem. 2003, 115, 2566–2586.
state.
Using building block 3b, we proceeded with the assembly
of Fmoc-protected ProM-7 (i.e., 1b) as shown in Scheme 4.
PyBop coupling of 3b and 4 afforded dipeptide 12, which
was obtained as a pure diastereomer after chromatography.
The minor isomers were not isolated. Subsequent conver-
sion of 12 by ring-closing metathesis with the use of
Grubbs II catalyst afforded bicyclic product 13 in 59% yield
over two steps. Deprotection/protection under our standard
conditions finally afforded Fmoc-protected ProM-7 (1b) in
3] Selected examples: a) R. E. Moellering, M. Cornejo, T. N.
Davis, C. Del Bianco, J. C. Aster, S. C. Blacklow, A. L. Kung,
D. G. Gilliland, G. L. Verdine, J. E. Bradner, Nature 2009, 462,
182–190; b) E. Ko, J. Liu, L. M. Perez, G. Lu, A. Schaefer, K.
Burgess, J. Am. Chem. Soc. 2011, 133, 462–477; c) J. H. Lee,
Q. Zhang, S. Jo, S. C. Chai, M. Oh, W. Im, H. Lu, H.-S. Lim,
J. Am. Chem. Soc. 2011, 133, 676–679; d) V. Hack, C. Reuter,
R. Opitz, P. Schmieder, M. Beyermann, J.-M. Neudörfl, R.
Kühne, H.-G. Schmalz, Angew. Chem. Int. Ed. 2013, 52, 9539–
65% yield.
9543; Angew. Chem. 2013, 125, 9718–9722; e) D. J. Witter, S. J.
Famiglietti, J. C. Cambier, A. L. Castelhano, Bioorg. Med.
Chem. Lett. 1998, 8, 3137–3142.
4] a) L. Ball, R. Kühne, J. Schneider-Mergener, H. Oschkinat, An-
[
gew. Chem. Int. Ed. 2005, 44, 2852–2869; Angew. Chem. 2005,
117, 2912–2930; b) E. Klussmann, J. Scott (Eds.), Handbook of
Experimental Pharmacology, vol. 186: Protein–Protein Interac-
tions as New Drug Targets, Springer, Berlin, 2008; for synthetic
approaches toward PPII helix-mimicking molecules, see also:
c) G. Chaubet, T. Coursindel, X. Morelli, S. Betzi, P. Roche,
Y. Guari, A. Lebrun, L. Toupet, Y. Collette, I. Parrot, J. Marti-
nez, Org. Biomol. Chem. 2013, 11, 4719–4726 and the refer-
ences cited therein.
[
5] J. Zaminer, C. Brockmann, P. Huy, R. Opitz, C. Reuter, M.
Beyermann, C. Freund, M. Müller, H. Oschkinat, R. Kühne,
H.-G. Schmalz, Angew. Chem. Int. Ed. 2010, 49, 7111–7115;
Angew. Chem. 2010, 122, 7265–7269.
Scheme 4. Synthesis of 1b. Reagents and conditions: (a) PyBop, Et-
iPr) N, MeCN, r.t., 15 h; (b) Grubbs II (10 mol-%), CH Cl , re-
, r.t., 1 h, then FmocCl, NaHCO , H O/
(
2
2
2
flux, 15 h; (c) TFA, CH
THF (2:1), r.t., 15 h.
2
Cl
2
3
2
[6] R. Kühne, H. Oschkinat, R. Opitz, M. Müller, H.-G. Schmalz,
C. Reuter, P. Huy, WO2013030111A1, 2013.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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