stirred for one hour at 0 ◦C. The solution was washed once with
HCl 1 N, twice with NaHCO3 5% and then dried on Na2SO4.
The solvent was removed in vacuo and the crude purified by FC
(CHCl3/MeOH 98:2), affording 54 mg (89%) of 11.
MD was further minimized. An average structure was created for
each MD simulation.
Acknowledgements
11. [a]23D = -62.2 (c = 2.1, CHCl3); FT IR (film): nmax = 3325,
Politecnico di Milano and CNR are gratefully acknowledged for
economic support
1
2961, 2244, 1634, 1539, 1446, 1390 cm-1; HNMR (400 MHz,
CDCl3): d = 7.92 (br s, 1H), 6.15 (br d, J = 5.0 Hz, 1H), 4.65 (dd,
J = 8.9,6.3 Hz, 1H), 4.50 (m, 1H), 3.83 (dd, J = 10.9, 2.7 Hz, 1H),
3.78 (m, 1H), 3.70 (m, 1H), 3.51 (m, 1H), 3.34 (m, 1H), 3.01 (s,
3H) 2.98 (s, 3H), 2.10 (m, 10H), 1.45 (ddd, J = 13.7, 10.6, 3.9 Hz,
1H), 1.24 (ddd, J = 13.7, 10.0, 3.0 Hz, 1H), 0.93 (m, 13H); 13C
NMR (100 MHz, CDCl3): d = 175.6, 172.3, 171.2, 170.0, 125.7 (Q,
J = 281.8 Hz), 60.5, 58.5 (Q, J = 27.4 Hz), 56.3, 55.6, 47.7, 42.2,
36.7, 36.0, 31.4, 29.1, 25.1, 24.5, 23.6, 21.0, 19.3, 17.8; 19F NMR
(235.4 MHz, CDCl3): d = -76.8 (d, J = 5.0 Hz); MS (70 eV): e/z
(%): 508 [M+ + 1] (10), 367(30), 294(98), 70(100).
Notes and references
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6 For a review on the trifluoethylamine unit, see: M. Sani, A. Volonterio
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NMR experiments
The NMR spectra were recorded on a Bruker AMX 600 spec-
trometer operating at a frequency of 600.13 MHz for 1H nucleus.
The chemical shifts (d) were measured in ppm and referenced
to external DSS signal for CDCl3 solution. Estimated accuracy
0.01 ppm. The experiments were performed at 25 ◦C. The
concentration of peptides was 4.5 mM. ROESY and COSYmqf
spectra were acquired in the phase sensitive TPPI mode, with
1K ¥ 512 complex FIDs, spectral width of 6329 Hz, recycling
delay of 1.2 s, 48 scans. The mixing times for ROESY experiments
ranged between 150 ms and 800 ms. TOCSY spectra were recorded
with the use of a MLEV-17 spin-lock pulse (field strength of
7550 Hz, 60 ms total duration, 2.5 ms of TRIM pulse). All
spectra were transformed and weighted with a 90◦ shifted sine-
bell squared function to 1K ¥ 1K real data points.13C NMR
spectra were obtained by means of one-bond and long range
correlation spectroscopy using HMQC and HMBC in the TPPI
mode. The NH temperature coefficients were obtained in CDCl3,
by monitoring the amide and amine NH chemical shifts over a
temperature range of 233 to 298 K. All changes in NH chemical
shifts (-Dd/DT) were linear over the above temperature range.
7 (a) W. C. Black, C. I. Bayly, D. E. Davies, S. Desmarais, J.-P. Falgueyret,
S. Le´ger, C. S. Li, F. Masse´, D. J. McKay, J. T. Palmer, M. D. Percival,
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Falgueyret, J. Y. Gauthier, D. B. Kimmel, S. Le´ger, F. Masse´, M. E.
McGrath, D. J. McKay, M. D. Percival, D. Riendeau, S. B. Rodan, M.
The´rien, V.-L. Truong, G. Wesolowski, R. Zamboni and W. C. Black,
Bioorg. Med. Chem. Lett., 2006, 16, 1985–1989; (c) W. C. Black and M.
D. Percival, ChemBioChem, 2006, 7, 1525–1535; (d) J. Y. Gauthier, N.
Chauret, W. Cromlish, S. Desmarais, L. T. Duong, J.-P. Falgueyret, D.
B. Kimmel, S. Lamontagne, S. Le´ger, T. LeRiche, C. Sing Li, F. Masse´,
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Percival, D. Riendeau, J. Robichaud, G. A. Rodan, S. B. Rodan, C.
Seto, M. The´rien, V.-L. Truong, M. C. Venuti, G. Wesolowski, R. N.
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8 J. D. Dunitz and R. Taylor, Chem. Eur. J., 1997, 3, 89–98.
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Molecular modeling
Molecular models were built using a Silicon Graphics 4D35GT
workstation running the Insight II & Discover software. Molecular
mechanics (MM) and molecular dynamics (MD) were carried out
using cvff force-fields. The starting geometry of the peptides was
generated usingstandard bond lengths and angles. The simulations
were performed in vacuo with relative permittivity e = 1.0. At
the first step we performed a minimization by Discover with
steepest-descendent algorithm followed by conjugate gradient
minimization for a maximum of 2000 iterations each or RMS
deviation of 0.001 Kcal/mol. Then we performed MD 100 ps
simulations at a constant temperature of 300 K with distance
constraints derived from the ROE cross peaks from the ROESY
spectra in CDCl3. Distance constraints with a force constant
10 M. Molteni, A. Volonterio and M. Zanda, Org. Lett., 2003, 5, 3887–
3890.
11 S. Bigotti, A. Volonterio and M. Zanda, Synlett, 2008, 958–962.
12 T. Billard, Chem. Eur. J., 2006, 12, 974–979.
13 For a review, see: F. A. Luzzio, Tetrahedron, 2001, 57, 915–945.
14 Nitro-alkene 2 was prepared starting from a commercial available
aqueous solution of fluoral hydrate: O. Klenz, R. Evers, R. Miethchen
and M. Michalik, J. Fluorine Chem., 1997, 81, 205–210See also:; M.
Molteni, R. Consonni, T. Giovenzana, L. Malpezzi and M. Zanda, J.
Fluorine Chem., 2006, 127, 901–908.
15 For a review of asymmetric conjugate additions to nitroalkenes, see: T.
A. Johnson, D. O. Jang, B. W. Slafer, M. D. Curtis and P. Beak, J. Am.
Chem. Soc., 2002, 124, 11689–11698 and references therein.
16 In a recent work concerning a tandem process involving an aza-Michael
reaction with fluorinated acceptors, we found that the polarity of the
˚
of 15 Kcal/A were applied with a range of lower and upper
˚
bound of 2.0–3.0, 3.0–4.0, 4.0–5.0 A in accordance with the
NOE intensities of strong, medium and weak, respectively. No
H-bonding constraints was used. Every structure obtained from
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