4160
C. Abbas et al. / Tetrahedron Letters 50 (2009) 4158–4160
5 into 6 can be performed in good yields by ‘one-pot’ reaction
involving first a secondary amine (pyrrolidine) followed by tert-bu-
tyl-dicarbonate (Boc2O) and, in the last step, methylamine as reac-
Supplementary data
Supplementary data associated with this article can be found, in
tants (Scheme 3). In this way, we obtained the expected 2:1-[
a/
aza]-oligomer precursors.
References and notes
Preliminary conformational studies by XR diffraction showed
that no intramolecular hydrogen bond took place in Boc-azXaa-
Ala-OMe compounds, resulting in an unfolded pseudodipeptide
(not shown). In contrast, when coupled to another amino acid,
the resulting pseudotripeptide Boc-Phe-azPhe-Ala-OMe 7 adopted
a b-turn-folded structure (Fig. 1).
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Weinstein, B., Ed.; Marcel Dekker: New York and Basel, 1983; Vol. 7, pp 267–357.
2. Singh, T. P.; Narula, P.; Patel, H. C. Acta Crystallogr., Sect. B 1990, 46, 539–545.
3. Toniolo, C. Janssen Chim. Acta 1993, 11, 10–16.
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6. Hart, M.; Beeson, C. J. Med. Chem. 2001, 44, 3700–3709.
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Sakamoto, M.; Tuhy, P. M. J. Biol. Chem. 1984, 259, 4288–4294.
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12. Boeglin, D.; Lubell, W. D. J. Comb. Chem. 2005, 7, 664–678.
13. The following abbreviations are used: azXaa, aza-analogue of Xaa a-amino acid
a
a
(N -substituted for C H).
14. (a) Brosse, N.; Grandeury, A.; Jamart-Grégoire, B. Tetrahedron Lett. 2002, 43,
2009–2011; (b) Bouillon, I.; Brosse, N.; Vanderesse, R.; Jamart-Grégoire, B.
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R.; Jamart-Grégoire, B. Tetrahedron 2007, 63, 2223–2234; (d) Bouillon, I.;
Vanderesse, R.; Brosse, N.; Fabre, O.; Jamart-Grégoire, B. Tetrahedron 2007, 63,
9635–9641; (e) Felten, A.-S.; Vanderesse, R.; Brosse, N.; Didierjean, C.; Jamart-
Grégoire, B. Tetrahedron Lett. 2008, 49, 156–158.
15. Brosse, N.; Pinto, M.-F.; Jamart-Grégoire, B. Eur. J. Org. Chem. 2003, 4757–4764.
16. Lipshutz, B. H.; Chung, D. W.; Rich, B.; Corral, R. Org. Lett. 2006, 8, 5069–5072.
17. General procedure: N-alkyl-N-tert-butyloxycarbonylaminophthalimides 2:
Under N2 to a dry THF solution of N-tert-butyloxycarbonylaminophthalimide
1 (1 equiv), PPh3 (1.5 equiv), and alcohol (3 equiv), was added in one portion
DEAD (1.5 equiv) under stirring at 0–5 °C. The resulting solution was stirred
overnight (monitored by TLC until completion) and concentrated under
vacuum. The residue was triturated with EtOAc, placed in the refrigerator
and most of the triphenylphosphine oxide removed by filtration. The filtrate
was evaporated and the residue was purified by column chromatography on
silica gel affording 2.N-Alkylaminophthalimides 3: To a solution of 2 (1 equiv)
in CH2Cl2 was added trifluoroacetic acid (10 equiv, 8% in CH2Cl2) at 0 °C. The
mixture was stirred overnight (monitored by TLC). The solution was
concentrated in vacuo. The residue was dissolved in CH2Cl2, neutralized with
a saturated solution of NaHCO3 (pH 7), and extracted three times with CH2Cl2.
The combined organic layers were dried over MgSO4 and evaporated in vacuo
giving 3 as a yellow solid which was used without further purification.Phth-
azXaa-Ala-OMe 5: Triphosgene (0.37 equiv) was dissolved in dry CH2Cl2 under
N2. A mixture of 3 (1 equiv) and DIEA (2.2 equiv) in dry CH2Cl2 was added
dropwise to the stirred solution of triphosgene. After a further 10 min stirring,
a solution of alanine methyl ester hydrochloride (1 equiv) and DIEA (1.5 equiv)
in dry CH2Cl2 was added in one portion. The reaction mixture was stirred
overnight at rt, evaporated to dryness, dissolved in CH2Cl2, washed with
aqueous HCl 1 N, aqueous NaHCO3 1 N and brine, dried over MgSO4, and
evaporated (For purification conditions see Supplementary data).Boc-azXaa-
Ala-OMe 6: To a solution of Phth-azXaa-Ala-OCH3 5 (1 equiv) in THF was added
pyrrolidine (3 equiv) at rt. The mixture was stirred at rt until completion
(overnight, monitored by TLC). The solvent and the excess of amine were
removed under vacuum. The obtained yellow solid was dissolved in THF. Then
Boc2O (1.5 equiv) and a catalytic amount of DMAP (0.2 equiv) were added. The
mixture was stirred at rt until completion (overnight, monitored by TLC). The
solvent was removed under vacuum, the residue was dissolved in THF and a
freshly prepared solution of methylamine (1.5 equiv, 2 M in MeOH) was added
at rt. After a night (monitored by TLC), the solvent and the excess of amine
were removed under vacuum and the residue was purified by column
chromatography on silica gel.Compound 6a (as an example): white solid,
mp: 84 °C; 1H NMR (300 MHz, CDCl3): d 1.39 (d, 3H, CH3), 1.49 (s, 9H, C(CH3)3),
3.11 (s, 3H, NCH3), 3.74 (s, 3H, COOCH3), 4.48 (q, 1H, CH), 5.87 (d, 1H, NH), 6.49
(br s, 1H, NHBoc); 13C NMR (300 MHz, CDCl3): d 19.4 (CH3), 28.8 (C(CH3)3), 36.3
(NCH3), 49.7 (CH), 52.9 (COOCH3), 82.7 (C(CH3)3), 155.2 (COOtBu), 158.1 (O@C–
NH), 174.9 (COOCH3). HR-MS (ESI) calculated for C11H22N3O5 [M+H]+ m/z
276.1554, found 276.1571.
Figure 1. Crystal structure of Boc-Phe-azPhe-Ala-OMe 7.
The crystal structure of the Boc-Phe-azPhe-Ala-OMe shows that
the a-nitrogen is not planar, with a distance of 0.24(2) Å from the
plane defined by the three atoms bonded to it, so that the aza-res-
idue exhibits an R (D-like) chirality. The pseudo tripeptide is folded
by a i+3?i hydrogen bond involving the (Ala)NH and (Boc)CO
groups. All the amide bonds are trans-planar and the values of
the torsional angles are typical of a bII-turn. This fold was already
observed by our group in the sequence Pro-azXaa (with Xaa = Ala
or Asn).18 The folded Boc-Phe-azPhe-Ala-OMe structure is interest-
ing because it shows that aza-residues do not need the proline for
the induction of b-folded structures. This result is in total agree-
ment with the NMR studies and ab initio calculations described
by Lee et al.19
In conclusion, we describe here a new general protocol for
obtaining various Boc-azXaa-Xbb-OMe building blocks for intro-
duction into biologically active peptides and oligomers. The fact
that the coupling of this building block with an amino acid induces
a bII-turn is very promising and we expect that the iteration of this
modification throughout the entire sequence will favor a highly
structured pseudopeptide. We are studying extensively the oligo-
merization of the aza-dipeptide building block aiming to obtain
new foldamers.
18. André, F.; Boussard, G.; Bayeul, D.; Didierjean, C.; Aubry, A.; Marraud, M. J. Pep.
Res. 1997, 49, 556–562.
Acknowledgment
19. (a) Lee, H. J.; Park, H. M.; Lee, K. B. Biophys. Chem. 2007, 125, 117–126; (b) Lee,
H. J.; Lee, K. B.; Ahn, I. A.; Ro, S.; Choi, K. H.; Choi, Y. S. J. Pept. Res. 2000, 56, 35–
46.
The authors thank the National Research Agency (ANR) for
financial support (No. NT05_4_42848).