Synthesis of mono Nα-trifluoroethylated cyclic dipeptides

Article abstract of DOI:10.1016/j.tetlet.2005.11.038

Trifluoroethylated N-termini in linear dipeptides l-TyrXOR [X = Gly, D-Ala, L-Leu, L-Phe, and L-Glu; R = H, Me, Et] exhibit sufficient nucleophilicity to give piperazine-2,5-dione ring formation through intramolecular cyclization reaction in acidic aqueou

Full text of DOI:10.1016/j.tetlet.2005.11.038

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 561–564
Synthesis of mono Na-trifluoroethylated cyclic dipeptides
Darryl D. DesMarteau* and Changqing Lu
Department of Chemistry, Clemson University, Clemson, SC 29634-0973, USA
Received 9 June 2005; revised 3 November 2005; accepted 8 November 2005
Available online 28 November 2005
Abstract—Trifluoroethylated N-termini in linear dipeptides L-TyrXOR [X = Gly, D-Ala, L-Leu, L-Phe, and L-Glu; R = H, Me, Et]
exhibit sufficient nucleophilicity to give piperazine-2,5-dione ring formation through intramolecular cyclization reaction in acidic
aqueous solutions. The reactions occur in high yield and with absolute configuration retention.
Ó 2005 Elsevier Ltd. All rights reserved.
Cyclic peptides are one class of naturally occurring priv-
ileged structures.1 In comparison to linear peptides, cyc-
lic peptides are more bioavailable and more stable to
degradative peptidases.1,2 Cyclic dipeptides (piperazine-
2,5-diones or 2,5-diketopiperazines DKPs) are among
the simplest peptide derivatives commonly found in nat-
ure.3,4 They are a small, conformationally constrained
heterocyclic scaffold that orientates its substituents in a
spatially defined manner,5,6 and they are typically stable
to proteolysis.7,8 These characteristics make cyclic dipep-
tides attractive scaffolds for medicinal chemistry,9–13 as
well as agricultural applications.14 The earliest report
of what was later found to be a cyclic dipeptide, cyclo-
[Leu-Leu], dates back to 1849.15 The spontaneous forma-
tion of cyclo-[Gly-Gly] from moist H-Gly-OEt was
reported in 1883.16 Soon, it was realized that cyclic
dipeptides could be synthesized efficiently from amino
acid esters.17 Since then, numerous symmetrical and
unsymmetrical cyclic dipeptides have been prepared
through both solution phase and solid phase synthesis,
followed by cyclization reactions.13,18–22 The cyclization
reactions have been shown to be either acid or base cat-
alyzed.18,20,22–24
Once the CF3CH2– group is transferred to the Na-group
of amino acids, it acts as a protecting group (like Boc,
Fmoc, Z, etc.) in conventional peptide synthesis except
that it is not removable under standard deprotection
conditions. Therefore, Na-trifluoroethylated amino
acids have been used as the N-terminus in peptide syn-
thesis.27 The question of whether or not the CF3CH2–
group is an absolute protecting group for a-amino acids
under any circumstances has not been answered. Previ-
ously we showed that pK2 for Na-CF3CH2-GlyOHÆHCl
was 5.3, compared to pKa 5.6 for CF3CH2NH2ÆHCl.
While the latter will couple with Z-PheOH, the former
did not under the same conditions. Since CF3CH2-
NHCH(CH3)Ph and CF3CH2NHCH2CH2Ph also failed
to undergo coupling under the same conditions, it was
reasoned that steric factors were probably important,
in addition to the decreased basicity of the nitrogen.26
Herein, we report the unexpected formation of 3-(S)-
[(4-hydroxyphenyl)methyl]-4-[(2,2,2-trifluoro)ethyl]-2,5-
piperazinedione 1 and its analogues via intramolecular
cyclization at the nitrogen of Na-trifluoroethylated
amino acids.
O
We have successfully transferred the trifluoroethyl
group (CF3CH2–) to the functionalities, –SH, –NH2,
–NH–, –COOH, and –OH, of a-amino acids using the
novel iodonium salt CF3CH2I(C6H5)N(SO2CF3)2.25,26
N
CF3CH2
NH
O
Keywords: Trifluoroethylation; Nucleophilicity; Intramolecular cycli-
zation; Cyclic dipeptide.
OH
*
Corresponding author. Tel.: +1 864 656 4705; fax: +1 864 656
0627; e-mail: fluorin@clemson.edu
1
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.038

562
D. D. DesMarteau, C. Lu / Tetrahedron Letters 47 (2006) 561–564
NH2
NH
CF3CH2
NH
CF3CH2
O
O
OH
O
O
O
a
b, c
OH
OH
OH
2
3
4
Scheme 1. Reagents and conditions: (a) CF3CH2I(C6H5)N(SO2CF3)2, CH2Cl2/H2O, NaHCO3, rt, 3 h; (b) 1 M NaOH, rt, 10 h; (c) 0 °C, concd HCl
to pH 4.5, overall 95% for 4.
The linear dipeptide ester Na-CF3CH2-L-Tyr-Gly-OEt 5
was synthesized as follows. The reaction of L-tyrosine
ethyl ester 2 with trifluoroethyl phenyliodonium bis-
((trifluoromethyl)sulfonyl)imide CF3CH2I(C6H5)N(SO2-
CF3)2 in the two phase solvents CH2Cl2/H2O resulted
in Na-trifluoroethylated L-tyrosine ethyl ester 3. The
ethyl ester was then cleaved by basic hydrolysis fol-
lowed by acidification with conc. HCl to pH between
4 and 5 to give Na-trifluoroethylated L-tyrosine 4
(Scheme 1). The dipeptide ester 5 was synthesized in
solution phase by coupling 4 with glycine ethyl ester
(Scheme 2).
zation of 5 was carried out in refluxing acidic aqueous
solution for 14 h to give 1 in 83% yield.
The X-ray structure of 1 is shown in Figure 1. The piper-
azine-2,5-dione ring is not planar, but slightly buckles
toward the boat conformation. Compound 1 has a
folded conformation in which the piperazine-2,5-dione
ring faces the aromatic ring. This conformation is
believed to result from either the interaction between
amide dipoles and dipoles induced in the aromatic p
electron cloud43 or a C(4)H/p interaction.44 The p–p
donor–acceptor interaction is not a major factor in sta-
bilizing the face-to-face arrangement of rings.45 The
crystal of cyclo-[Na-trifluoroethyl-L-tyrosyl-glycine] 1 is
monoclinic (space group P21), which is different from
orthorhombic (space group P212121)46,47 reported for
cyclo-[glycyl-L-tyrosine], presumably because of intro-
duction of CF3CH2– group onto the nitrogen atom of
L-tyrosine in 1.
Cyclic dipeptides have been shown to spontaneously
form from amino acid esters under mild condi-
tions,3,16,28 although amino ester salts are usually stable
as solids. The identity of the amino acid may determine
the degree to which spontaneous cyclic dipeptide forma-
tion occurs.22 Cyclic dipeptide formation, today
regarded by peptide chemists mostly as a troublesome
side reaction during peptide chain assembly,29–32 actu-
ally represented the first successful attempt at linking
two a-amino acids through a peptide bond.33,34 Most
symmetrical cyclic dipeptides can be synthesized simply
by heating the free amino acid esters.18 The unsymmet-
rical cyclic dipeptides could be synthesized by treating
dipeptide esters with methanolic ammonia. However,
the strongly basic conditions in this procedure could
result in epimerization.35 The other methods less prone
to loss of chiral integrity had also been developed. Lich-
tenstein36 used molten b-naphthol at 135–140 °C as the
solvent for the cyclization of peptides. Kopple and
Similarly, several other trifluoroethylated cyclic dipep-
tides 6–9 were synthesized in high yields (82–95% via
cyclization reaction). Both NMR data and X-ray struc-
ture analysis confirmed the absolute configuration reten-
tion of all chiral centers.
O
O
CF3CH2N
CF3CH2N
NH
NH
O
Ghazarian37 developed
a one-step conversion of
O
unblocked dipeptides or their hydrobromide salts to
cyclic dipeptides in hot phenol. Dipeptide esters were
cyclized in boiling 2-butanol/toluene mixtures38 or in
refluxing 2-butanol containing 0.1 M HOAc.39 For
many cyclic dipeptides, however, simple reflux of dipep-
tidyl methyl esters in low-boiling solvents, particularly
methanol, was effective.40 Thermal polymerization at
170–180 °C also provided cyclic dipeptides.41,42
OH
OH
6
7
O
O
O
O
CF3CH2N
CF3CH2N
OCH3
NH
Initially, we did not expect the trifluoroethylated a-ami-
no group in the linear dipeptides to have much reactivity
as a nucleophile.26 A sample of the linear dipeptide 5
was left in acidic aqueous solution at room temperature
for 2 months and crystals were observed. These unex-
pected crystals were subjected to X-ray structure analy-
sis, which showed that the linear dipeptide of 5 had
cyclized to piperazine-2,5-dione. Subsequently, the cycli-
NH
O
OH
OH
8
9

D. D. DesMarteau, C. Lu / Tetrahedron Letters 47 (2006) 561–564
NH
563
O
CF3CH2
NH
O
O
d
H2N
e
4
+
O
1
O
OH
5
Scheme 2. Reagents and conditions: (d) HOBt, EDAC, DIPEA, CH2Cl2, 0 °C to rt, 6 h, 93%; (e) H2O, concd HCl to pH 0.5, reflux, 14 h, 83% for 1.
tions used with I > 2r(I); 2hmax = 54.94°; 238 para-
meters; non-H atoms refined anisotropically; H atoms
˚
fixed in calculated positions (C–H = 0.96 A); full-matrix
least-squares on F2 refinement; R = 3.88%/Rw(F2) =
10.14%. CCDC 233027.
Acknowledgments
Financial support of this research by the National
Science Foundation is gratefully acknowledged. Crystal-
lographic data were supplied by Dr. Don VanDerveer.
We thank Dr. R. V. Rajagopal for useful discussions.
Figure 1. Crystal structure of 1.
Supplementary data
The spectral data and crystallographic data of com-
Under the same conditions, the Fmoc-protected linear
pounds 6–9 are included in the supplementary data.
dipeptide Fmoc-Gly-Phe-OMe did not undergo the
Supplementary data associated with this article can be
cyclization reaction.
found, in the online version, at doi:10.1016/j.tetlet.
2005.11.038.
From these results it is clear that the trifluoroethylated
N-termini in linear dipeptides can still undergo amide
bond formation through intramolecular cyclization
reaction in acidic aqueous solutions. Future work will
References and notes
be focused on the effects of bases on the cyclization
reaction of N-terminal trifluoroethylated linear dipep-
tides, given the lowered pKa of the trifluoroethylated
N-termini.
1. Horton, D. A.; Bourne, G. T.; Smythe, M. L. J. Comput.
Aided Mol. Des. 2002, 16, 415–430.
2. Kohli, R. M.; Walsh, C. T.; Burkart, M. D. Nature 2002,
418, 658–661.
3. Prasad, C. Peptides 1995, 16, 151–164.
4. Witiak, D. T.; Wei, Y. Prog. Drug Res. 1990, 35, 249–363.
5. Anteunis, M. J. O. Bull. Soc. Chim. Belg. 1978, 87,
627–650.
6. Herbert, R. H.; Kelleher, F. Tetrahedron Lett. 1994, 35,
5497–5500.
Spectral data for 1: dH (500.16 MHz, CD3CN): 2.52
(1H, d, J = 17.7 Hz), 3.09 (2H, mc (centered multiplet)),
3.49 (1H, dd, J = 17.7, 4.1 Hz), 3.57 (1H, mc), 4.23
(0.5H, d, J = 4.1 Hz), 4.24 (0.5H, d, J = 4.5 Hz), 4.70
(1H, mc), 6.63 (1H, br s), 6.75 (2H, d, J = 8.5 Hz),
6.96 (2H, d, J = 8.5 Hz); dF (470.62 MHz, CD3CN):
À69.4 (3F, t, J = 9.2 Hz); dC (125.76 MHz, CD3CN):
35.7, 43.6, 44.0 (q, J = 33.6 Hz), 62.6, 115.4, 124.7 (q,
J = 280.4 Hz), 125.6, 131.3, 156.8, 166.1, 167.5; MS
(EI) m/z: formula C13H13N2O3F3, calcd 302.08, found
302.04.
7. Morley, J. E.; Levine, A. S.; Prasad, C. Brain Res. 1981,
210, 475–478.
8. Szardnings, A. K.; Burkoth, T. S.; Lu, H. H.; Tien, D. W.;
Campbell, D. A. Tetrahedron 1997, 53, 6573–6593.
9. Rhee, K. H. Int. J. Antimicrob. Agents 2004, 24, 423–427.
10. Cui, C.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52,
12651–12666.
11. Funabashi, Y.; Horiguchi, T.; Iinuma, S.; Tanida, S.;
Harada, S. J. Antibiot. 1994, 47, 1202–1218.
12. Krchnak, V.; Weichsel, A. S.; Cabel, D.; Flegelova, Z.;
Lebl, M. Mol. Div. 1996, 1, 149–164.
13. Acharya, A. N.; Ostresh, J. M.; Houghten, R. A. J. Comb.
Chem. 2001, 3, 612–623.
14. Ienaga, K.; Nakamura, K.; Kurohashi, M.; Nakanishi, T.;
Ichii, T. Phytochemistry 1990, 29, 35–39.
15. Bopp, F. Liebigs Ann. Chem. 1849, 69, 16–37.
16. Curtius, T. Chem. Ber. 1883, 16, 753–757.
Crystallographic data for 1: Formula, C13H13N2O3F3;
monoclinic;
P21;
T = 293(2) K;
a = 7.6822(15),
b = 106.16(3)°;
; Z = 2; l =
˚
b = 10.906(2),
c = 8.7170(17) A,
V = 701.5(2) A ; Dcalc = 1.431 g cmÀ3
3
˚
0.128 mmÀ1; empirical absorption correction (0.9135–
0.9272); Mo-Ka radiation with graphite monochroma-
˚
tor, k = 0.71073 A; Rigaku AFC-8S diffractometer;
7203 measured reflections (Rint = 1.59%); 3068 reflec-

564
D. D. DesMarteau, C. Lu / Tetrahedron Letters 47 (2006) 561–564
17. Curtius, T.; Goebel, F. J. Prakt. Chem. 1888, 37, 173–181.
18. Fischer, P. M. J. Peptide Sci. 2003, 9, 9–35.
19. Muller-Hartwieg, J. C. D.; Akyel, K. G.; Zimmermann, J.
J. Peptide Sci. 2003, 9, 187–199.
20. Dinsmore, C. J.; Beshore, D. C. Tetrahedron 2002, 58,
3297–3312.
32. Fischer, P. M.; Solbakken, M.; Undheim, K. Tetrahedron
1994, 50, 2277–2288.
33. Kohler, A. Liebigs Ann. Chem. 1865, 134, 367–372.
34. Fischer, E.; Forneau, E. Chem. Ber. 1901, 34, 2868–2877.
35. Rosenmund, P.; Kaiser, K. Angew. Chem., Int. Ed. Engl.
1970, 9, 162–163.
21. Rodionov, I. L.; Rodionova, L. N.; Baidakova, L. K.;
Romashko, A. M.; Balashova, T. A.; Ivanov, V. T.
Tetrahedron 2002, 58, 8515–8523.
36. Lichtenstein, N. J. Am. Chem. Soc. 1938, 60, 560–563.
37. Kopple, K. D.; Ghazarian, H. G. J. Org. Chem. 1968, 33,
862–864.
22. del Fresno, M.; Alsina, J.; Royo, M.; Barany, G.;
Albericio, F. Tetrahedron Lett. 1998, 39, 2639–2642.
23. Akiyama, M.; Katoh, A.; Tsuchiya, Y. J. Chem. Soc.,
Perkin Trans. 1 1989, 235–239.
38. Nitecki, D. E.; Halpern, B.; Westley, J. W. J. Org. Chem.
1968, 33, 864–866.
39. Suzuki, K.; Sasaki, Y.; Endo, N.; Mihara, Y. Chem.
Pharm. Bull. 1981, 29, 233–237.
24. Sollis, S. L. J. Org. Chem. 2005, 70, 4735–4740.
25. DesMarteau, D. D.; Montanari, V. Chem. Commun. 1998,
20, 2241–2242.
26. DesMarteau, D. D.; Montanari, V. Chem. Lett. 2000, 9,
1052–1053.
27. DesMarteau, D. D.; Montanari, V. J. Fluorine Chem.
2001, 109, 19–23.
28. Kertscher, U.; Bienert, M.; Krause, E.; Sepetov, N. F.;
Mehlis, B. Int. J. Peptide Protein Res. 1993, 41, 207–211.
29. Goodman, M.; Stueben, K. C. J. Am. Chem. Soc. 1962, 84,
1279–1283.
40. Ueda, T.; Saito, M.; Kato, T.; Izumiya, N. Bull. Chem.
Soc. Jpn. 1983, 56, 568–572.
41. Hartmann, J.; Brand, M. C.; Dose, K. BioSystems 1981,
13, 141–147.
42. Obrecht, D.; Heimgartner, H. Helv. Chim. Acta 1987, 70,
102–115.
43. Kopple, K. D.; Marr, D. H. J. Am. Chem. Soc. 1967, 89,
6193–6200.
44. Umezawa, Y.; Tsuboyama, S.; Takahashi, H.; Uzawa, J.;
Nishio, M. Bioorg. Med. Chem. 1999, 7, 2021–2026.
45. Ziauddin; Kopple, K. D. J. Org. Chem. 1970, 35, 253–255.
46. Webb, L. E.; Lin, C. J. Am. Chem. Soc. 1971, 93, 3818–
3819.
30. Gisin, B. F.; Merrifield, R. B. J. Am. Chem. Soc. 1972, 94,
3102–3106.
31. Barany, G.; Albericio, F. J. Am. Chem. Soc. 1985, 107,
4936–4942.
47. Lin, C.; Webb, L. E. J. Am. Chem. Soc. 1973, 95, 6803–
6811.