A. Mollica et al. / Tetrahedron Letters 51 (2010) 1333–1335
1335
involvement of the near backbone amide groups, in the cyclization
reaction of the activated Glu side chain, adds useful information on
the synthesis of lactam-constrained dipeptides22 suggesting that,
under the adopted reaction conditions, the formation of a five-
membered ring prevails, as driving force of the reaction, on the
concurrent expected cyclization leading to a six-membered lactam
ring.
O
O
H
N
H
N
Boc
Boc
NH2
N
H
O
9
References and notes
O
O
1. Jones, J. In The Chemical Synthesis of Peptides; Rowlinson, J. S., Ed.; Clarendon
Press: Oxford, 1994; pp 93–94.
2. MacArthur, M. W.; Thornton, J. M. J. Mol. Biol. 1991, 218, 397–412.
3. Shi, T.; Spain, S. M.; Rabenstein, D. L. J. Am. Chem. Soc. 2004, 126, 790–796.
4. Shi, T.; Spain, S. M.; Rabenstein, D. L. Angew. Chem., Int. Ed. 2006, 45, 1780–
1783.
H
N
N
NH2
N
H
O
5. Che, Y.; Marshall, G. R. Biopolymers 2006, 81, 392–406.
6. Kang, Y. K. J. Phys. Chem. B 2006, 110, 21338–21348.
7. Rose, G. D.; Gierasch, L. M.; Smith, J. A. Adv. Protein Chem. 1985, 37, 1–109.
8. Hayashi, T.; Asai, T.; Ogoshi, H. Tetrahedron Lett. 1997, 38, 3039–3042.
9. Baeza, J. L.; Gerona-Navarro, G.; Perez de Vega, M. J.; Garcia-Lopez, M. T.;
González-Muñiz, R.; Martin-Martínez, M. J. Org. Chem. 2008, 73, 1704–1715.
10. Mutter, M. J. Am. Chem. Soc. 1977, 99, 8307–8314.
11. Rückle, T.; deLavallaz, P.; Keller, M.; Dumy, P.; Mutter, M. Tetrahedron 1999, 55,
11281–11288.
12. Pravda, Z.; Rudinger, J. Collect. Czech. Chem. Commun. 1955, 20, 1–8.
13. Monteiro, H. J. Synthesis 1974, 137.
14. Lawson, P. J.; McCarthy, M. J.; Sargeson, A. M. J. Am. Chem. Soc. 1982, 104, 6710–
6716.
15. Olsen, R. K.; Ramasamy, K.; Emery, T. J. Org. Chem. 1984, 49, 3527–3534.
16. Drauz, K.; Kleemann, A.; Martens, J.; Scherberich, P.; Effenberger, F. J. Org. Chem.
1986, 51, 3494–3498.
17. Yamaguchi, J.-i.; Ueki, M. Chem. Lett. 1996, 8, 621–622.
18. Córdova, A.; Reed, N. N.; Ashley, A. J.; Janda, K. D. Bioorg. Med. Chem. Lett. 1999,
9, 3119–3122.
19. Ma, Z.-s.; Li, P.; Chen, K.-x. Xibei Daxue Xuebao 2000, 30, 403–405.
20. Siebum, A. H. J.; Tsang, R. K. F.; van der Stehen, R.; Raap, J.; Lugtenburg, J. Eur. J.
Org. Chem. 2004, 4391–4396.
21. Jiang, S.; Li, P.; Lai, C. C.; Kelley, J. A.; Roller, P. P. J. Org. Chem. 2006, 71, 7307–
7314.
10
Figure 1. Structure of alternative cyclization products 9 and 10 cited in the text.
was induced by treatment with NaH (4 equiv) in anhydrous THF at
room temperature for 48 h. A crude single product was isolated
and purified by silica gel preparative layer chromatography (90%
yield). Examination of the 1H NMR spectrum in DMSO-d6 on this
compound revealed the presence, in addition to the urethane NH
doublet (6.81 d) of only one amide NH doublet (7.82 d) clearly cou-
a
pled with the Phe C H, confirmed by 1D TOCSY NMR experiments.
On the basis of these evidences the structure of Boc-Val-Pro-Phe-
NH2 (7) was assigned to the product and the assignment was
confirmed by its independent synthesis, performed by following a
synthetic pathway analogous to that reported in Scheme 1 for com-
pound 4 and by using Boc-Pro-OH in the place of Boc-Glu(OMe)-
OH.23
22. Freidinger, R. M.; Schwenk Perlow, D.; Veber, D. F. J. Org. Chem. 1982, 47, 104–
109.
It should be noted that in the adopted cyclization conditions
neither the a,a-disubstituted derivative 9 deriving from the intra-
23. Chemical and spectral data (1H NMR, 300 MHz, TMS, DMSO-d6,) for compounds
4–8: Compound 4: d = 0.76 (m, 6H, –CH(CH3)2), 1.35 (s, 9H, Boc), 1.71–1.91 (m,
residue alkylation of the Glu C -carbon atom,17 nor the Freidinger
d-lactam 1022 (Fig. 1) was found. However, when the starting tripep-
tide mesylate 6 was treated with a higher excess of NaH (Scheme 2,
route d) to induce the cyclization reaction, a mixture (about in equal
parts) of the homochiral tripeptide 7 and its diastereomer was ob-
tained. Isolation and preliminary examination of the 1H NMR data
of this new component suggested an epimerization at the phenylal-
anine chiral center of the tripeptide. By following this indication an
authentic specimen of Boc-Val-Pro-DPhe-NH2 (8) was synthesized
starting from Boc-Pro-DPhe-NH2 and by following the same proce-
dures reported in Scheme 1 and 2. Tripeptide 8 resulted to be
identical to that formed, together with 7, when prolonged reaction
time and higher excess of NaH were adopted in the cyclization
reaction.
a
3H, b-CH2-Glu and –CH(CH3)2), 2.25 (m, 2H,
CH2-Phe), 3.54 (s, 3H, –OCH3), 3.76 (m, 1H,
4.41 (m, 1H, -CH Phe), 6.82 (d, 1H, NH-Val), 7.07–7.41 (m, 7H, CONH2 and
c
-CH2-Glu), 2.73–3.01 (m, 2H, b-
a
-CH-Val), 4.26 (m, 1H, -CH-Glu),
a
a
aromatics), 7.83 (d, 1H, NH-Glu), 7.98 (d, 1H, NH-Phe).
Compound 5: d = 0.75 (m, 6H, –CH(CH3)2), 1.35 (s, 9H, Boc), 1.43–1.60 (m, 4H, b-
CH2 and
3.31 (m, 2H, –CH2OH), 3.75 (m, 1H,
1H, -CH-Phe), 6.52 (s, 1H, –OH), 6.75 (d, 1H, NH-Val), 7.04–7.34 (m, 7H,
c
-CH2-Glu), 1.89 (m, 1H, –CH(CH3)2), 2.77–2.97 (m, 2H, b-CH2-Phe),
a
-CH-Val), 4.20 (m, 1H, -CH-Glu), 4.41 (m,
a
a
CONH2 and aromatics), 7.75 (d, 1H, NH-Glu), 7.94 (d, 1H, NH-Phe).
Compound 6: d = 0.75 (m, 6H, –CH(CH3)2), 1.34 (s, 9H, Boc), 1.56–1.66 (m, 4H, b-
CH2 and
3.13 (s, 3H, –SO2CH3), 3.73 (m, 1H,
1H, -CH-Glu), 4.41 (m, 1H, -CH-Phe), 6.80 (d, 1H, NH-Val), 7.05–7.41 (m, 7H,
c
-CH2-Glu), 1.89 (m, 1H, –CH(CH3)2), 2.74–2.98 (m, 2H, b-CH2-Phe),
a
-CH-Val), 4.12 (m, 2H, –CH2O–), 4.28 (m,
a
a
CONH2 and aromatics), 7.82 (d, 1H, NH-Glu), 8.01 (d, 1H, NH-Phe).
Compound 7: d = 0.87 (m, 6H, –CH(CH3)2), 1.34 (s, 9H, Boc), 1.72–1.96 (m, 5H, b-
CH2 and
(m, 2H, d-CH2-Pro), 4.00 (m, 1H,
c
-CH2-Pro and –CH(CH3)2), 2.75–3.02 (m, 2H, b-CH2-Phe), 3.32–3.65
-CH-Val), 4.27 (m, 2H, -CH-Phe and -CH-
a
a
a
Pro), 6.81 (d, 1H, NH-Val), 7.04–7.23 (m, 7H, CONH2 and aromatics), 7.82 (d,
1H, NH-Phe). Rf 0.30 (Silica gel TLC; EtOAc). Anal. Calcd for C24H36N4O5: C,
62.59; H, 7.88; N, 12.16. Found: C, 62.54; H, 7.80; N, 12.20.
In summary, we have demonstrated that glutamic acid can be
converted into the constrained five-membered ring of proline after
its insertion in the peptide backbone and with maintenance of the
starting stereochemistry. This new result, although at the present
only applied to the N-Boc protected tripeptide amide 4 and still
requiring generalization, appears of interest in the chemistry of
peptides and should help to limit undesired cyclic or oligomeric
products during the syntheses. In addition to this, the lack of
Compound 8: d = 0.82 (m, 6H, –CH(CH3)2), 1.34 (s, 9H, Boc), 1.72–1.85 (m, 5H, b-
CH2 and
(m, 2H, d-CH2-Pro), 3.90 (m, 1H,
1H, -CH-Phe), 6.82 (d, 1H, NH-Val), 7.13–7.28 (m, 7H, CONH2 and aromatics),
c
-CH2-Pro and –CH(CH3)2), 2.62–3.18 (m, 2H, b-CH2-Phe), 3.38–3.68
a
-CH-Val), 4.20 (m, 1H, -CH-Pro), 4.32 (m,
a
a
8.36 (d, 1H, NH-Phe). Rf 0.35 (Silica gel TLC; EtOAc). Anal. Calcd for C24H36N4O5:
C, 62.59; H, 7.88; N, 12.16. Found: C, 62.65; H, 7.95; N, 12.10.