Methanophenylalanine
J. Am. Chem. Soc., Vol. 120, No. 37, 1998 9453
orientation, without necessarily modifying their chemical nature,
is of valuable interest.1
To study the influence of the side chain orientation on the
folding mode of a peptide, we have prepared the model
dipeptides RCO-L-Pro-Xaa-NHMe (RCO ) Z, Boc, or Piv),
where Xaa represents each of the four 2,3-methanophenylalanine
diastereoisomers (denoted as c3Phe in the following text),
1-aminocyclopropanecarboxylic acid (denoted as Ac3c), and L-
or D-phenylalanine. The two dipeptides incorporating phenyl-
alanine have already been shown to adopt the type II â-turn in
the solid state and the âI- or âII-turn structure, depending on
their stereochemistry, in CH2Cl2 solution.25 We have applied
Despite their potential utility, the conformational conse-
quences of selectively oriented side chains remain almost
unexplored.1 Cyclopropane (or 2,3-methano) amino acid ana-
logues are particularly attractive from this point of view. In
addition to the restrictions imposed by R,R-disubstitution, the
rigidity of the structure forces the side chain to adopt a well-
defined orientation with respect to the backbone, and this
orientation is different for each diastereoisomer. Evidence of
this interest is provided by the effort devoted during recent years
to the synthesis of these derivatives.8 Stereoselective procedures
for the preparation of cyclopropane analogues of methionine,9
phenylalanine,10 leucine,11 arginine,12 proline,13 aspartic acid,14
glutamic acid,15 and glutamine16 have recently been reported.
Although 1-aminocyclopropanecarboxylic acid has been inserted
into a certain number of peptides,2a-d,17 there are only a few
examples concerning substituted cyclopropane analogues of
proteinogenic amino acids. 2,3-Methanophenylalanine has been
incorporated into aspartame,18 enkephalin,19 and substance P.20
Various di- and tripeptides including 2,3-methanoaspartic acid
have been synthesized.21 Theoretical and spectroscopic analyses
of some 2,3-methanomethionine- or 2,3-methanoarginine-
containing peptides have been reported.22,23 The crystal mo-
lecular structure of only one dipeptide containing 2,3-methano-
phenylalanine has been described.24
1
IR and H NMR spectroscopy to the structural analysis of the
c3Phe derivatives in solution and compared their behavior to
that of the Ac3c- and Phe-containing dipeptides. Three of the
four c3Phe diastereoisomers gave crystallized dipeptides, which
have been investigated by X-ray diffraction. Preliminary results
have recently been published elsewhere.26
Experimental Section
Synthesis. The derivatives that have been synthesized are shown
in Table 1 with their abbreviated codes. Amino esters cis-8 and trans-8
(racemic form), as well as 9, were obtained by acid hydrolysis of their
respective diphenylmethylene imino esters (Figure 1), which were
prepared following previously reported procedures.28,29 The synthesis
of the four diastereoisomers 1-4 is presented in Figure 2. cis-8 and
trans-8 were coupled to N-tert-butyloxycarbonyl-L-proline by the
classical mixed anhydride method using isobutyl chloroformate as a
coupling agent30 to give 1b-4b. Subsequent treatment of these
compounds with methylamine in methanolic solution afforded the
corresponding methylamides 1a-4a in good yields. Due to steric
hindrance arising from R,R-disubstitution and the presence of the phenyl
group, the time required for completion of the reactions was in most
cases significantly longer than that under the standard conditions. The
cis diastereoisomeric esters 1b and 2b, and the trans diastereoisomeric
amides 3a and 4a, were separated by column chromatography on silica
gel. The Boc group in 1a-4a was removed by treatment with
trifluoroacetic acid, and the amino group was acylated with pivaloyl
chloride to give 1-4. At this stage, only 1 and 3a gave single crystals
suitable for X-ray diffraction experiments. L-Proline was taken as a
reference, and the resolution of the crystal structures revealed the
absolute configuration of the c3Phe residue to be (2R,3R) in series 1
and (2R,3S) in series 3. From these results, the stereochemistry of the
cyclopropane moiety in series 2 and 4 could be established as (2S,3S)
and (2S,3R), respectively (Figure 3). This assignment was verified with
the crystal structure of 2c, obtained from 2a by changing the Boc group
(8) (a) Stammer, C. H. Tetrahedron 1990, 46, 2231-2254. (b) Alami,
A.; Calmes, M.; Daunis, J.; Jacquier, R. Bull. Soc. Chim. Fr. 1993, 130,
5-24. (c) Burgess, K.; Ho, K. K.; Moye-Sherman, D. Synlett 1994, 575-
583.
(9) Burgess K., Ke C.-Y., Synthesis 1996, 1463-1467.
(10) (a) Williams, R. M.; Fegley, G. J. J. Am. Chem. Soc. 1991, 113,
8796-8806. (b) Williams, R. M.; Fegley, G. J. J. Org. Chem. 1993, 58,
6933-6935. (c) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong N.;
Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897-6907. (d) Davies, H. M.
L.; Huby, N. J. S.; Cantrell, W. R.; Olive J. L. J. Am. Chem. Soc. 1993,
115, 9468-9479. (e) Alcaraz, C.; Ferna´ndez, M. D.; de Frutos, M. P.;
Marco, J. L.; Bernabe´, M. Tetrahedron 1994, 50, 12443-12456.
(11) Burgess, K.; Li, W. Tetrahedron Lett. 1995, 36, 2725-2728.
(12) (a) Burgess, K.; Ho, K.-K. Tetrahedron Lett. 1992, 33, 5677-5680.
(b) Burgess, K.; Lim, D.; Ho, K.-K.; Ke, C.-Y. J. Org. Chem. 1994, 59,
2179-2185.
(13) Hercouet, A.; Bessie`res, B.; Le Corre, M. Tetrahedron: Asymmetry
1996, 7, 1267-1268.
(14) Jime´nez, J. M.; Rife´, J.; Ortun˜o, R. M. Tetrahedron: Asymmetry
1996, 7, 537-558.
(15) Jime´nez, J. M.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1996, 7,
3203-3208.
(16) Burgess, K.; Lim, D. Y. Tetrahedron Lett. 1995, 36, 7815-7818.
(17) (a) Zhu, Y.-F.; Yamazaki, T.; Tsang, J. W.; Lok, S.; Goodman, M.
J. Org. Chem. 1992, 57, 1074-1081. (b) Fabiano, N.; Valle, G.; Crisma,
M.; Toniolo, C.; Saviano, M.; Lombardi, A.; Isernia, C.; Pavone, V.; Di
Blasio, B.; Pedone, C.; Benedetti, E. Int. J. Pept. Protein Res. 1993, 42,
459-465. (c) Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone, C.; Santini,
A.; Barone, V.; Fraternali, F.; Lelj, F.; Bavoso, A.; Crisma, M.; Toniolo,
C. Int. J. Biol. Macromol. 1989, 11, 353-360. (d) Valle, G.; Crisma, M.;
Toniolo, C.; Holt, E. M.; Tamura, M.; Bland, J.; Stammer, C. H. Int. J.
Pept. Protein Res. 1989, 34, 56-65. (e) Crisma, M.; Bonora, G. M.; Toniolo,
C.; Barone, V.; Benedetti, E.; Di Blasio, B.; Pavone, V.; Pedone, C.; Santini,
A.; Fraternali, F.; Bavoso, A.; Lelj, F. Int. J. Biol. Macromol. 1989, 11,
345-352. (f) Barone, V.; Fraternali, F.; Cristinziano, P. L.; Lelj, F.; Rosa,
A. Biopolymers 1988, 27, 1673-1685. (g) Benedetti, E.; Di Blasio, B.;
Pavone, V.; Pedone, C.; Santini, A.; Crisma, M.; Valle, G.; Toniolo, C.
Biopolymers 1989, 28, 175-184. (h) Mapelli, C.; Newton, M. G.; Ringold,
C. E.; Stammer, C. H. Int. J. Pept. Protein Res. 1987, 30, 498-510.
(18) Mapelli, C.; Stammer, C. H.; Look, S.; Mierke, D. F.; Goodman,
M. Int. J. Pept. Protein Res. 1988, 32, 484-495.
(19) (a) Mapelli, C.; Kimura, H.; Stammer, C. H. Int. J. Pept. Protein
Res. 1986, 28, 347-359. (b) Shimohigashi, Y.; Costa, T.; Pfeiffer, A.; Herz,
A.; Kimura, H.; Stammer, C. H. FEBS Lett. 1987, 222, 71-74. (c)
Shimohigashi, Y.; Takano, Y.; Kamiya, H.; Costa, T.; Herz, A.; Stammer,
C. H. FEBS Lett. 1988, 233, 289-293.
(20) De´ry, O.; Josien, H.; Grassi, J.; Chassaing, G.; Couraud, J. Y.;
Lavielle, S. Biopolymers 1996, 39, 67-74.
(21) Godier-Marc, E.; Aitken, D. J.; Husson, H. P. Tetrahedron Lett.
1997, 38, 4065-4068.
(22) (a) Burgess, K.; Ho, K.-K.; Pettitt, B. M. J. Am. Chem. Soc. 1994,
116, 799-800. (b) Burgess, K.; Ho, K.-K.; Pettitt, B. M. J. Am. Chem.
Soc. 1995, 117, 54-65. (c) Burgess, K.; Ho, K.-K.; Pal, B. J. Am. Chem.
Soc. 1995, 117, 3808-3819. (d) Burgess, K.; Ke, C.-Y. J. Org. Chem. 1996,
61, 8627-8631. (e) Burgess, K.; Ke, C.-Y. J. Pept. Res. 1997, 49, 201-
209. (f) Malin, D. H.; Payza, K.; Lake, R.; Corriere, L. S.; Benson, T. M.;
Smith, D. A.; Kelley, R. S.; Ho, K.-K.; Burgess, K. Peptides 1993, 14,
47-51. (g) Malin, D. H.; Lake, R.; Payza, K.; Corriere, L. S.; Benson, T.
M.; Garber, T. L.; Waller, M. L.; Luu, T.-A.; Kelley, R. S.; Smith, D. A.;
Ho, K.-K.; Burgess, K. Peptides 1993, 14, 731-734.
(23) Lim, D.; Burgess, K. J. Am. Chem. Soc. 1997, 119, 9632-9640.
(24) Varughese, K. I.; Wang, C. H.; Kimura, H.; Stammer, C. H. Int. J.
Pept. Protein Res. 1988, 31, 299-300. Due to the erroneous stereochemistry
of the L-Leu residue, the chirality of the 2,3-methanophenylalanine must
be changed into (2S,3R).
(25) Aubry, A.; Cung, M. T.; Marraud, M. J. Am. Chem. Soc. 1985,
107, 7, 7640-7647.
(26) Jime´nez, A. I.; Vanderesse, R.; Marraud, M.; Aubry, A.; Cativiela,
C. Tetrahedron Lett. 1997, 38, 7559-7562.
(27) Bardi, R.; Piazzesi, A. M.; Toniolo, C.; Sen, N.; Balaram, H.;
Balaram, P. Acta Crystallogr., Sect. C 1988, 44, 1972-1976.
(28) Cativiela, C.; D´ıaz-de-Villegas, M. D.; Jime´nez, A. I. Tetrahedron
1994, 50, 9157-9166.
(29) Cativiela, C.; D´ıaz-de-Villegas, M. D.; Jime´nez, A. I. Synth.
Commun. 1992, 22, 2955-2963.
(30) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis;
Springer-Verlag: Berlin, Germany, 1994.