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Fig. 2 Conformations of 12a and 12b.
minor diequatorial conformer would not be expected to be
observable at room temperature by NMR analysis, and 1H NMR
VT analysis provided no evidence for the diequatorial con-
former even at 223 K. The stability of the diaxial conformer
could be attributed to the presence of A-strain35 between the two
substituents and the planar amide system; the importance of
torsional strain in five- and six-membered ring heterocycles for
the control of stereochemistry has been investigated in detail,36
although its importance in lactams has only recently been
appreciated.37 Thus, the diaxial conformer minimises the
interations of the relatively bulky C(2) and C(4) substituents
with the planar amide function (which would occur in the
diequatorial conformer 12a) by placing C(2)-H and C(4)-H in
an eclipsing conformation with the lactam system 12b (Fig. 2).
Using the energy minimised structure for 11, some calculated
dihedral angles are given in Table 1; the diaxial conformer most
closely resembles a Type VIa (cis) b-turn.38 Thus, this
compound could be considered to be a conformationally
restricted l-Ala-l-Ala dipeptide analogue, with the central
amide bond constrained in the cis orientation, and the
pyrrolidone ring capable of providing a reverse turn in an
attached peptide chain; as such it represents a potential low
molecular weight non-hydrophobic turn inducer. A related
aminopyrrolidone has also been reported to induce Type IIA b-
turn folding in a short peptide, and to exhibit hypoglycaemic
activity.39
25 Structures optimised with Chem3D Pro 3.5, available from Cambridge
Scientific (MM2 Parameters).
26 J. A. Monn, M. J. Valli, R. A. True, D. D. Schoepp, J. D. Leander and
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resolution mass spectrometric or analytical data.
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59, 7259.
Table 1 Dihedral angles for energy minimiseda conformations of 11
29 R. Shankar and A. I. Scott, Heterocycles, 1996, 42, 145.
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33 S. Derrer, N. Feeder, S. J. Teat, J. E. Davies and A. B. Holmes,
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Conformation
Y1 (°)
F2 (°)
Diequatorial
Diaxial
2139
+94
+137
297
a
Structures optimised with Chem3D Pro 3.5, available from Cambridge
34 N. Isaacs, Physical Organic Chemistry, Longman, London, 1995.
35 R. W. Hoffmann, Chem. Rev., 1989, 1841.
Scientific (MM2 parameters).
36 D. Seebach, B. Lamatsch, R. Amstutz, A. K. Beck, M. Dobler, M. Egli,
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M. Maestro, T. Maetzke, A. Mourino, E. Pfammatter, D. A. Plattner, C.
Schlickli, W. B. Schweizer, P. Seiler, G. Stucky, W. Petter, J. Escalante,
E. Juaristi, D. Quintana, C. Miravitlles and E. Molins, Helv. Chim. Acta,
1992, 75, 913.
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38 G. D. Rose, L. M. Gierasch and J. A. Smith, Adv. Protein Chem., 1985,
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1998, 120, 3894.
In view of the increasing interest in the use of variously
modified proline derivatives for subtle conformational control
in short peptide sequences,40–44 the ready synthetic accessibility
of enantiopure functionalised pyrrolidones may enable their
application as amino acid surrogates particularly where well-
defined conformational restriction is required.
We thank The Felix Foundation for funding of a scholarship
to R. G., the EPSRC Chemical Database Service at Daresbury45
and the EPSRC National Mass Spectrometric Service Centre at
Swansea.
Notes and references
43 E. Beausoleil, R. Sharma, S. W. Michnick and W. D. Lubell, J. Org.
Chem., 1998, 63, 6572.
44 P. Dumy, M. Keller, D. E. Ryan, B. Rohwedder, T. Wohr and M.
Mutter, J. Am. Chem. Soc., 1997, 119, 918.
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4 J. Gante, Angew. Chem., Int. Ed. Engl., 1994, 1699.
5 S. H. Gellman, Acc. Chem. Res., 1998, 31, 173.
Communication 9/06297A
2334
Chem. Commun., 1999, 2333–2334