J. Am. Chem. Soc. 2000, 122, 11037-11038
11037
that D,L-alternating (i.e., heterochiral) polypyrrolinones might also
preferentially adopt a turn conformation. Indeed, a Monte Carlo
conformational search performed on the simple D,L,D,L-tetrapyr-
rolinone 1 indicated that the low-energy conformations do in fact
adopt a â-turn conformation (Figure 1).
Design, Synthesis, and Solution Structure of a
Pyrrolinone-Based â-Turn Peptidomimetic
Amos B. Smith, III,* Wenyong Wang,
Paul A. Sprengeler, and Ralph Hirschmann*
Department of Chemistry
UniVersity of PennsylVania
Philadelphia, PennsylVania 19104
ReceiVed August 9, 2000
The design and synthesis of privileged nonpeptide scaffolds1
that can adopt the three principal secondary structures analogous
to peptides and proteins constitutes a significant advance in
molecular mimicry. Such scaffolds hold considerable promise for
the development of selective, low-molecular weight nonpeptide
ligands for biomedically important receptors. Ideally, conforma-
tional control of the privileged nonpeptide scaffold would be
effected via simple structural modifications of the individual
monomers. To date, however, most designed scaffolds can adopt
only a single conformation;2 exceptions include the Schreiber
vinylogous amides,3 the Hamilton oligoanthranilamides4 and the
â-peptides of Gellman5 and Seebach.6
Having established the 3,5-linked (nitrogen displaced) homo-
chiral polypyrrolinone motif as an excellent â-sheet/â-strand
peptidomimetic both in the solid state7a,b and in solution,7c
including the design and synthesis of a potent, orally bioavailable
HIV-1 protease inhibitor7d and a competent ligand for the class
II MHC protein HLA-DR1,7e we sought to extend the diversity
of conformational space available to the polypyrrolinone structure
motif. The observation of Ghadiri et al.8,9 that alternating D- and
L-cyclic peptides assemble into nanotubes, in conjunction with
the recollection that D-amino acids stabilize â-turns10 suggested
Figure 1. Tetrapyrrolinone 1 and Monte Carlo conformational search.
However, since previous studies7b have demonstrated that the
use of methyl side-chain substituents is an oversimplification, we
set (-)-9 as our initial target. Additional conformational searches
supported this choice.
The requisite R,R-disubstituted amino esters (i.e., 2, 5, and 8;
Scheme 1) required for the synthesis of the D,L-mixed polypyr-
rolinones exploiting our polypyrrolinone synthetic protocol,7b were
prepared via the enantioretentive alkylation tactic developed by
Kadary11a and Seebach.11b Construction of the D,L-mixed tetrapyr-
rolinone (-)-9 was prepared as illustrated in Scheme 1; the overall
Scheme 1
(1) For a discussion of the term “privileged structure (scaffold)” see: Evans,
B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter,
W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti,
V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.;
Hirshfield, J. J. Med. Chem. 1988, 31, 2235.
(2) (a) Gude, M.; Piarulli, U.; Potenza, D.; Salom, B.; Gennari, C.
Tetrahedron Lett. 1996, 37, 8589; Gennari, C.; Salom, B.; Potenza, D.;
Williams, A. Angew. Chem., Int. Ed, Engl. 1994, 33, 2067. (b) Nowick, J. S.;
Mahrus, S.; Smith, E. M.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 1066.
(c) Lokey, R. S.; Iverson, B. L. Nature 1995, 375, 303. (d) Cho, C. Y.; Moran,
E. J.; Cherry, S. R.; Stephans, J. C.; Fodor, S. P. A.; Adams, C. L.; Sundaram,
A.; Jacobs, J. W.; Schultz, P. G. Science (Washington D. C.) 1993, 261, 1303.
(e) Murray, T. J.; Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114, 4010.
(3) Hagihara, M.; Anthony, N. J.; Stout, T. J.; Clardy, J.; Schreiber, S. L.
J. Am. Chem. Soc. 1992, 114, 6568.
(4) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1996,
118, 7529
(5) (a) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. Chem. 1994, 116,
1054; review see: Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(6) (a) Seebach, D.; Overhand, M.; Ku¨hnle, F. N. M.; Martinoni, B.; Oberer,
L.; Hommel, U. and Widmer, H. HelV. Chim. Acta 1996, 79, 913. (b) For a
review, see: Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015.
(7) (a) Smith, A. B., III; Keenan, T. P.; Holcomb, R. C.; Sprengeler, P.
A.; Guzman, M. C.; Wood, J. L.; Carroll, P. J.; Hirschmann, R. J. Am. Chem.
Soc. 1992, 114, 10672. (b) Smith, A. B., III; Guzman, M. C.; Sprengeler, P.
A.; Keenan, T. P.; Holcomb, R. C.; Wood, J. L.; Carroll, P. J.; Hirschmann,
R. J. Am. Chem. Soc. 1994, 116, 9947. (c) Guzman, M. C. Ph.D. Thesis,
University of Pennsylvania, 1995. (d) Smith, A. B., III; Hirschmann, R.;
Pasternak, A.; Yao, W.; Sprengeler, P. A.; Holloway, M. K.; Kuo, L. C.;
Chen, Z.; Darke, P. L.; Schleif, W. A. J. Med. Chem. 1997, 40, 2440. (e)
Smith, A. B., III; Benowitz, A. B.; Sprengeler, P. A.; Barbosa, J.; Guzman,
M. C.; Hirschmann, R.; Schweiger, E. J.; Bolin, D. R.; Nagy, Z.; Campbell,
R. M.; Cox, D. C.; Olson, G. L. J. Am. Chem. Soc. 1999, 121, 9286.
(8) Ghadiri, M. R.; Kobayashi, K.; Granja, J. R.; Chadha, R. K.; McRee,
D. E. Angew. Chem., Int. Ed. Engl. 1995, 34, 93. See also: Chiang, C. C.;
Karle, I. L. Int. J. Pept. Res. 1982, 20, 133.
yield was 18%. The structure of (-)-9 was confirmed by a series
1
of H, 13C, COSY, TOCSY, and NOESY NMR experiments.
To assign the solution structure of (-)-9, we first performed
1H NMR analysis to determine the lowest concentration at which
(9) Ciufolini and co-workers subsequently reported that R-N-coupling of
piperazic acid of given configuration (D or L) with an R-aminoacyl unit of
opposite configuration (L or D) produces dipeptides that exist in a conformation
conducive to the formation of a peptide turn. Xi, N.; Alemany, L. B.; Ciufolini,
M. A. J. Am. Chem. Soc. 1998, 120, 80.
(10) Nutt, R. F.; Veber, D. F.; Saperstein, R.; Hirschmann, R. Int. J. Pept.
Protein Res. 1983, 21, 66.
(11) (a) Karady, S.; Amato, J. S.; Weinstock, L. M. Tetrahedron Lett. 1984,
25, 4337. (b) Seebach, D.; Fadel, A. HelV. Chim. Acta 1985, 68, 1243.
10.1021/ja002964w CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/24/2000