ORGANIC
LETTERS
2000
Vol. 2, No. 14
2037-2040
A Second-Generation Synthesis of
Polypyrrolinone Nonpeptidomimetics:
Prelude to the Synthesis of
Polypyrrolinones on Solid Support
Amos B. Smith, III,* Hu Liu, and Ralph Hirschmann*
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
Received April 11, 2000
ABSTRACT
A second-generation asymmetric synthesis of polypyrrolinones (3) has been achieved exploiting scalemic r-aminolactones (1) as building
blocks. Imine formation between an appropriate lactone (1) and aldehyde (2), followed in turn by pyrrolinone ring construction promoted by
KHMDS in the presence of 18-crown-6 and modified Swern oxidation furnished pyrrolinone aldehyde 3. This iterative, efficient three-step
protocol paves the way for the synthesis of polypyrrolinones on solid support.
In 1992 we reported the design and synthesis of nonpeptide
peptidomimetics based on the 3,5,5-trisubstituted pyrrolin-
4-one ring system.1 Depending on the structure, these
polypyrrolinones, which are stable to both strong acid and
proteases, can adopt diverse conformations including those
analogous to â-strands,1a,d â-turns, and helices.1i Exploiting
the â-strand structural motif, we designed and synthesized
several potent, bioavailable inhibitors of the HIV-1 aspartic
acid protease1c,f,h which exhibited improved membrane
transport properties2 relative to their peptidal counterparts.
The improved transport was attributed to the presence of
intramolecular hydrogen bonds between adjacent pyrrolinone
rings (NH and CO), which led to a reduction in desolvation
energy upon membrane transport.1c,3 We have also success-
fully employed a bispyrrolinone in the construction of a
pyrrolinone-peptide hybrid ligand, which bound the Class
II MHC protein HLA-DR1 in an extended â-strand-like
conformation with potency similar to that of the native
peptide.4 Taken together, these results suggest that the
polypyrrolinone scaffold holds considerable promise for the
design of a wide variety of peptidomimetics.
(1) (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; Holcomb, R. C.;
Guzman, M. C.; Keenan, T. P.; Sprengeler, P. A.; Hirschmann, R.
Tetrahedron Lett. 1993, 34, 63. (c) Smith, A. B., III; Hirschmann, R.;
Pasternak, A.; Akaishi, R.; Guzman, M. C.; Jones, D. R.; Keenan, T. P.;
Sprengeler, P. A.; Darke, P. L.; Emini, E. A.; Holloway, M. K.; Schleif,
W. A. J. Med. Chem. 1994, 37, 215. (d) 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. (e) Smith, A. B.,
III; Akaishi, R.; Jones, D. R.; Keenan, T. P.; Guzman, M. C.; Holcomb, R.
C.; Sprengeler, P. A.; Wood, J. L.; Hirschmann, R.; Holloway, M. K.
Biopolymers (Peptide Science) 1995, 37, 29. (f) Smith, A. B., III;
Hirschmann, R.; Pasternak, A.; Guzman, M. C.; Yokoyama, A.; Sprengeler,
P. A.; Darke, P. L.; Emini, E. A.; Schleif, W. A. J. Am. Chem. Soc. 1995,
117, 11113. (g) Smith, A. B., III; Benowitz, A. B.; Favor, D. A.; Sprengeler,
P. A.; Hirschmann, R. Tetrahedron Lett. 1997, 38, 3809. (h) 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. (i) Smith, A. B., III; Favor, D. A.; Sprengeler, P. A.;
Guzman, M. C.; Carroll, P. J.; Furst, G. T.; Hirschmann, R. Bioorg. Med.
Chem. 1999, 9.
The cornerstone of our initial iterative polypyrrolinone
syntheses entailed imine formation followed by metalloimine
(2) Thompson, W. J.; Fitzgerald, P. M. D.; Holloway, M. K.; Emini, E.
A.; Darke, P. L.; McKeever, B. M.; Schleif, W. A.; Quintero, J. C.; Zugay,
J. A.; Tucker, T. J.; Schwering, J. E.; Homnick, C. F.; Nunberg, J.; Springer,
J. P.; Huff, J. R. J. Med. Chem. 1992, 35, 1685.
(3) Hirschmann, R.; Smith, A. B., III; Sprengeler, P. A. In New
PerspectiVes in Drug Design; Dean, P. M., Jolles, G., Newton, C. G., Eds.;
Academic: London, 1995; pp 1-14.
10.1021/ol0059293 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/09/2000