ORGANIC
LETTERS
2000
Vol. 2, No. 1
37-39
Synthesis of Multiply Substituted, Ion
Channel Forming Octi(p-phenylene)s:
Theme and Variations
Fabien Robert,† Jean-Yves Winum,†,‡ Naomi Sakai,†,‡ David Gerard,† and
,†,‡
Stefan Matile*
Department of Organic Chemistry, UniVersity of GeneVa,
CH-1211 GeneVa, Switzerland, and Department of Chemistry,
Georgetown UniVersity, Washington, D.C. 20057
Received November 2, 1999
ABSTRACT
To facilitate the access to unique models for biological processes, we examined six different synthetic routes to octi(p-phenylene) rods with
lateral and terminal substitutents R and R . This systematic study allowed us to increase to overall yield for the synthesis of a new class of
L
T
oligo(p-phenylene) ionophores about 20 times and to provide general insights into the practicability of synthetic routes to multiply substituted
molecular rods.
Push-pull octi(p-phenylene) rod 1 but not the structurally
almost identical pull-pull rod 2 was recently found to
recognize and depolarize polarized biomembranes.1 Because
this finding identified a new route toward cell membrane
recognition,2 voltage-dependent ion channel formation,3 and,
perhaps, biomimetic antibiotics that we hope can be used to
resist microbial resistance,4 we felt that increased efforts to
improve the unsatisfactory synthesis of multiply substituted
oligo(p-phenylene) rods were appropriate.5
Push-push rod 3 was selected as a target molecule for
this study for the following reasons. It can be converted
Gokel, G. W. Angew. Chem., Int. Ed. 1998, 37, 1534. (j) Fyles, T. M.;
Loock, D.; Zhou, X. J. Am. Chem. Soc. 1998, 120, 2997. (k) Meillon, J.-
C.; Voyer, N. Angew. Chem., Int. Ed. Engl. 1997, 36, 967. (l) Pechulis, A.
D.; Thompson, R. J.; Fojtik, J. P.; Schwartz, H. M.; Lisek, C. A.; Frye, L.
L. Bioorg. Med. Chem. 1997, 5, 1893. (m) Wagner, H.; Harms, K.; Koert,
U.; Meder, S.; Boheim, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 2643.
(n) Tanaka, Y.; Kobuke, Y.; Sokabe, M. Angew. Chem., Int. Ed. Engl. 1995,
34, 693.
(4) (a) Niccolai, D.; Tarsi, L.; Thomas, R. Chem. Commun. 1997, 2333.
(b) Travis, J. Science 1994, 264, 360, references therein and in this Science
issue. (c) Bechinger, B. J. Membr. Biol. 1997, 156, 197. (d) Wieprecht, T.;
Dathe, M.; Beyermann, M.; Krause, E.; Maloy, W. L.; MacDonald, D. L.;
Bienert, M. Biochemistry 1997, 36, 6124. (e) Saberwal, G.; Nagaraj, R.
Biochim. Biophys. Acta 1994, 1197, 109. (f) Lear, J. D.; Schneider, J. P.;
Kienker, P. K.; DeGrado, W. F. J. Am. Chem. Soc. 1997, 119, 3212. (g)
Juvvadi, P.; Vunnam, S.; Merrifield, R. B. J. Am. Chem. Soc. 1996, 118,
8989. (h) Oiki, S.; Koeppe II, R. E.; Andersen, O. S. Proc. Natl. Acad. Sci.
U.S.A. 1995, 92, 2121.
† University of Geneva.
‡ Georgetown University.
(1) Winum, J.-Y.; Matile, S. J. Am. Chem. Soc. 1999, 121, 7961.
(2) Ghebremariam, B.; Sidorov, V.; Matile, S. Tetrahedron Lett. 1999,
40, 1445 and references therein.
(3) Reviews on nonpeptide ion channels and channel models: (a) Gokel,
G. W.; Murillo, O. Acc. Chem. Res. 1996, 29, 425. (b) Fyles, T. M.; van
Straaten-Nijenhuis, W. F. In ComprehensiVe Supramolecular Chemistry;
Reinhouldt, N. D., Ed.; Elsevier: Oxford, 1996; Vol. 10, p 53. (c) Voyer,
N. Top. Curr. Chem. 1996, 184, 1. Some recent references: (d) Qi, Z.;
Sokabe, M.; Donowaki, K.; Ishida, H. Biophys. J. 1999, 76, 631. (e) Abel,
E.; Maguire, E. M.; Murillo, O.; Suzuki, I.; DeWall, S. L.; Gokel, G. W. J.
Am. Chem. Soc. 1999, 121, 9043. (f) Otto, S.; Osifshin, M.; Regen, S. L.
J. Am. Chem. Soc. 1999, 121, 7276. (g) Li, C.; Budge, L. P.; Driscoll, C.
D.; Willardson, B. M.; Allman, G. W.; Savage, P. B. J. Am. Chem. Soc.
1999, 121, 931. (h) Fritz, M. G.; Walde, P.; Seebach, D. Macromolecules
1999, 32, 574. (i) de Mendoza, J.; Cuevas, F.; Prados, P.; Meadows, E. S.;
10.1021/ol991210n CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/15/1999