variety of hydroxyaromatic building blocks compared to its
oxime counterpart. Oxime bond formation was not possible
with 2-alkoxy phenols such as anisole and could not be
envisioned with ketones due to the formation of Z/E isomeric
mixtures. By contrast, ether bond formation succeeded with
almost all building blocks tested irrespective of steric and
electronic factors. In addition, the possiblity of using ketones
opens the way to the preparation of chiral products.16
While only 84 oligomers were prepared here, a total of
over 30 000 oligomers are theoretically possible counting
dimers, trimers, tetramers, and pentamers from the 13
building blocks used here. The fact that the relative position-
ing of the two ether attachment points can be varied between
different building blocks (o-, m-, p- for the phenol, benzylic,
homobenzylic, etc., for the alcohol) implies that the diversity
of molecular shapes available from ether oligomers (e.g.,
Figure 2) is larger than with peptides or peptide-like
oligomers bearing side-chain appendages to a regular back-
bone. Diversity can be further increased by changing the
initiating benzylic alcohol. In addition, directed ether bond
formation protocols exist for all types of ether bonds
(aliphatic-aliphatic, aliphatic-aromatic, aromatic-aro-
matic),5,17 such that a very large variety of building blocks
are suitable for assembling ether oligomers both in solution
and on solid support.18 It should be possible to adapt this
approach to a solid-supported format to construct libraries
of diverse ether oligomers for biological testing.
Figure 4. Inhibition of R-chymotrypsin by ether oligomer 25.
Assay conditions: 5 µg/mL R-chymotrypsin (from Bovine Pancreas,
Sigma C-7762), 500 µM N-succinyl-Ala-Ala-Pro-Phe p-nitroanilide
(Sigma S-7388), 5 mM aq Bis Tris, pH 7.2, 26 °C, and inhibitor
25 at (b) 0, (b) 3, (b) 6, (4) 9, (b) 12, and (b) 15 or (+) no
enzyme.
not caused by nonspecific aggregation.13 However, and in
contrast to our oxime oligomers, the inhibitory ether oligo-
mers did not show any protease inhibition when tested with
the bovine serume albumin/calcein sensor system (0.5 mg/
mL BSA).14 This effect might be due to competitive binding
of the oligomers to BSA, which possesses binding sites for
serum transport of hydrophobic molecules.15
Both the cross-reactivity against serine proteases and the
interaction with BSA indicate that ether oligomers are less
selective than their oxime counterparts. This could be caused
by a larger conformational flexibility from the freely rotatable
bonds in the ether linkage, allowing for multiple binding
conformations. Nevertheless, these somewhat less promising
bioactivity properties are outweighed by the much larger
flexibility of the synthetic route. Indeed, the ether oligomer-
ization sequence gives higher yields with a much broader
Acknowledgment. This work was supported by the Swiss
National Science Foundation and the Novartis Foundation.
The X-ray data sets were measured by the BENEFRI Small
Molecule Crystallography Service directed by Prof. Helen
Stoeckli-Evans.
Supporting Information Available: Spectroscopic data
of active compounds 25, 41, 49, 50, 75, and 76 and basic
crystallographic details of oligomers 43 and 59. This material
OL036300D
(10) Bieth, J.; Spiess, B.; Wermuth, C. G. Biochem. Med. 1974, 11, 350.
(11) Gaertner, H. F.; Puigserver, A. J. Enzyme Microb. Technol. 1992,
14, 150.
(12) Ether oligomer (10 µM), almond â-glucosidase (0.6 U/ml, 111 µg/
mL), or Aspergillus oryzae â-galactosidase (0.2 U/ml, 17 µg/mL), aq HEPES
buffer pH 6.8, 25 °C, 10% v/v DMSO, and nitrophenyl â-D-glucoside or
â-D-galactoside as a substrate.
(13) McGovern, S. L.; Caselli, E.; Grigorieff, N.; Shoichet, B. K. J. Med.
Chem. 2002, 45, 1712.
(16) For example, an enantioselective reduction or aldehyde alkylation
can be performed on the growing oligomer. Alternatively, chiral alcohol
building blocks can be prepared optically pure and used in the Mitsunobu
coupling with either the phenolic hydroxyl group or the benzylic hydroxyl
group blocked by a removable protecting group.
(17) Larock, R. C. In ComprehensiVe Organic Transformations. A Guide
to Functional Group Preparations, 2nd ed.; Wiley: New York, 1999; p
885.
(14) (a) Klein, G.; Reymond, J.-L. Angew. Chem., Int. Ed. 2001, 40,
1771. (b) Dean, K.; Klein, G.; Renaudet, O.; Reymond, J.-L. Bioorg. Med.
Chem. Lett. 2003, 13, 1653.
(15) Curry, S.; Mandelkow, H.; Brick, P.; Franks, N. Nat. Struct. Biol.
1998, 5, 751.
(18) For selected references about supported Mitsunobu ether formation,
see: (a) Krchna`c, V.; Flegelova`, Z.; Weichsel, A. S.; Lebl, M. Tetrahedron
Lett. 1995, 36, 6193. (b) Rano, T. A.; Rano, C. K. T. Tetrahedron Lett.
1995, 36, 3789. (c) Gentles, R. G.; Wodka, D.; Park, D. C.; Vasudevan, A.
J. Comb. Chem. 2002, 4, 442.
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Org. Lett., Vol. 6, No. 3, 2004