C O M M U N I C A T I O N S
Scheme 1. Strategy for Polymer Synthesisa
Figure 2. Quantitative precipitation of ConA with mannose-bearing
polymers. Stoichiometric composition of precipitate was calculated as
previously described.15,18 Ratios depicted are the number of ConA tetramers
estimated to be clustered with each mannose polymer.
to that of many other functional groups. In addition, the reversibility
of the furan Diels-Alder reaction provides a means to release the
polymer from the solid support and a handle for further function-
alization. We postulate that the strained alkene that results can
participate in additional ROMP reactions to build branched
copolymers. Alternatively, other reactive species could be used to
trap the dienophile (e.g., thiolates) to produce block copolymers
that display a range of functionality. We anticipate that the flexibility
of this strategy will markedly accelerate the synthesis of soluble
polymers with novel functions.
a Polymers displaying N-hydroxysuccinimidyl esters (M:I 100:1 or 50:
1) and a short maleimide-substituted block (M:I of 10:1) were generated.
A Diels-Alder reaction between polymer maleimide and a resin-bound furan
results in immobilization. After conjugation of amine-bearing groups,
cleavage can be effected using a diene, which irreversibly traps the incipient
polymer maleimide groups in solution.
cleavage15 indicates that the amide bond-forming reaction is
efficient; it appears to proceed in quantitative yield based on the
NHS ester. To complete our solid-phase synthesis, a method to
liberate polymer from the resin was required. The tendency of furan
to engage in reversible Diels-Alder reactions underlies our cleavage
strategy. Treatment of the resin with cyclopentadiene, which forms
irreversible Diels-Alder adducts with dienophiles, such as male-
imide, resulted in polymer cleavage. To verify that the majority of
the polymer was liberated, we exposed the resin to acid to sever
the Rink amide linker. No additional polymer was detected in the
resulting eluent. Additionally, chromatographic analysis of the
functionalized polymers indicated that they have the expected
molecular masses and possess narrow polydispersity indices.15 These
investigations demonstrate the utility of our synthetic strategy.
The properties of block copolymers and homopolymers can vary.
To determine whether our method affords functional polymers with
activities similar to their homopolymer counterparts, we compared
the ability of polymers 6a,b and 8a,b to interact with the target
protein, concanavalin A (ConA). Multivalent displays of saccharides
can cluster and thereby precipitate lectins.17,18 We found that the
initial rates of ConA precipitation mediated by polymer 6a,b are
comparable to those obtained with 8a,b.15 To test whether differ-
ences in activities that depend on polymer length are preserved,
we used quantitative precipitation to estimate the stoichiometric
composition of precipitated polymer cross-linked lectin com-
plexes.17,19 The concentration of ligand required to completely
precipitate the ConA was extrapolated to determine the relative
stoichiometry of ConA and polymer15 (Figure 2). Our results
indicate that activities of the polymers do not depend on the method
used for their synthesis. Thus, our solid-phase synthetic method
can be used to generate polymers with desired properties.
Acknowledgment. We thank Prof. H. E. Blackwell and M.
Bowman for helpful discussions. This research was supported by
the NIH (GM55984, AI55258) and the Keck Foundation. M.J.A.
thanks the NIH for a postdoctoral fellowship (AI603052); E.S.U.
thanks the Molecular Bioscience Training Program (GM07215).
Supporting Information Available: Synthetic methods and ex-
perimental details for the development of the methodology. This
References
(1) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
Germany, 2003; Vol. 1-3, pp 1-1204.
(2) Strong, L. E.; Kiessling, L. L. J. Am. Chem. Soc. 1999, 121, 6193-6196.
(3) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S. Org. Lett. 1999, 1, 1083-
1086.
(4) Slugovc, C. Macromol. Rapid Commun. 2004, 25, 1283-1297.
(5) Dolle, R. E. J. Comb. Chem. 2004, 6, 623-679.
(6) Weck, M.; Jackiw, J. J.; Rossi, R. R.; Weiss, P. S.; Grubbs, R. H. J. Am.
Chem. Soc. 1999, 121, 4088-4089.
(7) Melis, K.; DeVos, D.; Jacobs, P.; Verpoort, F. J Mol. Catal. A: Chem.
2001, 169, 47-56.
(8) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(9) Owen, R. M.; Gestwicki, J. E.; Young, T.; Kiessling, L. L. Org. Lett.
2002, 4, 2293-2296.
(10) Riegler, S.; Slugovc, C.; Trimmel, G.; Stelzer, F. Macromol. Symp. 2004,
217, 231-246.
(11) Keller, K. A.; Guo, J.; Punna, S.; Finn, M. G. Tetrahedron Lett. 2005,
46, 1181-1184.
(12) Blanco, L.; Bloch, R.; Bugnet, E.; Deloisy, S. Tetrahedron Lett. 2000,
41, 7875-7878.
(13) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem.,
Int. Ed. 2002, 41, 4035-4037.
(14) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9225-9283.
(15) For details of analysis, see the Supporting Information.
(16) Pontrello, J. K. New Strategies for Multivalent Ligand Synthesis. Ph.D.
Thesis, University of Wisconsin, Madison, 2005.
(17) Cairo, C. W.; Gestwicki, J. E.; Kanai, M.; Kiessling, L. L. J. Am. Chem.
Soc. 2002, 124, 1615-1619.
The data presented suggest this solid-phase route can be used
for the synthesis of libraries of soluble polymers. Our conjugation
strategy is effective for generating polymers of the lengths needed
to probe biological systems. Moreover, use of the Diels-Alder
reaction of furan offers many advantages for immobilization.11,12
As discussed, the reactivity of the reaction partners is orthogonal
(18) Gestwicki, J. E.; Strong, L. E.; Cairo, C. W.; Boehm, F. J.; Kiessling, L.
L. Chem. Biol. 2002, 9, 163-169.
(19) Kahn, M. I.; Mandal, D. K.; Brewer, C. F. Carbohydr. Res. 1991, 213,
69-77.
JA053931P
9
J. AM. CHEM. SOC. VOL. 127, NO. 42, 2005 14537