ORGANIC LETTERS
A Generic Recognition-Based Approach to the Acceleration of Cycloaddition Reactions
2002 Vol. 4, No. 2 273-276
Sarah J. Howell,† Neil Spencer,‡ and Douglas Philp*,† Centre for Biomolecular Sciences, School of Chemistry, UniVersity of St. Andrews, North Haugh, St Andrews KY16 9ST, United Kingdom, and School of Chemical Sciences, UniVersity of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
[email protected] Received November 13, 2001
ABSTRACT
Dicarboxylic acids accelerate the rate of cycloaddition reactions between either an azide or a furan and a maleimide through the formation of a reactive 1:1:1 complex stabilized by four hydrogen bonds.
Harnessing solution phase recognition processes to accelerate and direct the outcome of chemical reactions1 and the emulation of the efficiency of enzymes2 is an ongoing objective of supramolecular chemistry. In our previous work, we have developed3 systems that located complementary * To whom correspondence should be addressed. † University of St Andrews. ‡ University of Birmingham. (1) (a) Tominaga, M.; Konishi, K.; Aida, T. J. Am. Chem. Soc. 1999, 121, 7704. (b) Kavallieratos, K.; Crabtree, R. H. Chem. Commun. 1999, 2109. (c) Kang, J.; Hilmersson, G.; Santamaria, J.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 120, 3650. (d) Clyde-Watson, Z.; Vidal-Ferran, A.; Twyman, L. J.; Walter, C. J.; McCallien, D. W. J.; Fanni, S.; Bampos, N.; Wylie, R. S.; Sanders, J. K. M. New J. Chem. 1998, 493. (e) Breslow, R.; Schmuck, C. J. Am. Chem. Soc. 1996, 118, 6601. (f) Alca´zar, V.; Mora´n, J. R.; de Mendoza, J. Tetrahedron Lett. 1995, 36, 3941. (g) Jubian, V.; Veronese, A.; Dixon, R. P.; Hamilton, A. D. Angew. Chem., Int. Ed. Engl. 1995, 34, 1237. (h) Raposo, C.; Almaraz, M.; Crego, M.; Mussons, M. L.; Pe´rez, N.; Caballero, M. C.; Mora´n, J. R. Tetrahedron Lett. 1994, 35, 7065. (i) Kelly, T. R.; Meghani, P.; Ekkundi, V. S. Tetrahedron Lett. 1990, 31, 3381. (2) (a) Silverman, R. B. The Organic Chemistry of Enzyme-Catalyzed Reactions; Academic Press: New York, 2000. (b) Kirby, A. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 707. (c) Murakami, Y.; Kikuchi, J.; Hisaeda, Y.; Hayashida, O.; Chem. ReV. 1996, 96, 721. (d) Breslow, R. Acc. Chem. Res. 1995, 28, 146. (e) Page, M. I. Philos. Trans. R. Soc. London B 1991, 332, 149. (f) The Chemistry of Enzyme Action; Page, M. I., Ed.; Elsevier: Amsterdam, 1984. 10.1021/ol017044c CCC: $22.00 Published on Web 01/04/2002
© 2002 American Chemical Society
recognition sites on the two partners in a chemical reaction. These recognition sites allow the formation of a complex in which the reaction between the two components becomes pseudointramolecular.4 This approach can, however, require time-consuming design and synthesis. More attractive is a generic approach (Figure 1) in which the same recognition site is appended to both of the reactive partners A and B. A third molecule, cofactor C bearing two recognition sites which are complementary to those on the reagents, serves to assemble the two reactive partners in a 1:1:1 complex [A‚B‚C]. Within this complex, the reaction between A and B is pseudointramolecular, and, hence, we might expect significant acceleration of the chemical reaction between A and B through its formation. Additionally, the approach of A to B as they enter the transition state is controlled, to some extent, (3) (a) Booth, C. A.; Philp, D. Tetrahedron Lett. 1998, 39, 6987. (b) Robertson, A.; Philp, D.; Spencer, N. Tetrahedron 1999, 55, 11365. (c) Bennes, R. M.; Kariuki, B. M.; Harris, K. D. M.; Philp, D. Org. Lett. 1999, 1, 1087. (d) Bennes, R. M.; Sapro-Babiloni, M.; Hayes, W.; Philp, D. Tetrahedron Lett. 2001, 42, 2377. (4) (a) Page, M. I.; Jencks, W. P. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1678. (b) Kirby, A. J. AdV. Phys. Org. Chem. 1980, 17, 183. (c) Bruice, T. C.; Lightstone, F. C. Acc. Chem. Res. 1999, 32, 127.
Figure 1. Reaction of A and B occurs either via the bimolecular reaction channel or by a cycle mediated by the cofactor C. In principle, these two pathways can lead to products, P and P* with different regio- and/or stereochemistry.
by the structure of C. Hence, we might envisage that the product of the reaction between A and B within [A‚B‚C] complex (P) might have different regio- and/or stereochemistry to that formed by the bimolecular reaction pathway (P′). Clearly, the complex [A‚B‚C] is not the only ternary complex which can be formed in this system. However, the complexes [A2‚C] and [B2‚C] are unreactive. Thus, as long as [A‚B‚C], [A2‚C], and [B2‚C] are in fast exchange, CurtinHammett-Winstein-Holness kinetics5 will operate, obviating any requirement that the reactive complex [A‚B‚C] should be the dominant species in solution for rate acceleration to be observed. Previously, we reported6 a simple system based on the association between two benzo-15-crown-5 recognition sites and a potassium cation which accelerates a base-promoted aldol reaction using the cofactor methodology described above. However, to be useful synthetically, our cofactor methodology must be able to operate with reactions which are more complex in a regio- and/or stereochemical sense and using cofactors which are more complex structurally. Therefore, we designed (Figure 2) and synthesized 1,3-dipole, azide A1, and a diene, furan A2, which can act as 4π components in cycloaddition reactions in which the maleimide B acts as the 2π component. A1, A2, and B all possess an amidopyridine residue that is capable of recognizing and binding carboxylic acids. Thus, we envisaged that the addition of a dicarboxylic acid C to a solution containing either A1 or A2 and B should lead to the formation of a reactive ternary complex (Figure 2). (5) (a) Curtin, D. Y. Rec. Chem. Prog. 1954, 15, 111. (b) Winstein, S.; Holness, N. J. J. Am. Chem. Soc. 1955, 77, 5562. (c) Seeman, J. I. J. Chem. Educ. 1986, 63, 42. (d) Seeman, J. I. Chem. ReV. 1983, 83, 83. (6) Ashton, P. R.; Howell, S. J.; Spencer, N.; Philp, D. Org. Lett. 2001, 3, 353. 274
Figure 2. Cofactor C can assemble either A1 or A2 and B in a reactive ternary complex. Molecular mechanics calculations indicate that compounds 1-4 are suitable identities for C.
Molecular mechanics calculations suggested that glutaric acid 1 should be a suitable cofactor for the reaction between azide A1 and maleimide B. Initially, we measured the rate of the reaction between A1 and B in the absence of any cofactor. Accordingly, we measured the rate of the reaction between A1 and B in CDCl3 solution at 50 °C at a starting concentration of each reagent of 20 mM. The course of the reaction was followed using 400 MHz 1H NMR spectroscopy and the concentration of the product cycloadduct 5 was determined by deconvolution of the appropriate resonances arising from the starting materials and the product. This experiment served as the baseline against which subsequent reactions would be compared. We then performed a further four experiments, under identical conditions, in which the reaction between A1 and B took place in the presence of one of the cofactors 1-4 at a concentration of 20 mM. To rule out acid catalysis, we also performed the reaction between A1 and B in the presence of 2 equiv (40 mM) of acetic acid. Although we have recorded time course data for all of the reactions described here, it is more instructive, in the first instance, to assess the differences between cofactors 1-4 by considering the concentration of 5 after 10 h (Figure 3). The reaction between A1 and B is relatively slow under the conditions employed. However, addition of glutaric acid 1 almost doubles (+98%) the concentration of product present7 in the reaction mixture after 10 h. The other cofactors, 2-4, also show modest enhancements (+20% to +50%), but are universally less efficient than glutaric acid itself. Reassur(7) To confirm that the effects observed were the result of dynamic equilibria involving [A1‚B‚1], [A12‚1], and [B2‚1], we prepared separate solutions containing [A12‚1] and [B2‚1]. These solutions were mixed and the rate of reaction monitored as before. The rate of this reaction is indistinguishable from the case where A1, B, and 1 are dissolved in the same vessel at the start of the reaction. Org. Lett., Vol. 4, No. 2, 2002
Figure 3. Concentration of cycloadduct 5 present after 10 h in reactions between A1 and B in CDCl3 at 50 °C and a starting concentration of 20 mM in the presence of various cofactors and controls.
ingly, the addition of acetic acid results in no rate enhancement. We envisaged that the use of a chiral cofactor, (1R,3S)(+)-camphoric acid 4, might result in a stereospecific reaction between A and B. However, analyses by 1H NMR spectroscopy of the product of the reaction between A1 and B in the presence of 4 did not provide conclusive evidence of stereochemical induction in 5 by the presence of 4. Additionally, our efforts to use optical rotation as a probe were thwarted by our inability to remove all traces of the cofactor from the product. Therefore, to test whether the cofactor could indeed influence the stereochemical outcome of a reaction, we turned to the Diels-Alder reaction between furan A2 and B. The reaction between A2 and B was performed in CDCl3 solution at 50 °C at a starting concentration of each reagent of 20 mM. Under these conditions, an approximately 1:1 ratio of the two product cycloadducts, exo-6 and endo-6 are formed. In the presence of glutaric acid (20 mM), the overall rate of reaction between A2 and B is increased by 40% (Figure 4). A more interesting picture emerges when the relative concentrations of exo-6 and endo-6 are considered. Formation of the exo cycloadduct is enhanced by 80% whereas the formation of the endo cycloadduct is actually suppressed (by 4%) relative to the case where the cofactor is not present. Once again, molecular mechanics calculations indicate that the glutaric acid cofactor tethers A2 and B in such a manner Org. Lett., Vol. 4, No. 2, 2002
Figure 4. Concentration of cycloadduct 6 present after 10 h in reactions between A2 and B in CDCl3 at 50 °C 20 mM in the presence or absence of glutaric acid. Solid bars represent the total concentration of 6 ([exo-6] + [endo-6]) and unfilled bars represent the concentrations of individual isomers.
that the largest proportion of reactive coconformations favor the formation of exo-6. The relative inefficiency of cofactors 2-4 can be rationalized in terms of their molecular structure. The common structural feature of these three compounds is the geminal non-hydrogen substituents in the middle of the chain linking the two carboxylic acidsstwo fluorine atoms in the case of 2 and two carbon substituents (methyl or methylene) in the cases of 3 and 4. To elucidate the effect that these non-hydrogen substituents have on the stability of the [A‚B‚C] complex and, hence, on the transition state for the cycloaddition reaction, we performed a series of molecular mechanics calculations.8 Since the transition states of cycloaddition reactions are generally late, we decided to calculate the structures of the complexes formed between 5 and each of the cofactors. In the case of gluratic acid 1, the structure of the [1‚5] reveals that the glutaric acid is easily (8) All molecular mechanics calculations were carried out using the AMBER* force field as implemented in Macromodel (Version 7.0: Schro¨dinger, Inc., 1500 First Avenue, S. W.; Suite 1180 Portland, OR 97201) together with the GB/SA solvation model (Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J. Am. Chem. Soc. 1990, 112, 6127) for CHCl3. All calculations were performed on a Silicon Graphics O2 workstation. Conformational searching was carried out using 10 000 step Monte Carlo simulations, and all conformation located within 50 kJ of the global minimum were minimized. The sets of conformations generated by these searches were then filtered appropriately using the analysis tools available within Macromodel. 275
Figure 5. Concentration-time profiles for the reaction between A1 and B in the presence of 1 (open circles) and in the presence of 7 (filled circles). Both reactions were carried out in CDCl3 at 50 °C at starting reagent concentrations of 20 mM.
accommodated by 5, and, by implication, the transition state leading to 5, forming 4 hydrogen bonds with the two amidopyridine groups. By contrast, examination of the structure of the [4‚5] complex reveals that the additional bulk of the geminal methyl groups and the cyclopentane ring in 4 results in considerable steric crowding within the complex. This crowding will also, by inference, be present when the two reactive groups from A1 and B are placed in a reactive coconformation. This steric crowding will reduce the efficiency of the reaction within the [A1‚B‚C] complex by destabilizing the transition state for the cycloaddition reaction when cofactors 2-4 are utilized. To test this hypothesis concerning the effect of geminal substituents in the cofactor, we designed and synthesized cofactor 7. This cofactor has only one substituent in the center of the methylene chain, and molecular mechanics calculations suggested that the complex [5‚7] was similar in structure to [1‚5].
when it is performed in the presence of 1. Accordingly, we measured the rate of the reaction between A1 and B in CDCl3 solution at 50 °C at a starting concentration of each reagent of 20 mM in the presence of cofactor 7 at a concentration of 20 mM. The course of the reaction was followed using 400 MHz 1H NMR spectroscopy, and the concentration of the product cycloadduct 5 was determined as before. Figure 5 shows the results of this experiment. The results demonstrate clearly that our hypothesis is correct. The rate profiles for the reaction between A1 and B in the presence of cofactors 1 and 7 are essentially identical, indicating that the system can indeed tolerate one geminal substituent in the cofactor, but not two. An additional benefit of cofactor 7 is its increased solubility in CDCl3: 150 mM solutions of 7 can be prepared easily. This increased solubility allowed us to assess the association of the cofactors with the cycloadduct 5. If the cofactor binds too tightly to the product of the reaction, it accelerates, then inhibition will occur and a true catalysis will be impossible. We determined the association constant for the [5‚7] complex at 50 °C in CDCl3 by a 500 MHz 1H NMR titration experiment. The Ka value of 750 ( 12 M-1 obtained indicates that this complex is significantly lower9 than expected, and this result suggests that optimization of the reaction conditions should lead to the development of a truly catalytic system. In summary, we have demonstrated it is possible to exploit the Curtin-Hammett principle, as applied to supramolecular assemblies, to achieve rate enhancements of cycloaddition reactions with a highly flexible cofactor such as 1 or 7. Although we have demonstrated that our approach based on the Curtin-Hammett principle is viable, optimization of the reaction conditions is clearly required. The attachment of the cofactor to a reusable solid support is also key to realizing the true utility of this approach as compared to others that rely on complementary recognition sites. Our current research efforts are directed toward reaching all of these objectives. Acknowledgment. This work was supported by the Engineering and Physical Sciences Research Council (Quota Award to S.J.H.) and the Universities of Birmingham and St Andrews. OL017044C
We therefore envisaged that reaction of A1 and B in the presence of 7 should proceed at a similar rate to that observed
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(9) On the basis of our measured Ka value of 75 ( 3 M-1 for a single amidopyridine‚carboxylic acid interaction at 50 °C in CDCl3, a value of 5625 M-1 (75 × 75 M-1) might be expected in the absence of positive or negative cooperativity. The low Ka value measured for [5‚7] suggests that the structure of 5 is poorly adapted to bind 7 strongly.
Org. Lett., Vol. 4, No. 2, 2002
