5920
J. Org. Chem. 1996, 61, 5920-5931
Combination of Calix[4]arenes and Resorcin[4]arenes for the Complexation of Steroids Irene Higler, Peter Timmerman, Willem Verboom, and David N. Reinhoudt* Laboratory of Organic Chemistry, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands Received February 7, 1996X
Receptor molecules with large cavities synthesized by the combination of building blocks that already possess a cavity, viz. calix[4]arenes and resorcin[4]arenes, are described. These receptor molecules are synthesized by reaction of one or two upper rim 1,2-difunctionalized calix[4]arene fragments oriented either endo or exo toward a cavitand unit. The endo:exo ratio depends on the substituents at the 3- and 4-positions of the calix[4]arenes. These novel receptor molecules complex steroids with association constants of (0.9-9.5) × 102 M-1 in CDCl3. Introduction In the first 25 years of host-guest chemistry the work has been mainly focused on receptors for small guests like cations, anions, and small neutral molecules. Recently, there has been an increasing interest in the complexation of larger guest molecules such as steroids by synthetic receptor molecules. Most of these complexation studies have been performed in aqueous solutions, in which hydrophobic interactions govern the stability and selectivity of the complexation. Diederich et al.1 described the synthesis of a double cyclophane that complexes cholesterol with an association constant of 1.5 × 105 M-1 in water. Cage-type cyclophanes were studied by Murakami et al.2 for the binding of steroids in D2O/ CD3OD (3:1 v/v); they reported association constants between 3.6 and 13.0 × 102 M-1. Several groups used cyclodextrins for the complexation of steroids. Pitha et al.3a,b described that hydroxypropyl-derivatized β-cyclodextrins solubilize cholesterol in water. Hamada et al.3c have used a γ-cyclodextrin derivative as a fluorescent receptor molecule for a number of cholic acid derivatives. In their studies of β-cyclodextrin‚steroid inclusion complexes Djedani et al.3d showed that the substitution pattern of the steroid determines the stoichiometry of inclusion. Aoyama et al.4 found that in apolar organic media CH-π interactions play an important role in the complexation of steroids by resorcin[4]arenes. They demonstrated that the formation of hydrogen-bonded complexes in chloroform involves an additional substantial contribution (up to ca. 1.4 kcal/mol) of attractive guest-host CH-π interaction. Whitcombe et al.5 have used polymers obtained via molecular imprinting to bind cholesterol.6 * To whom correspondence should be addressed. Tel.: +31 53 4892980. Fax: +31 53 4894645. E-mail:
[email protected]. X Abstract published in Advance ACS Abstracts, August 1, 1996. (1) (a) Peterson, B. R.; Mordasini-Denti, T.; Diederich, F. Chem. Biol. 1995, 2, 139. (b) Peterson, B. R.; Wallimann, P.; Carcanague, D. R.; Diederich, F. Tetrahedron 1995, 51, 401. (c) Peterson, B. R.; Diederich, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1625. (d) Carcanague, D. R.; Diederich, F. Angew. Chem., Int. Ed. Engl. 1990, 29, 769. (2) (a) Murakami, Y.; Hayashida, O.; Ito, T.; Hisaeda, Y. Pure Appl. Chem. 1993, 65, 551. (b) Murakami, Y.; Hayashida, O.; Ito, T.; Hisaeda, Y. Chem. Lett. 1992, 497. (3) (a) Gerloczy, A.; Hoshino, T.; Pitha, J. J. Pharm. Sci. 1994, 83, 193. (b) Irie, T.; Fukunaga, K.; Pitha, J. J. Pharm. Sci. 1992, 81, 521. (c) Hamada, F.; Kondo, Y.; Ito, R.; Suzuki, I.; Osa, T.; Ueno, A. J. Inclusion Phenom. Mol. Recogn. Chem. 1993, 15, 273. (d) Djedaı¨ni, F.; Perly, B. J. Pharm. Sci. 1991, 80, 1157. (4) Kobayashi, K.; Asakawa, Y.; Kikuchi, Y.; Toi, H.; Aoyama, Y. J. Am. Chem. Soc. 1993, 115, 2648.
S0022-3263(96)00256-3 CCC: $12.00
Our new strategy for the synthesis of artificial receptor molecules comprises the combination of medium-sized building blocks. The building blocks should be easily accessible and have relatively rigid structures, and it should be possible to introduce selectively different functional groups. We have already synthesized different classes of large synthetic receptor molecules by the combination of calix[4]arenes with β-cyclodextrins7 and porphyrins.8 The combination of calix[4]arenes9 with resorcin[4]arenes10 or cavitands11 can be achieved in different ways. Recently, we reported the synthesis of compound 1 by combination of 1,3-bis(chloroacetamido)calix[4]arene12 and tetrahydroxycavitand 2 (see Chart 1).10 Combination of two calix[4]arenes and two resorcin[4]arenes in a cyclic array leads to the extremely rigid holand 3,13 in which the calix[4]arene and cavitand moieties are connected via highly organized amido spacers. A systematic search for suitable guest molecules for holand 3 using the computer simulation program DOCK14 (5) Whitcombe, M. J.; Rodriguez, M. E.; Villar, P.; Vulfson, E. N. J. Am. Chem. Soc. 1995, 117, 7105. (6) Parini et al. studied the interaction of p-tert-butylcalix[6]- and -[8]arenes with steroids in the solid state. Parini, C.; Colombi, S.; Casnati, A. J. Inclusion Phenom. Mol. Recogn. Chem. 1994, 18, 341. (7) (a) van Dienst, E.; Snellink, B. H. M.; von Piekartz, I.; Engbersen, J. F. J.; Reinhoudt, D. N. J. Chem. Soc., Chem. Commun. 1995, 1151. (b) van Dienst, E.; Snellink, B. H. M.; von Piekartz, I.; Grote Gansey, M. H. B.; Venema, F.; Feiters, M. C.; Nolte, R. J. M.; Engbersen, J. F. J.; Reinhoudt, D. N. J. Org. Chem. 1995, 60, 6537. (8) (a) Rudkevich, D. M.; Verboom, W.; Reinhoudt, D. N. Tetrahedron Lett. 1994, 35, 7131. (b) Rudkevich, D. M.; Verboom, W.; Reinhoudt, D. N. J. Org. Chem. 1995, 60, 6585. (9) (a) Gutsche, C. D. In Calixarenes; Stoddart, J. F., Ed.; Monographs in Supramolecular Chemistry, Vol. 1; Royal Society of Chemistry: Cambridge, 1989. (b) Vicens, J., Bo¨hmer, V., Eds. Calixarenes: a Versatile Class of Macrocyclic Compounds; Kluwer Academic Publishers: Dordrecht, 1991. (c) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (10) Timmerman, P.; Nierop, K. G. A.; Brinks, E. A.; Verboom, W.; van Veggel, F. C. J. M.; van Hoorn, W. P.; Reinhoudt, D. N. Chem. Eur. J. 1995, 1, 132. (11) (a) Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1996, 52, 2663. (b) Cram, D. J.; Cram, J. M. Container Molecules and Their Guests; Stoddart, J. F., Ed.; Monographs in Supramolecular Chemistry, Vol. 4; Royal Society of Chemistry: Cambridge, 1994. (12) We have given each of the calix[4]arene aromatic rings a number (1-4); substituents are always at the para position relative to the phenolic oxygen. (13) Timmerman, P.; Verboom, W.; van Veggel, F. C. J. M.; van Hoorn, W. P.; Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl. 1994, 33, 1292. (14) (a) Desjarlais, R. L.; Sheridan, R. P.; Dixon, J. C.; Kuntz, I. D.; Venkataraghavan, R. J. Med. Chem. 1986, 29, 2149. (b) Desjarlais, R. L.; Sheridan, R. P.; Seibel, G. L.; Dixon, J. C.; Kuntz, I. D. J. Med. Chem. 1988, 31, 722.
© 1996 American Chemical Society
Complexation of Steroids
J. Org. Chem., Vol. 61, No. 17, 1996 5921 Chart 1
showed that steroids are a suitable class of guest compounds. However, so far we have found no complexation at all by holand 3, probably because the extreme rigidity of holand 3 prevents the structural deformations that might be necessary for complexation. Receptor molecules 4-6, composed of two calix[4]arenes and one resorcin[4]arene (see Chart 2), have a cavity very similar to that of holand 3 but are more flexible; this might allow them to accommodate the structural deformations necessary for complexation. In this paper we describe the synthesis of a series of such potential receptor molecules by combination of calix[4]arenes (7, 8, 12, 16, 19, and 22) with tetrahydroxycavitand 2. We have systematically varied the substituents at the 3- and 4-positions and studied their influence on the stereochemistry of the products. The affinity of both the 1:1 and the 2:1 products15 for prednisolone-21acetate and derivatives was studied by 1H NMR titration experiments.16 (15) Throughout this paper the 1:1 addition products are simplified to endo-23 and exo-24 and the 2:1 addition products to endo,endo-4, endo,exo-5, and exo,exo-6.
Results and Discussion Synthesis of 1,2-Difunctionalized Calix[4]arenes. Previously, we described the synthesis of 1,2-bis(chloroacetamido)calix[4]arenes 713 and 817 that have either hydrogens or nitro groups at the remaining p-positions of the aromatic rings of the calix[4]arene moieties (Chart 3). For the synthesis of 1,2-bis(chloroacetamido)calix[4]arenes with two phthalimido,18 acetamido, or cyano groups at the remaining p-positions of the aromatic rings, we used the dinitrocalix[4]arenes 9 and 10, carrying either two iodo or two phthalimido groups. These were also used as starting materials in the synthesis of calix[4]arene 8.17 Reduction of 1,2-dinitro-3,4-diphthalimidocalix[4]arene 10 with SnCl2‚2H2O in refluxing ethanol gave 1,2diamino-3,4-diphthalimidocalix[4]arene 11 in 89% yield; (16) A small part of this work was published as a preliminary communication: Timmerman, P.; Brinks, E. A.; Verboom, W.; Reinhoudt, D. N. J. Chem. Soc., Chem. Commun. 1995, 417. (17) Timmerman, P.; Verboom, W.; Reinhoudt, D. N.; Arduini, A.; Grandi, S.; Sicuri, A. R.; Pochini, A.; Ungaro, R. Synthesis 1994, 185. (18) Throughout this paper the abbreviation "pht" is used in the text and charts for a phthalimido group.
5922 J. Org. Chem., Vol. 61, No. 17, 1996 Chart 2
the absorption around 6.0 ppm in the 1H NMR spectrum is characteristic for aromatic hydrogens ortho to an amino group. Subsequent reaction with R-chloroacetyl chloride afforded 1,2-bis(chloroacetamido)-3,4-diphthalimidodicalix[4]arene 12 in 89% yield. Deprotection of the masked amino groups in 10 gave 1,2-diamino-3,4-dinitrocalix[4]arene 13,17 which was converted to 1,2-bis(acetamido)3,4-dinitrocalix[4]arene 14 by reaction with acetyl chloride in 67% yield. Reduction of the nitro groups with hydrazine led to 1,2-diacetamido-3,4-diaminocalix[4]arene 15, and subsequent acylation with R-chloroacetyl chloride gave 1,2-diacetamido-3,4-bis(chloroacetamido)calix[4]arene 16 in 80% overall yield. Previously, we described the direct replacement of two adjacent tert-butyl groups via ipso aromatic nitration as a useful method for the preparation of 1,2-di-tert-butyl3,4-dinitrocalix[4]arene 17.19 Reduction of 17 with hydrazine gave 1,2-diamino-3,4-di-tert-butylcalix[4]arene 18 (19) Verboom, W.; Durie, A.; Egberink, R. J. M.; Asfari, Z.; Reinhoudt, D. N. J. Org. Chem. 1992, 57, 1313.
Higler et al. Chart 3
in quantitative yield. The 1,2-di-tert-butyl-3,4-bis(chloroacetamido)calix[4]arene 19 was prepared in 83% yield by acylation of calix[4]arene 18. 1,2-Diiodo-3,4-dinitrocalix[4]arene 9 was converted into 1,2-dicyano-3,4-dinitrocalix[4]arene 20 in quantitative yield by reaction with Cu(I)CN followed by treatment with FeCl3. Reduction of the nitro groups in calix[4]arene 20 with hydrazine does not affect the cyano groups and gave 1,2-diamino-3,4dicyanocalix[4]arene 21 in 77% yield. Subsequent reaction of calix[4]arene 21 with R-chloroacetyl chloride afforded 1,2-bis(chloroacetamido)-3,4-dicyanocalix[4]arene 22 in 50% yield. Reactions of 1,2-Bis(chloroacetamido)calix[4]arenes (7, 8, 12, 16, 19, and 22) with Tetrahydroxycavitand 2: Synthesis of Receptor Molecules 4, 5, 6, 23, and 24. Previously, we have described the synthesis of receptor molecules via the reaction between 1,2-bis(chloroacetamido)calix[4]arenes and tetrahydroxycavitand 2. Reaction of 1,2-bis(chloroacetamido)calix[4]arene 7 and 2 afforded the 1:1 products endo 23a and exo 24a (entry 1 in Table 1, Chart 4), and the 2:1 isomers endo,endo-4a, endo,exo-5a, and exo,exo-6a (entry 2 in Table 1) in nearly statistical yields.10 For these compounds, we have shown that an amide hydrogen resonating at lower field (8.7-9.8 ppm) corresponds to an endo-coupled calix[4]arene moiety, whereas an exo-coupled amide gives rise to a signal at somewhat higher field (8.0-8.3 ppm).20 Throughout this paper we have used this difference in chemical shift to assign the stereochemistry of all coupled products 4-6, 23, and 24. The 1H NMR spectra of 2:1 isomers 4e, 5e, and 6e in CDCl3 are given in Figure 1. (20) The position of the amide hydrogen signal is influenced by the subsituents at the remaining 3- and 4-positions of the calix[4]arene moiety.
Complexation of Steroids
J. Org. Chem., Vol. 61, No. 17, 1996 5923
Table 1. Results of Coupling Reactions between 1,2-Bis(chloroacetamido)calix[4]arenes 7, 8, 12, 16, 19, and 22 and Tetrahydroxycavitand 2a entry
calixarene
ratio calix:2
yield (%) endo-23
yield (%) exo-24
1 2 3 4 5 6 7 8 9 10
7 7 8 8 12 12 16 16 19 22
1 2 1 2 0.33 1 0.33 2 2 2
19
32
a
yield (%) endo,endo-4
yield (%) endo,exo-5
yield (%) exo,exo-6
16
39
20
20 8 14
21 8 18
14 4
27 18 6
42 41 26 45 17
4 3
Results described in entries 1-4 were published previously.10
Chart 4
Figure 1. 1H NMR spectra of endo,endo-4e, endo,exo-5e, and exo,exo-6e (R1 ) -tert-butyl) in CDCl3 at room temperature.
Reaction between tetrahydroxycavitand 2 and 1,2-bis(chloroacetamido)-3,4-dinitrocalix[4]arene 8 in a 1:1 ratio exclusively gave endo-23b (entry 3 in Table 1).21 Reaction of this product with a second equivalent of 8 gave a statistical mixture of endo,endo-4b and endo,exo isomer 5b (entry 4 in Table 1).10 The absence of both the exo (21) Because of its instability isomer endo-23b was isolated after silylation of the free hydroxyl groups with tert-butyldimethylsilyl chloride.
and the exo,exo products prompted us to conclude that the stereochemistry of the 1:1 products is determined during the formation of the second bond between the two building blocks; after formation of the first bond both isomers can still be formed (see Figure 2). In route a) the calix[4]arene moiety has to rotate toward the cavitand moiety, and this leads to the endo isomer. In route b) the calix[4]arene moiety has to rotate away from the cavitand moiety, which leads to the exo isomer. Therefore, the preference for an endo or exo orientation of the first calix[4]arene moiety will be determined by intramolecular interactions. The stereochemistry of the 2:1 products, however, is already established with the formation of the first bond to the second calix[4]arene unit; after formation of the first bond only one isomer can be formed because only one chloroacetamido functionality and one hydroxyl group remain. Consequently, the orientation of the second calix[4]arene is exclusively determined before formation of the first bond and therefore by intermolecular interactions. In this paper, we address the question whether the stereochemistry of the products can be influenced by the functionality at the 3- and 4-positions of the 1,2-bis(chloroacetamido)calix[4]arene. Reaction between 1,2-bis(chloroacetamido)-3,4-diphthalimidodicalix[4]arene 12 and tetrahydroxycavitand 2, performed under different reaction conditions, gave only three of the five possible products. The results are summarized in Table 2. Reaction in CH3CN (1:1 ratio) (entry 1 in Table 2) produced in addition to 26% of endo
5924 J. Org. Chem., Vol. 61, No. 17, 1996
Higler et al.
Table 2. Total Yield and Product Distribution of the Reaction between Calix[4]arene 12 and Tetrahydroxycavitand 2 under Different Reaction Conditions entry
ratio 12/2
solvent
[12], mM
reaction timea (h)
total yield (%)
yield (%) endo-23c
yield (%) endo,endo-4c
yield (%) endo,exo-5c
1 2 3 4
1.0 0.33 2.1 2.1
CH3CN CH3CN CH3CN DMFe
2.0 1.8 4.3 4.3
7+8 6 + 10 8 + 32 8+9
72b 71c 10d 6
26 41
14 8 5 3
18 8 5 3
a Time used for addition of 12 plus additional reaction time. b Includes an additional 14%, which was obtained as a mixture of isomers 24c, 4c, and 5c (6%, 8%, and 8%, respectively, according to 1H NMR). c Includes an additional 14%, which was obtained as a mixture of isomers 23c and 24c (both 7%, according to 1H NMR). d Unreacted 12 was isolated in 46% yield. e Reaction was performed at 100 °C.
Figure 2. Intramolecular interaction leading to endo-23 (route a), or exo-24 (route b).
23c considerable amounts of endo,endo-4c and endo,exo5c (14% and 18%, respectively). A small amount of exo24c was observed (∼4%) but could not be separated from unreacted tetrahydroxycavitand 2. When the reaction was carried out with 3 equiv of tetrahydroxycavitand 2 (entry 2 in Table 2) the yield of endo-23c improved to 41% but the 2:1 isomers endo,endo-4c and endo,exo-5c were still formed in 8% yield each. Also in this case a small amount of exo-24c was found. Reaction in a 2:1 ratio in CH3CN (entry 3 in Table 2) for 40 h at reflux temperature gave only small amounts (5%) of the 2:1 products endo,endo-4c and endo,exo-5c together with unreacted 1,2-bis(chloroacetamido)-3,4-bis(phthalimido)calix[4]arene 12 (46%). Even in DMF (2:1 ratio) at elevated temperatures (100 °C, entry 4 in Table 2), only very small amounts of 2:1 isomers endo,endo-4c and endo,exo-5c (∼3% each) were isolated. Because the endo isomer 23c is stable under the conditions used, the most likely explanation for these results is polymerization of calix[4]arene and cavitand fragments. Reaction between 1,2-bis(acetamido)-3,4-bis(chloroacetamido)calix[4]arene 16 and an excess of tetrahydroxycavitand 2 in CH3CN (entry 7 in Table 1) gave endo isomer 23d in 45% yield. Reaction in a 2:1 ratio (entry 8 in Table 1) afforded only the endo,exo-coupled product 5d and the endo-coupled product 23d in 27% and 17% yield, respectively. Traces of other products were present but could not be isolated. In order to investigate whether bulky substituents at the 3- and 4-positions of the 1,2-bis(chloroacetamido)calix[4]arene influence the isomer distribution, we studied the reaction between 1,2-di-tert-butyl-3,4-bis(chloroacetamido)calix[4]arene 19 and tetrahydroxycavitand 2 (entry 9 in Table 1). Reaction in DMF gave the three 2:1 isomers in moderate yields: 14% of endo,endo-4e, 18%
of endo,exo-5e, and 4% of exo,exo-6e. Reaction between 1,2-bis(chloroacetamido)-3,4-dicyanocalix[4]arene 22 and tetrahydroxycavitand 2 in DMF (entry 10 in Table 1) gave the three 2:1 isomers 4-6f in an almost statistical ratio in a total yield of 13%. The fact that both the exo-24 and the exo,exo-6 isomers are virtually absent in the coupling reactions between tetrahydroxycavitand 2 and the 1,2-bis(chloroacetamido)calix[4]arenes 8 (R1 ) -NO2), 12 (R1 ) -pht), and 16 (R1 ) -NHC(O)CH3) indicates that there is a strong preference for an endo orientation of the first calix[4]arene moiety with respect to the cavitand moiety. This can be attributed to a favorable interaction of the polar functional groups at the 3- and 4-positions of the calix[4]arene during formation of the second bond. In the reaction leading to the exo isomer the functional groups at the 3- and 4-positions are too remote to have an interaction with the cavitand moiety. The results of the coupling reaction with 1,2-bis(chloroacetamido)calix[4]arenes 19 (R1 ) -tert-butyl) and 22 (R1 ) -CN) indicate that the directing effect of these substituents is much smaller or even negligible. The statistical distribution of 2:1 products endo,endo4, endo,exo-5, and exo,exo-6 (R1 ) -H, -NO2, -pht, or -tert-butyl)22 indicates that there is no preference for an endo or exo orientation in the reaction of a 1:1 product with the second calix[4]arene. Apparently, there is no specific interaction during the reaction. An exception to this statistical distribution is the coupling with 1,2-bis(acetamido)-3,4-bis(chloroacetamido)calix[4]arene 16, where exclusively the endo,exo isomer 5d was formed. There has to be an intermolecular interaction between previously formed endo-23d and a second equivalent of calix[4]arene, which favors the formation of the second calix[4]arene in an exo-fashion with respect to endo-23d. From the literature,4 it is known that acetyl groups show strong interactions with a cavitand. In the case of calix[4]arene 16, acetamido groups could penetrate inside the cavity of endo isomer 23d (see a in Figure 3). Assuming that the other acetamido functionality will interact with an amido bridge or an acetamido group of the endo isomer 23d (b in Figure 3), formation of the endo,exo isomer 5d is most likely because one of the chloroacetamido functionalities is in close proximity to one of the two remaining hydroxyl groups (c in Figure 3, the hydroxyl group at the aromatic ring in the back) while the other chloroacetamido group is not close to one of the hydroxyl groups. After formation of this bond the calix[4]arene moiety has to rotate away from the 1:1 endo cavity to make it possible to form the second bond between the remaining chloroacetamido and hydroxyl groups. Reac(22) The results of the coupling reactions in a 1:1 ratio are taken into consideration: if no exo isomer was found the statistical distribution of 2:1 products endo,endo-4, endo,exo-5, and exo,exo-6 is 1:1:0, if the exo isomer was found this distribution is 1:2:1.
Complexation of Steroids
J. Org. Chem., Vol. 61, No. 17, 1996 5925
Figure 3. Intermolecular interaction between endo-23d (R1 ) -NHC(O)CH3) and calix[4]arene 16 exclusively leading to the formation of endo,exo-5d.
tion following this pathway can only lead to an exo orientation of the second calix[4]arene moiety. Conformational Properties of 2:1 Receptor Molecules 5a, d, and e. The 1H NMR spectrum of endo,exo isomer 5d (R1 ) -NHC(O)CH3) at room temperature in CDCl3 showed an additional four peaks in the amide region indicating the presence of minor conformers (see Figure 4a). ROESY NMR spectroscopy23 showed cross peaks between the major endo amide hydrogen and a set of two signals and cross peaks between the major exo amide hydrogen and another set of two signals (see Figure 4b). Although rotation of one amide bridge results in principle in four different amide hydrogens, it is reasonable to assume that the rotation of an amide bridge on one side of the 2:1 isomer does not influence the amide hydrogens on the other side to a large extent. This means that there are two minor conformers present, one in which one of the endo amide bridges is rotated and one in which one of the exo amide bridges is rotated.24 ∆G°298 values of ∼6 kJ mol-1 were calculated for both the endo and the exo amide bridge. By using ROESY NMR spectroscopy ∆Gq303 values of 70 and 83 kJ mol-1 were determined for the rotation of endo and exo amide bridges, respectively. Because the minor conformers are only present in a small amount, the conformer in which two amide bridges are rotated (either two on one side or one on both sides) does not appear in the NMR spectra. In contrast with the 1H NMR spectrum of endo,exo-5d (R1 ) -NHC(O)CH3), the 1H NMR spectra of endo,exo isomers 5a (R1 ) -H) and 5e (R1 ) -tert-butyl) in CDCl3 at room temperature do not exhibit the presence of a minor conformer. Cooling leads to a broadening of the signal for the exo amide proton at -60 °C in the case of product 5e, indicating that the rotation of the exo amido bridge becomes slow on the NMR time scale. At -80 °C broadening of the signal for the exo amide hydrogen of product 5a occurs. Therefore, we can conclude that the parent endo,exo isomer 5a (R1 ) -H) shows the fastest rotation of the amide bridge (has the lowest ∆Gq value), the tert-butyl groups in endo,exo isomer 5e hinder this rotation, while the acetamido groups of endo,exo isomer
5d slow the rotation to such extent that two minor conformers are present at room temperature. This behavior can be explained by an intramolecular interaction between the amide bridge and the acetamido groups at the 3- and 4-positions of the calix[4]arenes. Complexation Properties. Following the results of the DOCK study with holand 3, which showed that steroids are potential guest compounds, we studied the affinity of 2:1 isomers 4-6, having a cavity very similar to that of holand 3, for steroids, in particular corticosteroids. Corticosteroids are hormonal steroids characterized by an oxygen function at C11, which are widely used against rheumatoid arthritis, severe asthma, and other inflammatory diseases.25 First, the complexation behavior of the 2:1 isomers 4a, 5a, and 6a (R1 ) -H) was studied. Upon addition of prednisolone 21-acetate (25, Chart 5) to a solution of one of these compounds in CDCl3 at 25 °C, the amide hydrogen signals in the 1H NMR spectrum split into two signals of equal intensity. This splitting is a result of the chirality of the guest, which makes the overall complex chiral. Due to fast exchange between the free host and the complex on the 1H NMR chemical shift time scale, only two signals are observed for the four amide
(23) Bothner-By, A. A.; Stephens, R. L.; Lee, J.; Warren, C. D.; Jeanloz, R. W. J. Am. Chem. Soc. 1984, 106, 811. (24) It is not clear from the experiments whether this is an interconversion between the trans and the cis amide or a rotation of the bond between the aromatic carbon and the amide nitrogen.
(25) (a) Ganong, W. F. Review of Medical Physiology, 14th ed.; Prentice Hall: London, 1989; Chapter 4. (b) Siegel, S. C. J. Allergy Clin. Immunol. 1985, 76, 312. (26) de Boer, J. A. A.; Reinhoudt, D. N.; Harkema, S.; van Hummel, G. J.; de Jong, F. J. Am. Chem. Soc. 1982, 104, 4073.
Figure 4. (a) 1H NMR spectrum of endo,exo-5d (R1 ) -NHC(O)CH3) in CDCl3 at room temperature and (b) ROESY NMR spectrum of endo,exo-5d (R1 ) -NHC(O)CH3) in CDCl3 at 30 °C.
5926 J. Org. Chem., Vol. 61, No. 17, 1996
Higler et al.
Chart 5
Table 3. Results of Prednisolone 21-Acetate (25) Complexation by Receptor Molecules 4a, 5a-e, and 6aa entry 1 2 3 4 5 6 7 a
receptor
Kassoc (M-1)
∆G298 (kJ mol-1)
4a 5a 5b 5c 5d 5e 6a
4.3 × 8.3 × 102
