Spirodienone Derivatives of a Spherand-Type Calixarene - The

Dynamic equilibrium between dissociation and regeneration of the C–C bond in trispiro-conjoined cyclopropane compound. Saiko Kiyohara , Koji Ishizuk...
0 downloads 0 Views 157KB Size
Download PDF
VOLUME 66, NUMBER 9

MAY 4, 2001

© Copyright 2001 by the American Chemical Society

Articles Spirodienone Derivatives of a Spherand-Type Calixarene Kasim Agbaria,† Oleg Aleksiuk,† Silvio E. Biali,*,† Volker Bo¨hmer,‡ Michael Frings,‡ and Iris Thondorf§ Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel, Fachbereich Chemie und Pharmazie, Abteilung Lehramt Chemie, Johannes-Gutenberg Universita¨ t, Duesbergweg 10-14, D-55099 Mainz, Germany, and Institut fu¨ r Biochemie, Fachbereich Biochemie/Biotechnologie, Martin-Luther-Universita¨ t, Halle-Wittenberg, Kurt-Mothes-Str. 3, D-06099, Halle, Germany [email protected] Received November 20, 2000

Oxidation of the spherand-type calixarene 4 with 1 or 2 equiv of phenyltrimethylammonium tribromide/base afforded mono- and bis(spirodienone) derivatives (8b and 9, respectively). The spirodienone groups are derived from the oxidation of two phenols connected by a common methylene group. NOESY data indicated that 9 possesses a “head to tail” arrangement of the spirodienone groups. Oxidation of 4 with 3 equiv of the oxidizing reagent afforded two tris(spirodienone) calixarene derivatives 11 and 10 with C1 and C3 symmetries, respectively. The same tris(spirodienone) products were obtained by oxidation of 9 with I2/aq KOH. Tris(spirodienone) 11 displayed NOE cross-peaks in the NOESY NMR spectrum consistent with a nonalternant disposition of carbonyl and ether groups. Upon heating 10 and 11 isomerize in the solid state and in solution. The major component in the equilibration mixtures is 11, indicating that this is the thermodynamically more stable tris(spirodienone) isomer. Introduction The calix[n]arenes (1) are synthetic macrocycles consisting of a cyclic array of phenols connected by methylene groups.1 Mild oxidation of calixarenes in the presence of base affords spirodienone derivatives.2,3 This transformation is of interest since carbonyl and ether func†

The Hebrew University of Jerusalem. Johannes-Gutenberg Universita¨t. Martin-Luther-Universita¨t. (1) For recent reviews on calixarenes, see: (a) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (b) Gutsche, C. D. Aldrichim. Acta 1995, 28, 1. (c) Gutsche, C. D. Calixarenes Revisited; Royal Society of Chemistry: Cambridge, 1998. ‡ §

tionalities as well as spiro stereocenters are introduced in the macrocycle in a single synthetic step. Oxidation of the parent p-tert-butylcalix[4]arene (1a) with phenyltrimethylammonium tribromide affords a mixture of three isomeric bis(spirodienone) calixarene derivatives (2) For reviews on spirodienone calixarene derivatives, see: Aleksiuk, O.; Grynszpan, F.; Litwak, M. A.; Biali, S. E. New J. Chem. 1996, 20, 473. For a review on the oxidation and reduction of calixarenes, see: Biali, S. E. In Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer Academic Publishers: Dordrecht, 2001; pp 266-279. (3) For a recent example of spirodienone derivatives of calixnaphthols, see: Georghiou, P. E.; Ashram, M.; Clase, H. J.; Bridson, J. N. J. Org. Chem. 1998, 63, 1869.

10.1021/jo001648x CCC: $20.00 © 2001 American Chemical Society Published on Web 04/10/2001

2892

J. Org. Chem., Vol. 66, No. 9, 2001

(2a-c, eq 1) that result from the possible arrangements of the carbonyl and ether groups (alternant or nonalternant) and from the different possible configurations of the spiro stereocenters.4 The alternant meso-bis(spiro-

dienone) 2a can be obtained in a regio- and stereoselective fashion by oxidation of 1a with I2/PEG 200/25% aq KOH/CHCl3, and these reagents have been used also for the oxidation of other calix[4]arene derivatives.5 The larger the calixarene, the larger the number of potential isomers of the poly(spirodienone) derivative,6 but products with alternant arrangements of the ether and carbonyl groups are usually formed preferentially.6,7 Oxidation of 1a-c with an equimolar amount of the oxidation reagent and a weaker base affords the mono(spirodienone) calixarene derivatives 3a-c.8 These compounds have proved useful as key intermediates for the preparation of selectively functionalized systems (e.g., proximally disubstituted calix[4]arene derivatives)8a and, via reaction with hydrazines, for the preparation of calixarenes in which one of the OH groups has been replaced by an amino group or a hydrogen atom.8b,9 Replacement of two distal OH groups of 1a by methyl groups has been accomplished via addition of MeLi to 2a, followed by reaction with Et3SiH/CF3COOH.10 (4) Litwak, A. M.; Grynszpan, F.; Aleksiuk, O.; Cohen, S.; Biali, S. E. J. Org. Chem. 1993, 58, 8, 393. (5) Wang, W.-G.; Zhang, W.-C.; Huang, Z.-T. J. Chem. Res., Synop. 1998, 462. (6) Grynszpan, F.; Aleksiuk, O.; Biali, S. E. Pure Appl. Chem. 1996, 60, 1249. (7) Grynszpan, F.; Biali, S. E. J. Org. Chem. 1996, 61, 9512. (8) (a) Aleksiuk, O.; Grynszpan, F.; Biali, S. E. J. Chem. Soc., Chem. Commun. 1993, 11. (b) Aleksiuk, O.; Cohen, S.; Biali, S. E. J. Am. Chem. Soc. 1995, 117, 9645. (9) Aleksiuk, O.; Grynszpan, F.; Biali, S. E. J. Org. Chem. 1993, 58, 1994. (10) Van Gelder, J. M.; Brenn, J.; Thondorf, I.; Biali, S. E. J. Org. Chem. 1997, 62, 3511.

Agbaria et al.

The preparation of 4 by base-catalyzed condensation of a 2,2′-dihydroxybiphenyl derivative (5a) with paraformaldehyde was reported by Yamato and co-workers.11,12 The macrocycle 4 contains structural features of both the calixarenes (1) and the spherands13 (e.g., 6) and thus can be viewed as a hybrid between both families of compounds.14 The spherand-type calixarenes and related

compounds are of interest from a stereochemical point of view due to the presence of the 2,2′-dihydroxybiphenyl subunits. These substituted biphenyl subunits, which prefer a noncoplanar conformation, may bestow chirality to the macrocycle. Compound 4 exists in the solid state in a chiral conformation with C1 symmetry in which the biphenyl subunits possess different configurations (RRS/ SSR).15 The spirodienone derivatives of 4 are of interest as synthetic precursors for the preparation of modified spherand-type calixarenes and per se as potential ligands. In this article we report the synthesis and structural characterization of the mono-, bis-, and tris(spirodienone) derivatives of 4. Results and Discussion Oxidation of 2,2′-Dihydroxy-3,3′,5,5′-tetra-tertbutylbiphenyl. The mild oxidation of “classic” calixarenes 1 yields spirodienone derivatives with a fivemembered dihydrofuran ring connected in a spiro fashion to a six-membered cyclohexadienone ring (a “[5-6]” spiro system). This course of the reaction is feasible also for 4, but in addition to this possibility, the oxidation could occur in principle within a given 2,2′-dihydroxybiphenyl unit. This pathway could yield a spiro system possessing (11) (a) Yamato, T.; Hasekawa, K.; Saruwatari, Y.; Doamekpor, L. K. Chem. Ber. 1993, 126, 1435. (b) Yamato, T.; Zhang, F.; Yasumatsu, M. J. Chem. Res., Synop. 1997, 466. (12) See also: O’Sullivan, P.; Bo¨hmer, V.; Vogt, W.; Paulus, E. F.; Jakobi, R. A. Chem. Ber. 1994, 127, 427. (13) Cram, D. J. Angew. Chem., Int. Ed. Engl. 1986, 25, 1039. (14) For macrobicyclic hybrids of calixarene and spherands (“calixspherands”), see, for example: Groenen, L. C.; Brunink, J. A. J.; Iwema Bakker, W. I.; Harkema, S.; Wijmenga, S. S.; Reinhoudt, D. N. J. Chem. Soc., Perkin Trans. 2 1992, 1899. (15) Agbaria, K.; Biali, S. E.; Bo¨hmer, V.; Brenn, J.; Cohen, S.; Frings, M.; Grynszpan, F.; Harrowfield, J. McB.; Sobolev, A. N.; Thondorf, I. J. Org. Chem. 2001, 66, 2900.

Spirodienone Derivatives of a Spherand-Type Calixarene

a four-membered ring connected to a six-membered ring (a “[4-6]” spiro system). In fact, the oxidation of 2,2′-dihydroxy-3,3′,5,5′-tetra-tert-butylbiphenyl (5b) with mild oxidation reagents such as I2/AcOH has been claimed to afford the [4-6] spirodienone derivative 7a (“benzoxete”).16 However, Meier et al. reassigned to the oxidation product the oxepino benzofuran structure 7b.17,18

Mono(spirodienone) Derivative of 4. Considering the mild oxidation of 4, not only [4-6] and [5-6] monospirodienone derivatives (8a and 8b, respectively) may be expected but also oxepino benzofuran derivatives. The presence of a spirodienone moiety in the product can be readily detected by the presence (inter alia) of a carbonyl resonance in the 13C NMR spectrum. The vinylic signals corresponding to the β and δ protons of a [5-6] spirodienone can be readily assigned in the 1H NMR spectrum since the two signals are well separated, with the δ proton resonating at a higher field than the β one.4 Oxidation of 4 with an equimolar amount of phenyltrimethylammonium tribromide/base afforded a mixture of a mono- and a bis(spirodienone) derivative, which were separated by column chromatography. The 1H NMR spectrum of the monospirodienone derivative at room temperature (400 MHz, CDCl3) displayed both broad high intensity and low intensity signals. The broad peaks with low intensity (observed in the aromatic, vinyl and tert-butyl region) become sharper upon cooling and are ascribed to a low populated conformer. The major conformer displayed in the methylene region three sharp doublets (integrating for one proton each) and a broad doublet (integrating for three protons), which became sharper at higher temperatures. The anisochrony of the methylene protons is due to the presence of the chiral spiro stereocenter, which renders these protons diastereotopic, even under conditions in which all rotations around Ar-CH2 and Ar-Ar bonds are fast on the NMR time scale.4 The broadening of several methylene signals suggests that a dynamic process exchanging different conformers is present. Two vinylic signals were observed at 6.99 and 6.36 ppm in the regions characteristic of the β and δ dienone protons of a [5-6] spirodienone derivative. A NOESY spectrum indicated that the higher field proton is proximal to a methylene group. In addition, one aromatic proton displayed NOE cross-peaks of similar intensities with the two protons of one methylene group. This is in agreement with the presence of a [5-6] spiro subunit. In such a spirodienone system, the aromatic plane nearly bisects the neighboring spiro methylene protons (in contrast to ArCH2Ar groups) and the similar distances between this aromatic proton and the methylene ones (cf. Scheme 1) results in NOE peaks of similar strengths. On the basis of these NOE data, structure 8b is assigned to the monospirodienone product. The carbonyl carbon resonates in the 13C NMR at 201 ppm, in the region characteristic for the carbonyls of the spirodienone calixarene derivatives.

J. Org. Chem., Vol. 66, No. 9, 2001 2893 Scheme 1

Bis(spirodienone) Derivative of 4. Assuming by analogy to 8b that the spirodienone subunits possess [5-6] structures, and disregarding conformational isomerism, 10 isomeric bis(spirodienone) derivatives of 4 are possible. They correspond to two meso forms and four pairs of enantiomers (Figure 1). The bis(spirodienone) derivative obtained as side product in the synthesis of 8b was obtained in good yield by oxidation of 4 with 2 equiv of phenyltrimethylammonium tribromide. The bis(spirodienone) structure was readily evident from the 13C NMR spectrum, which displayed two carbonyl signals at 199.72 and 195.23 ppm. A single signal at 90.67 ppm was observed for the two spiro carbons, due to accidental isochrony. The signals

Figure 1. Schematic representation of the ten isomeric forms of a [5-6] bis(spirodienone) derivative of 4. The dots represent phenol rings, clockwise and counterclockwise curved arrows represent the sense of direction of the spirodienone subunits (arbitrarily defined at the bottom of the figure), and empty and filled circles represent the configuration (R or S) of the spiro stereocenters.

2894

J. Org. Chem., Vol. 66, No. 9, 2001

Agbaria et al.

Figure 2. 1H NMR spectrum (400 MHz, CDCl3, 210 K) of 9. Top: expansions of the aromatic and vinylic (left) and methylene (right) regions.

of the OH groups appeared in the 1H NMR spectrum at 7.98 and 7.23 ppm, and were readily identified in the NOESY spectrum by the strong mutual cross-peaks indicating magnetization transfer due to chemical exchange. The aromatic region displayed some signal overlap, but at a lower temperature (210 K) all the aromatic proton signals were resolved (Figure 2). A complete assignment of the signals was achieved by COSY and NOESY spectra. As observed for other spirodienone derivatives, in the 1H NMR spectrum the tertbutyl groups on the cyclohexadienone rings resonated at higher field than the tert-butyl group on the aromatic rings.7 Additional structural characterization of the product as a bis(spirodienone) derivative was carried out by means of a 1H NMR NOESY spectrum. This spectrum displayed a NOE cross-peak between the vinylic β proton of a spirodienone unit and an aromatic proton of the second spirodienone group, in agreement with an alternant (“head to tail”) disposition of carbonyl and ether groups (i.e., 9). A similar alternant disposition of groups was obtained for the bis(spirodienone) derivative obtained as the kinetic product in the oxidation of 1b.7 A summary of the NOESY interactions is displayed in Scheme 2. As observed for 8b, in each spirodienone subunit the aromatic proton vicinal to the dihydrofuran group displayed two cross-peaks of similar intensities with the methylene protons of the group. On the basis of the NMR data, it was not possible to decide whether the two spiro stereocenters of 9 possess

Scheme 2

identical or different configurations. Chemical evidence supporting a structure with an alternant arrangement of ether and carbonyl groups and identical configurations of stereocenters was obtained by oxidation of 9. The oxidation was conducted using I2/ KOH since treatment of 9 with phenyltrimethylammonium tribromide/base afforded a complex mixture of products. This oxidation yielded a mixture of two tris(spirodienone) derivatives (10 and 11) which on the basis of their NMR spectra (see below) were assigned to structures possessing C3 and C1 symmetries, respectively. The C3 form must possess identical configurations of the three stereocenters and alternant arrangements of the carbonyls and ether groups since all other possibilities are incompatible with the 3-fold symmetry axis. Provided no isomerization takes place during the oxidation, the tris(spirodienone) derivative 10 can only be generated from a bis(spirodienone) derivative with an alternant disposition of

Spirodienone Derivatives of a Spherand-Type Calixarene

J. Org. Chem., Vol. 66, No. 9, 2001 2895

Figure 3. Crystal structure of 9. The acetonitrile solvent molecules (which could not be refined) and some of the occupied positions of the disordered p-tert-butyl groups are omitted for clarity.

carbonyl and ether groups and identical configuration of the two stereocenters, thus allowing the structural assignment of the starting material 9.

A single crystal of 9 grown from acetonitrile was submitted to X-ray crystallography. The structure displayed disordered solvent molecules and tert-butyl groups and therefore it could be refined only to a relatively high R factor. However, the gross structural features obtained are trustworthy (Figure 3) and confirm the structural assignment obtained by spectroscopic and chemical methods. The crystal structure conclusively demonstrates that the compound possesses two [5-6] spirodienone substructures with alternant ether and carbonyl groups and identical configurations (RR/SS) of the two stereocenters (top left structure in Figure 1). The two carbonyl groups (O4, O6) are oriented in parallel fashion. The two phenols

units adopt a syn conformation where the OH groups (O1, O2) point nearly in the same direction as the carbonyl groups. This is the conformation usually adopted in “conventional” calixarenes since its enables an intramolecular hydrogen bond between the OH groups, which may be concluded in this case from a distance O1-O2 ) 2.74 Å.19 Tris(spirodienone) Spherand-Type Calixarenes. As in the case of the tris(spirodienone) derivatives of p-tert-butylcalix[6]arene,7 12 isomers (six pairs of enantiomers) are possible for the tris(spirodienone) derivatives of 4 (Figure 4). Since the system possesses three stereocenters, all isomers are chiral and no achiral meso form is possible. Oxidation of the trispherand 4 with 3 equiv of phenyltrimethylammonium tribromide afforded a mixture of two tris(spirodienone) derivatives that were separated by column chromatography. As observed for the mono(spirodienone) derivative 8b, both compounds displayed in the DCI MS a peak cluster with maxima at a m/z corresponding to [MH2 + H]+, indicating that some reduction or disproportionation took place under the mass spectral conditions. In the 1H NMR spectrum, the minor product showed two tert-butyl signals and two doublets for the methylene protons, in agreement with a structure of C3 symmetry in which necessarily the ether and carbonyl groups are arranged in an alternant fashion and all the stereocenters possess identical configurations (RRR/SSS, 10). (16) Mu¨ller, E.; Mayer, R.; Narr, B.; Rieker, A.; Scheffler, K. Justus Liebigs Ann. Chem. 1961, 645, 25. (17) Meier, H.; Schneider, H.-P.; Rieker, A.; Hitchcock, P. B. Angew. Chem., Int. Ed. Engl. 1978, 17, 121. (18) Oxidation of 5b with K3Fe(CN)6/base has been claimed (Jamois, D.; Tessier, M.; Marechal, E. J. Polymer Sci. Part A: Polym. Chem. 1993, 31, 1923) to afford 7a, but on the basis of the reported 1H NMR spectrum it can be concluded that the product obtained was indeed 7b. (19) The distances O2-O4 ) 2.83 Å and to a lesser extent O1-O6 ) 2.92 Å do not completely rule out O-H‚‚‚OdC hydrogen bonds.

2896

J. Org. Chem., Vol. 66, No. 9, 2001

Agbaria et al. Scheme 4

Figure 4. Twelve isomeric forms of a [5-6] tris(spirodienone) derivative of 4. The two tris(spirodienone) derivatives isolated (10 and 11) correspond to structures A and F, respectively.

For the major isomer six tert-butyl signals and six signals for methylene protons, indicate the absence of any symmetry element (C1 symmetry). The structure of the major isomer was deduced by a combination of COSY and NOESY NMR experiments in acetone-d6. A summary of the NOE interactions is shown in Scheme 3. The NOESY Scheme 3

spectrum displayed cross-peaks between a pair of aromatic protons at 7.08 and 6.94 ppm indicating that two aromatic rings are in steric proximity. These cross-peaks are only in agreement with a non alternant disposition of carbonyl and ether groups and with a vicinal arrangement of two aryl groups (and consequently also of two cyclohexadienone rings). On the basis of the spectroscopic data, structure 11 is assigned to the major product. Since 11 was obtained also from the oxidation of 9, the stereocenters of the two spirodienone subunits connected in head to tail fashion must possess the same configuration. However on the basis of the NMR evidence it is difficult to conclude whether the configuration of the third stereocenter is identical (cf. structure F in Figure 4) or opposite (structure C) to the configurations of the stereocenters of the two spirodienone subunits arranged in head to tail fashion. Isomerization Studies. We found that samples of the tris(spirodienone) derivative 10 slowly isomerize to a mixture consisting of 11 (major product), traces of 10, and small amounts of two additional products (Scheme 4). This isomerization requires several weeks at room temperature. Similar isomerizations have been observed

in solution for the bis(spirodienone) derivatives of 1a and 1b and for the tris(spirodienone) derivatives of 1c.7 The isomerization can take place by homolytic cleavage of the spiro C-O bond yielding a biradical, followed by regeneration of the C-O bond either with inversion or retention of the configuration of the spiro carbon. Since either of the two phenoxy rings formed by the cleavage can serve as the source of the newly formed cyclohexadienone ring, the process can result also in the interconversion between alternant and nonalternant derivatives.20 Solution isomerization experiments were conducted by heating samples of 10 and 11 in benzene at 343 K.21 The reaction was followed by integration of the 1H NMR signals of the δ vinyl protons. The equilibrium mixture consisted of essentially 11 (>95% of the equilibrium mixture), small amounts of two additional species of C1 symmetry and traces of 10 (Figure 5). The isomerization experiments indicate that tris(spirodienone) derivative 11 is the thermodynamically most stable isomer and that its free energy is at least 2.1 kcal mol-1 lower than any other tris(spirodienone) isomer.22 Since the equilibrium

Figure 5. 1H NMR spectra (400 MHz, CDCl3, rt) of the vinyl regions of tris(spirodienone) 10 (A), compound 10 after heating in benzene at 343 K (B), and of the tris(spirodienone) derivative 11 (C).

Spirodienone Derivatives of a Spherand-Type Calixarene

Figure 6.

1H

J. Org. Chem., Vol. 66, No. 9, 2001 2897

NMR spectrum of 9 in the absence and presence of the chiral solvating agent.

mixture is strongly biased toward 11, the transformation 10 f 11 can be viewed as an irreversible reaction. The molar fraction of 10 at different times was determined by 1H NMR from the integration ratio taking advantage that the proton at the δ position of the cyclohexadienone rings are well separated form the rest of the signals, and that the signals corresponding to 10 and 11 are well resolved. The molar fraction of 10 was determined from the ratio between the δ vinyl signal of 10 and the total integral of all the δ vinyl signals present (including the one belonging to 10). A plot of ln of the molar fraction of 10 vs t (min) is linear indicating first-order kinetics. From the slope of this plot, the rate constant for the disappearance of 10 was determined as k ) 0.0052 min-1 (t1/2 ) 133 min at 343 K). Notably, we found that the isomerization also takes place in the solid state. For example, heating a sample of 11 to 406 K (below its mp) for 2 h resulted (as judged by dissolving the sample in CDCl3 and determining the 1 H NMR spectrum) in a 94:6 mixture of 11 and 10. Heating a sample of 10 at 406 K for 12 h followed by 1H NMR analysis indicated that the mixture consisted of a 2:1 mixture of 11 and a new spirodienone of C1 symmetry together with small amounts of 10. The rather facile isomerization observed in the solid state is probably due to the low activation energy necessary to cleave the spiro C-O bond and the relatively small change in atomic positions required by the reaction. NMR Spectra in a Chiral Nonracemic Medium. The mono-, bis-, and tris(spirodienone) derivatives pre(20) An alternative mechanism involves a [3.3] sigmatropic reaction (ref 4). See also: Yamato, T.; Matsumoto, J.; Fujita, K. J. Chem. Soc., Perkin Trans. 1 1998, 123. (21) Under the same reaction conditions, the bis(spirodienone) derivative 9 does not isomerize but rather decomposes. (22) Since the equilibrium constant (K) between 11 and any other isomer is g19, a lower limit of 2.1 kcal mol-1 can be estimated for the free energy difference from the equation -∆G° ) RT ln K.

pared and characterized in the present study (8b, 9, 10 and 11), are all chiral racemic compounds. In the presence of a chiral nonracemic medium, pairs of signals for enantiotopic atoms or groups (by external comparison) on enantiomers should become anisochronous. Addition of 45 mg of the chiral solvating agent (CSA) (S)-2,2,2trifluoro-1-(anthryl)ethanol23 to solutions of 9, 10, and 11 obtained by dissolving 20 mg of the compound in 0.75 mL of solvent resulted in splitting of signals in the 1H NMR spectrum (Figure 6). The largest effect was observed when benzene-d6 was used as solvent, since the nonpolar solvent does not compete with the substrate in the association process with the CSA. Splitting of signals was observed also in the 13C NMR spectra of 9, and three signals each were observed for the carbonyl (δ 200.38, 196.00, 195.95) and spiro (δ 85.54, 85.51, and 85.37) carbons. In each case, only the splitting of one of the two carbonyl and spiro carbons was sufficiently large (∆δ ) 0.05 and 0.03 ppm, respectively) to allow its detection under the experimental conditions. Similarly, in the 1H NMR the higher field δ proton (assigned to the unique cyclohexadienone ring connected to a phenol) was split (∆δ ) 0.01 ppm) while the second δ proton remained unchanged. The largest splitting in the methylene region (∆δ ) 0.02 ppm) was observed for the group connecting the two phenol rings. Calculations. Molecular mechanics calculations (MM3(96))24,25 were carried out for the alternant isomer 10 and for 11 with nonalternant dispositions of the carbonyl and ether group. They indicate for 11 that structure F (cf. Figure 4) is more stable than the isomeric (23) Pirkle, W. H.; Beare, S. D. J. Am. Chem. Soc. 1969, 91, 5150. (24) (a) Allinger, N. L.; Yuh, Y. H.; Lii, J.-H. J. Am. Chem. Soc. 1989, 111, 8551. (b) Lii, J.-H.; Allinger, N. L. J. Am. Chem. Soc. 1989, 111, 8566. (c) Lii, J.-H.; Allinger, N. L. J. Am. Chem. Soc. 1989, 111, 8576. (25) MM3(96) is included in the Sybyl 6.5 program package (Tripos Associates, Inc., St. Louis, MO 63144).

2898

J. Org. Chem., Vol. 66, No. 9, 2001

Agbaria et al.

Table 1. MM3 Calculated Relative Energies (kcal/mol) and Dihedral Anglesa between the Spirodienone Subunits of 10A and the Isomers of 11 ∆E

φ1

φ2

φ3

10A 57 122 62 11Fb 0.0 54 90 124 11D 3.3 97 41 -50 11E 4.6 -44 134 33 11C 5.1 47 -55 136 a In each case, the angles refer to the enantiomer that possesses the largest number of R spiro stereocenters. b Definition of the dihedral angles φ1-φ3:

forms D, E, and C (Table 1). On the basis of the large energy difference between structures F and C, we conclude that the stereocenters in the isolated compound 11 most likely possess the same configuration (RRR/ SSS). In this isomer 11F, the carbonyl groups of the adjacent cyclohexadienone rings assume an anti arrangement while they are oriented in syn fashion in the alternating spirodienone units. For 10, the RRR/SSS isomer A was found exclusively in the set of structures obtained from the conformational search which suggests a large energy difference between isomers 10A and 10B.26 In the most stable, C1 symmetrical conformer of 10A all carbonyl groups point into the same direction indicating an energetically unfavorable orientation of the CO dipoles. Since 10 and 11 possess different connectivities, the steric energies obtained from the MM3 calculations cannot be directly compared. Instead, the heats of formation obtained from the semiempirical PM3 method were used to estimate the stability difference of both compounds. While the calculated energetical sequence of the stereoisomers of 11 corresponds to those depicted above, PM3 predicts that 10A is more stable by 1.4 kcal/mol than the RRR/SSS diastereomer of 11 (structure F). If the entropic contribution due to the symmetry of 10 (T∆S343K ) -0.7 kcal/mol) is considered (11F is statistically favored by a factor 3 over 10A), this energy difference is reduced to 0.7 kcal/mol. Due to the relatively low accuracy of semiempirical methods, this small calculated energy difference can be interpreted as indicating a similar thermodynamic stability of both compounds. This is in contrast to the experiments which clearly demonstrate that 11 is substantially more stable than any other isomer. Conclusions Mild oxidation of 4 affords mono-, bis-, and tris(spirodienone) derivatives containing [5-6] spiro subunits. Although several isomeric bis- and tris(spirodienone) derivatives are possible, the oxidation proceeds with high stereoselectivity. The RRR/SSS tris(spirodienone) derivative with a nonalternant disposition of carbonyls and (26) For 10, altogether 23 conformers in an energy range of 9.7 kcal/ mol were obtained from the stochastic search, while for 11 altogether 92 conformational and configurational isomers in an energy range of 8.9 kcal/mol resulted from this method.

ether groups (11F) is the thermodynamically most stable isomer among the tris(spirodienones).

Experimental Section Preparation of the Mono(spirodienone) Derivative 8b. A solution of 0.8 g (2.18 mmol) of phenyltrimethylammonium tribromide in 60 mL of CH2Cl2 was dropped with stirring during 20 min to a solution of 2 g (2.15 mmol) of 4 in 350 mL of CH2Cl2, followed by 300 mL of aqueous saturated NaHCO3. After the mixture was stirred for 24 h, the solvent was evaporated and the residue treated with 50 mL of MeOH. The insoluble material (unreacted 4) was filtered off, and the solvent was removed by evaporation. Chromatography of the residue (silica, CH2Cl2/hexane 3:1 or benzene/hexane 4:1) yielded 0.4 g (20%) of yellow 8b: mp 230-235 °C; 1H NMR (300.13 MHz, CDCl3, rt) major conformer δ 9.54 (br, OH), 9.12 (br, OH), 7.81 (br, OH), 7.70 (br, OH), 7.39 (d, J ) 2.3 Hz, ArH, 1H), 7.35 (d, J ) 2.4 Hz, ArH, 1H), 7.29 (overlapping d, 4H, ArH), 7.22 (d, J ) 2.5 Hz, ArH, 1H), 7.14 (d, J ) 1.8 Hz, ArH, 1H), 7.09 (d, J ) 2.5 Hz, ArH, 1H), 7.08 (d, J ) 2.0 Hz, ArH, 1H), 6.99 (d, J ) 2.5 Hz, CdCH, 1H), 6.36 (d, J ) 2.5 Hz, CdCH, 1H), 4.26 (d, J ) 14.2 Hz, CH2, 1H), 4.03 (broad dd, CH2, 3H), 3.71 (d, J ) 14.3 Hz, CH2, 1H), 3.37 (d, J ) 16.1 Hz, CH2, 1H), 1.38 (s, t-Bu, 9H), 1.31 (s, t-Bu, 9H), 1.31 (s, t-Bu, 9H), 1.29 (s, t-Bu, 9H), 1.28 (s, t-Bu, 9H), 1.20 (s, t-Bu, 9H); 13C NMR (100.62 MHz, CDCl3, rt) δ 201.4 (CdO), 153.08, 150.30, 148.07, 147.95, 147.75, 145.72, 144.24, 144.08, 143.96, 143.90, 142.98, 134.9, 130.32, 129.09, 129.04, 128.54, 128.29, 127.99, 127.76, 127.64, 127.41, 127.37, 127.27, 127.02, 126.96, 126.73, 126.61, 125.53, 124.58, 124.49, 123.91, 123.34, 121.68, 119.97, 90.67 (C(spiro)-O), 39.22, 34.56, 34.42, 34.23, 34.22, 34.15, 34.06, 32.71, 31.82, 31.71, 31.61, 31.56, 31.53, 28.57 ppm; IR νOH 3320, νCO 1685 cm-1; MS (DCI) m/z 931.4 ([MH2 + H]+). Anal. Calcd for C63H76O6 : C, 81.43; H, 8.24. Found: C, 81.11; H, 8.42. Preparation of the Bis(spirodienone) Derivative 9. A solution of 0.8 g (2.12 mmol) of phenyltrimethylammonium tribromide dissolved in CH2Cl2 was dropped with stirring during 15 min into a solution of 1 g (1.07 mmol) of 4 in 100 mL of CH2Cl2, followed by addition of 300 mL of a saturated NaHCO3 solution during 30 min. After the mixture was stirred for 24 h, the organic phase was washed with water, dried (MgSO4), and evaporated, yielding 0.92 g of crude 9. After chromatography (SiO2, eluent: CHCl3/hexane 4:1), 0.65 g (65%) of pure 9 was obtained: mp 275-280 °C; 1H NMR (400.13 MHz, CDCl3) δ 7.98 (s, OH), 7.48 (d, J ) 2.4 Hz, ArH, 2H), 7.47 (d, J ) 2.4 Hz, CdCH, 1H), 7.35 (d, J ) 2.1 Hz, ArH, 1H), 7.34 (d, J ) 1.9 Hz, ArH, 1H), 7.28 (d, J ) 2.5 Hz, ArH, 1H), 7.23 (br s, ArH + OH, 2H), 7.18 (br s, ArH, 1H), 7.11 (d, J ) 2.4 Hz, ArH, 1H), 6.91 (d, J ) 2.5 Hz, CdCH, 1H), 6.22 (d, J ) 2.4 Hz, CdCH, 1H), 6.10 (d, J ) 2.5 Hz, CdCH, 1H), 4.37 (d, J ) 13.9 Hz, CH2, 1H), 4.26 (d, J ) 15.6 Hz, CH2, 1H), 3.74 (d, J ) 15.9 Hz, CH2, 1H), 3.58 (d, J ) 14.0 Hz, CH2, 1H), 3.45 (d, J ) 15.9 Hz, CH2, 1H), 3.21 (d, J ) 15.5 Hz, CH2, 1H), 1.43 (s, t-Bu, 9H), 1.42 (s, t-Bu, 9H), 1.415 (s, t-Bu, 9H), 1.41 (s, t-Bu, 9H), 1.24 (s, t-Bu, 9H), 1.20 (s, t-Bu, 9H) ppm; 13C NMR (100.62 MHz, CDCl , rt) δ 199.72 (CdO), 195.23 3 (CdO), 153.42, 153.26, 150.75, 149.06, 146.91, 145.69, 144.78, 143.82, 143.00, 142.65, 141.82, 136.95, 134.33, 130.46, 128.84, 128.79, 127.54, 127.45, 127.31, 127.08, 127.05, 126.12, 125.84, 125.51, 125.11, 124.84, 124.01, 123.10, 122.07, 121.97, 119.18, 116.34, 84.99 (C(spiro)-O), 84.84 (C(spiro)-O), ppm), 40.56, 35.24, 34.48, 34.32, 34.05, 33.82, 31.78 (C(CH3)3), 31.72 (C(CH3)3), 31.66, 31.53 (C(CH3)3), 31.51 (C(CH3)3), 28.40 (C(CH3)3), 28.31 (C(CH3)3) ppm; IR νOH 3364, νCO 1668, 1699 cm-1; MS (CI) m/z 927.2 (MH+). Anal. Calcd for C63H74O6: C, 81.60; H, 8.04. Found: C, 81.25; H, 8.11. Tris(spirodienone) Derivatives of 4. To a stirred solution of 0.86 g (0.92 mmol) of 4 dissolved in CH2Cl2 was slowly added during 0.5 h a solution of 1.06 g (2.82 mmol) of phenyltrimethylammonium tribromide dissolved in 70 mL of CH2Cl2, and the mixture was stirred for an additional 1 h. Then aqueous NaOH (50 mL, 28%) was added, and the mixture was

Spirodienone Derivatives of a Spherand-Type Calixarene

J. Org. Chem., Vol. 66, No. 9, 2001 2899

stirred overnight. The organic phase was separated and washed several times with water. After evaporation of the solvent, the residue was chromatographed (silica/CH2Cl2) giving 11 (0.177 g, 21%) as a yellow solid, mp 175-180 °C dec. The second compound was eluted by a mixture of CH2Cl2/ MeOH (40:1), giving 0.196 g (23%) of 10: mp >170 °C dec. Spectroscopic data for 11: 1H NMR (400.13 MHz, CDCl3, rt) δ 7.47 (d, J ) 2.4 Hz, ArH, 1H), 7.21 (m, ArH, 2H), 7.15 (d, J ) 2.0 Hz, ArH, 1H), 7.06 (s, ArH, 2H), 6.93 (d, J ) 2.4 Hz, ArH, 1H), 6.90 (d, J ) 2.6 Hz, ArH, 1H), 6.84 (d, J ) 1.9 Hz, ArH, 1H), 6.26 (d, J ) 2.5 Hz, CdCH, 1H), 6.07 (d, J ) 2.5 Hz, CdCH, 1H), 5.91 (d, J ) 2.5 Hz, CdCH, 1H), 3.99 (d, J ) 15.6 Hz, CH2, 1H), 3.47 (d, J ) 15.9 Hz, CH2, 1H), 3.43 (d, J ) 15.9 Hz, CH2, 1H), 3.24 (d, J ) 15.5 Hz, CH2, 1H), 3.05 (d, J ) 15.5 Hz, CH2, 1H), 3.01 (d, J ) 15.1 Hz, CH2, 1H), 1.35 (s, t-Bu, 9H), 1.30 (s, t-Bu, 9H), 1.29 (s, t-Bu, 9H), 1.16 (s, t-Bu, 9H), 1.09 (s, t-Bu, 9H), 1.08 (s, t-Bu, 9H); 13C NMR (100.62 MHz, CDCl3, rt) δ 195.62 (CdO), 193.41 (CdO), 193.15 (CdO), 155.31, 154.80, 152.44, 148.25, 143.55, 143.36, 143.24, 143.00, 140.92, 140.24, 139.64, 139.22, 135.04, 134.30, 129.79, 127.19, 126.75, 126.23, 126.19, 125.90, 125.36, 125.27, 124.97, 121.68, 121.20, 121.09, 120.06, 119.56, 118.57, 89.29 (C spiro), 83.39 (C spiro), 82.79 (C spiro), 44.91, 41.55, 35.33, 34.47, 34.43, 34.33, 34.30, 34.26, 34.08, 31.81, 31.78, 31.74, 28.61, 28.48, 28.43 ppm; IR νCO 1692 cm-1 ; MS (DCI) m/z 927.6 (MH2 + H+). Spectroscopic data for 10: 1H NMR (400.13 MHz, CDCl3, rt) δ 7.11 (s, ArH, 3H), 7.07 (d, J ) 2.3 Hz, ArH, 3H), 6.97 (d, J ) 2.4 Hz, ArH, 1H), 6.90 (d, J ) 2.6 Hz, ArH, 1H), 6.84 (d, J ) 1.9 Hz, ArH, 1H), 6.26 (d, J ) 1.5 Hz, ArH, 3H), 6.12 (d, J ) 2.3 Hz, CdCH, 3H), 3.52 (d, J ) 15.4 Hz, CH2, 3H), 3.12 (d, J ) 15.4 Hz, CH2, 3H), 1.27 (s, t-Bu, 27H), 1.16 (s, t-Bu, 27H); 13C NMR (100.62 MHz, CDCl3, rt) δ 193.65 (CdO),

155.09, 142.95, 142.51, 139.11, 132.62, 130.05, 126.09, 125.49, 121.92, 117.22, 83.73 (C spiro), 41.18, 34.36, 34.25, 31.76, 28.72; IR νCO 1686 cm-1; MS (DCI) m/z 927.5 (MH2 + H+). Oxidation of the Bis(spirodienone) Derivative 9. Iodine (0.7 g, 0.49 mmol) was added to a solution of 0.3 g (0.32 mmol) of 9 in 10 mL of CH2Cl2 and 0.7 g of PEG 200, and 15 mL of a 30% solution of aqueous KOH was then dropped into the reaction mixture. After the mixture was stirred at room temperature for 6 h, the organic layer was separated and washed several times with brine and finally with water. Evaporation of the solvent yielded 0.26 g (84%) of a mixture of 10 and 11. Molecular Mechanics and Semiempirical Calculations. Compounds 10 and 11 were subjected to a conformational search using the stochastic search routine of MM3(96).25 Missing force field parameters were taken directly from the parameter estimator. Semiemipirical calculations were performed using the PM3 Hamiltonian included in MOPAC 6.0 (keywords PRECISE, EF).27,28

Acknowledgment. We thank Dr. Shmuel Cohen for the crystal structure determination of 9. Supporting Information Available: Stereoscopic view of the crystal structure of 9, 1H NMR spectra of 10 and 11, and X-ray data of 9. This material is available free of charge via the Internet at http://pubs.acs.org. JO001648X (27) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209. (28) MOPAC (version 6.0), program number 455, Quantum Chemistry Program Exchange at Indiana University, Bloomington, IN.