Structures of Brucinium Cholate: Bile Acid and Strychnine Derivatives

Feb 17, 2009 - ABSTRACT: Single crystals concomitantly containing brucine 1a and a bile acid derivative (cholic acid 2H or 3-epicholic acid 3H) were...
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Structures of Brucinium Cholate: Bile Acid and Strychnine Derivatives Meet in the Crystals Ichiro Hisaki,* Norie Shizuki, Kazuaki Aburaya, Masanori Katsuta, Norimitsu Tohnai, and Mikiji Miyata*

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 3 1280–1283

Department of Material and Life Science, Graduate School of Engineering, Osaka UniVersity, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan ReceiVed December 10, 2008; ReVised Manuscript ReceiVed February 2, 2009

ABSTRACT: Single crystals concomitantly containing brucine 1a and a bile acid derivative (cholic acid 2H or 3-epicholic acid 3H) were

successfully constructed. In these crystals, cholate 2- constructs inherent robust hydrogen bonded 21 helical assemblies and brucinium 1aH+ achieves 21 helical assemblies through weak interactions. These assemblies excellently synchronize helical pitches to one another. 3-Epicholate 3-, on the other hand, is unable to form a robust hydrogen-bonded motif because of inversion of the hydroxyl group at the 3 position. The present systems are the first example of steroidal bile acid molecules that cocrystallize with equal-sized alkaloidal molecules even when a salt bridge is formed. Design and construction of multicomponent organic crystals such as hydrogen-bonded (H-bonded) molecular complexes, salts, and solvates have had substantial interest in the fields of both supramolecular and pharmaceutical chemistry.1,2 Thus far, well-designed multicomponent organic crystals with significant properties such as nonlinear optical properties3 and chiral discrimination abilities4 have been reported. On the other hand, those which have unexpected combinations among organic substances are fascinating from a viewpoint of making novel materials. In particular, construction of multicomponent crystals containing highly asymmetric compounds, such as naturally occurring compounds, with (1) complicated polycyclic skeletons, (2) multiple stereogenic centers, and (3) multiple groups providing strong and/or weak H-bonds still remain challenging because its rational design is almost impossible at present. In this context, we focused on two kinds of naturally occurring compounds, brucine (2,3-dimethoxystrychnine) 1a and a series of bile acids 2H-7H and amide 8 (Chart 1). Historically, 1a has been investigated not only as a physiologically active substance for blood pressure control but also as a separator of racemic mixtures by cocrystallization with guest molecules containing acidic functional groups.5 Gould and Walkinshaw reported that 1a forms a characteristic corrugated monolayer sheet as a common motif, which is stabilized by weak interactions, such as CH/O and CH/π interactions.5a,f Białon´ska discussed the structure based on characteristic 21 helical motifs.5h-k Recently, we also reported supramolecualr tilt-chirality of the helical motifs of 1a.5l,m On the other hand, bile acid derivatives, which are produced by the liver and assist in dietary fat processing in the body, also forms inclusion crystals with various small organic molecules. In particular, cholic acid 2H is competent to make inclusion crystals due to its characteristic robust motif (vide infra).6 An intriguing question here is whether the steroidal and alkaloidal compounds, each of which has an unique skeleton and assembly manner, can coexist in the same crystal or not, and if possible, how they build up the crystal. Indeed, there are no reports of a crystal containing both strychnine derivatives and bile acid derivatives. Herein, we first report exotic crystal structures of salts containing 1a and bile acid, that is, 1a · 2H and 1a · 3H, in which both components individually form 21 helical assemblies with excellently synchronized helical pitches. Each of the bile acids 2H-7H and amide 8 was dissolved in various organic solvents with 1a in a 1:1 molar ratio and thoroughly * To whom correspondence should be addressed. E-mail: [email protected] (I.H.), [email protected].

Chart 1. Brucine 1a, Strychnine 1b, and Bile Acid Derivatives 2H-7H and 8

crystallized by slow evaporation of the solvents. Then, only two combinations (1a · 2H and 1a · 3H) yielded single crystals from methanol or ethanol, but did not from larger alcohols such as 1-propanol and 2-propanol. The other bile acids resulted in filmlike or gelated materials.7 Although the mixture of amide 8 and 1a gave a single crystal, crystallographic analysis revealed that the crystal contained only the amide. These results imply that a bile acid should require at least three hydroxyl and one carboxyl groups for cocrystallization with 1a. Packing diagrams of the obtained crystals are shown in Figure 1. Crystal 1a · 2H obtained from ethanol consists of brucinium (1aH+), cholate (2-), ethanol, and water in a molar ratio of 1:1:1:1 (crystal A) (Figure 1a).8 Crystal 1a · 2H from methanol consists of 1aH+, 2-, and methanol in a molar ratio of 1:1:2 (crystal B),9 in which the components 1aH+ and 2- pack in the same manner as in crystal A (Figure 1b). The crystal 1a · 3H obtained from ethanol has a complex composition, which contains 1aH+, 3-epicholate (3-), ethanol, and water in a molar ratio of 2:2:4:3 (crystal C) (Figure 1c).10 The carboxyl groups in 2H and 3H are deprotonated to generate carboxylates, and N(19) atom in 1a is protonated, judging from the C · · · O distances of the carboxyl groups: 1.233(6) and 1.268(5) Å for 2- in crystal A, 1.246(4) and 1.274(4) Å for 2- in crystal B, and 1.234(9)-1.268(10) Å for 3+ in crystal C. Absorption for the carbonyl stretching vibration at 1685 and 1658 cm-1 for crystal A, at 1685 and 1662 cm-1 for crystal B, and at 1658 cm-1 for crystal C also indicates the salt formation. Crystals A and B belong to space group of P21 and have almost the same cell parameters. In both crystals, 2- forms multiple

10.1021/cg801336t CCC: $40.75  2009 American Chemical Society Published on Web 02/17/2009

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Figure 1. Packing diagrams of crystal A (a), B (b), and C (c). Intermolecular H-bonds are shown as the brown dotted lines. Hydrogen atoms are omitted for clarity.

H-bonds to construct a 21 helical assembly along the b axis, and 1aH+ also forms a 21 helical assembly among the assemblies of 2- along the same direction. Solvent molecules, that is, methanol or ethanol and water, locate at void spaces and participate in H-bonds with the carboxylate moiety of 2- in the crystals. The fact that no crystals precipitated from propanol may be caused by the too large molecular size of propanol to stay in the void spaces. In Figure 2, the detailed structure of crystal A is shown. Cholate 2- forms cooperative intermolecular H-bonds among hydroxyl groups: O2(25)-H · · · O2(29)B and O2(29) · · · H-O2(25)A with a O · · · O distance of 2.753 Å, and O2(25) · · · H-O2(26)A and O2(26)-H · · · O2(25)B with O · · · O distance of 2.891 Å [symmetry codes: (A) 1 - x, 1/2 + y, 2 - z; (B) 1 - x, -1/2 + y, 2 - z] to give the well-known 21 helical assemblies (Figure 2a). The pitch of the helical motif (8.03 Å) is quite similar to those reported conventionally (7.80-8.61 Å).6 In addition, the carboxylate moiety, ethanol, and water form the H-bond bridge O2(28) · · · H-OEtOH · · · H-Owater-H · · · O2(27)C [symmetry codes: (C) x, y + 1, z, in Figure 2a]. The assemblies of 1aH+, on the other hand, contain only weaker intermolecular interactions than those of 2- (Figure 2b): four CH/O contacts, O1(28) · · · H-C1(27)A, C1(27)-H · · · O1(28)B, C1(15)-H · · · O1(26)B, and O1(26) · · · H-C1(15)A (with a O · · · C distance of 3.647 Å for the former two and 3.421 Å for the later two) and CH/π contacts such as C1(14)-H · · · C1(4)C and C1(27)B-H · · · C1(6), with C · · · C distances of 3.826 and 3.690 Å, respectively, to give a 21 helical superstructure. Two kinds of the helical assemblies are connected via intercolumnar linkages, which include a weak H-bond O2(29)-H · · · O1(24) (with a O · · · O distance of 2.905 Å) and a salt bridge between O2(28)A in the carboxylate moiety and the protonated ternary nitrogen atom N1(19) with the distance of 2.608 Å [symmetry codes: (A) -x, 1/2 + y, 1 - z] as shown in Figure 2c. Interestingly, a control experiment indicates that the methoxy groups of 1aH+ play an important role in cocrytallization. Namely, a mixture of 2H and strychnine 1b, which has the same structure with 1a except for the methoxy groups, did not cocrystallize but gave a monocomponent crystal of 1b even though they can be connected by a strong salt bridge. Crystal B has the same H-bond networks with that of crystal A except for the H-bonds involving the ethanol and water as shown in Figure 2a (inset), where the H-bond is not continuous but isolated

Figure 2. Helical assemblies of 2- (a) and 1aH+ (b) and intermolecular linkage between 1aH+ and 2- (c) in crystal A with 50% thermal ellipsoids. Inset: H-bond networks involving methanol molecules in crystal B. Symmetry codes for (a): (A) 1 - x, 1/2 + y, 2 - z; (B) 1 x, -1/2 + y, 2 - z; (C) x, y + 1, z: for (b) (A) 1 - x, -1/2 + y, 1 z; (B) 1 - x, -1/2 + y, 1 - z; (C) x, 1+ y, z: for (c) (A) -x, 1/2 + y, 1 - z.

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Figure 3. Comparison of the crystal structures between crystal A (b) and intrinsic assembly motifs of 2H (a) and 1a (c). The motifs (a) and (c) were extracted from the crystal structures of 2H · C6H6 and 1a · C3H7OH, respectively.

(O2(28) · · · H-OMeOH(1) · · · H-OMeOH(2)), indicating that the H-bond bridge in this part is not important for formation of the crystal. Characteristic features of the present systems are disclosed by comparison of the crystal structure of crystal A with that of conventional crystal of 1a or 2H; for example, the crystal of 2H including benzene (2H · C6H6)11 or that of 1a including 1-propanol (1a · C3H7OH).5l As shown in Figure 3a, 2H makes multi-H-bonded networks (red dotted lines) involving three hydroxyl groups to yield the robust 21 helical columnar assemblies. The assemblies are linked with the adjacent ones by other H-bonds (blue dotted line) involving the hydroxyl groups and the carboxyl group [O(28)-H · · · O29 and O(27) · · · H-O(26)] as well as by shape-well-fitted hydrophobic interactions between the back sides of 2H, giving robust lattice with cavities whose size ranges ca. 180-290 Å3. In the cavities, small molecules such as benzene and substituted benzenes are accommodated. However, in crystal A (Figure 3b), the H-bonded intercolumnar linkages are interrupted, instead of this, 1aH+ mediating and forming the heterointercolumnar H-bond and salt linkages. The heterocolumnar linkages enable the framework of 2- to be extended to accommodate 1aH+ in the cleaved space.12 Figure 3c shows the typical motif of the 21 helical assembly of 1a observed in conventional systems, where the molecules are arranged almost cofacially into a zigzag fashion via weak interactions such as CH/O and CH/π interactions [i.e., C(27)-H · · · O(24) and C(11)-H · · · C(1)]. Pitches of the conventional 21 helical assemblies are in a range of 12.08-12.89 Å.5 It is noteworthy that the present assembly has a pitch of 8.03 Å, much shorter than the conventional ones, to synchronize with the helical assembly of 2-. The remarkable shrinkage of the pitch was achieved by alteration of the weak molecular interactions and by inclining the molecular plane from the 2-fold screw axis by ca. 45°. Thus, the robust H-bonded assembly of 2- and tolerant tunable assembly of 1aH+ successfully form the synchronized superstructure cooperatively. Crystal C belongs to the space group of P1, although the crystal system has almost C2 symmetry. In the asymmetry unit, two pairs of 1aH+ and 3- are involved. In the crystal, 1aH+ form a columnar assembly through intermolecular interactions observed in crystals A and B. The assembly has pseudo 2-fold screw axis with a helical pitch of 8.04 Å. On the other hand, contrary to 2- in crystals A and B, 3- is unable to form robust helical assembly due to inversion of the hydroxyl group at the 3 position [O3(25)H], which is directed to the carbonyl group of 1aH+ [CdO1(25)], to form O3(25)sH · · · O1(25)A ) C bond (with an O · · · O distance of 2.816 Å) (Figure 4). The hydroxyl groups at the 7 and 12 positions form H-bonds with ethanol; O3(29) · · · HOEtOH and O3(26)H · · · OEtOH with O · · · O distances of 2.734 and 2.793 Å, respectively. Thus, the hydroxyl groups of 3- are totally satisfied in H-bond formation, despite a lack of an inherent self-assembly form.13 This system

Figure 4. Crystal structure (a) and heteromolecular linkages (b) in crystal C. Thermal ellipsoids are shown with 50% probability. Symmetry codes for (a) (A) x, 1 + y, z: for (b) (A) x, 1 + y, z; (B) x, 1 + y, -1 + z.

also has three kinds of interactions between 1a and 3H, that is, ) C and weak H-bonds O3(25)sH · · · O1(25)A O3(29)sH · · · O1(24)A and salt bridge O3B(27) · · · N1(19)A [symmetry codes: (A) x, 1 + y, z; (B) x, 1 + y, -1 + z], enabling them to be concomitant in the same crystal (Figure 4). In summary, we successfully synthesized crystals containing both brucine (1a) and bile acid 2H or 3H, which are specifically obtained in a thorough trial of cocrystallization of 1a with each of the bile acid derivatives 2H-7H and 8. To our knowledge, this is the first example of steroidal bile acid molecules that cocrystallize with an equal-sized alkaloidal molecule even when a salt bridge is formed. In the crystals, cholate 2- constructs the inherent H-bonded 21 helical assembly and brucinium 1aH+ achieves 21 helical assemblies through weak directional interactions. These assemblies excellently synchronize helical pitches to one another. 3-Epicholic acid (3H), on the other hand, is unable to form a robust H-bonded motif because of the geometrical misfit caused by inversion of the hydroxyl group at the 3 position. Instead 3- forms alternate

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Figure 5. Schematic representation of a crystal composed of two kinds of helical motifs. To construct the crystal structure, the components are forced to change their original assembly motifs in the structures, intercolumnar linkages, and the helical pitches.

H-bonded networks involving 1aH+ and the solvents to form the single crystal. Finally, we would like to propose that the crystals described in the communication, that is, those composed of multitype helical motifs (Figure 5), can be regarded as a new class of multicomponent crystals in the field of crystal engineering.

Acknowledgment. This work was financially supported by a Grant-in-Aid for Scientific Research and by the Cooperation for Innovative Technology and Advanced Research in Evolutional Area (CITY AREA) program from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Supporting Information Available: IR spectra of salts and X-ray crystallographic files (CIF). This material is available free of charge via the Internet at http://pubs.acs.org. (10)

References (1) (a) Herbstein, F. H. Crystalline Molecular Complexes and Compounds; Oxford University Press: New York, 2005; Vol. 1, 2. (b) Aakero¨y, C. B.; Schultheiss, N. In Making Crystals by Design; Braga, D., Grepioni, F. Eds.; Wiley-VCH: Weinheim, 2007; pp 209-240. (2) For example, see. (a) Aakero¨y, C. B.; Salmon, D. J. CrystEngComm 2005, 7, 439–448. (b) Banerjee, R.; Bhatt, P. M.; Ravindra, N. V.; Desiraju, G. R. Cryst. Growth Des. 2005, 5, 2299–2309. (c) Babu, N. J.; Reddy, L. S.; Aitipamula, S.; Nangia, A. Chem.sAsian J. 2008, 3, 1122–1133. (3) (a) Koshima, H.; Kamada, M.; Yagi, I.; Uosaki, K. Cryst. Growth Des. 2001, 1, 467–471. (b) Prakash, M. J.; Radhakrishnan, T. P. Cryst. Growth Des. 2005, 5, 721–725. (4) (a) Imai, Y.; Sato, T.; Kuroda, R. Chem. Commun. 2005, 3289–3291. (b) Kodama, K.; Kobayashi, Y.; Saigo, K. Chem.sEur. J. 2007, 13, 2144–2152. (c) Imai, Y.; Kawaguchi, K.; Tajima, N.; Sato, T.; Kuroda, R.; Matsubara, Y. Chem. Commun. 2008, 362–364. (5) (a) Gould, R. O.; Walkinshaw, M. D. J. Am. Chem. Soc. 1984, 106, 7840–7842. (b) Dijksma, F. J. J.; Gould, R. O.; Parsons, S.; Taylor,

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P.; Walkinshaw, M. D. Chem. Commun. 1998, 745–746. (c) Boiadjiev, S. E.; Person, R. V.; Puzicha, C.; Knobler, C.; Maverick, E.; Trueblood, K. N.; Lightner, D. A. J. Am. Chem. Soc. 1992, 114, 10123–10133. (d) Kuwata, S.; Tanaka, J.; Onda, N.; Yamada, T.; Miyazawa, T.; Sugiura, M.; In, Y.; Doi, M.; Inoue, M.; Ishida, T. Bull. Chem. Soc. Jpn. 1993, 66, 1501–1510. (e) Wright, J. L.; Caprathe, B. W.; Downing, D. M.; Glase, S. A.; Heffner, T. G.; Jaen, J. C.; Johnson, S. J.; Kesten, S. R.; MacKenzie, R. G.; Meltzer, L. T.; Pugsley, T. A.; Smith, S. J.; Wise, L. D.; Wustrow, D. J. J. Med. Chem. 1994, 37, 3523–3533. (f) Dijksma, F. J. J.; Gould, R. O.; Parsons, S.; Taylor, P.; Walkinshaw, M. D. Chem. Commun. 1998, 745–746. (g) Laursen, J. B.; Jorgensen, C. G.; Nielsen, J. Bioorg. Med. Chem. 2003, 11, 723–731. (h) Białon´ska, A.; Cinuik, Z. CrystEngComm 2004, 6, 276– 279. (i) Białon´ska, A.; Cinuik, Z. Acta Crystallogr., Sect. C 2004, 60, o853-o855. (j) Białon´ska, A.; Cinuik, Z.; Popek, T.; Lis, T. Acta Crystallogr., Sect. C 2005, 61, o88-o91. (k) Białon´ska, A.; Cinuik, Z. CrystEngComm 2006, 8, 66–74. (l) Watabe, T.; Kobayashi, K.; Hisaki, I.; Tohnai, N.; Miyata, M. Bull. Chem. Soc. Jpn. 2007, 80, 464–475. (m) Watabe, T.; Hisaki, I.; Tohnai, N.; Miyata, M. Chem. Lett. 2007, 36, 234–235. (a) Miyata, M.; Sada, K. In ComprehensiVe Supramolecular Chemistry; MacNicol, D. D., Toda, F., Bishop, R., Eds.; Pergamon: Oxford, 1996, Vol. 6, pp 147-176. (b) Miyata, M.; Sada, K.; Yoswathananont, N. In Encyclopedia of Supramolecular Chemistry; Atwood, J. L., Steed, J. W., Eds.; Marcel Dekker: New York, 2004; Vol. 1, pp 441-451. (c) Miyata, M.; Tohnai, N.; Hisaki, I. Acc. Chem. Res. 2007, 40, 694– 702, and refs. cited therein. Although crystalline materials did not yield, 1a and each of bile acid derivatives 4H-7H gave salts, judging from IR absorption at the carbonyl stretching vibration region, see Supporting Information. Crystal data for crystal A: C49H74N2O11, Mw ) 867.13, monoclinic, space group P21 (No. 4), Z ) 2, a ) 14.3988(3) Å, b ) 8.03443(15) Å, c ) 19.3290(4) Å, β ) 94.6951(12)°, V ) 2228.60(7) Å3, T ) 93 K, µ(Cu KR) 0.7325 mm-1, Dc ) 1.292 g cm-3, 0.40 × 0.30 × 0.15 mm, 22160 total reflections, 7129 unique (Rint 0.075), 6298 observed [I > 2σ(I)]. 569 parameters. The final R1 [I > 2σ(I)] and wR2 values 0.051 and 0.129, respectively. CCDC 719979. Crystal data for crytal B: C49H74N2O11, Mw ) 867.13, monoclinic, space group P21 (No. 4), Z ) 2, a ) 14.2453(3) Å, b ) 8.05940(19) Å, c ) 19.2594(4) Å, β ) 94.7880(15)°, V ) 2203.42(9) Å3, T ) 93 K, µ(Cu KR) 0.7409 mm-1, Dc ) 1.307 g cm-3, 0.40 × 0.30 × 0.10 mm, 21952 total reflections, 6650 unique (Rint 0.063), 5766 observed [I > 2σ(I)]. 560 parameters. The final R1 [I > 2σ(I)] and wR2 values 0.059 and 0.167, respectively. CCDC 719978. Crystal data for crystal C: C102H156N4O25, Mw ) 1838.37, triclinic, space group P1 (No. 1), Z ) 1, a ) 8.0373(2) Å, b ) 17.3175(5) Å, c ) 18.8337(6) Å, R ) 87.7000(18), β ) 77.7010(17), γ ) 76.5790(17)°, V ) 2491.16(13) Å3, T ) 213 K, µ(Cu KR) 0.7067 mm-1, Dc ) 1.225 g cm-3, 0.70 × 0.40 × 0.10 mm, 25388 total reflections, 14330 unique (Rint 0.055), 5766 observed [I > 2σ(I)]. 560 parameters. The final R1 [I > 2σ(I)] and wR2 values 0.067 and 0.205, respectively. CCDC 719980. Nakano, K.; Sada, K.; Miyata, M. Chem. Lett. 1994, 137–140. In a way, 1a in the present crystals is regarded as the largest guest molecule with a volume of 373 Å3 among bile acid inclusion crystals ever reported. To our knowledge, the present crystals are the first example for bile acids to cocrystallize with an equal-sized alkaloidal molecule, judging from the search on Cambridge Structural Database (ver. 5.28), even though the components are not neutral but form a salt in the crystal. Because of the subtle balance of the H-bonds between 3- and the solvent molecules, single crystal C is rarely obtained despite of a number of trials.

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