Enantioresolution and Chameleonic Mimicry of 2-Butanol with an

Publication Date (Web): February 5, 2010 ... Francisco Meijide , Alvaro Antelo , Mercedes Alvarez Alcalde , Aida Jover , Luciano Galantini , Nicolae V...
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DOI: 10.1021/cg9009064

Enantioresolution and Chameleonic Mimicry of 2-Butanol with an Adamantylacetyl Derivative of Cholic Acid

2010, Vol. 10 1124–1129

Javier Miragaya, Aida Jover, Francisco Fraga, Francisco Meijide, and Jose V azquez Tato* Departamentos de Quı´mica Fı´sica y Fı´sica Aplicada, Facultad de Ciencias, Universidad de Santiago de Compostela, Avda. Alfonso X El Sabio s/n, 27002 Lugo, Spain Received August 3, 2009; Revised Manuscript Received December 14, 2009

ABSTRACT: [3β,5β,7R,12R]-3[(Adamantyl-1-acetyl)-amino]-7-12-dihydroxycholan-24-oic acid (AdCH2CA) was synthesized by the reaction between 1-adamantyl acetyl chloride and the methyl ester of 3β-amino-cholic acid and hydrolysis of the ester. The acid was recrystallized from racemic 2-butanol (0.1% water). Crystals are orthorhombic (P212121) and form inclusion complexes with water and 2-butanol with a 1:1:1 stoichiometry. Only the S-enantiomer is included into the structure of the crystal, exhibiting a chameleonic mimicry with the steroid bilayers. The isolation of crystals allows the enantioresolution of the racemate with a high purity (≈99%) of S-2-butanol. The steroid molecules are disposed in an antiparallel orientation in the hydrophobic layer and a parallel orientation in the hydrophilic one.

Introduction Practical methods of enantiomer separation are important both in the research laboratory and in several industries. The main methods, consisting of the use of inclusion complexation, biological methods, and HPLC, have been reviewed in a recent book edited by Toda.1 When a chiral host compound includes selectively one enantiomer of a racemic guest compound, optical resolution of the guest can be accomplished. In these cases, guest molecules are accommodated in a cavity formed by the host compound or belonging to it and, frequently, the process is accomplished in the solid state during recrystallization. Although for a full knowledge of the process the crystal must be resolved, the absence of crystals suitable for X-ray analysis does not mean that resolution (at least partial) of a racemic mixture is not occurring. Bile acids and their derivatives form inclusion crystals with many organic compounds.2-5 Among other factors that affect the steroidal assembly in the crystalline state, the effect of the length of the side chain of the main natural bile acids has been systematically studied by Miyata et al.6 by making one-by-one insertions and suppressions of methylene spacers into the sidechain of steroidal bile acids. For example, bishomocholic acid (with two additional methylene units) includes various organic substances,7 while bisnorcholic acid (with two decreased units) does not.4 This causes a diversity of host frameworks with characteristic hydrogen-bonding networks,8 a fact also observed for cholanamide crystals in which many alcohols are included.9 It is interesting to notice that the inclusion behavior of aliphatic alcohols in cholamide and in cholic acid is completely different since 54 alcohols can be included in the bilayer-type structures of cholamide, but only two in those of cholic acid.10,11 Since bile acids are highly asymmetric, it can be expected that enantioresolution could take place in the steroidal crystals. From the first paper published by Miyata et al.12 related to the optical resolution of lactones by the inclusion method using cholic acid as the host, the number of chiral guests that *To whom correspondence should be addressed. E-mail: jose.vazquez@ usc.es. pubs.acs.org/crystal

Published on Web 02/05/2010

have been efficiently resolved by their selective complexation with bile acids has increased steadily. Among them we can mention lactones (cholic acid),12-14 alcohols (cholanamide, 3-epideoxycholic acid, lithocholanamide),10,15-17 sulfoxides (dehydrocholic acid),18 cyclic ketones (cholic and deoxycholic acids),19 epoxides (cholic acid),20 amines (cholic acid),21 N-nitrosopiperidines (cholic and deoxycholic acids),22 and cyclic amides (dehydrocholic acid).23 Hosts are given in parentheses. Generally, it is not so easy to perform enantioresolutions with a high enantiomeric excess. The subject has been reviewed by Bortolini et al.24 We have recently synthesized several bile acid derivatives in which the hydrophobicity of natural bile acids has been extended by attaching a bulk hydrophobic group at C3. As a consequence, different packing structures in crystals25,26 and new supramolecular structures (as lamellae25 and tubes27,28) were obtained in solution. In particular, the packing structure in crystals of modified bile acids is highly dependent on the size of the group and length of the binding bridge between the attached group and the steroid nucleus. For instance, when a norbornyl-2-acetyl derivative of cholic acid26 (NbCH2CA) is recrystallized from DMSO, acetone, and 2-propanol, all guests are located in the region of the bridge forming a hydrogen bond with the amide of the bridge. However, when the hydrophobic adamantyl group is attached to the 3-position of cholic acid (compound named Ad-HC),25 the adamantyl moieties are mutually interlocked in the crystal without leaving free space for solvent guests. The remarkable effects of the length of the side chain on the assembly of bile acids, largely studied by Miyata et al.,8 together with the last mentioned observations, suggest that the length of the bridge between the two residues and the size of the hydrophobic bulky residue should be investigated more systematically. For this reason, we have synthesized a new derivative (AdCH2CA, Figure 1) obtained by reacting the 1-adamantyl acetic acid with the 3β-amino derivative of cholic acid. Compared to its predecessor Ad-HC, the bridge between the two residues has been extended by a methylene group. Because of the importance of the enantioresolution mentioned above, we have recrystallized AdCH2CA in racemic 2-butanol with the confidence of getting the enantioresolution of the r 2010 American Chemical Society

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mixtures because of the high asymmetry of the host molecule. As Aburaya et al.29 pointed out, enantioresolution of secondary aliphatic alcohols still remains a challenging problem because of the fourth substituent at the stereogenic carbon is the small hydrogen atom. Several methods have been proposed for the enantioresolution of 2-butanol. Among them we can mention, apart from cholanamide,15 enzymatic methods,30 HPLC,31 metal complexes of O,O0 -dibenzoyltartaric acid,32 and reaction with specific compounds as 2-methoxy2-(1-naphthyl)propionic acid.33,34 Experimental Section Synthesis of [3β, 5β, 7r, 12r]-3[(Adamantyl-1-acetyl)-amino]-712-dihydroxycholan-24-oic acid (AdCH2CA). The compound is obtained by the reaction between 1-adamantyl acetyl chloride and the methyl ester of 3β-amino-cholic acid. To synthesize 1-adamantyl acetyl chloride, a mixture of 0.59 g of 1-adamantyl acetic acid and 2 mL of thionile chloride are refluxed during 2 h under a CaCl2 trap

Figure 1. Structure and conventional numbering of AdCH2CA. Table 1. Crystal Data, Data Collection and Refinement solvent empirical formula formula weight temperature (K) wavelength (A˚) crystal system, space group a (A˚) b (A˚) c (A˚) R (°) β (°) γ (°) cell volume (A˚3) Z, calculated density (g/cm3) absorption coefficient (mm-1) F(000) crystal size (mm3) theta range (data collection) (o) index ranges data/restraints/parameters goodness-of fit on F2 final R indices [I > 2σ(I)] R indices (all data) ΔFmax and ΔFmin (e A˚-3)

racemic 2-butanol C36H57NO5, C4H10O, H2O 675.96 100 (2) 0.71073 orthorhombic, P212121 9.4616(16) 17.690(2) 22.405(4) 90.00 90.00 90.00 3750.1(10) 4, 1.197 0.08 1488 0.19  0.08  0.07 1.47-26.46 -11 e h e 11, 0 e k e 22, 0 e l e 27 4311/3/457 0.978 R1 = 0.0555, wR2 = 0.1207 R1 = 0.1460, wR2 = 0.1552 0.309 and -0.278

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and concentrated under a vacuum. The methyl ester of 3β-aminocholic acid is obtained from 3β-amino-cholic acid (the synthesis of this amine derivative from commercial cholic acid has been described elsewhere).35,36 1.5 g of this compound is dissolved in 20 mL of chloroform and 2 mL of triethylamine under nitrogen and cooled in an ice-salt bath (-10 to -15 °C). The previously obtained 1-adamantyl acetyl chloride dissolved in chloroform is added dropwise under stirring and the reaction mixture is maintained during 18 h at r.t. before concentration in a rotavapor. The mixture is purified in a silica gel column using 20:1 ethyl acetate/ methanol as eluent and dried in a vacuum oven. Yield: 40%. The last step is the hydrolysis of the ester derivative. For this purpose, 0.8 g of the methyl ester in 15 mL of 1 M KOH in methanol are refluxed during 1 h. After evaporation of methanol, 200 mL of water and concentrated HCl are added to neutralize the potassium salt. The suspension formed is filtered, washed with water, and dried at 70 °C with P2O5. Yield: 90%. 1 H NMR of the methyl ester of AdCH2CA (DMSO, 300 MHz, δ/ppm): 7.38 (d NH-CdO); 3.55 (s OCH3); 2.43-1 (steroid nucleus and adamantine protons); 0.89 (d H21); 0.84 (s H19); 0.57 (s H18). 13C NMR of the methyl ester of AdCH2CA (DMSO; 75 MHz, δ/ppm): 174.51 (O-C24dO), 170.06 (NH-C26dO), 71.72 (C12), 66.98 (C7), 51.86 (OCH3), 23.53 (C19), 17.59 (C21), 12.99 (C18). MALDI-TOF, SDHB matrix, m/z: M: 598.55, [M þ Na]þ: 622.5, [M þ K]þ: 636.55; theoretical M: 597.44, [M þ Na]þ: 620.43, [M þ K]þ: 636.40. MALDITOF of the methyl ester of AdCH2CA, SDHB matrix, m/z: M: 584.40, [M þ Na]þ: 606.40, [M þ K]þ: 622.38; theorethical M: 583.42, [M þ Na]þ: 606.41, [M þ K]þ: 622.39. For crystallization, racemic 2-butanol (p.a 99% and 0.1% of water; Panreac, Barcelona, Spain) was used. Fifteen milligrams of AdCH2CA was dissolved into 1 g of racemate and the mixture was heated and left to reach room temperature. Colorless crystals were formed after 1 month. X-ray Diffraction. A colorless prismatic crystal of the compound was mounted on a glass fiber and used for data collection. Data were collected on a Bruker AXS APEXII-CCD area dectector diffractometer. Molecular graphics were from Mercury (http:// www.ccdc.cam.ac.uk/prods/mercury) and Accelrys DS Visualizer v2.0 (http://accelrys.com/products/discovery-studio/visualization/ discovery-studio-visualizer.html). A summary of the crystal data,

Figure 3. Mimicry of 2-butanol with the AdCH2CA molecule.

Figure 2. Crystal packing of AdCH2CA recrystallized from 2-butanol/water viewed along the a axis.

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Figure 4. Carbon-carbon distances of interdigitated methyl goups of steroid molecules and distances of the C4 of 2-butanol to methyl steroidal groups and adamantyl methylene groups. and experimental details are listed in Table 1. CCDC-742154 contains the supplementary crystallographic data for the crystal. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Optical rotations were determined on a Dr. Kernchen Propol Digital Automatic polarimeter (resolution 0.0001°) at the sodium D line at 20 °C, with a path length of 0.2 dm.

Results and Discussion A summary of the crystal data is listed in Table 1. Crystals are orthorhombic (P212121) and form inclusion complexes with water and 2-butanol with a 1:1:1 stoichiometry. The crystal packing along the a-axis is shown in Figure 2. A bilayer structure with hydrophobic and hydrophilic regions is clearly distinguished with the β sides of the steroid molecules disposed in an antiparallel orientation and methyl groups C18 and C19 having an R-interdigitation. The distance between steroid h planes26,37 with a back-to-back hydrophobic interaction is 5.3 A˚, while the distance between steroid planes with hydrophilic interactions is 6.0 A˚. Thus, the width of the bilayer in the crystal is 11.3 A˚, half of the c length of the unit cell. However, the orientation of the steroidal molecules at the hydrophilic interface of the bilayers is parallel. This arrangement (parallel and antiparallel for hydrophilic and hydrophobic layers, respectively) is just the opposite of that observed by Aburaya et al.29 for the inclusion of 2,2-dimethyl3-hexanol by cholamide where the hydrophilic interface of the bilayers is antiparallel while the lipophilic one is parallel. This bilayer structure is different from those observed by Yoswathananont et al.11 of any of the 58 inclusion crystals of cholanamide with aliphatic alcohols since such a reversion in the lipophilic sides is very rare in the case of bile acids and their derivatives. It is noteworthy the parallelism between the steroid nucleus plane and the direction of the lamellae. In Figure 2, the 2-butanol molecule exhibits a remarkable chameleonic mimicry with the steroid molecules. A “third” methyl group (of the ethylene group of 2-butanol), directed toward the hydrophobic layer, as well as a “third” hydroxyl group directed toward the hydrophilic layer, are observed. The two carbon atoms linked to the stereogenic carbon atom of 2-butanol are in the same plane of the steroid nucleus since their distances to this plane (in yellow color in Figure 2, top) are 0.116 (methyl) and 0.049 (methylene) A˚. Furthermore, the distance of the hydroxyl group of 2-butanol to the hydrophilic plane (defined by the hydroxyl groups of AdCH2CA; in red color in Figure 2, bottom) is only 0.063 A˚, while the distance of the methyl group of the ethylene residue of 2-butanol to the

Figure 5. Parallel and transversal orientation of the hydrogen atom and the methyl group of 2-butanol with respect to the direction of the steroid molecules.

hydrophobic plane (defined by the methyl groups of the steroid nucleus of AdCH2CA; in blue color in Figure 2, bottom) is ˚ ). That is, 2-butanol is fully mimetic negligible (equal to 0.009 A with the facial amphiphilicity of the steroid (Figure 3). It is time to recognize that only S-2-butanol is included in the crystal although the recrystallization process was perform in racemic 2-butanol; that is, AdCH2CA crystal exhibits a full enantioselectivity. To confirm this enantioselectivity, optical rotation measurements were carried out. It is necessary to consider that both components of the crystal (2-butanol and AdCH2CA) are optically active. When crystals are redissolved in racemic 2-butanol, the observed optical rotation is the sum of the contribution of each component, that is, R = RS-2-butanol þ RAdCH2CA, where each contribution is given by Ri = [R]20 D  l  ci/100 (l is the path length in decimeters, ci is the concentration of the i-th component in g/100 mL, and [R]20 D is the specific rotation measured at 20 °C at the wavelength of the sodium D line). Because of the stoichiometry of the crystal, the molar concentration of both components is the same, and the following equation results   MAdCH2 CA 20 20 ½RD ðAdCH2 CAÞ R ¼ ½RD ðS-2-butÞ þ MS-2-but l  cS-2-but =100 (MAdCH2CA and MS-2-but being the molar mass of each component). That is, the R vs cS-2-but plot should be linear,

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with a slope value of 35.0° (calculated by using the values 20 of þ20.64° and þ13.52° for [R]20 D AdCH2CA and [R]D (S-2-but), respectively. Measurements of the optical rotation were made in the concentration range 0.8-6.0 mg/mL of cS-2-but, and the obtained experimental slope is 34.8 ( 0.2°. Therefore, within an experimental error of ≈1% the isolated S-2-butanol from the crystal is enantiomerically pure. If the guest were the R enantiomer the expected value for the slope would be 29.6°. This powerful enantioselectivity means that the cavity where the guest is accommodated is chiral. We will analyze this chirality in a similar way as the four location model does.38 For this purpose, some distances from 2-butanol atoms to their neighbors will be considered.39 The orientation of the hydroxy group of 2-butanol can be considered fixed toward the hydrophilic layer of the crystal, forming a hydrogen bond with a water molecule. Similarly, the ethylene group of butanol has the right length for its interdigitation with the methyl groups of the steroid and a methylene group of the adamantyl residue. Figure 4 shows

Figure 6. Hydrogen (linked to the stereogenic carbon)-hydrogen (closest neighbor molecules) distances.

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that the distances between carbon atoms for these interactions are very similar to those of the interdigitated steroid methyl groups. Thus, the hydroxy and ethylene groups are perpendicular to the laminar structure of the crystal. Consequently, the other two groups have to be in parallel and transversal orientations with respect to the longitudinal direction of the steroid molecules, defining the configuration R or S of the chiral carbon atom (see Figure 5 for the actual orientation of these groups). Figure 6 shows that there are six hydrogen atoms in the neighborhood of hydrogen which are located at a distance less ˚ . It must be noticed that the closest ones (at 2.34, 2.40, than 4 A and 3.2 A˚) are almost transversal with respect to the longitudinal direction. This means that under the geometrical restrictions imposed by the host molecules the methyl group does not have enough space to be oriented toward the transversal direction, except if the gap between parallel steroid molecules is broadening. The methyl group finds a better accommodation along the longitudinal axis, parallel or antiparallel to the direction of the steroid molecules. A water molecule (which is forming a hydrogen bond with the alcohol hydroxy group, see below) is almost at the opposite direction of the actual methyl group location, at a distance of 3.76 A˚ of the stereogenic carbon of the alcohol. Thus, there is not free space for the inversion of the chiral atom without the displacement of the water molecule, disturbing the whole lamellar structure of the crystal. Furthermore, there are two hydrogen atoms of the adamantyl residue located at less than 4.5 A˚ from the stereogenic carbon atom which would also bear a steric hindrance for this alternative location of the methyl group after chiral inversion. Therefore, the inversion of the stereogenic carbon atom of 2-butanol would oblige a full rearrangement of the bilayer structure of the crystal. Obviously, the parallel orientation of the methyl group corresponds to the minimum energy for the actual bilayer structure of the crystal. Further clarification is given by Figure 7, in which S-2butanol is included in the bilayer structure of the crystal, squeezed by the steroid molecules. For comparison, R-2butanol is also drawn to illustrate that this enantiomer cannot

Figure 7. Front and back views of the S-2-butanol after sequential rotations of 45° of the crystal AdCH2-CA. Mirror images of the R enantiomer are also shown.

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Figure 8. Solvent surface of the neighbors next to S-2-butanol. For clarity, some atoms have not been considered and the surface is drawn in two left and right halves.

Acknowledgment. The authors thank the Ministerio de Ciencia y Tecnologı´ a, Spain, (Project MAT2006-61721) for financial support. J.M. also thanks the Ministerio de Ciencia y Tecnologı´ a, Spain, for a scholarship.

References

Figure 9. Hydrogen bond network for AdCH2CA crystal in water/ butanol.

be accommodated in this place. In the figure, the sequential images correspond to rotations of the crystal around an axis located on the guest molecule. For comparison, the R enantiomer is drawn as shadow mirror images. Finally, Figure 8 shows a visualization of butanol cushioned by the surface of the surrounding molecules which interact with it, forming the chiral cavity where the guest is included. Four steroid molecules are required to fully describe the hydrogen network of the crystal. The water molecule plays a central role as it interacts with three of these steroid molecules and with the S-2-butanol molecule which acts only as a donor toward water; that is, it does not exhibit double hooks (Figure 9).9,26 Each bile acid molecule is linked to three other steroid molecules. This hydrogen bond network interconnects the hydrophilic groups of the lamellar structure. The network scheme and lengths are shown in Figure 9, all of them being within typical values for hydrogen bond interactions. The N-H group of the amide bond does not participate in the hydrogen bond network. Conclusion When AdCH2CA is recrystallized in racemic 2-butanol, only the S-enantiomer is included in the bilayer structure of the crystal, allowing the enantioresolution of the racemate by isolation of crystals. The steroid molecules are disposed in antiparallel orientation in the hydrophobic layer and parallel in the hydrophilic one. The guest S-2-butanol exhibits a chameleonic mimicry with the steroid bilayers suggesting that this behavior can be further exploited in designing new host molecules for the enantioresolution of other alkyl alcohols.

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