Handedness Determination of 21 Helical Motifs and Hierarchical

Oct 21, 2010 - are no reports about the handedness of 21 helical assemblies. In this study ... and thus, it is impossible to distinguish its handednes...
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DOI: 10.1021/cg101111f

Handedness Determination of 21 Helical Motifs and Hierarchical Analysis of Crystal Structures Based on the Motifs: The Case of Cinchona Alkaloid Derivatives

2010, Vol. 10 5262–5269

Ichiro Hisaki,* Norie Shizuki, Toshiyuki Sasaki, Yuka Ito, Norimitsu Tohnai, and Mikiji Miyata* Department of Material and Life Science, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan Received August 24, 2010; Revised Manuscript Received September 30, 2010

ABSTRACT: A molecular assembly with a two-fold screw axis, a so-called 21 helical assembly, is one of the most fundamental and important motifs of organic noncentrosymmetric crystals. 21 Helical assemblies are observed frequently in the crystals of Cinchona alkaloids, crucial compounds for asymmetric organic syntheses. Despite of importance of their superstructures, there are no reports about the handedness of 21 helical assemblies. In this study, we revealed crystal structures of BH3 complexes with a series of Cinchona alkaloids: cinchonidine, quinine, hydroquinine, cinchonine, quinidine, and hydroquinidine (Cnd 3 BH3, Qn 3 BH3, HyQn 3 BH3, Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3, respectively), and we first defined the handedness of 21 helical assemblies of Cinchona alkaloids on the basis of a supramolecular-tilt-chirality method we have proposed. Interestingly, in crystalline states, Qn 3 BH3 and HyQn 3 BH3 form 32 helical motifs, while Cnd 3 BH3 forms a left-handed 21 motif and Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3 form right-handed 21 helices despite their similar O-H 3 3 3 N intermolecular hydrogen bonds. Therefore, this set of these structures, which is the first example of crystal structures obtained for a series of Cinchona alkaloids or their derivatives chemically modified in the same way, enables us to elucidate a chiral relationship between molecular structures and supramolecular assembly manners.

Introduction The International Table for Crystallography, Vol. A presents the following sentence at pp 718: “In practical crystallography one wants to distinguish between right- and left-handed screws and does not want to change from a right-handed to a left handed coordinate system.”1 In order to avoid such transformations and, besides, to distinguish the right- and left-handed screws, eleven space-group types in the 219 affine space-group types have been split into the pairs of enantiomorphic space-group types, for example, P41-P43 and P31-P32, providing totally the 230 crystallographic space-group types.1 The handedness of the two-fold screw, however, was not distinguished at that time. This seems to be reasonable when one considers that the two-fold screw axis operation involves a 180-degree rotation, and thus, it is impossible to distinguish its handedness, i.e. rightor left-handed. A molecular assembly with a two-fold screw axis, a so-called 21 helical assembly, is a common chiral object,2 and is one of the most fundamental and important motifs of organic crystals, particularly of noncentrosymmetric crystals. 21 Helical assemblies, therefore, have been attracting interest in connection with nonlinear optical properties,3 polarized optical properties,4 and enantioresolution.5 Molecules prefer to be packed with 21 symmetry in the crystalline state, as Kitaigorodskii already described.2 Indeed, the 21 helical motif is a quite common structure: more than 332,000 crystals (66.7%) have a 21 helical axis among the 498,000 crystals registered in the CSD (the Cambridge Structural Database).6 *E-mail: [email protected] (I.H.); [email protected]. ac.jp (M.M.). pubs.acs.org/crystal

Published on Web 10/21/2010

The handedness of 21 helical motifs, however, has never been defined and never even been discussed since establishment of crystallography because of the reason described in the first paragraph.7 On the other hand, our systematic study on crystalline supramolecular assemblies of steroids8 and alkaloids9 enabled us to conclude that the handedness of a 21 helical assembly can be defined by considering the molecular shape and assembly manners, and we proposed the supramolecular-tilt-chirality method to define the handedness. Namely, as schematically shown in Figure 1, given the molecules in front of a 21 screw axis inclined to the right or left, the assemblies can be defined to be right- or left-handed, respectively.10 The remarkable system in our previous study is the 21 helical superstructure of benzene.10a Although benzene itself is highly symmetric (D6h) and has no functional groups to connect to molecules, its 21 helix was observed in the inclusion channels of cholic acid.10a The chiral channels induced benzene molecules to be packed with 21 symmetry, giving a homochiral helix with right handedness (Figure 2a). Subsequently, we wished to adapt our idea to other crystalline 21 helical systems composed of expanded planar aromatic molecules.11,12 In contrast with the induced-helix of benzene, in order to achieve a helical superstructure that spontaneously forms without chiral environments such as the chiral inclusion channels of cholic acid, namely, a self-supported helical structure, aromatic compounds may be required to have functional groups for making intermolecular connections such as hydrogen bonds as well as asymmetric stereogenic centers to form homochiral helices (Figure 2b). Cinchona alkaloids are exactly the compounds that satisfy such structural requirements.13,14 Indeed, we can find the above-mentioned 21 helical structures in their reported crystal structures. However, there has not been any description related r 2010 American Chemical Society

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Scheme 1. Series of Cinchona Alkaloids Complexed with BH3

Figure 1. Concept of supramolecular-tilt-chirality of 21 helical assemblies. If molecules in the front of the 21 screw axis incline to the left, the assembly is defined as a left-handed helix (vice versa).

higher-ordered superstructures, i.e. 2D sheet motifs and 3D whole crystal structures, are interpreted hierarchically (Figure 2c).15 Interestingly, we found that a series of Cinchona alkaloids boronated at the quinuclidine N atom yielded single crystals suitable for X-ray structural analysis.16 This is, for our best knowledge, the first example of crystal structures obtained for a series of Cinchona alkaloid derivatives chemically modified in the same way. This finally enables one to compare their crystal structures and discuss the effect of chirality on the stereogenic centers and the effect of substituent differences on the superstructures of Cinchona alkaloids. Results and Discussion

Figure 2. Schematic representation for formation of 21 helical assemblies of (a) benzene in the chiral inclusion space of cholic acid and (b) a quinoline derivative. The handedness of the helical motifs can be determined by the supramolecular-tilt-chirality method we proposed before.10 The quionoline derivative forms a right- or lefthanded 21 helix depending on the chiral center. The 21 helix then forms respective highly ordered superstructures as shown in part (c). The right- and left-handed helical motifs given in phase (I) form the corresponding right- and left-handed 2D sheet motifs in phase (II), followed by 3D superstructures belonging to the P21 or P212121 crystallographic space groups in phase (III).

with the handedness of the 21 helices. Furthermore, during our search for crystal structures of Cinchona alkaloid derivatives in the CSD, we realized that there is no set of crystal structures obtained for a series of Cinchona alkaloids (i.e., cinchonidine (Cnd), quinine (Qn), hydroquinine (HyQn), cinchonine (Cnn), quinidine (Qd), and hydroquinidine (HyQd)) or their derivatives. For example, among a series of Cinchona alkaloids, only quinine did not yield crystals, except for its solvates. In connection with these, we herein describe the supramolecular tilt chirality of the 21 or 31 helices of BH3 complexes with Cinchona alkaloids (Cnd 3 BH3, Qn 3 BH3, HyQn 3 BH3, Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3 in Scheme 1) and a relationship between molecular chirality and helicity of the superstructures. Subsequently, based on the 1D helical motifs,

Crystal Structures of BH3-Cinchona Alkaloid Complexes. According to the preparation of Qn 3 BH3 reported in the literature,17 boronation of a series of Cinchona alkaloids was performed to give the complexes Cnd 3 BH3, HyQn 3 BH3, Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3, as well as Qn 3 BH3. Recrystallization of the resultant complexes was performed with various common organic solvents. As a result, single crystals of Cnd 3 BH3, Qn 3 BH3, and HyQn 3 BH3 were obtained by slow evaporation of the acetone, methanol, and ethanol/ acetone solutions, respectively. These three crystals include guest molecules in their void spaces: acetone for Cnd 3 BH3, methanol for Qn 3 BH3, and water for HyQn 3 BH3. The derivatives Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3 were also crystallized by slow evaporation of the acetone, ethanol, and ethanol solutions, respectively, to give single crystals without guest molecules included. These packing diagrams and crystallographic parameters are shown in Figure 3 and Table 1, respectively. Cnd 3 BH3 crystallized into the P21 space group with accompanying inclusion of acetone. Cnd 3 BH3 forms a layer parallel to the (100) plane, and the layers alternatively stack with solvents along the c axis. Qn 3 BH3 and HyQn 3 BH3 crystallized into the R3 space group. The structures are the same as that Wartchow, Hoffmann, and co-workers reported: they form duplicated 32 helical motifs along the c axis (vide infra). In these cases, substituent differences at the C(3) atom, i.e. vinyl group for Qn 3 BH3 or ethyl group for HyQn 3 BH3, did not affect the molecular packing. Solvent molecules, methanol or water, are included in the channels though their positions are disordered (Figure 3b and c). Interestingly, the channels allow various alkanols to be included in them: for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, and 1-hexanol. Cnn 3 BH3 crystallized into the space group P212121. A sheet motif parallel to the (100) plane stacks in an antiparallel manner. Qd 3 BH3 and HyQd 3 BH3 gave P21 crystals. Although their crystallographic parameters differ due to a symmetry

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Figure 3. Packing diagrams with a stick-model for crystals (a) Cnd 3 BH3(acetone), (b) Qn 3 BH3(1/2MeOH), (c) HyQn 3 BH3(water), (d) Cnn 3 BH3, (e) Qd 3 BH3, and (f ) HyQd 3 BH3, where included solvents were provided in parentheses. Atoms of carbon, nitrogen, oxygen, and boron are colored by green, blue, red, and pink. Hydrogen atoms are omitted for clarity.

Table 1. Crystallographic Data of BH3-Cinchona Alkaloid Complexes formula formula weight crystal system space group a (A˚) b (A˚) c (A˚) R (deg) β (deg) γ (deg) V (A˚3) Z D (g/cm3) T (K) collected reflection unique reflection R1 (I > 2.0σ(I )) wR2 (all data) GOF

Cnd 3 BH3 (acetone)

Qn 3 BH3 (1/2MeOH)

HyQn 3 BH3 (water)

C22H31BN2O2 366.31 monoclinic P21 9.4430(4) 10.8755(5) 11.0869(4) 90 108.809(2) 90 1077.80(7) 2 1.129 153 11205 3795 0.0537 0.1332 1.094

C20.5H29BN2O2.5 354.27 trigonal R3 26.3708(8) 26.3708(8) 7.4637(3) 90 90 120 4495.0(2) 9 1.195 153 15664 3616 0.0570 0.1704 1.102

C20H31BN2O3 358.29 trigonal R3 26.5157(5) 26.5157(5) 7.59654(18) 90 90 120 4625.44(17) 9 1.158 153 15770 3526 0.0501 0.1435 1.109

Cnn 3 BH3 C19H25BN2O 308.23 orthorhombic P212121 9.1793(3) 11.5240(3) 15.7571(4) 90 90 90 1666.82(8) 4 1.228 213 9948 3025 0.0485 0.11 1.078

Qd 3 BH3 C20H27BN2O2 338.26 monoclinic P21 9.6059(2) 11.0417(3) 18.1746(4) 90 91.8651(15) 90 1926.66(8) 4 1.166 153 20029 6872 0.0489 0.1467 1.110

HyQd 3 BH3 C20H29BN2O2 340.27 monoclinic P21 9.58186(17) 10.56990(19) 10.40266(19) 90 114.6154(9) 90 957.83(3) 2 1.180 153 9994 3401 0.0415 0.1020 1.091

Table 2. Parameters of Molecular Conformations and the Helical Motifs of Cnd 3 BH3, Qn 3 BH3, HyQn 3 BH3, Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3 substituents at C(60 ) chirality on C(9) Ra/deg βb/deg helical type handedness helical pitch/A˚ A(Q/Q)c/deg O 3 3 3 N distance/A˚ A(O-H-N)d/deg d

Cnd 3 BH3

Qn 3 BH3

HyQn 3 BH3

Cnn 3 BH3

OMe R 60.79 25.16 21 left 10.88 94.61 2.733 173.51

OMe R 57.87 27.94 32 left 14.81 77.96 2.821 176.70

H R 58.13 26.35 32 left 15.19 76.05 2.811 174.49

H S 40.94 12.57 21 right 11.52 102.92 2.799 177.45

Qd 3 BH3 OMe S 43.84, 43.09 13.07, 21.88 pseudo-21 right 11.04 84.54 2.736, 2.787 173.71, 161.34

HyQd 3 BH3 OMe S 42.54 15.30 21 right 10.57 81.96 2.786 166.79

a R: dihedral angle of C(9)-C(8)-N(10 )-B. b β: dihedral angle of O(1)-C(9)-C(40 )-C(30 ). c A(Q/Q): dihedral angle of the adjacent quinoline rings. A(O-H-N): O-H-N angle of the hydrogen bond.

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Figure 4. Helical motifs with 50% thermal ellipsoids observed in crystals of (a) Cnd 3 BH3(acetone), (b) Qn 3 BH3(1/2MeOH), (c) HyQn 3 BH3(water), (d) Cnn 3 BH3, (e) Qd 3 BH3, and (f ) HyQd 3 BH3. Two 32 helices of Qn 3 BH3 duplicate to give a double helical strand (g). Symmetry codes: for (a) (A) 2 - x, -1/2 þ y, -z; for (b) and (c) (A) 2/3 - y, 1/3 þ x - y, -2/3 þ z; for (d) (A) -x, -1/2 þ y, 1/2 - z; for (e) (A) x, 1 þ y, z; for (f ) (A) 1 - x, -1/2 þ y, 2 - z; for (g) (A) x, y, -1 þ z; (B) 1/3 - x þ y, 2/3 - x, -4/3 þ z. The two molecules denoted by mol.X and mol.Y in (e) are symmetrically independent.

decrease of the Qd 3 BH3 crystal (Z0 = 2), the molecules in both crystals arrange in almost the same way, as shown in Figure 3e and f. In the crystals described in Figure 3, Cinchona alkaloid derivatives form helical superstructures as motifs. To define the handedness of their helical motifs and understand how subtle molecular structure differences affect the superstructures of the Cinchona alkaloids, we performed hierarchical analysis15 of the crystal structures in the order of molecular conformation, one-dimensional helical motifs, two-dimensional sheet motifs, and three-dimensional crystal structures. Conformational Differences. First we compared molecular conformations among the crystals and found that the vinyl groups at different positions affect the molecular conformations. In Table 2, dihedral angles of R, C(9)-C(8)-N(1)-B, and β, O(1)-C(9)-C(40 )-C(30 ), are shown as parameters remarkably describing conformational differences. The values of R for Cnd 3 BH3, Qn 3 BH3, and HyQn 3 BH3 (58.1-60.8°) are larger than those for Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3 (40.9-43.8°). Similarly, the values of β for Cnd 3 BH3, Qn 3 BH3, and HyQn 3 BH3 (25.2-27.9°) are larger than those for Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3 (12.6-21.9°). Interestingly, these tendencies depend on neither the space group nor the methoxy group at the C(60 ) atom but the position of the vinyl group. This is probably caused by packing

forces depending on different steric effects of the vinyl groups. Superstructures and Handedness of Helical Motifs. The helical superstructures constructed in the crystals are shown in Figure 4. Cnd 3 BH3, Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3 form 21 or pseudo-21 helical superstructures,18 in which the quinoline rings are arranged in a similar way as that of the benzene rings in the channel of the cholic acid crystal.10a The molecules of Cnd 3 BH3, Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3 are connected by intermolecular hydrogen bonds between the hydroxyl group and the N atom in the quinoline ring: the O 3 3 3 N distance ranges from 2.73 A˚ to 2.82 A˚, as shown in Table 2. Careful comparison of the obtained 21 (pseudo-21) helical structures revealed that helical periods (pitches) and dihedral angles of the adjacent quinoline rings range from 10.6 to 11.5 A˚ and from 81.96 to 102.92°, respectively (Table 2). These facts indicate that the motifs are tolerant for expansion or contraction of the pitches to achieve favorable packing of the motifs. Qn 3 BH3 and HyQn 3 BH3, on the other hand, gave interesting 32 helical motifs (Figure 4b and c), which then made double helices, as Wartchow and Hoffmann reported.17 The double helices of Qn 3 BH3 are shown in Figure 4g, where the single strand is colored with green or yellow. As shown in Figure 4g(bottom), the boron atom of one helix contacts with

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Hisaki et al. Table 3. Helical Handedness of 21 Assemblies in Crystals of Cinchona Alkaloid Derivatives Registered in the CSD

Figure 5. Selective helical motifs with accentuated quinoline rings: (a) Cnd 3 BH3, (b) Qn 3 BH3, (c) Cnn 3 BH3, and (d) Qd 3 BH3. Twofold screw axes are shown with yellow bars for clarity.

the hydrogen atom at C(7)A in the other helix with a B 3 3 3 H distance of 3.16 A˚. The adjacent quinoline rings (A and B) are held in a 3-fold helix with the dihedral angle of 78.0° through effective CH/π interactions: C(30 )B-H 3 3 3 C(90 )A, C(30 )B-H 3 3 3 C(100 )A, and C(20 )B-H 3 3 3 C(20 )A with C 3 3 3 H distances of 2.87, 2.85, and 2.85 A˚, respectively, as shown in Figure 4g(top). It is noteworthy that even though the main intermolecular interactions of Qn 3 BH3 and HyQn 3 BH3 to form the helical motifs are the same O-H 3 3 3 N hydrogen bonds as those of the other derivatives, the subtle structural differences drastically determine the symmetry of the assemblies. Namely, Cnd 3 BH3, which has the same structure as Qn 3 BH3 except for the methoxy group, and Qd 3 BH3, which has an enantiostructure with Qn 3 BH3 except for the position of the vinyl group, form no 32 helix but 21 helices. Indeed, these substituent groups participate in the key interactions to construct 32 helical assemblies. For example, the methoxy group (-OC(110 )H3) in one helix of Qn 3 BH3 interacts with the quinoline moiety of the other helix through a weak hydrogen bond of C(110 )-H 3 3 3 N(10 )A (C 3 3 3 N distance, 3.68 A˚; C-H-N angle, 167.0°), to hold the double helix as shown in Figure 4g(bottom). To obtain a crystal with a two-fold screw axis, crystallization of Qn 3 BH3 was attempted with various solvents, resulting in no crystals but R3 crystals at present. Supramolecular-Tilt-Chirality of the Helical Motifs. As we presented in the Introduction, 21 helical supramolecular assemblies have fatal problems in their handedness. The present systems are no exception. To overcome the problem, we adopted the concept of supramolecular-tilt-chirality10 for the present systems. We determined the handedness of the 21 helical superstructures of Cinchona alkaloids based on the tilt of the quinoline ring against the screw axes (Figure 5). Namely, given the quinoline ring in front of the two-fold screw axis (yellow bars) inclining to the right or left, the assemblies are defined to be right- or left-handed, respectively. Cnn 3 BH3 and Qd 3 BH3 provide right-handed 21

Refcode

handedness

parent compound

space group

ref

BUWYIB DADCUH DALZUM JIHCIM LABXUH MAYGEY MEKGUE SIFJUM TICMIB BEYTIJ DADCUG DAPJAF ECAMOK GARJUF GAWSUT HIBZEX MOHBOA TURJIZ XAZPAP YANNIL

right right right right right right right right right left left left left left left left left left left left

Qd Qd Cnn Cnn Cnn Qd Qd Qd Qd Qn Qn Qn Qn Cnd Cnd Qn Qn Cnd Cnd Qn

P212121 P212121 P21 P21 P212121 P21 P21 P21 P212121 P212121 P212121 P212121 P21 P212121 P212121 P212121 P212121 P212121 P212121 P212121

19 20 21 22 23 21 24 25 26 27 28 29 30 31 31 32 33 34 35 36

helices, while Cnd 3 BH3 has a left-handed 21 helix. These facts imply that the helical handedness depends on the chirality of the stereogenic center of the C(9) atom. Cnn 3 BH3 and Qd 3 BH3 have the S configuration on the C(9) atom, resulting in righthanded helical superstructures, while Cnd 3 BH3 has the R configuration on the C(9) atom, resulting in a left-handed helix. Therefore, the helical handedness of the 21 assemblies of Cinchona alkaloid derivatives can be predicted by molecular chirality, particularly that at the C(9) atom. Indeed, 20 crystals composed of Cinchona alkaloid derivatives follow this rule, as shown in Table 3. It is notable that the proposed method is adaptable not only to 21 helical assemblies but also to the 32 helices of Qn 3 BH3. Namely, the quinoline ring of Qn 3 BH3 tilts to the left against the helical axis (Figure 5b), meaning the helices have left handedness. Therefore, the proposed method allows the 21 helix of Cinchona alkaloids to be related to so-called helices, such as a 3-fold helix. Stack Manner of the Sheet Motifs. Although Cnd 3 BH3, Qd 3 BH3, HyQd 3 BH3, and Cnn 3 BH3 gave similar 21 or pseudo21 helical motifs, the differences on the vinyl and methoxy groups must affect formation of whole crystal structures (P21 or P212121 crystal). To understand this, the assembly manners of their helical motifs are interpreted hierarchically as follows. The higher-ordered motif next to the 1D helical motif is probably a sheet structure. Right- or left-handed 21 helical motifs make parallel-stacked right- or left-handed sheet motifs by fitting their zigzag wavy surfaces one next to another as shown in phase II in Figure 2c. The sheet motifs of Cnd 3 BH3, Qd 3 BH3, HyQd 3 BH3, and Cnn 3 BH3 are laid on the (100), (101), (101), and (100) plane of the corresponding crystal systems. Their structures and surface plots are shown in Figure 6a-c (the sheet motif of HyQd 3 BH3 was omitted because of its similarity with that of Qd 3 BH3). It is remarkable that surfaces of the sheet motifs exhibit completely different profiles from each other, despite their similar stacking manners. The Cnd 3 BH3 sheet (Figure 6a) has a relatively flat surface and discrete cavities surrounded by rims made up of the quinuclidine (i), quinoline (ii), and vinyl (iii) groups. The Qd 3 BH3 sheet (Figure 6b) also has discrete cavities on the surface. However, its surface is more rugged than the former: the vinyl group (iii) rings jut from the

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Figure 6. Side (left) and top (right) views of surface plots of the sheet motifs, (a) Cnd 3 BH3, (b) Qd 3 BH3, and (c) Cnn 3 BH3, as well as schematic representation for (d) Cnd 3 BH3, (e) Qd 3 BH3, and (f ) Cnn 3 BH3. Top views are described partly by a stick model to clarify molecular arrangements. Moieties marked by i, ii, iii, iv, and v denote the quinuclidine, quinoline, vinyl, methoxy, and BH3 groups, respectively. The surface plots were generated with PyMOL software to clearly represent concavity and convexity on the sheets.

surface. The methoxy groups (iv) also are on the surface. The Cnn 3 BH3 sheet (Figure 6c) exhibits zigzag shaped continuous convexity and concavity (so-called terrace and valley, respectively) running along the a axis on the surface. The terrace part is composed of an edge of the quinoline ring (ii) and the BH3 group (v) of the quinuclidine ring. The vinyl group (iii) is located on the surface of the valley. In addition to the case of helical motifs, the chirality of the surfaces is clearly affected by the tilt of the quinoline rings. One can recognize that the edges of the quinoline rings (i) of Cnd 3 BH3 tilt to the left, while those of Cnn 3 BH3 tilt to the right on the surfaces. It is natural that these three sheets stack in different ways from each other due to their surface profiles. The self-complementarity of surfaces, particularly, seems to be important for stacking behavior. The flat surface with cavities of Cnd 3 BH3 sheets (Figure 6d) need something to fill the cavities. Indeed, the Cnd 3 BH3 sheet forms parallel stacked layers with accommodating solvents in the cavities, giving the left-handed P21 crystal (Figure 2c). The Qd 3 BH3 sheet (Figure 6e), on the other hand, has both cavities and jutes on its surface, which enables formation of self-complementally stacked parallel layers without any molecular inclusion, giving the righthanded P21 crystal (Figure 2c). The Cnn 3 BH3 sheet (Figure 6f ) also has terraces and valleys on its surface, giving selfcomplementally stacked layer structures. In this case, however, the sheets stack in an antiparallel way, giving the righthanded crystal belonging to the space group P212121 (Figure 2c). Conclusion In summary, we first reported crystal structures of boron complexes with a series of Cinchona alkaloids, enabling us to elucidate a relationship between molecular structures and supramolecular assembly manners. In the crystals, Qn 3 BH3 and HyQn 3 BH3 form 32 helical motifs, while Cnd 3 BH3, Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3 form 21 helices despite their similar O-H 3 3 3 N intermolecular hydrogen bonds. Furthermore, although the latter four derivatives formed similar

21 helical motifs, they then gave different higher-order assemblies, due to subtle differences of the substituent groups, i.e. the methoxy and vinyl groups. We also first define the handedness of 21 helical motifs composed of Cinchona alkaloid derivatives by applying the tilt-chirality method to the quinoline ring moieties. Cnd 3 BH3 gave a left-handed 21 helix, while Cnn 3 BH3, Qd 3 BH3, and HyQd 3 BH3 gave right-handed ones. Determination of the 21 helical handedness may help one to classify chiral crystals and, subsequently, to understand the chirality of the superstructures and the chiral recognition mechanism in complex crystalline systems involving alkaloids.37 Experimental Section Boronation of Cinchona Alkaloids. To a solution of Cinchona alkaloid (1 equiv) dissolved in THF was added dropwise at 0 °C a 1 M BH3 3 THF solution dissolved in THF (1 equiv). The reaction mixture was then stirred for 24 h at room temperature. The solvent was removed in vacuo, and the resultant material was purified by column chromatography (silica gel, hexane/AcOEt = 1:3 v/v) to give the corresponding BH3 complex as a white solid. Cnd 3 BH3. 79% yield; mp 112.6 °C; 1H NMR (270 Mz, CDCl3) δ 8.90 (d, J = 4.3 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.77-7.61 (m, 3H), 6.85 (br s, 1H), 5.53 (ddd, J = 7.3, 10.5, 17.3 Hz, 1H), 5.00-4.88 (m, 2H), 4.00-3.89 (m, 1H), 3.35 (dd, J = 10.8, 14.3 Hz, 1H), 3.16-3.09 (m, 1H), 3.00-2.92 (m, 2H), 2.63-2.49 (br m, 2H), 2.09-1.95 (m, 3H), 1.79-1.50 (m, 3H), 1.26-1.17 (m, 1H); IR (KBr) 2376, 2322, 2276 cm-1; HR-MS (FAB-): m/z calcd for [M þ Hþ] C19H26BN2O: 309.2138; found: 309.2151. Qn 3 BH3. 35% yield; mp 180.5 °C; 1H NMR (270 Mz, CDCl3) δ 8.74 (d, J = 4.3 Hz, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 4.6 Hz, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.38 (dd, J = 2.7, 9.2 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 5.57 (ddd, J = 6.8, 10.2, 17.0 Hz, 1H), 4.89 (d, J = 17.0 Hz, 1H), 4.94 (d, J = 10.5 Hz, 1H), 4.00 (s, 3H), 3.98-3.88 (m, 1H), 3.37 (dd, J = 10.8, 14.0 Hz, 1H), 3.15-3.08 (m, 1H), 3.01-2.88 (m, 2H), 2.55 (br s, 1H), 2.39 (d, J = 4.1 Hz, 1H), 2.01-1.50 (br m, 6H), 1.33-1.23 (m, 1H); IR (KBr) 2376, 2322, 2276 cm-1; HR-MS (FAB-): m/z calcd for [M þ Hþ] C20H28BN2O2: 339.2260; found: 339.2255. HyQn 3 BH3. 53% yield; mp 179.9 °C; 1H NMR (270 Mz, CDCl3) δ 8.74 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.63 (d, J = 4.6 Hz, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.38 (d, J = 2.7, 9.2 Hz, 1H), 6.76

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(br d, J = 3.5 Hz, 1H), 4.00 (s, 3H), 3.99-3.58 (m, 1H), 3.36 (dd, J = 10.5, 14.0 Hz, 1H), 3.11-3.04 (m, 1H), 2.97-2.86 (m, 1H), 2.64-2.55 (m, 1H), 2.40 (d, J = 4.1 Hz, 1H), 2.10-1.99 (m, 3H), 1.93-1.90 (br m, 1H), 1.74-1.50 (br m, 3H), 1.28-1.12 (m, 3H), 0.78 (t, J = 7.3 Hz, 3H); IR (KBr) 2372, 2345, 2272, cm-1; HR-MS (FABþ): m/z calcd for [M þ Hþ] C20H30BN2O2: 341.2400; found: 341.2416. Cnn 3 BH3. 71% yield; mp (dec) 217.7 °C; 1H NMR (270 Mz, CDCl3) δ 8.92 (d, J = 4.6 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 7.77-7.60 (m, 3H), 6.85 (br d, J=5.4 Hz, 1H), 6.01 (ddd, J = 7.3, 10.4, 17.6 Hz, 1H), 5.20-5.14 (m, 2H), 3.86-3.77 (m, 1H), 3.18-3.02 (m, 5H), 2.55-2.45 (m, 2H), 2.48-2.21 (m, 1H), 1.87-1.50 (m, 4H), 0.94-0.82 (m, 1H); IR (KBr) 2380, 2314, 2264 cm-1; HR-MS(FAB-): m/z calcd for [M þ Hþ] C19H26BN2O: 309.2138; found: 309.2140. Qd 3 BH3. 76% yield; mp (dec) 216.9 °C; 1H NMR (270 Mz, CDCl3) δ 8.74 (d, J = 4.6 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 4.3 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.37 (dd, J = 2.4, 9.2 Hz, 1H), 6.76 (br d, J = 4.3 Hz, 1H), 6.03 (ddd, J = 7.6, 10.3, 17.6 Hz, 1H), 5.20-5.14 (m, 2H), 3.98 (s, 3H), 3.88-3.79 (m, 1H), 3.16-3.00 (m, 5H), 2.62 (d, J = 4.6 Hz, 1H), 2.54-2.44 (m, 1H), 2.35-2.26 (m, 1H), 1.88-1.50 (br m, 4H), 0.97-0.87 (m, 1H); IR (KBr) 2380, 2322, 2276 cm-1; HR-MS (FABþ): m/z calcd for [M þ Hþ] C20H28BN2O2: 339.2260; found: 339.2255. HyQd 3 BH3. 58% yield; mp 209.5 °C; 1H NMR (270 Mz, CDCl3) δ 8.75 (d, J = 4.3 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 4.6 Hz, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.37 (dd, J = 2.4, 9.2 Hz, 1H), 6.74 (br d, J = 4.6 Hz, 1H), 3.98 (s, 3H), 3.60-3.51 (m, 1H), 3.14-2.98 (m, 5H), 2.56 (d, J = 4.6 Hz, 1H), 2.28-2.19 (m, 1H), 1.86-1.78 (br m, 1H), 1.74-1.48 (br m, 6H), 0.94-0.83 (m, 4H); IR (KBr) 2364, 2341, 2276, cm-1; HR-MS (FABþ): m/z calcd for [M þ Hþ] C20H30BN2O2: 341.2400; found: 341.2406. Crystal Structure Determination. X-ray diffraction data were collected on a Rigaku R-AXIS RAPID diffractometer with a 2D area detector using graphite-monochromatized Cu KR radiation (λ = 1.54187 A˚). Direct methods (SIR-97) were used for the structure solution.38 All calculations were performed with the observed reflections [I > 2σ(I )] by the program CrystalStructure crystallographic software packages39 except for refinement, which was performed using SHELXL-97.40 All non-hydrogen atoms were refined with anisotropic displacement parameters, and hydrogen atoms were placed in idealized positions and refined as rigid atoms with the relative isotropic displacement parameters.

Acknowledgment. This work was financially supported by a Grant-in-Aid for Scientific Research by the Ministry of Education, Culture, Sports, Science, and Technology (Japan). Supporting Information Available: X-ray crystallographic files in CIF format for the reported compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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