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Molecular structure and pseudopolymorphism of squamtin A from Annona squamosa
Journal of Molecular Structure 655 (2003) 157–162 www.elsevier.com/locate/molstruc
Molecular structure and pseudopolymorphism of squamtin A from Annona squamosa Ren-Wang Jianga, Yang Lua,*, Zhi-Da Minb, Qi-Tai Zhenga a
Institute of Materia Medica, Analytical Chemistry, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xiannongtan street, Beijing 100050, People’s Republic of China b Department of Natural Pharmaceutical Chemistry, China Pharmaceutical University, Nanjing, People’s Republic of China Received 25 November 2002; revised 4 April 2003; accepted 8 April 2003
Abstract The cyclopeptide, squamtin A (1, formula: C39H60O11N8S), was found to crystallized in two pseudopolymorphisms, i.e. 1·(H2O)3.5 and 1·(H2O)3.9. The composition of the amino acids and their linkage sequences are the same. The main differences between the two kinds of crystals lie in the positions and occupancies of the water molecules, the positions of the sulfur atoms and the conformation of the side chains. The absolute configuration of 1 is established by X-ray analysis in combination with the Marfey’s analysis of its hydrolysates. q 2003 Elsevier Science B.V. All rights reserved. Keywords: Squamin A; Cyclopeptide; Pseudopolymorphism; Annona squamosa
1. Introduction Cyclopeptides are characterized by the macrocyclic skeleton constructed from natural or modified amino acids, e.g. stelladellins A [1], or in some case together with some auxiliary structural units, e.g. antanapeptin A [2]. They are widely distributed among plants [3], fungi [4], and marine natural products [5], and many of them possess potent biological activities, for instances, antifungus [6], antivirus [7], antitumor [8], and inhibition of protein synthesis [9]. Structure determination of previously reported cyclopeptides were based mostly on * Corresponding author. Tel.: þ86-10-6316-5212; fax: þ 86-106301-7757. E-mail address: [email protected] (Y. Lu).
spectroscopic methods. Although a wide variety of cyclopeptides have been isolated from nature so far, and macrocycles of this kind bear both intricate structures and rich stereocenters, literature reports on their crystal structures and stereochemistry are rather rare [10]. As part of our effort to investigate the cyclopeptide components from natural sources, we have investigated the chemical components of the seeds of Annona squamosa, and a novel cyclopeptide named squamin A (1) was isolated [11]. The amino acid compositions and their linkage sequence have been determined by FABMS and 2D-NMR spectra and amino acid analysis of its hydrolysates. However, its biological activity was not studied due to the restricted natural availability. Proposing a practical synthetic method and insight into its biological and
0022-2860/03/$ - see front matter q 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0022-2860(03)00227-8
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physicochemical functions at the molecular level require a precise understanding of the primary and secondary structures. Diffraction method is particularly useful for obtaining such structural information. In this paper, we report the X-ray crystallographic studies on compound 1.
2. Results and discussion Compound 1 is composed of seven natural amino acids, i.e. tyrosine, glycine, threonine, valine, alanine, isoleucine and proline, and an oxidized methionine (Fig. 1). It is interesting that compound 1 can form two kind of hydrates, i.e. 1·(H2O)3.5 and 1·(H2O)3.9. The two crystals belong to the same orthorhombic system (space group P212121); however, the unit cell ˚ 3). In both of 1·(H2O)3.5 has a bigger volume (þ 86.0 A hydrates the amino acids form a 24-membered macrocyclic ring which is stabilized by the intramo˚ ), N-4 lecular hydrogen bonds, i.e. N-3 O-7 (2.961 A ˚ ), N-5 O-11 (2.809 A ˚ ) and N-7 O-2 O-8 (2.954 A ˚ ) for 1·(H2O)3.5 and the corresponding (2.989 A
distances for 1·(H2O)3.9 are 2.945, 2.923, 2.727, ˚ , respectively. 2.980 A The asymmetric unit of 1·(H2O)3.5 consists of an independent molecule of 1 and six water positions with an occupancy of 0.4, 0.7, 0.8, 1.0, 0.2 and 0.4, respectively (Fig. 2). The asymmetric unit of 1·(H2O)3.9 also consists of an independent molecule of 1 and six water positions but with an occupancy of 0.3, 1.0, 1.0, 1.0, 0.3 and 0.3, respectively. (Fig. 3) The water molecules are distributed outside of the peptide chain and connected to 1 by complex hydrogen bonds involving the water molecules serving as donors and the carbonyl oxygen atoms serving as acceptors (Table 1). The position of O-w6 (0.4968, 0.4823, 0.0333) for 1·(H2O)3.5 is different from that of 1·(H2O)3.9 (0.5170, 1.4447, 0.0211), which leads to different hydrogen bond patterns, e.g. no hydrogen bond is observed between O-w6 O-5 in the latter as compared with the hydrogen bond O-w6 ˚ , 1 þ x; y; z) in the former. O-5 (2.816 A The presence of the oxidized methionine is confirmed by the shortened bond distances (S– O-11, ˚ for 1·(H2O)3.5 and 1.583 A ˚ for 1·(H2O)3.9) 1.498 A and the atom displacement parameters. The S – O
Fig. 1. (a) Amino acid compositions and their linkage sequence of 1. (b) Structural formula of 1.
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159
Fig. 2. Molecular structure of 1·(H2O)3.5, showing the asymmetric unit and the atom labeling scheme. The intermolecular hydrogen bonds in the asymmetric unit are indicated by dashed lines. The hydrogen atoms are omitted for clarity.
distance of 1·(H2O)3.9 is longer than that of 1·(H2O)3.5 due to the significantly thermal motion of O-11 in the former. Similarly, the oxidized methionine was also found in annosqumosin A [12], a cyclopeptide from the same plant. In 1·(H2O)3.5, the sulfur atom has only one positions (0.4762, 0.8731, 0.0349). However, in 1·(H2O)3.9, the sulfur atom is disordered over two positions (0.5814, 0.8587, 0.0239 and 0.4670, 0.8642, 0.0346) being represented by S with a site occupancy factor (sof) ¼ 0.85 and S0 with sof ¼ 0.15, respectively. It can be seen that the sulfur atom of the former is only consistent with the position of the latter having a smaller occupancy. The disorder
of the sulfur atom leads to the different bending of the side chain of oxo-methionine as shown by the torsion angle C-22 – C-23 – S –C-24 of 68.6 and 170.78 for 1·(H2O)3.5 and 1·(H2O)3.9, respectively. The five-membered ring of the proline is nearly ˚. planar in 1·(H2O)3.9 with a mean deviation of 0.029 A In contrast, the five-membered ring adopts an envelop conformation in 1·(H2O)3.5 with C-28 displaced by ˚ from the corresponding least-squares plane of 0.449 A the remaining four atoms. Such conformation difference is also indicated by the torsion angles C-26 –C27– C-28 – C-29 of 6.9 and 32.08 for 1·(H2O)3.9 and 1·(H2O)3.5, respectively.
Fig. 3. Molecular structure of 1·(H2O)3.9, showing the asymmetric unit and the atom labeling scheme. The intermolecular hydrogen bonds in the asymmetric unit are indicated by dashed lines. The hydrogen atoms and the intermolecular hydrogen bonds between O-w5 and O-9 and O-10 are omitted for clarity.
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Table 1 Hydrogen bonds in 1·(H2O)3.5 and 1·(H2O)3.9 Hydrogen bonds
N-3· · ·O-7 N-4· · ·O-8 N-5· · ·O-11 N-7· · ·O-2 O-w1· · ·O-9 O-w2· · ·O-5 O-w3· · ·O-2 O-w3· · ·O-10 O-w4· · ·O-3 O-w4· · ·O-6 O-w5· · ·O-5 O-w5· · ·O-9 O-w5· · ·O-10 O-w6· · ·O-5a O-w6· · ·O-9a N-8· · ·O-w4 O-w1· · ·O-w1 O-w1· · ·O-w2 O-w1· · ·O-w6a O-w1· · ·O-w6a O-w3· · ·O-w4 O-w5· · ·O-w6a O-w6· · ·O-w6a a
1·(H2O)3.5
1·(H2O)3.9
˚) Distance (A
Symmetry code
˚) Distance (A
Symmetry code
2.962 2.954 2.809 2.989 2.851 2.674 2.711 2.794 2.699 2.899 2.576 3.035 3.057 2.815 2.841 2.970 2.701 2.824 3.058 3.036 2.888 2.393 2.595
x; y; z x; y; z x; y; z x; y; z x; 1 2 y; 2z x; y; z 1 2 x; 0:5 þ y; 0:5 2 z 2x; 0:5 þ y; 0:5 2 z x; y; z 1 2 x; 20:5 þ y; 0:5 2 z 1 þ x; 21 þ y; z x; y; z x; y; z 1 þ x; y; z x; 1 þ y; z 1 2 x; 0:5 þ y;0:5 2 z x; 2y; 2z x; y; z x; y; z x; 2y; 2z x; y; z x; 21 þ y; z x; 2y; 2z
2.945 2.923 2.727 2.980 2.851 2.572 2.743 2.777 2.678 2.875 2.544 3.013 3.089 – 2.694 2.986 2.226 2.792 2.920 2.348 2.836 2.556 2.199
x; y; z x; y; z x; y; z x; y; z x; 1 2 y; 2z x; y; z 1 2 x; 0:5 þ y;0:5 2 z 2x; 0:5 þ y; 0:5 2 z x; y; z 1 2 x; 20:5 þ y; 0:5 2 z 1 þ x; 21 þ y; z x; y; z x; y; z – x; y; z 1 2 x; 0:5 þ y;0:5 2 z x; 2y; 2z x; y; z x; 21 þ y; z x; 1 2 y; z x; y; z x; y; z x; 2 2 y; 2z
Hydrogen bonds that are different between 1·(H2O)3.5 and 1·(H2O)3.9.
It can be seen that the main differences between the two kinds of crystals lie in the positions and occupancies of the water molecules, the positions of the sulfur atoms and the conformation of the side chains. Compound 1 represents a rare example of pseudopolymorphism whereby the host encloses water molecules with different positions and occupancies when the mixed solvent system is varied. Pseudopolymorphism occurs when a compound co-crystallizes with different solvents or the same solvent but in different stoichiometric ratios [13]. Such phenomenon is common in host-guest systems [14], but also observed among natural products; for example, caesalmin D can be crystallized as a methanol solvate and a hydrate [15]. The phenomenon of pseudopolymorphism highlights the role of solvent control in the organic molecular packing arrangement. The configuration of the chiral centers in the two kinds of crystals are the same as shown in Figs. 2 and 3. Except for glycine, the relative configurations of the a-carbons (C-4, C-6, C-12, C-21, C-26, C-31
and C-37) in the other seven amino acid residues were all established to be S: Combining this result with the configuration of the hydrolysates of compound 1 established by Marfey’s analysis [11] permits assignment of the absolute configuration of compound 1 as shown in Fig. 1.
3. Conclusions We have carried out an X-ray crystallographic investigation of the molecular structures of two kinds of hydrates of 1. To our knowledge, compound 1 represents the first example of pseudopolymorphism for cyclopeptides. The two hydrates differ from each other by the positions and occupancies of the water molecules, the positions of the sulfur atoms and the conformation of the side chains due to their different crystallization environments. The absolute configuration of 1 is established by X-ray analysis in combination with the Marfey’s analysis of its
R.-W. Jiang et al. / Journal of Molecular Structure 655 (2003) 157–162
hydrolysates. Cyclopeptide are generally difficult to crystallize. Crystallization of compound 1 as its hydrates highlights the important role of water molecules in stabilizing a cyclopeptide lattice. 4. Experimental A mixture of water and organic solvents were used in the crystallization experiments due to its moderate solubility in water. X-ray diffraction qualified crystals of 1·(H2O)3.5 were crystallized from a mixture of methanol, water and acetone, and 1·(H2O)3.9 were grown from a mixture of methanol and water. The X-ray diffraction data of 1·(H2O)3.5 and 1·(H2O)3.9 were each collected over a hemisphere of reciprocal space by a combination of 36 images of exposure (v scan mode, 58 per image) on a MacDIP2030 K diffractometer equipped with a rotating anode The crystal and Mo Ka radiation ðl ¼ 0:71073 AÞ: structure was solved by the direct method and refined using the NOMCSDP software package [16]. In the final structure refinements, non-H atoms were refined with anisotropic temperature factors. H-atoms bonded to carbons were placed geometrically calculated positions, and positions for H-atoms bonded to oxygen and nitrogen were located from different Fourier syntheses and included in the calculation of structure factors with isotropic temperature factors. A summary of crystallographic data and ,structural refinement parameters of 1·(H2O)3.5 and 1·(H2O)3.9 are given in Table 2. In the crystal structure of 1·(H2O)3.9, S, O-5, O-11, C-17, C18, C-22, C-23, C-24, C-28, C-34 and C-35, and the solvent molecules (water) exhibit a significant degree of librational disorder. Thus the R indices of 1·(H2O)3.9 is higher than usual. 5. Supporting information available Complete lists of refined atomic coordinates, bond distances and bond angles for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Center as supplementary materials. The CCDC numbers are shown in Table 2. These materials are available free of charge via application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: þ 44-1223-336033; e-mail: [email protected].
161
Table 2 Crystal data and structure refinement for 1·(H2O)3.5 and 1·(H2O)3.9 Compound
1·(H2O)3.5
1·(H2O)3.9
CCDC deposit no. Color/shape Cryst dimens (mm3) Chemical formula Formula weight Temperature (K) Crystal system Space group Unit cell dimensions
196170
196169
Colorless/block 0.3 £ 0.3 £ 0.6
Colorless/block 0.3 £ 0.5 £ 0.6
C39H60O11 N8S·(H2O)3.5 912.08
C39H60O11N8S·(H2O)3.9 919.29
293(2) Orthorhombic
293(2) Orthorhombic
P221 21 (No. 18)
P221 21 (No. 18)
a ¼ 9:258ð1Þ; b ¼ 13:818ð1Þ; ˚ c ¼ 38:271ð1Þ A 4895.9(6) 4 1.224
a ¼ 9:296ð1Þ; b ¼ 13:769ð1Þ; ˚ c ¼ 37:578ð1Þ A 4809.9(2) 4 1.241
˚ 3) Volume (A Z Density (mg/m3) Abs 0.14 0.12 coeff (mm21) Diffractometer/scan MacDIP-2030K MacDIP-2030K u range 1.50–25.00 1.50–25.00 (deg) Indepnt 4275 4582 reflns Obsd 4154 3622 reflns ½I . 2:5sI R1 ½I . 2:5sðIÞ 0.067 0.096 wR2 (all data) 0.067 0.083 P P P P R1 ¼ llFo l2lFc ll= lFo l; wR2 ¼½ ½wðFo2 2Fc2 Þ2 = ½wðFo2 Þ2 1=2 :
Acknowledgements Partial support of this research was provided by the national science foundation of China (29875035). References [1] C.M. Li, N.H. Tan, Q. Mu, H.L. Zheng, X.J. Hao, Y. Wu, J. Zhou, Phytochemistry 45 (1997) 521–523. [2] L.M. Nogle, W.H. Gerwick, J. Nat. Prod. 65 (2002) 21–24. [3] S.R. Giacomelli, F.C. Missau, M.A. Mostardeiro, U.F. da Silva, I.I. Dalcol, N. Zanatta, A.F. Morel, J. Nat. Prod. 64 (2001) 997 –999. [4] J. Malmstrøm, A. Ryager, U. Anthoni, P.H. Nielsen, Phytochemistry 60 (2002) 869 –872.
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[5] D.P. Clark, J. Carroll, S. Naylor, P. Crews, J. Org. Chem. 63 (1998) 8757–8764. [6] E.W. Schmidt, D.J. Faulkner, Tetrahedron 54 (1998) 3043–3056. [7] M.A. Rashid, K.R. Gustafson, L.K. Cartner, N. Shigematsu, L.K. Pannell, M.R. Boyd, J. Nat. Prod. 64 (2001) 117 –121. [8] (a) K. Umezawa, Y. Ikeda, Y. Uchihata, H. Naganawa, S. Kondo, J. Org. Chem. 65 (2000) 459 –463. (b) H. Uemoto, Y. Yahiro, H. Shigemori, M. Tsuda, T. Takao, Y. Shimonishi, J. Kobayashi, Tetrahedron 54 (1998) 6719–6724. [9] D. Ahuja, A. Geiger, J.M. Ramanjulu, M.D. Vera, B. SirDeshpande, A. Pfizenmayer, M. Abazeed, D.J. Krosky, D. Beidler, M.M. Joullie´, P.L. Toogood, J. Med. Chem. 43 (2000) 4212–4218.
[10] (a) W.F. Tinto, A.J. Lough, S. Mclean, W.F. Reynolds, M. Yu, W.R. Chan, Tetrahedron 54 (1998) 4451–4458. (b) Y.S. Che, D.C. Swenson, J.B. Gloer, B. Koster, D. Malloch, J. Nat. Prod. 64 (2001) 555–558. [11] J.X. Shi, H.M. Wu, F.H. He, K. Inoue, Z.D. Min, Chin. Chem. Lett. 10 (1999) 299–302. [12] Y.R. Zhao, J. Zhou, X.K. Wang, H.M. Wu, X.L. Huang, C. Zhou, Phytochemistry 46 (1997) 709– 714. [13] A. Nangia, G.R. Desiraju, Chem. Commun. (1999) 605– 606. [14] R. Thaimattam, F. Xue, J.A.P. Sarma, T.C.W. Mak, G.R. Desiraju, J. Am. Chem. Soc. 123 (2001) 4432. [15] R.W. Jiang, S.C. Ma, P.P.H. But, T.C.W. Mak, J. Nat. Prod. 64 (2001) 1266–1272. [16] B.M. Wu, Y. Lu, Chin. Chem. Lett. 3 (1992) 637 –640.
Molecular structure and pseudopolymorphism of squamtin A from Annona squamosa Ren-Wang Jianga, Yang Lua,*, Zhi-Da Minb, Qi-Tai Zhenga a
Institute of Materia Medica, Analytical Chemistry, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xiannongtan street, Beijing 100050, People’s Republic of China b Department of Natural Pharmaceutical Chemistry, China Pharmaceutical University, Nanjing, People’s Republic of China Received 25 November 2002; revised 4 April 2003; accepted 8 April 2003
Abstract The cyclopeptide, squamtin A (1, formula: C39H60O11N8S), was found to crystallized in two pseudopolymorphisms, i.e. 1·(H2O)3.5 and 1·(H2O)3.9. The composition of the amino acids and their linkage sequences are the same. The main differences between the two kinds of crystals lie in the positions and occupancies of the water molecules, the positions of the sulfur atoms and the conformation of the side chains. The absolute configuration of 1 is established by X-ray analysis in combination with the Marfey’s analysis of its hydrolysates. q 2003 Elsevier Science B.V. All rights reserved. Keywords: Squamin A; Cyclopeptide; Pseudopolymorphism; Annona squamosa
1. Introduction Cyclopeptides are characterized by the macrocyclic skeleton constructed from natural or modified amino acids, e.g. stelladellins A [1], or in some case together with some auxiliary structural units, e.g. antanapeptin A [2]. They are widely distributed among plants [3], fungi [4], and marine natural products [5], and many of them possess potent biological activities, for instances, antifungus [6], antivirus [7], antitumor [8], and inhibition of protein synthesis [9]. Structure determination of previously reported cyclopeptides were based mostly on * Corresponding author. Tel.: þ86-10-6316-5212; fax: þ 86-106301-7757. E-mail address: [email protected] (Y. Lu).
spectroscopic methods. Although a wide variety of cyclopeptides have been isolated from nature so far, and macrocycles of this kind bear both intricate structures and rich stereocenters, literature reports on their crystal structures and stereochemistry are rather rare [10]. As part of our effort to investigate the cyclopeptide components from natural sources, we have investigated the chemical components of the seeds of Annona squamosa, and a novel cyclopeptide named squamin A (1) was isolated [11]. The amino acid compositions and their linkage sequence have been determined by FABMS and 2D-NMR spectra and amino acid analysis of its hydrolysates. However, its biological activity was not studied due to the restricted natural availability. Proposing a practical synthetic method and insight into its biological and
0022-2860/03/$ - see front matter q 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0022-2860(03)00227-8
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physicochemical functions at the molecular level require a precise understanding of the primary and secondary structures. Diffraction method is particularly useful for obtaining such structural information. In this paper, we report the X-ray crystallographic studies on compound 1.
2. Results and discussion Compound 1 is composed of seven natural amino acids, i.e. tyrosine, glycine, threonine, valine, alanine, isoleucine and proline, and an oxidized methionine (Fig. 1). It is interesting that compound 1 can form two kind of hydrates, i.e. 1·(H2O)3.5 and 1·(H2O)3.9. The two crystals belong to the same orthorhombic system (space group P212121); however, the unit cell ˚ 3). In both of 1·(H2O)3.5 has a bigger volume (þ 86.0 A hydrates the amino acids form a 24-membered macrocyclic ring which is stabilized by the intramo˚ ), N-4 lecular hydrogen bonds, i.e. N-3 O-7 (2.961 A ˚ ), N-5 O-11 (2.809 A ˚ ) and N-7 O-2 O-8 (2.954 A ˚ ) for 1·(H2O)3.5 and the corresponding (2.989 A
distances for 1·(H2O)3.9 are 2.945, 2.923, 2.727, ˚ , respectively. 2.980 A The asymmetric unit of 1·(H2O)3.5 consists of an independent molecule of 1 and six water positions with an occupancy of 0.4, 0.7, 0.8, 1.0, 0.2 and 0.4, respectively (Fig. 2). The asymmetric unit of 1·(H2O)3.9 also consists of an independent molecule of 1 and six water positions but with an occupancy of 0.3, 1.0, 1.0, 1.0, 0.3 and 0.3, respectively. (Fig. 3) The water molecules are distributed outside of the peptide chain and connected to 1 by complex hydrogen bonds involving the water molecules serving as donors and the carbonyl oxygen atoms serving as acceptors (Table 1). The position of O-w6 (0.4968, 0.4823, 0.0333) for 1·(H2O)3.5 is different from that of 1·(H2O)3.9 (0.5170, 1.4447, 0.0211), which leads to different hydrogen bond patterns, e.g. no hydrogen bond is observed between O-w6 O-5 in the latter as compared with the hydrogen bond O-w6 ˚ , 1 þ x; y; z) in the former. O-5 (2.816 A The presence of the oxidized methionine is confirmed by the shortened bond distances (S– O-11, ˚ for 1·(H2O)3.5 and 1.583 A ˚ for 1·(H2O)3.9) 1.498 A and the atom displacement parameters. The S – O
Fig. 1. (a) Amino acid compositions and their linkage sequence of 1. (b) Structural formula of 1.
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159
Fig. 2. Molecular structure of 1·(H2O)3.5, showing the asymmetric unit and the atom labeling scheme. The intermolecular hydrogen bonds in the asymmetric unit are indicated by dashed lines. The hydrogen atoms are omitted for clarity.
distance of 1·(H2O)3.9 is longer than that of 1·(H2O)3.5 due to the significantly thermal motion of O-11 in the former. Similarly, the oxidized methionine was also found in annosqumosin A [12], a cyclopeptide from the same plant. In 1·(H2O)3.5, the sulfur atom has only one positions (0.4762, 0.8731, 0.0349). However, in 1·(H2O)3.9, the sulfur atom is disordered over two positions (0.5814, 0.8587, 0.0239 and 0.4670, 0.8642, 0.0346) being represented by S with a site occupancy factor (sof) ¼ 0.85 and S0 with sof ¼ 0.15, respectively. It can be seen that the sulfur atom of the former is only consistent with the position of the latter having a smaller occupancy. The disorder
of the sulfur atom leads to the different bending of the side chain of oxo-methionine as shown by the torsion angle C-22 – C-23 – S –C-24 of 68.6 and 170.78 for 1·(H2O)3.5 and 1·(H2O)3.9, respectively. The five-membered ring of the proline is nearly ˚. planar in 1·(H2O)3.9 with a mean deviation of 0.029 A In contrast, the five-membered ring adopts an envelop conformation in 1·(H2O)3.5 with C-28 displaced by ˚ from the corresponding least-squares plane of 0.449 A the remaining four atoms. Such conformation difference is also indicated by the torsion angles C-26 –C27– C-28 – C-29 of 6.9 and 32.08 for 1·(H2O)3.9 and 1·(H2O)3.5, respectively.
Fig. 3. Molecular structure of 1·(H2O)3.9, showing the asymmetric unit and the atom labeling scheme. The intermolecular hydrogen bonds in the asymmetric unit are indicated by dashed lines. The hydrogen atoms and the intermolecular hydrogen bonds between O-w5 and O-9 and O-10 are omitted for clarity.
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Table 1 Hydrogen bonds in 1·(H2O)3.5 and 1·(H2O)3.9 Hydrogen bonds
N-3· · ·O-7 N-4· · ·O-8 N-5· · ·O-11 N-7· · ·O-2 O-w1· · ·O-9 O-w2· · ·O-5 O-w3· · ·O-2 O-w3· · ·O-10 O-w4· · ·O-3 O-w4· · ·O-6 O-w5· · ·O-5 O-w5· · ·O-9 O-w5· · ·O-10 O-w6· · ·O-5a O-w6· · ·O-9a N-8· · ·O-w4 O-w1· · ·O-w1 O-w1· · ·O-w2 O-w1· · ·O-w6a O-w1· · ·O-w6a O-w3· · ·O-w4 O-w5· · ·O-w6a O-w6· · ·O-w6a a
1·(H2O)3.5
1·(H2O)3.9
˚) Distance (A
Symmetry code
˚) Distance (A
Symmetry code
2.962 2.954 2.809 2.989 2.851 2.674 2.711 2.794 2.699 2.899 2.576 3.035 3.057 2.815 2.841 2.970 2.701 2.824 3.058 3.036 2.888 2.393 2.595
x; y; z x; y; z x; y; z x; y; z x; 1 2 y; 2z x; y; z 1 2 x; 0:5 þ y; 0:5 2 z 2x; 0:5 þ y; 0:5 2 z x; y; z 1 2 x; 20:5 þ y; 0:5 2 z 1 þ x; 21 þ y; z x; y; z x; y; z 1 þ x; y; z x; 1 þ y; z 1 2 x; 0:5 þ y;0:5 2 z x; 2y; 2z x; y; z x; y; z x; 2y; 2z x; y; z x; 21 þ y; z x; 2y; 2z
2.945 2.923 2.727 2.980 2.851 2.572 2.743 2.777 2.678 2.875 2.544 3.013 3.089 – 2.694 2.986 2.226 2.792 2.920 2.348 2.836 2.556 2.199
x; y; z x; y; z x; y; z x; y; z x; 1 2 y; 2z x; y; z 1 2 x; 0:5 þ y;0:5 2 z 2x; 0:5 þ y; 0:5 2 z x; y; z 1 2 x; 20:5 þ y; 0:5 2 z 1 þ x; 21 þ y; z x; y; z x; y; z – x; y; z 1 2 x; 0:5 þ y;0:5 2 z x; 2y; 2z x; y; z x; 21 þ y; z x; 1 2 y; z x; y; z x; y; z x; 2 2 y; 2z
Hydrogen bonds that are different between 1·(H2O)3.5 and 1·(H2O)3.9.
It can be seen that the main differences between the two kinds of crystals lie in the positions and occupancies of the water molecules, the positions of the sulfur atoms and the conformation of the side chains. Compound 1 represents a rare example of pseudopolymorphism whereby the host encloses water molecules with different positions and occupancies when the mixed solvent system is varied. Pseudopolymorphism occurs when a compound co-crystallizes with different solvents or the same solvent but in different stoichiometric ratios [13]. Such phenomenon is common in host-guest systems [14], but also observed among natural products; for example, caesalmin D can be crystallized as a methanol solvate and a hydrate [15]. The phenomenon of pseudopolymorphism highlights the role of solvent control in the organic molecular packing arrangement. The configuration of the chiral centers in the two kinds of crystals are the same as shown in Figs. 2 and 3. Except for glycine, the relative configurations of the a-carbons (C-4, C-6, C-12, C-21, C-26, C-31
and C-37) in the other seven amino acid residues were all established to be S: Combining this result with the configuration of the hydrolysates of compound 1 established by Marfey’s analysis [11] permits assignment of the absolute configuration of compound 1 as shown in Fig. 1.
3. Conclusions We have carried out an X-ray crystallographic investigation of the molecular structures of two kinds of hydrates of 1. To our knowledge, compound 1 represents the first example of pseudopolymorphism for cyclopeptides. The two hydrates differ from each other by the positions and occupancies of the water molecules, the positions of the sulfur atoms and the conformation of the side chains due to their different crystallization environments. The absolute configuration of 1 is established by X-ray analysis in combination with the Marfey’s analysis of its
R.-W. Jiang et al. / Journal of Molecular Structure 655 (2003) 157–162
hydrolysates. Cyclopeptide are generally difficult to crystallize. Crystallization of compound 1 as its hydrates highlights the important role of water molecules in stabilizing a cyclopeptide lattice. 4. Experimental A mixture of water and organic solvents were used in the crystallization experiments due to its moderate solubility in water. X-ray diffraction qualified crystals of 1·(H2O)3.5 were crystallized from a mixture of methanol, water and acetone, and 1·(H2O)3.9 were grown from a mixture of methanol and water. The X-ray diffraction data of 1·(H2O)3.5 and 1·(H2O)3.9 were each collected over a hemisphere of reciprocal space by a combination of 36 images of exposure (v scan mode, 58 per image) on a MacDIP2030 K diffractometer equipped with a rotating anode The crystal and Mo Ka radiation ðl ¼ 0:71073 AÞ: structure was solved by the direct method and refined using the NOMCSDP software package [16]. In the final structure refinements, non-H atoms were refined with anisotropic temperature factors. H-atoms bonded to carbons were placed geometrically calculated positions, and positions for H-atoms bonded to oxygen and nitrogen were located from different Fourier syntheses and included in the calculation of structure factors with isotropic temperature factors. A summary of crystallographic data and ,structural refinement parameters of 1·(H2O)3.5 and 1·(H2O)3.9 are given in Table 2. In the crystal structure of 1·(H2O)3.9, S, O-5, O-11, C-17, C18, C-22, C-23, C-24, C-28, C-34 and C-35, and the solvent molecules (water) exhibit a significant degree of librational disorder. Thus the R indices of 1·(H2O)3.9 is higher than usual. 5. Supporting information available Complete lists of refined atomic coordinates, bond distances and bond angles for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Center as supplementary materials. The CCDC numbers are shown in Table 2. These materials are available free of charge via application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: þ 44-1223-336033; e-mail: [email protected].
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Table 2 Crystal data and structure refinement for 1·(H2O)3.5 and 1·(H2O)3.9 Compound
1·(H2O)3.5
1·(H2O)3.9
CCDC deposit no. Color/shape Cryst dimens (mm3) Chemical formula Formula weight Temperature (K) Crystal system Space group Unit cell dimensions
196170
196169
Colorless/block 0.3 £ 0.3 £ 0.6
Colorless/block 0.3 £ 0.5 £ 0.6
C39H60O11 N8S·(H2O)3.5 912.08
C39H60O11N8S·(H2O)3.9 919.29
293(2) Orthorhombic
293(2) Orthorhombic
P221 21 (No. 18)
P221 21 (No. 18)
a ¼ 9:258ð1Þ; b ¼ 13:818ð1Þ; ˚ c ¼ 38:271ð1Þ A 4895.9(6) 4 1.224
a ¼ 9:296ð1Þ; b ¼ 13:769ð1Þ; ˚ c ¼ 37:578ð1Þ A 4809.9(2) 4 1.241
˚ 3) Volume (A Z Density (mg/m3) Abs 0.14 0.12 coeff (mm21) Diffractometer/scan MacDIP-2030K MacDIP-2030K u range 1.50–25.00 1.50–25.00 (deg) Indepnt 4275 4582 reflns Obsd 4154 3622 reflns ½I . 2:5sI R1 ½I . 2:5sðIÞ 0.067 0.096 wR2 (all data) 0.067 0.083 P P P P R1 ¼ llFo l2lFc ll= lFo l; wR2 ¼½ ½wðFo2 2Fc2 Þ2 = ½wðFo2 Þ2 1=2 :
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