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Crystal structure of the thalidomide analog (3aR*,7aS*)-2-(2,6-dioxopiperidin-3-yl)hexa­hydro-1H-iso­indole-1,3(2H)-dione

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aDepartment of Chemistry and Earth Sciences, Qatar University, Doha, Qatar, bDepartment of Chemistry, Richard Stockton College of New Jersey, Galloway, NJ 08205, USA, cDepartment of Chemistry, Keene State College, 229 Main Street, Keene NH 03435, USA, and dDepartment of Chemistry, Howard University, 525 College Street NW, Washington, DC 20059, USA
*Correspondence e-mail: rbutcher99@yahoo.com

Edited by A. J. Lough, University of Toronto, Canada (Received 23 August 2018; accepted 10 October 2018; online 16 October 2018)

The title compound, C13H16N2O4, crystallizes in the monoclinic centrosymmetric space group, P21/c, with four mol­ecules in the asymmetric unit, thus there is no crystallographically imposed symmetry and it is a racemic mixture. The structure consists of a six-membered unsaturated ring bound to a five-membered pyrrolidine-2,5-dione ring N-bound to a six-membered piperidine-2,6-dione ring and thus has the same basic skeleton as thalidomide, except for the six-membered unsaturated ring substituted for the aromatic ring. In the crystal, the mol­ecules are linked into inversion dimers by R22(8) hydrogen bonding involving the N—H group. In addition, there are bifurcated C—H⋯O inter­actions involving one of the O atoms on the pyrrolidine-2,5-dione with graph-set notation R12(5). These inter­actions along with C—H⋯O inter­actions involving one of the O atoms on the piperidine-2,6-dione ring link the mol­ecules into a complex three-dimensional array. There is pseudomerohedral twinning present which results from a 180° rotation about the [100] reciprocal lattice direction and with a twin law of 1 0 0 0 [\overline{1}] 0 0 0 [\overline{1}] [BASF 0.044 (1)].

1. Chemical context

Thalidomide (1) is one of the most notorious drugs in pharmaceutical history because of the humanitarian disaster in the 1950s (Burley & Lenz, 1962[Burley, D. M. & Lenz, W. (1962). Lancet, 279, 271-272.]; Stephans, 1988[Stephans, T. D. (1988). Teratology, 38, 229-239.]; Bartlett et al., 2004[Bartlett, J. B., Dredge, K. & Dalgleish, A. G. (2004). Nat. Rev. Cancer, 4, 314-322.]; Wu et al., 2005[Wu, J. J., Huang, D. B., Pang, K. R., Hsu, S. & Tyring, S. K. (2005). Br. J. Dermatol. 153, 254-273.]; Melchert & List, 2007[Melchert, M. & List, A. (2007). Int. J. Biochem. Cell Biol. 39, 1489-1499.]). Thalidomide possesses a single stereogenic carbon in the glutarimide ring, and it is conceivable that the unexpected teratogenic side effects are ascribed to the (S)-enanti­omer of 1 (Blaschke et al., 1979[Blaschke, G., Kraft, H. P., Fickentscher, K. & Köhler, F. (1979). Arzneim.-Forsch. 29, 1640-1642.]). However, this has been a matter of debate because considerable chiral inversion should take place during the incubation of enanti­omerically pure 1 (Nishimura et al., 1994[Nishimura, K., Hashimoto, Y. & Iwasaki, S. (1994). Chem. Pharm. Bull. 42, 1157-1159.]; Knoche & Blaschke, 1994[Knoche, B. & Blaschke, G. (1994). J. Chromatogr. A, 666, 235-240.]; Wnendt et al., 1996[Wnendt, S., Finkam, M., Winter, W., Ossig, J., Raabe, G. & Zwingenberger, K. (1996). Chirality, 8, 390-396.]). Despite the tragic disaster, the unique biological properties of 1 prompted its return to the market in the 21st century for the treatment of multiple myeloma and leprosy (Matthews & McCoy, 2003[Matthews, S. J. & McCoy, C. (2003). Clin. Ther. 25, 342-395.]; Hashimoto et al., 2004[Hashimoto, Y., Tanatani, A., Nagasawa, K. & Miyachi, H. (2004). Drugs Fut. 29, 383-391.]; Franks et al., 2004[Franks, M. E., Macpherson, G. R. & Figg, W. D. (2004). Lancet, 363, 1802-1811.]; Brennen et al., 2004[Brennen, W. N., Cooper, C. R., Capitosti, S., Brown, M. L. & Sikes, R. A. (2004). Clin. Prostate Cancer, 3, 54-61.]; Luzzio et al., 2004[Luzzio, F. A. & Figg, W. D. (2004). Expert Opin. Ther. Pat. 14, 215-229.]; Sleijfer et al., 2004[Sleijfer, S., Kruit, W. H. J. & Stoter, G. (2004). Eur. J. Cancer, 40, 2377-2382.]; Kumar et al., 2004[Kumar, S., Witzig, T. E. & Rajkumar, S. V. (2004). J. Clin. Oncol. 22, 2477-2488.]; Hashimoto, 2008[Hashimoto, Y. (2008). Arch. Pharm. Chem. Life Sci. 341, 536-547.]; Knobloch & Rüther, 2008[Knobloch, J. & Rüther, U. (2008). Cell Cycle, 7, 1121-1127.]). Furthermore, a large number of papers on novel medical uses of 1 continue to appear in the biological and medicinal literature (Matthews & McCoy, 2003[Matthews, S. J. & McCoy, C. (2003). Clin. Ther. 25, 342-395.]; Hashimoto et al., 2004[Hashimoto, Y., Tanatani, A., Nagasawa, K. & Miyachi, H. (2004). Drugs Fut. 29, 383-391.]; Franks et al., 2004[Franks, M. E., Macpherson, G. R. & Figg, W. D. (2004). Lancet, 363, 1802-1811.]; Brennen et al., 2004[Brennen, W. N., Cooper, C. R., Capitosti, S., Brown, M. L. & Sikes, R. A. (2004). Clin. Prostate Cancer, 3, 54-61.]; Luzzio et al., 2004[Luzzio, F. A. & Figg, W. D. (2004). Expert Opin. Ther. Pat. 14, 215-229.]; Sleijfer et al., 2004[Sleijfer, S., Kruit, W. H. J. & Stoter, G. (2004). Eur. J. Cancer, 40, 2377-2382.]; Kumar et al., 2004[Kumar, S., Witzig, T. E. & Rajkumar, S. V. (2004). J. Clin. Oncol. 22, 2477-2488.]; Hashimoto, 2008[Hashimoto, Y. (2008). Arch. Pharm. Chem. Life Sci. 341, 536-547.]; Knobloch & Rüther, 2008[Knobloch, J. & Rüther, U. (2008). Cell Cycle, 7, 1121-1127.]).

[Scheme 1]

Thus, over the years, there has been increasing inter­est in thalidomide and its derivatives for the treatment of various hematologic malignancies (Singhal et al., 1999[Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., Munshi, N., Anaissie, E., Wilson, C., Dhodapkar, M., Zeldis, J., Siegel, D., Crowley, J. & Barlogie, B. (1999). N. Engl. J. Med. 341, 1565-1571.]; Raje & Anderson, 1999[Raje, N. & Anderson, K. (1999). N. Engl. J. Med. 341, 1606-1609.]), solid tumors (Kumar et al., 2002[Kumar, S., Witzig, T. E. & Rajkumar, S. V. (2002). J. Cell. Mol. Med. 6, 160-174.]), and a variety of inflammatory and autoimmune diseases (Tseng et al., 1996[Tseng, S., Pak, G., Washenik, K., Pomeranz, M. K. & Shupack, J. L. (1996). J. Am. Acad. Dermatol. 35, 969-979.]). Recent studies have uncovered a variety of mechanisms of thalidomide action. It was reported in 1991 that thalidomide is a selective inhibitor of tumor necrosis factor-α (TNF-α) production in lipopolysaccharide (LPS) stimulated human monocytes (Moreira et al., 1993[Moreira, A. L., Sampaio, E. P., Zmuidzinas, Z., Frindt, P., Smith, K. A. & Kaplan, G. J. (1993). Exp. Med, 177, 1675-1680.]; Sampaio et al., 1991[Sampaio, E. P., Sarno, E. N., Galilly, R., Cohn, Z. A. & Kaplan, G. (1991). J. Exp. Med, 173, 699-703.]). TNF-a is a key pro-inflammatory cytokine, and elevated levels have been linked with the pathology of a number of inflammatory and autoimmune diseases including rheumatoid arthritis, Crohn's disease, aphthous ulcers, cachexia, graft versus host disease, asthma, ARDS and AIDS (Eigler et al., 1997[Eigler, A., Sinha, B., Hartmann, G. & Endres, S. (1997). Immunol. Today, 18, 487-492.]). Taken together, the immunomodulatory properties of thalidomide, which are dependent on the type of immune cell activated as well as the type of stimulus that the cell receives, provide a rationale for the mechanism of thalidomide action in the context of autoimmune and inflammatory disease states. Other pharmacologic activities of thalidomide include its inhibition of angiogenesis (D'Amato et al., 1994[D'Amato, R. J., Loughnan, M. S., Flynn, E. & Folkman, J. (1994). Proc. Natl Acad. Sci. USA, 91, 4082-4085.]) and its anti-cancer properties (Bartlett et al., 2004[Bartlett, J. B., Dredge, K. & Dalgleish, A. G. (2004). Nat. Rev. Cancer, 4, 314-322.]). In the late 1990′s it was reported that thalidomide is efficacious for the treatment of multiple myeloma (MM), a hematological cancer caused by growth of tumor cells derived from the plasma cells in the bone marrow (Singhal et al., 1999[Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., Munshi, N., Anaissie, E., Wilson, C., Dhodapkar, M., Zeldis, J., Siegel, D., Crowley, J. & Barlogie, B. (1999). N. Engl. J. Med. 341, 1565-1571.]; Raje & Anderson, 1999[Raje, N. & Anderson, K. (1999). N. Engl. J. Med. 341, 1606-1609.]).

A medicinal chemistry program to optimize the immunomodulatory properties of thalidomide and reduce its side-effects led to the discovery of lenalidomide (2), which is a potent immunomodulator that is ∼800 times more potent as an inhibitor of TNF-α in LPS-stimulated hPBMC (Muller et al., 1999[Muller, G., Chen, R., Huang, S.-Y., Corral, L., Wong, L., Patterson, R., Chen, Y., Kaplan, G. & Stirling, D. (1999). Bioorg. Med. Chem. Lett. 9, 1625-1630.]; Zeldis et al., 2011[Zeldis, J., Knight, R., Hussein, M., Chopra, R. & Muller, G. (2011). Ann. N. Y. Acad. Sci. 1222, 76-82.]). In the US, lenalidomide was approved by the FDA in 2005 for low- or inter­mediate-1-risk myelodysplastic

Structural optimization of thalidomide, 1 also led to the discovery of pomalidomide (3), which is tenfold more potent than lenalidomide as a TNF-a inhibitor and IL-2 stimulator (Muller et al., 1999[Muller, G., Chen, R., Huang, S.-Y., Corral, L., Wong, L., Patterson, R., Chen, Y., Kaplan, G. & Stirling, D. (1999). Bioorg. Med. Chem. Lett. 9, 1625-1630.]; Zeldis et al., 2011[Zeldis, J., Knight, R., Hussein, M., Chopra, R. & Muller, G. (2011). Ann. N. Y. Acad. Sci. 1222, 76-82.]). Pomalidomide is currently undergoing late-stage clinical development for the treatment of multiple myeloma and myeloproliferative neoplasm-associated myelofibrosis (Galustian & Dalgleish, 2011[Galustian, C. & Dalgleish, A. (2011). Drugs Fut. 36, 741-750.]; Begna et al., 2012[Begna, K., Pardanani, A., Mesa, R., Litzow, M., Hogan, W., Hanson, C. & Tefferi, A. (2012). Am. J. Hematol. 87, 66-68.]). In clinical trials for multiple myeloma, pomalidomide has been shown to be effective in overcoming resistance to lenalidomide and thalidomide, as well as the proteosome inhibitor bortezomib (Schey & Ramasamy, 2011[Schey, S. & Ramasamy, K. (2011). Expert Opin. Investig. Drugs, 20, 691-700.]).

These studies have shown the efficacy of a continued search for more pharmacologically active analogs of thalidomide and its derivatives. Focus has previously been on modifying the basic thalidomide skeleton by changing its substituents. However, there have been very few studies on related derivatives where the six-membered ring is changed from an aromatic to an unsaturated ring. In view of the wide inter­est in these types of compounds for their pharmacological activities, the structure of (3aR,7aS)-2-(2,6-dioxopiperidin-3-yl)hexa­hydro-1H-iso­indole-1,3(2H)-dione, 4, is reported where the only change to thalidomide is the substitution of an unsaturated six-membered for the aromatic ring.

As a result of this inter­est in thalidomide, the crystal structure of this mol­ecule in both the racemic and enanti­o­merically pure forms have been determined multiple times (Lovell, 1970[Lovell, F. M. (1970). ACA Abstr. Papers (Winter), 30.], 1971[Lovell, F. M. (1971). ACA Abstr. Papers (Summer), 36.]; Reepmeyer et al., 1994[Reepmeyer, J. C., Rhodes, M. O., Cox, D. C. & Silverton, J. V. (1994). J. Chem. Soc. Perkin Trans. 2, pp. 2063-2067.]; Allen & Trotter, 1971[Allen, F. H. & Trotter, J. (1971). J. Chem. Soc. B, pp. 1073-1079.]; Caira et al., 1994[Caira, M. R., Botha, S. A. & Flanagan, D. R. (1994). J. Chem. Crystallogr. 24, 95-99.]; Suzuki et al., 2010[Suzuki, T., Tanaka, M., Shiro, M., Shibata, N., Osaka, T. & Asahi, T. (2010). Phase Transit. 83, 223-234.]; Maeno et al., 2015[Maeno, M., Tokunaga, E., Yamamoto, T., Suzuki, T., Ogino, Y., Ito, E., Shiro, M., Asahi, T. & Shibata, N. (2015). Chem. Sci. 6, 1043-1048.]). Two polymorphs of the racemic derivative have been determined crystallizing in the space groups P21/n (Allen & Trotter, 1971[Allen, F. H. & Trotter, J. (1971). J. Chem. Soc. B, pp. 1073-1079.]; Suzuki et al., 2010[Suzuki, T., Tanaka, M., Shiro, M., Shibata, N., Osaka, T. & Asahi, T. (2010). Phase Transit. 83, 223-234.]; Maeno et al., 2015[Maeno, M., Tokunaga, E., Yamamoto, T., Suzuki, T., Ogino, Y., Ito, E., Shiro, M., Asahi, T. & Shibata, N. (2015). Chem. Sci. 6, 1043-1048.]) and P21/c (Lovell, 1970[Lovell, F. M. (1970). ACA Abstr. Papers (Winter), 30.]) or C2/c (Reepmeyer et al., 1994[Reepmeyer, J. C., Rhodes, M. O., Cox, D. C. & Silverton, J. V. (1994). J. Chem. Soc. Perkin Trans. 2, pp. 2063-2067.]; Caira et al., 1994[Caira, M. R., Botha, S. A. & Flanagan, D. R. (1994). J. Chem. Crystallogr. 24, 95-99.]). The crystal packing in the C2/c structure is determined by inter­molecular N–H⋯O hydrogen bonding that is more extensive than that reported for the racemate of thalidomide crystallizing in space group P21/n.

2. Structural commentary

The title compound, C13H16N2O4, 4 (Fig. 1[link]), crystallizes in the monoclinic centrosymmetric space group, P21/c, with four mol­ecules in the asymmetric unit, thus there is no crystallographically imposed symmetry and it is a racemic mixture. The structure consists of a six-membered unsaturated ring bound to a five-membered pyrrolidine-2,5-dione ring N-bound to a six-membered piperidine-2,6-dione ring and thus has the same basic skeleton as thalidomide, 1, except for the six-membered unsaturated ring substituted for the aromatic ring. In the five-membered pyrrolidine-2,5-dione ring, the atoms O1, C1, N1, C8 and O2 form a plane (r.m.s. deviation of fitted atoms = 0.0348 Å) with C2 and C7 deviating from this plane by −0.186 (7) and 0.219 (7) Å, respectively. The ring itself adopts a conformation in which it is twisted about the C2–C7 axis [P = 257.4 (5) and τ = 22.5 (2); Rao et al., 1981[Rao, S. T., Westhof, E. & Sundaralingam, M. (1981). Acta Cryst. A37, 421-425.]]. In the six-membered piperidine-2,6-dione ring, the group, O3, C10, N2, C11and O4 is also planar (r.m.s. deviation of fitted atoms = 0.0042 Å). The cyclo­hexane ring adopts a chair conformation [puckering parameters Q = 0.536 (3), θ = 157.7 (3)° and φ = 324.2 (8)°; Boeyens, 1978[Boeyens, J. C. A. (1978). J. Cryst. Mol. Struct. 8, 317-320.]). Otherwise, the metrical parameters for all bonds are in the standard range for such structures.

[Figure 1]
Figure 1
The molecular structure of the title compound 4, with the atom-numbering scheme. Atomic displacement parameters are drawn at the 30% probability level.

3. Supra­molecular features

Similarly to the hydrogen-bonding patterns found in both the enanti­omerically pure form of thalidomide (Lovell, 1971[Lovell, F. M. (1971). ACA Abstr. Papers (Summer), 36.]; Maeno et al., 2015[Maeno, M., Tokunaga, E., Yamamoto, T., Suzuki, T., Ogino, Y., Ito, E., Shiro, M., Asahi, T. & Shibata, N. (2015). Chem. Sci. 6, 1043-1048.]) and the racemic P21/n polymorph (Allen & Trotter, 1971[Allen, F. H. & Trotter, J. (1971). J. Chem. Soc. B, pp. 1073-1079.]; Suzuki et al., 2010[Suzuki, T., Tanaka, M., Shiro, M., Shibata, N., Osaka, T. & Asahi, T. (2010). Phase Transit. 83, 223-234.]; Maeno et al., 2015[Maeno, M., Tokunaga, E., Yamamoto, T., Suzuki, T., Ogino, Y., Ito, E., Shiro, M., Asahi, T. & Shibata, N. (2015). Chem. Sci. 6, 1043-1048.]), the mol­ecules of the title compound are linked into inversion dimers by R22(8) (Etter et al., 1990[Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256-262.]) hydrogen bonding (Table 1[link]) involving the N—H group as shown in Fig. 2[link]. In addition, there are bifurcated C—H⋯O inter­actions involv­ing O2 with graph-set notation R21(5). These inter­actions, along with C—H⋯O inter­actions involving O4, link the mol­ecules into a complex three-dimensional array.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
N2—H2N⋯O3i 0.88 (5) 2.07 (5) 2.928 (3) 165 (4)
C7—H7A⋯O4ii 1.00 2.42 3.150 (3) 129
C9—H9A⋯O1iii 1.00 2.65 3.385 (3) 130
C12—H12A⋯O2ii 0.99 2.53 3.143 (3) 120
C13—H13A⋯O2 0.99 2.56 3.142 (3) 118
C13—H13B⋯O2ii 0.99 2.52 3.163 (3) 122
Symmetry codes: (i) -x+1, -y+2, -z+1; (ii) [-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]; (iii) -x+1, -y+1, -z+1.
[Figure 2]
Figure 2
Packing diagram viewed along the a axis showing the extensive N—H⋯O and C—H⋯O inter­actions (drawn as dashed lines) linking the mol­ecules into a complex three-dimensional array.

4. Database survey

A search of the Cambridge Structural Database (CSD version 5.39; Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) using a skeleton containing the three rings as in thalidomide but without the ketone substituents gave 39 hits but not a single example where the six-membered aromatic ring in the isoindoline moiety is changed to an unsaturated six-membered ring.

5. Synthesis and crystallization

Some details of the synthesis have been previously reported (Benjamin & Hijji, 2017[Benjamin, E. & Hijji, Y. M. (2017). J. Chem. pp. 1-6.]). cis-1,2-Cyclo­hexane di­carb­oxy­lic acid anhydride (0.10 g, 0.65 mmol), glutamic acid (0.095 g, 0.65 mmol), DMAP (0.02 g, 0.16 mmol), and ammonium chloride (NH4Cl) (0.040 g, 0.75 mmol) were mixed thoroughly in a CEM-sealed vial with a magnetic stirrer. The sample was heated for 6 min at 423 K in a CEM Discover microwave powered at 150 W. It was then cooled rapidly to 313 K and dissolved in 15 ml of (1:1) ethyl acetate:acetone. The organic layer was washed with 2× 10 ml of distilled water and dried over sodium sulfate (anhydrous). The organic layer was concentrated under vacuum and precipitated with hexa­nes (30 ml) affording a white solid. Crystals suitable for X-ray experiments were grown by slow evaporation of an ethyl acetate/acetone (1:1) solution. M.p. 463–465 K, (0.12 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1 H, NH), 4.9 (dd, 1 H, 12.5, 5.5 Hz, CHCO), 3.0 (m, 1 H), 2.8 (m, 1 H), 2.8 (m, 1 H), 2.5 (m, 1 H), 1.9 (m, 1 H), 1.7 (m, 3 H),, 1.6 (m, 1 H), 1.4 (m, 4 H); 13C NMR (100 MHz, DMSO-d6) 178.8 (C=O), 178.7 (C=O), 172.7 (C=O), 169.4 (C=O), 48.7 (CH), 39.1 (CH), 38.8 (CH), 30.7 (CH2), 23.1 (CH2), 22.9 (CH2), 21.1 (CH2), 21.05 (CH2), 21.00 (CH2); MS 264 (M+); 236, 210, 179, 154, 112, 82, 67, 54, 41.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. H atoms were positioned geometrically and treated as riding on their parent atoms and refined with C—H distances of 0.99–1.00 Å and Uiso(H) = 1.2Ueq(C). The H attached to N2 was refined isotropically. There is pseudomerohedral twinning present, which results from a 180° rotation about the [100] reciprocal lattice direction and with a twin law of 1 0 0 0 [\overline{1}] 0 0 0 [\overline{1}] [BASF 0.044 (1)].

Table 2
Experimental details

Crystal data
Chemical formula C13H16N2O4
Mr 264.28
Crystal system, space group Monoclinic, P21/c
Temperature (K) 123
a, b, c (Å) 11.4519 (3), 9.2370 (3), 11.8727 (4)
β (°) 90.475 (3)
V3) 1255.87 (7)
Z 4
Radiation type Cu Kα
μ (mm−1) 0.87
Crystal size (mm) 0.42 × 0.34 × 0.18
 
Data collection
Diffractometer Rigaku Oxford Diffraction Xcalibur, Ruby, Gemini
Absorption correction Multi-scan (CrysAlis PRO; Rigaku OD, 2012[Rigaku OD (2012). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.])
Tmin, Tmax 0.822, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections 9733, 2626, 2572
Rint 0.024
(sin θ/λ)max−1) 0.633
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.066, 0.208, 1.19
No. of reflections 2626
No. of parameters 177
H-atom treatment H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3) 0.33, −0.35
Computer programs: CrysAlis PRO (Rigaku OD, 2012[Rigaku OD (2012). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]), SHELXS97 and SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]) and SHELXL2018/3 (Sheldrick, 2015[Sheldrick, G. M. (2015). Acta Cryst. C71, 3-8.]).

Supporting information


Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2012); cell refinement: CrysAlis PRO (Rigaku OD, 2012); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

(3aR*,7aS*)-2-(2,6-Dioxopiperidin-3-yl)hexahydro-1H-isoindole-1,3(2H)-dione top
Crystal data top
C13H16N2O4F(000) = 560
Mr = 264.28Dx = 1.398 Mg m3
Monoclinic, P21/cCu Kα radiation, λ = 1.54178 Å
a = 11.4519 (3) ÅCell parameters from 7629 reflections
b = 9.2370 (3) Åθ = 3.7–77.3°
c = 11.8727 (4) ŵ = 0.87 mm1
β = 90.475 (3)°T = 123 K
V = 1255.87 (7) Å3Prism, colorless
Z = 40.42 × 0.34 × 0.18 mm
Data collection top
Rigaku Oxford Diffraction Xcalibur, Ruby, Gemini
diffractometer
2572 reflections with I > 2σ(I)
Detector resolution: 10.5081 pixels mm-1Rint = 0.024
ω scansθmax = 77.5°, θmin = 3.7°
Absorption correction: multi-scan
(CrysAlisPro; Rigaku OD, 2012)
h = 914
Tmin = 0.822, Tmax = 1.000k = 1011
9733 measured reflectionsl = 1414
2626 independent reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.066Hydrogen site location: mixed
wR(F2) = 0.208H atoms treated by a mixture of independent and constrained refinement
S = 1.19 w = 1/[σ2(Fo2) + (0.1179P)2 + 1.1244P]
where P = (Fo2 + 2Fc2)/3
2626 reflections(Δ/σ)max < 0.001
177 parametersΔρmax = 0.33 e Å3
0 restraintsΔρmin = 0.35 e Å3
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. Refined as a two-component twin

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.66960 (17)0.4309 (2)0.56402 (17)0.0291 (4)
O20.67111 (18)0.8499 (2)0.76606 (18)0.0305 (5)
O30.58392 (17)0.8448 (2)0.51862 (17)0.0299 (5)
O40.21720 (17)0.9000 (2)0.64578 (19)0.0339 (5)
N10.64254 (19)0.6373 (2)0.66901 (18)0.0228 (5)
N20.4008 (2)0.8685 (2)0.58537 (19)0.0263 (5)
H2N0.393 (4)0.952 (5)0.550 (3)0.043 (10)*
C10.7100 (2)0.5317 (3)0.6160 (2)0.0233 (5)
C20.8368 (2)0.5762 (3)0.6283 (2)0.0240 (5)
H2A0.8869270.4914480.6488920.029*
C30.8713 (2)0.6388 (3)0.5124 (2)0.0288 (6)
H3A0.8931120.5581460.4617910.035*
H3B0.8028370.6884010.4785810.035*
C40.9729 (2)0.7454 (3)0.5201 (2)0.0311 (6)
H4A1.0431510.6954750.5497790.037*
H4B0.9909520.7832220.4442180.037*
C50.9407 (2)0.8704 (3)0.5979 (2)0.0295 (6)
H5A1.0032260.9443670.5972750.035*
H5B0.8673890.9163440.5712000.035*
C60.9248 (2)0.8128 (3)0.7171 (2)0.0278 (6)
H6A0.8991780.8930480.7663410.033*
H6B1.0010370.7777270.7460540.033*
C70.8356 (2)0.6895 (3)0.7240 (2)0.0236 (5)
H7A0.8500090.6369360.7963980.028*
C80.7103 (2)0.7412 (3)0.7241 (2)0.0235 (5)
C90.5186 (2)0.6584 (3)0.6460 (2)0.0236 (5)
H9A0.4913230.5763480.5976250.028*
C100.5061 (2)0.7980 (3)0.5776 (2)0.0239 (5)
C110.3047 (2)0.8261 (3)0.6481 (2)0.0264 (5)
C120.3171 (2)0.6889 (3)0.7153 (2)0.0285 (6)
H12A0.2887110.6063880.6694600.034*
H12B0.2678040.6954980.7831530.034*
C130.4435 (2)0.6608 (3)0.7512 (2)0.0260 (5)
H13A0.4706380.7379790.8029750.031*
H13B0.4493140.5668260.7909990.031*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0298 (9)0.0199 (9)0.0374 (10)0.0011 (7)0.0051 (8)0.0043 (7)
O20.0306 (10)0.0200 (9)0.0407 (11)0.0001 (7)0.0028 (8)0.0059 (7)
O30.0280 (10)0.0269 (10)0.0347 (10)0.0042 (7)0.0006 (8)0.0055 (7)
O40.0266 (9)0.0273 (10)0.0478 (12)0.0052 (8)0.0031 (8)0.0019 (9)
N10.0226 (10)0.0164 (9)0.0294 (10)0.0004 (8)0.0062 (8)0.0003 (8)
N20.0260 (11)0.0189 (10)0.0337 (11)0.0043 (8)0.0044 (9)0.0023 (9)
C10.0265 (12)0.0173 (11)0.0259 (11)0.0017 (9)0.0049 (9)0.0024 (9)
C20.0245 (11)0.0177 (11)0.0297 (12)0.0005 (9)0.0039 (9)0.0002 (9)
C30.0297 (13)0.0276 (13)0.0291 (13)0.0027 (10)0.0008 (10)0.0019 (10)
C40.0306 (13)0.0319 (14)0.0309 (13)0.0046 (11)0.0008 (10)0.0011 (10)
C50.0286 (13)0.0252 (13)0.0345 (14)0.0050 (10)0.0035 (10)0.0027 (10)
C60.0250 (12)0.0275 (12)0.0309 (13)0.0053 (10)0.0045 (10)0.0006 (10)
C70.0240 (11)0.0216 (11)0.0253 (11)0.0020 (9)0.0039 (9)0.0014 (9)
C80.0250 (11)0.0195 (11)0.0258 (11)0.0010 (9)0.0043 (9)0.0017 (9)
C90.0219 (11)0.0170 (11)0.0319 (12)0.0015 (8)0.0070 (9)0.0005 (9)
C100.0253 (11)0.0180 (11)0.0283 (11)0.0021 (9)0.0054 (9)0.0006 (9)
C110.0242 (12)0.0213 (12)0.0336 (13)0.0007 (9)0.0054 (10)0.0053 (10)
C120.0245 (12)0.0217 (12)0.0393 (14)0.0016 (9)0.0017 (10)0.0001 (10)
C130.0239 (12)0.0218 (12)0.0322 (13)0.0007 (9)0.0034 (10)0.0030 (9)
Geometric parameters (Å, º) top
O1—C11.207 (3)C4—H4B0.9900
O2—C81.208 (3)C5—C61.525 (4)
O3—C101.217 (3)C5—H5A0.9900
O4—C111.213 (3)C5—H5B0.9900
N1—C81.394 (3)C6—C71.532 (3)
N1—C11.397 (3)C6—H6A0.9900
N1—C91.456 (3)C6—H6B0.9900
N2—C101.374 (3)C7—C81.513 (3)
N2—C111.390 (4)C7—H7A1.0000
N2—H2N0.88 (5)C9—C131.522 (4)
C1—C21.515 (3)C9—C101.531 (3)
C2—C71.544 (3)C9—H9A1.0000
C2—C31.548 (4)C11—C121.503 (4)
C2—H2A1.0000C12—C131.528 (4)
C3—C41.527 (4)C12—H12A0.9900
C3—H3A0.9900C12—H12B0.9900
C3—H3B0.9900C13—H13A0.9900
C4—C51.525 (4)C13—H13B0.9900
C4—H4A0.9900
C8—N1—C1112.6 (2)C5—C6—H6B108.9
C8—N1—C9122.3 (2)C7—C6—H6B108.9
C1—N1—C9123.4 (2)H6A—C6—H6B107.8
C10—N2—C11127.0 (2)C8—C7—C6113.4 (2)
C10—N2—H2N118 (3)C8—C7—C2103.24 (19)
C11—N2—H2N115 (3)C6—C7—C2117.1 (2)
O1—C1—N1123.9 (2)C8—C7—H7A107.5
O1—C1—C2128.4 (2)C6—C7—H7A107.5
N1—C1—C2107.5 (2)C2—C7—H7A107.5
C1—C2—C7103.9 (2)O2—C8—N1123.9 (2)
C1—C2—C3105.49 (19)O2—C8—C7128.2 (2)
C7—C2—C3113.9 (2)N1—C8—C7107.8 (2)
C1—C2—H2A111.1N1—C9—C13113.9 (2)
C7—C2—H2A111.1N1—C9—C10107.4 (2)
C3—C2—H2A111.1C13—C9—C10111.9 (2)
C4—C3—C2112.8 (2)N1—C9—H9A107.8
C4—C3—H3A109.0C13—C9—H9A107.8
C2—C3—H3A109.0C10—C9—H9A107.8
C4—C3—H3B109.0O3—C10—N2121.2 (2)
C2—C3—H3B109.0O3—C10—C9122.6 (2)
H3A—C3—H3B107.8N2—C10—C9116.2 (2)
C5—C4—C3109.7 (2)O4—C11—N2119.1 (2)
C5—C4—H4A109.7O4—C11—C12124.1 (3)
C3—C4—H4A109.7N2—C11—C12116.8 (2)
C5—C4—H4B109.7C11—C12—C13112.1 (2)
C3—C4—H4B109.7C11—C12—H12A109.2
H4A—C4—H4B108.2C13—C12—H12A109.2
C6—C5—C4109.2 (2)C11—C12—H12B109.2
C6—C5—H5A109.8C13—C12—H12B109.2
C4—C5—H5A109.8H12A—C12—H12B107.9
C6—C5—H5B109.8C9—C13—C12108.3 (2)
C4—C5—H5B109.8C9—C13—H13A110.0
H5A—C5—H5B108.3C12—C13—H13A110.0
C5—C6—C7113.2 (2)C9—C13—H13B110.0
C5—C6—H6A108.9C12—C13—H13B110.0
C7—C6—H6A108.9H13A—C13—H13B108.4
C8—N1—C1—O1179.5 (2)C9—N1—C8—C7174.9 (2)
C9—N1—C1—O115.2 (4)C6—C7—C8—O234.8 (4)
C8—N1—C1—C25.3 (3)C2—C7—C8—O2162.5 (3)
C9—N1—C1—C2160.0 (2)C6—C7—C8—N1147.1 (2)
O1—C1—C2—C7167.9 (2)C2—C7—C8—N119.4 (3)
N1—C1—C2—C717.2 (2)C8—N1—C9—C1367.6 (3)
O1—C1—C2—C372.0 (3)C1—N1—C9—C13128.4 (2)
N1—C1—C2—C3102.9 (2)C8—N1—C9—C1056.9 (3)
C1—C2—C3—C4155.2 (2)C1—N1—C9—C10107.1 (3)
C7—C2—C3—C441.9 (3)C11—N2—C10—O3179.1 (2)
C2—C3—C4—C558.7 (3)C11—N2—C10—C90.4 (4)
C3—C4—C5—C664.9 (3)N1—C9—C10—O325.9 (3)
C4—C5—C6—C755.2 (3)C13—C9—C10—O3151.6 (2)
C5—C6—C7—C880.1 (3)N1—C9—C10—N2154.6 (2)
C5—C6—C7—C240.0 (3)C13—C9—C10—N228.9 (3)
C1—C2—C7—C821.7 (2)C10—N2—C11—O4179.6 (2)
C3—C2—C7—C892.6 (2)C10—N2—C11—C120.4 (4)
C1—C2—C7—C6147.1 (2)O4—C11—C12—C13151.1 (3)
C3—C2—C7—C632.8 (3)N2—C11—C12—C1328.9 (3)
C1—N1—C8—O2172.5 (2)N1—C9—C13—C12178.0 (2)
C9—N1—C8—O26.9 (4)C10—C9—C13—C1255.9 (3)
C1—N1—C8—C79.4 (3)C11—C12—C13—C956.1 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2N···O3i0.88 (5)2.07 (5)2.928 (3)165 (4)
C7—H7A···O4ii1.002.423.150 (3)129
C9—H9A···O1iii1.002.653.385 (3)130
C12—H12A···O2ii0.992.533.143 (3)120
C13—H13A···O20.992.563.142 (3)118
C13—H13B···O2ii0.992.523.163 (3)122
Symmetry codes: (i) x+1, y+2, z+1; (ii) x+1, y1/2, z+3/2; (iii) x+1, y+1, z+1.
 

Funding information

This report was made possible by a NPRP award [NPRP-7-495-1-094] from Qatar National Research Fund (a member of The Qatar Foundation). The statements made herein are solely the responsibility of the authors. RJB is grateful for the NSF award 1205608, Partnership for Reduced Dimensional Materials, for partial funding of this research as well as the Howard University Nanoscience Facility access to liquid nitro­gen. RJB also acknowledges the NSF MRI program (grant No. CHE-0619278) for funds to purchase an X-ray diffractometer.

References

First citationAllen, F. H. & Trotter, J. (1971). J. Chem. Soc. B, pp. 1073–1079.  Google Scholar
First citationBartlett, J. B., Dredge, K. & Dalgleish, A. G. (2004). Nat. Rev. Cancer, 4, 314–322.  Web of Science CrossRef PubMed CAS Google Scholar
First citationBegna, K., Pardanani, A., Mesa, R., Litzow, M., Hogan, W., Hanson, C. & Tefferi, A. (2012). Am. J. Hematol. 87, 66–68.  Web of Science CrossRef PubMed Google Scholar
First citationBenjamin, E. & Hijji, Y. M. (2017). J. Chem. pp. 1–6.  Web of Science CrossRef Google Scholar
First citationBlaschke, G., Kraft, H. P., Fickentscher, K. & Köhler, F. (1979). Arzneim.-Forsch. 29, 1640–1642.  Google Scholar
First citationBoeyens, J. C. A. (1978). J. Cryst. Mol. Struct. 8, 317–320.  CrossRef Web of Science Google Scholar
First citationBrennen, W. N., Cooper, C. R., Capitosti, S., Brown, M. L. & Sikes, R. A. (2004). Clin. Prostate Cancer, 3, 54–61.  CrossRef PubMed Google Scholar
First citationBurley, D. M. & Lenz, W. (1962). Lancet, 279, 271–272.  CrossRef Google Scholar
First citationCaira, M. R., Botha, S. A. & Flanagan, D. R. (1994). J. Chem. Crystallogr. 24, 95–99.  CSD CrossRef CAS Web of Science Google Scholar
First citationD'Amato, R. J., Loughnan, M. S., Flynn, E. & Folkman, J. (1994). Proc. Natl Acad. Sci. USA, 91, 4082–4085.  PubMed Web of Science Google Scholar
First citationEigler, A., Sinha, B., Hartmann, G. & Endres, S. (1997). Immunol. Today, 18, 487–492.  CrossRef PubMed Web of Science Google Scholar
First citationEtter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256–262.  CSD CrossRef CAS Web of Science IUCr Journals Google Scholar
First citationFranks, M. E., Macpherson, G. R. & Figg, W. D. (2004). Lancet, 363, 1802–1811.  Web of Science CrossRef PubMed Google Scholar
First citationGalustian, C. & Dalgleish, A. (2011). Drugs Fut. 36, 741–750.  CrossRef Google Scholar
First citationGroom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179.  Web of Science CSD CrossRef IUCr Journals Google Scholar
First citationHashimoto, Y. (2008). Arch. Pharm. Chem. Life Sci. 341, 536–547.  Web of Science CrossRef Google Scholar
First citationHashimoto, Y., Tanatani, A., Nagasawa, K. & Miyachi, H. (2004). Drugs Fut. 29, 383–391.  Web of Science CrossRef Google Scholar
First citationKnobloch, J. & Rüther, U. (2008). Cell Cycle, 7, 1121–1127.  Web of Science CrossRef PubMed Google Scholar
First citationKnoche, B. & Blaschke, G. (1994). J. Chromatogr. A, 666, 235–240.  CrossRef Web of Science Google Scholar
First citationKumar, S., Witzig, T. E. & Rajkumar, S. V. (2002). J. Cell. Mol. Med. 6, 160–174.  Web of Science CrossRef PubMed Google Scholar
First citationKumar, S., Witzig, T. E. & Rajkumar, S. V. (2004). J. Clin. Oncol. 22, 2477–2488.  Web of Science CrossRef PubMed Google Scholar
First citationLovell, F. M. (1970). ACA Abstr. Papers (Winter), 30.  Google Scholar
First citationLovell, F. M. (1971). ACA Abstr. Papers (Summer), 36.  Google Scholar
First citationLuzzio, F. A. & Figg, W. D. (2004). Expert Opin. Ther. Pat. 14, 215–229.  CrossRef Google Scholar
First citationMaeno, M., Tokunaga, E., Yamamoto, T., Suzuki, T., Ogino, Y., Ito, E., Shiro, M., Asahi, T. & Shibata, N. (2015). Chem. Sci. 6, 1043–1048.  Web of Science CrossRef PubMed Google Scholar
First citationMatthews, S. J. & McCoy, C. (2003). Clin. Ther. 25, 342–395.  Web of Science CrossRef PubMed Google Scholar
First citationMelchert, M. & List, A. (2007). Int. J. Biochem. Cell Biol. 39, 1489–1499.  Web of Science CrossRef PubMed Google Scholar
First citationMoreira, A. L., Sampaio, E. P., Zmuidzinas, Z., Frindt, P., Smith, K. A. & Kaplan, G. J. (1993). Exp. Med, 177, 1675–1680.  CrossRef Web of Science Google Scholar
First citationMuller, G., Chen, R., Huang, S.-Y., Corral, L., Wong, L., Patterson, R., Chen, Y., Kaplan, G. & Stirling, D. (1999). Bioorg. Med. Chem. Lett. 9, 1625–1630.  Web of Science CrossRef PubMed Google Scholar
First citationNishimura, K., Hashimoto, Y. & Iwasaki, S. (1994). Chem. Pharm. Bull. 42, 1157–1159.  CrossRef PubMed Google Scholar
First citationRaje, N. & Anderson, K. (1999). N. Engl. J. Med. 341, 1606–1609.  Web of Science CrossRef PubMed Google Scholar
First citationRao, S. T., Westhof, E. & Sundaralingam, M. (1981). Acta Cryst. A37, 421–425.  CrossRef CAS IUCr Journals Web of Science Google Scholar
First citationReepmeyer, J. C., Rhodes, M. O., Cox, D. C. & Silverton, J. V. (1994). J. Chem. Soc. Perkin Trans. 2, pp. 2063–2067.  CSD CrossRef Web of Science Google Scholar
First citationRigaku OD (2012). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.  Google Scholar
First citationSampaio, E. P., Sarno, E. N., Galilly, R., Cohn, Z. A. & Kaplan, G. (1991). J. Exp. Med, 173, 699–703.  CrossRef PubMed Web of Science Google Scholar
First citationSchey, S. & Ramasamy, K. (2011). Expert Opin. Investig. Drugs, 20, 691–700.  Web of Science CrossRef PubMed Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationSheldrick, G. M. (2015). Acta Cryst. C71, 3–8.  Web of Science CrossRef IUCr Journals Google Scholar
First citationSinghal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., Munshi, N., Anaissie, E., Wilson, C., Dhodapkar, M., Zeldis, J., Siegel, D., Crowley, J. & Barlogie, B. (1999). N. Engl. J. Med. 341, 1565–1571.  Web of Science CrossRef PubMed Google Scholar
First citationSleijfer, S., Kruit, W. H. J. & Stoter, G. (2004). Eur. J. Cancer, 40, 2377–2382.  Web of Science CrossRef PubMed Google Scholar
First citationStephans, T. D. (1988). Teratology, 38, 229–239.  PubMed Web of Science Google Scholar
First citationSuzuki, T., Tanaka, M., Shiro, M., Shibata, N., Osaka, T. & Asahi, T. (2010). Phase Transit. 83, 223–234.  Web of Science CrossRef Google Scholar
First citationTseng, S., Pak, G., Washenik, K., Pomeranz, M. K. & Shupack, J. L. (1996). J. Am. Acad. Dermatol. 35, 969–979.  CrossRef PubMed Web of Science Google Scholar
First citationWnendt, S., Finkam, M., Winter, W., Ossig, J., Raabe, G. & Zwingenberger, K. (1996). Chirality, 8, 390–396.  CrossRef PubMed Google Scholar
First citationWu, J. J., Huang, D. B., Pang, K. R., Hsu, S. & Tyring, S. K. (2005). Br. J. Dermatol. 153, 254–273.  Web of Science CrossRef PubMed Google Scholar
First citationZeldis, J., Knight, R., Hussein, M., Chopra, R. & Muller, G. (2011). Ann. N. Y. Acad. Sci. 1222, 76–82.  Web of Science CrossRef PubMed Google Scholar

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