Synthesis and Crystal Structures of Novel Glycoluryl Carboxylic Acids Conglomerates

The two novel conglomerats were obtained by crystallization of racemic (S)-2-((3aS,6aR)- and (R)-2-((3aR,6aS)-2,5-dioxohexahydroimidazo[4,5-d]imidazole-1(2H)-yl)-3-methylbutanoic acids (racemate I), (R)-2-(3aR,6aR)- and (S)-2-((3aS,6aS)-4,6-dimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazole-1(2H)-yl)pentanoic acids (racemate II), which were synthesized by highly diastereoselective condensation of 4,5-dihydroxyimidazolidine-2-ones with racemic ureido acids for the rst time. The differences in the molecular geometry of I and II are studied by X-ray diffraction that showed them to crystallize as conglomerates in non-centrosymmetric space groups Pna2 1 and P2 1 2 1 2 1 , respectively.


Introduction
The course of many biological processes is based on molecular recognition, in which various classes of chemical compounds are involved. The processes of crystal formation can serve as models for studying such phenomena in biosystems [1]. In particular, crystallization is used to separate racemic drugs into enantiomers, since it is well known that enantiomers can exhibit different pharmacological activities. It is known that only (S)-thalidomid is a teratogen, (R)-enanthiomer is an anti-in ammatory, immunomodulatory, and antiangiogenic properties [2][3][4]. (S)-Ketamine has an approximately 4-fold greater analgesic potency, compared with (R)-ketamine [5], but only S-isomer is responsible for agitation, hallucination, and restlessness [6]. Only (S)-penicillamine can be used clinically, because of (R)-isomer is excessive toxicity [7]. (-)-(3aS,6aS)-Albicar is stimulating effect on central nervous system (CNS), but (+)-(3aR,6aR)-Albicar is inhibitory effect on CNS [8].
General procedure for the synthesis of compounds 3a,b (Scheme 1, Scheme 2) KCNO (8.505 g, 0.105 mol) by portionwise slowly was added to boiling solution (R,S)-Val 1a (11.7 g, 0.1 mol) or (R,S)-nor-Val 1b (11.7 g, 0.1 mol) in 200 mL of H 2 O and re uxed for 20 min. The reaction mixture was cold to 10°C at the ice bath and (10.6 mL, 35%) hydrochloric acid was added dropwise to pH 1. Obtained white powder of product 3a or 3b was ltered off and washed with 10 mL H 2 O and dried at the air.
The crystals I were obtained by crystallization from MeOH.   = 3369, 1710, 1649, 1502, 1467, 1413, 1397,  1371, 1314, 1259, 1228, 1190, 1171, 1100, 1083, 1038, 986, 940, 890, 865, 810, 787, 762, 733, 697, 671  X-ray data collection and re nement X-ray diffraction data for I and II were collected at 120 K with a Bruker APEXII DUO CCD diffractometer, using the graphite monochromated Mo-Kα radiation (l = 0.71073 Å). Using Olex2 [41], the structures were solved with the ShelXT structure solution program [42] using Intrinsic Phasing and re ned with XL re nement package [43] using Least Squares minimisation. Hydrogen atoms of OH and NH groups were located in difference Fourier synthesis. Positions of other hydrogen atoms were calculated, and they all were re ned in the isotropic approximation in the riding model. Crystal data and structure re nement parameters for the three crystallosolvates are given in Table 1. CCDC 2089267 and 2089265 contain the supplementary crystallographic data for I and II, respectively.

Synthesis
It is known that 4,5-dihydroxyimidazilidine-2-ones (DHI) exist in the form of two isomers, which differ in the cisand trans-arrangement of hydroxy groups at the C (4) and C (5) atoms relative to the plane of the imidazolidine ring [32]. They are obtained by diastereoselective reactions of ureas with α-dicarbonyl compounds. The ratio of diastereomers is determined from the integral intensity of signals from the protons of CH-CH groups in the 1 H NMR spectra [44].

Single-crystal X-ray diffraction
The study of crystallization processes for the production of conglomerates is an important task in crystal chemistry. This nature-like process is widely used to obtain enantiomerically pure compounds [47].
Therefore, we investigated the crystallization of racemates I and II from H 2 O, MeOH, i-PrOH and a mixture of H 2 O:i-PrOH. Single crystals I and II were obtained from a mixture of Н 2 О:i-PrOH (in a 1:1 ratio) and from МеОН, respectively. Their X-ray diffraction analysis (Fig. 2) showed them to crystallize as conglomerates in non-centrosymmetric space groups Pna2 1 and P2 1 2 1 2 1 with two and one symmetryindependent molecules, respectively. Owing to the different substituents at the carbon atom C(5), the isopropyl or the propyl group, these compounds features an important difference in their molecular geometry, which is the rotation of the COOH group relative to the bond C(2)-C (5). The corresponding torsion angle N(1)C(5)C(6)O(3) being much higher in I (76.0(4) and 77.3(4)° in its two symmetricallyindependent molecules) than in II (23.6(3)°) may be attributed to the steric effect of the bulky isopropyl group in the former compound.
Two extra methyl groups at the nitrogen atoms in II results in its supramolecular organization being different from one in I. In both cases, the main structural motif is an in nite chain (Fig. 3) formed by a hydrogen bond between the hydroxyl group and one of the carboxy groups of the heterocyclic core (O…O 2.596(5) and 2.557(2) Å, OHO 173.8(2) and 171.64(11)° в I и II, respectively). In I, they hold together different symmetry-independent molecules that alternate to produce a 3D-framework through hydrogen bonds of three NH groups (N…O 2.779 (6)  Two new conglomerates (as gauged by space groups Pna2 1 and P2 1 2 1 2 1 ) were identi ed by X-ray diffraction among the crystallization products of the racemates I and II. The key difference between these two compounds, which is the different rotation of the COOH group relative to the bond C(2)-C(5), may be attributed to the steric effect of the bulky isopropyl group in I.

Declarations
Supplementary Information The online version contains supplementary material available at  General view of I (left) and II (right). Hereinafter, hydrogen atoms except those of OH and NH groups are omitted, and non-hydrogen atoms are shown as thermal ellipsoids at 50% probability level. Fragments of the crystal packing in I (top) and II (bottom) illustrating the formation of hydrogen-bonded chains along the crystallographic axes b and a, respectively.