(R)-Methyl {[(2-carboxybicyclo[2.2.2]octan-1-yl)ammonio]methyl}phosphonate dichloromethane 0.25-solvate

The carboxylic acid molecule of the title compound, C11H20NO5P·0.25CH2Cl2, exists as a zwitterion with the H atom of the phosphonate group being transferred to the imine N atom. In the asymmetric unit, there are two crystallographically independent acid molecules adopting the same absolute configuration and differing slightly in their geometrical parameters. In each molecule, the imino and carboxyl groups are connected via an intramolecular N—H⋯O hydrogen bond. Intermolecular O—H⋯O and N—H⋯O hydrogen bonds induce the formation of layers parallel to the ab plane. The dichloromethane solvent molecule, with a site occupancy of 0.5, is located between the layers.

The carboxylic acid molecule of the title compound, C 11 H 20 NO 5 PÁ0.25CH 2 Cl 2 , exists as a zwitterion with the H atom of the phosphonate group being transferred to the imine N atom. In the asymmetric unit, there are two crystallographically independent acid molecules adopting the same absolute configuration and differing slightly in their geometrical parameters. In each molecule, the imino and carboxyl groups are connected via an intramolecular N-HÁ Á ÁO hydrogen bond. Intermolecular O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds induce the formation of layers parallel to the ab plane. The dichloromethane solvent molecule, with a site occupancy of 0.5, is located between the layers.
istry at the α-carbon atom plays an important role in the biological activity of the molecule, the synthesis of chiral α-aminophosphonates and α-aminophosphonic acids has been a focus of considerable attention in synthetic organic chemistry as well as in modern pharmaceutical chemistry. This is underlined by an increasing number of industrial applications in the field of the synthesis of enantio enriched α-aminophosphonic acid derivatives (Kafarski & Lejczak, 2001;Troev, 2006;Naydenova et al., 2010). This, together with their low mammalian toxicity makes the α-aminophosphonic acids an important class of antimetabolites and a potential source of medicinal lead compounds (Naydenova et al., 2008;Orsini et al., 2010).
The title compound has been obtained in an enantiopure form. Herein, we synthesized and characterized a new α-aminophosphonate containing bicyclo[2.2.2]octane-moiety by Kabachnik-Fields reaction. This reaction is performed without epimerization. The optically active (R)-1-(N-(methoxyphosphonomethyl)aminobicyclo [2.2.2]octane-2-carboxylic acid was purified by column chromatography on silica gel using a mixture of dichloromethane/methanol (9.5/0.5) with 0.1% acetic acid as eluent to give the title compound.
The studied compound C 11 H 10 NPO 5 crystallizes as a dichloromethane 0.5 solvate with two crystallographically nonequivalent molecules (molecules A and B in Fig. 1). NMR analyses ( 1 H, 13 C and 31 P) has been applied for compositional and geometrical characterization of the organic molecule. The 1 H-NMR data were not indicative for the presence of NH2 or P-OH groups. From the other hand the difference Fourier analyses around imine N and PO 3 group show presence of two hydrogen atoms around the nitrogen. More over the P-O distances of 1.491 (4), 1.494 (4) Å and 1.459 (5), 1.481 (4) Å for molecules A and B, respectively, suppose charge distribution between the phosphonate O atoms. This suggests that both molecules exist as zwitterions with H atom of the phosphonate group being transferred to the imine N atom. The absolute configuration of the independent C 11 H 10 NPO 5 molecules is identical as deduced by the Flack parameter. The rotation of the bicyclo[2.2.2]octane-2-carboxylic fragment along axis described by N1,C6, C3 and N21, C26, C23 atoms for A and B molecules respectively differ by less than 10° [57.6 (2)° for A and 64.7 (1) ° for B molecule].
The imino and carboxylic groups are involved in intramolecular hydrogen bond in both of the molecules. The O-H···O and N-H···O intermolecular interactions induce the formation of layers parallel to the crystallographic ab plane. The dichloromethane moieties are located in the cavities near by the zigzag layer.

Experimental
Paraformaldehyde (1.827 mmol), methanol (5 ml), and triethylamine (190 υl) were put into a three-necked flask equipped with a condenser, magnetic stirrer, thermometer and dropping funnel and argon inert. The reaction mixture was heated to supplementary materials sup-2 reflux temperature and held there for 45 min, after which it became a clear solution. (R)-1-Aminobicyclo[2.2.2]octane-2carboxylic acid (1.175 mmol) and triethylamine (0.24 ml) were added to this solution. The suspension was heated at 65 -70°C and after 3.5 h it became a clear solution. Dimethyl hydrogen phosphonate 122 µl (146.5 mg, 1.331 mmol) was added to this solution for approximately 10 min. This reaction mixture was heated at 65-70 °C and after maintaining this temperature for 5.5 h, it was cooled to room temperature and concentrated under reduced pressure. The crude compound was dissolved in methanol and the non-reacting (R)-1-aminobicyclo[2.2.2]octane-2-carboxylic acid was removed by precipitation with diethyl ether and collected by filtration. The filtrate was evaporated to give a residue which was purified by flash column chromatography on silica gel using a mixture of dichloromethane/methanol (9.5/0.5) with 0.1% acetic acid as eluent to yield the 1-(N-methoxyphosphonomethyl)aminobicyclo[2.2.2]octane-2-carboxylic acid.