N-Methyl-l-leucyl-l-leucine hydrochloride monohydrate

In the title compound C13H27N2O3 +·Cl−·H2O, obtained by deprotecting the amino and carboxyl groups of an intermediate in the synthesis of the cyclic pentapeptide Galaxamide, a number of hydrogen-bonding interactions occur including aminium N—H⋯Cl, amide–carboxyl N—H⋯O, water O—H⋯Cl and carboxyl–water O—H⋯O associations. The aminium N—H⋯Cl⋯H—N bridging extensions give rise to zigzag chains extending along the a axis, the overall two-dimensional structure lying in the (110) plane.

In the title compound C 13 H 27 N 2 O 3 + ÁCl À ÁH 2 O, obtained by deprotecting the amino and carboxyl groups of an intermediate in the synthesis of the cyclic pentapeptide Galaxamide, a number of hydrogen-bonding interactions occur including aminium N-HÁ Á ÁCl, amide-carboxyl N-HÁ Á ÁO, water O-HÁ Á ÁCl and carboxyl-water O-HÁ Á ÁO associations. The aminium N-HÁ Á ÁClÁ Á ÁH-N bridging extensions give rise to zigzag chains extending along the a axis, the overall two-dimensional structure lying in the (110) plane.

Experimental
Data collection: CrysAlis PRO (Agilent, 2011); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2. Galaxamide , obtained by deprotecting the amino and carboxyl groups of the intermediate (Rodriguez et al., 2007). The purpose was to explore the activity targets of the intermediates in relation to those of the target compound (Liao et al., 2007. In the crystal structure of the title compound, there are a number of intermolecular hydrogen-bonding interactions (Table 1), including aminium N-H···Cl, amide N-H···O carboxyl , water O-H···Cl and carboxylic acid O-H···O water associations. The aminium N-H···Cl···H-N bridging extensions give zigzag chains extending along the a axis in the unit cell, the overall two-dimensional structure lying along (110) (Fig 2).

Experimental
Diisopropylethylamine (DIPEA) (6 mmol, 1.1 ml) was added dropwise to a stirred solution of L-leucine benzyl ester p-toluenesulfonate (6 mmol, 2.36 g) in anhydrous THF (8 ml) at 273 K under nitrogen and stirred for 15 min. The coupling reagent DEPBT (6 mmol, 1.8 g) was added to a stirred solution of N-Boc-Me-L-Leu-OH (5 mmol, 1.30 g) in anhydrous THF (5 ml) at 273 K under nitrogen and the suspension was stirred for 15 min. A suspension of L-leucine benzyl ester p-toluenesulfonate was added by cannula to the N-Boc-Me-L-Leu-OH suspension at 273 K under nitrogen and the mixture was allowed to warm to room temperature over the course of 24 h, then evaporated in vacuo. The crude product was then purified by chromatography on silica using n-hexane/acetone (20:1) as eluent to give the dipeptide as colorless crystals (yield 2.1g: 92.5%). This dipeptide (4 mmol, 1.8 g) was dissolved in CH 2 Cl 2 (7 ml) and 2 ml of TFA was added dropwise at 273 K under nitrogen using a constant pressure funnel. The mixture was stirred at 273 K until the starting material disappeared (monitored by TLC). The solution was concentrated in vacuo, the residue was dissolved in CH 2 Cl 2 2 and concentrated again to remove the Boc dipeptide derivative which was dried in vacuo. This Boc derivative (3 mmol, 1.91 g) was reduced with hydrogen (0.1 Mpa) and 10% Pd-C (0.62 g) in ethyl acetate (40 ml) until the starting material disappeared (monitored using TLC). The Pd-C was filtered, and the filtrate was concentrated in vacuo to obtain the title compound (yield 1.85 g: 97%). Colourless crystals suitable for X-ray analysis grew over a period of a week from a solution in methanol containing a small amount of dilute HCl, when exposed to air.

Refinement
The C-bound and O-bound H atoms were positioned geometrically and were included in the refinement in the riding-model approximation, with distances 0.96 Å (CH 3 ), 0.97 Å (CH 2 ), 0.98 (CH), or 0.85 Å (OH) and U iso (H) = 1.2U eq (C, O) for methine, methylene, hydroxyl and carboxyl H atoms, and U iso = 1.5U eq (C) for methyl H atoms. The N H-atoms were located in a difference-Fourier synthesis and then refined as riding on the N atoms with U iso (H) = 1.2U eq (N). The known S absolute configuration for L-leucine [(S)-2-amino-4-methylvaleric acid] was invoked for both chiral centres in the title molecule (C1S,C3S). Fig. 1. The molecular structure of the title compound showing the atom numbering scheme.

Figures
Inter-species hydrogen bonds are shown as dashed lines and displacement ellipsoids are drawn at the 50% probability level.

Special details
Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell esds are taken into account in the estimation of distances, angles and torsion angles Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.