Ethyl (3S)-3-[(3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[4,5-d][1,3]dioxol-5-yl]-3-{(3S)-3-[(3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[4,5-d][1,3]dioxol-5-yl]-5-oxoisoxazolidin-2-yl}propanoate chloroform monosolvate

The Flack and Watkin 2AD plot based on 1941 acentric Friedel pairs for the title chloroform solvate shows that the observed intensity differences for Friedel opposites are dominated by random and systematic errors, erasing information about resonant scattering.

The title compound, C 22 H 33 NO 12 ÁCHCl 3 , was obtained as a product of a double aza-Michael addition of hydroxylamine on a Chiron with a known absolute configuration. The enantiopure compound crystallized as a chloroform solvate, in space group P1, and diffraction data were collected at room temperature with Ag K radiation. The Flack parameter refined to x = À0.01 (16); however, the Flack and Watkin 2AD plot clearly shows that differences between Friedel opposites (the D component of the plot) do not carry any reliable information about resonant scattering of Cl atoms, and are rather dominated by random and systematic errors. The R D factor calculated using 1941 acentric Friedel pairs is R D = 0.995. On the other hand, the 2A component of the plot, related to average intensities of Friedel pairs, shows that data are of good quality (R A = 0.069). This example illustrates that while using Ag K radiation ( = 0.56083 Å ), scatterers heavier than Cl should be present in a chiral crystal in order to determine confidently the absolute structure of the crystal.

Structure description
The Chiron known as 7,3-LXF (7,3-lactone-xylofuranose derivative; Ramírez et al., 2017), derived from d-glucose, is a versatile starting material for the synthesis of natural products, for example the metabolites produced by Trichoderma spp and Penicillium data reports isolates (Pé rez-Bautista et al., 2016). In a work aimed at the synthesis of 1-deoxynojirimycin (DNJ), an azasugar alkaloid presenting -glucosidase inhibitor properties, the title compound was obtained (Amaro Herná ndez, 2019). The total synthesis of DNJ has been reported, for example starting from d-glucose (Khobare et al., 2016). However, the stereochemistry of 7,3-LXF matches the stereochemistry of the target molecule, and 7,3-LXF is thus considered to be an ideal Chiron for the synthesis of DNJ. Moreover, we developed an efficient procedure for the preparation of 7,3-LXF at the gram scale.
The title compound was obtained while attempting an aza-Michael addition of hydroxylamine to 7,3-LXF, at pH 7. Under our experimental conditions, a double aza-Michael addition was observed, followed by a transesterification in ethanol, affording a disubstituted isoxazolidinone, which was characterized by X-ray diffraction. This compound is also closely related to other isoxazolidinone derivatives obtained through an Amadori rearrangement, which were studied for their potential antioxidant properties, and their application as flood flavouring agents (Hodge, 1955;Mills & Hodge, 1976;Mills, 1979).
The enantiopure molecule was crystallized as a chloroform solvate, in space group P1 (Fig. 1). The core isoxazolidinone ring has the expected envelope conformation, with C5 as the flap. The ring is, however, close to being flat, with a puckering parameter q 2 = 0.190 (5) Å . The ring is substituted at C5 and N1 by the bicyclic groups provided by the Chiron. The absolute configuration at C5 is imposed as 5S, while the stereochemistry at N1 is not imposed by the Michael addition.
Substituents at C5 and N1 are thus arranged trans with respect to the isoxazolidinone plane, avoiding in this way any steric hindrance. In the crystal structure, only weak intermolecular O-HÁ Á ÁO hydrogen bonds are formed, involving hydroxy groups O10 and O19 (Table 1). The chloroform lattice molecule does not interact with the organic molecule.
For this Cl-containing crystal, intensities were collected at room temperature using Ag K radiation. With such an experimental setup, the refined Flack (1983) parameter converges to x = À0.01 (16) for the correct absolute structure, and x = 0.85 (16) for the inverted structure, giving the false impression that chlorine anomalous dispersion allows the reliable determination of the absolute configuration for the molecule. Similar metrics are obtained using the Parsons intensity quotients method (Parsons et al., 2013), or by refining the structure as an inversion twin (Sheldrick, 2015b). However, the 2AD graphs devised by David Watkin and Howard Flack are a valuable tool for estimating whether real information about resonant scattering is present in the measured intensities (Flack et al., 2011;Parsons et al., 2012). The average (A) and difference (D) intensities for Friedel opposites are defined by A(h) = 1 2 [|F(h)| 2 + |F(Àh)| 2 ] and D(h) = |F(h)| 2 À |F(Àh)| 2 . In a 2AD graph, D obs against D model of the acentric reflections is plotted, as well as 2A obs against 2A model for weak reflections. For the 2A plot, a distribution of points spread around a straight line of slope 1 passing through the origin indicates that diffraction data are of good quality, Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) x þ 1; y; z; (ii) x; y þ 1; z.

Figure 2
2AD plot for 1941 acentric Friedel pairs retrieved from the SHELXL fcf file for the last refinement cycle of the title compound (Sheldrick, 2015b

Figure 1
Structure of the title compound, with displacement ellipsoids for non-H atoms at the 30% probability level. For the disordered ethyl group in the ester functionality, only one disordered position is retained [A site, with occupancy of 0.58 (5)]. and this is indeed the case for the title compound (Fig. 2). The D plot is much more instructive regarding the accuracy of data for measuring anomalous dispersion: the greater the slope of this distribution deviates from 1, the more the effects of anomalous dispersion are overwhelmed by random uncertainty and systematic errors. This is clearly the case for the title compound, despite the presence of three Cl atoms in the asymmetric unit: for the D distribution, all data points are placed close to D model = 0 on the D obs axis, as is the case for any centrosymmetric structure (Fig. 2). Classical R unweighted factors can also be computed for A and D, which reflect the deviation from the unity-slope distribution: where the summations are over paired acentric reflections h and Àh (note that in space group P1, all reflections are acentric, and that R A is then conceptually close to R int ). For the title compound, R A = 0.069 and R D = 0.995. The large R D factor is obviously in line with the large standard uncertainty of the refined Flack parameter, u(x) = 0.16. In the crystal studied here, undue reliance should not be placed on the Flack parameter, and the absolute configuration of the molecule should instead be assigned by relying on the chemistry. In conclusion, we have shown that a CHCl 3 molecule is certainly not sufficient for determining the absolute structure of a chiral crystal if Ag K radiation is used for collecting intensities. On a broader front, it is worth reminding that the standard uncertainty in the Flack parameter, u(x), is the key to its correct interpretation (Flack & Bernardinelli, 2000;Thompson & Watkin, 2009). The use of 2AD plots is thus strongly advised for the validation of absolute-structure determinations (Flack, 2012), together with Flack x and Hooft y parameters. Unfortunately, these plots are not yet used on a routine basis in chemical crystallography.

Synthesis and crystallization
A solution of NH 2 OHÁHCl (85 mg, 0.025 mmol) in water (1 ml) was neutralized with a solution of NaHCO 3 (pH 7). After 10 min., a solution of 7,3-LXF (50 mg, 0.23 mmol) in ethanol (3 ml) was added over 30 s. and the mixture was left under stirring at room temperature. The reaction was complete after one h. The mixture was filtered over celite/ Na 2 SO 4 , and the filtrate was reduced to give yellow solids, which were purified by column chromatography (hexane:ethyl acetate, 1:1), to afford 95 mg of the title compound (yield: 80%). Colourless single crystals were obtained by slow evaporation of a MeOH/CHCl 3 solution.