Synthesis and characterization of 3-methyl-6-[(propynyloxy)methyl]-1,4-dioxane-2,5-dione

The synthesis of a new asymmetrically substituted hemilactide is reported and its structural analysis, including X-ray crystallographic data, is reported.

The number of known asymmetrically substituted hemilactides, important precursors for obtaining regular derivatives of polylactide polymers, is still limited and structural characterization of most of them is incomplete. In the title racemic 1,4-dioxane-2,5-dione derivative, C 9 H 10 O 5 , the hemilactide heterocycle exhibits a twist-boat conformation. The bulkier propynyloxymethyl group is in an axial position with a gauche conformation for the CH 2 -O-CH 2 -C segment. In the crystal, molecules are linked by pairs of C-HÁ Á ÁO hydrogen bonds, forming inversion dimers. The dimers are linked by further C-HÁ Á ÁO contacts, forming a three-dimensional structure.

Chemical context
Cyclic dilactides, or hemilactides, close structural analogs of 1,4-dioxane-2,5-dione (glycolide) with methyl-or methylenecontaining substituents at the sp 3 C atoms, are the most important precursors for obtaining polylactide polymers, which are widely employed in biodegradable plastics and in the food and biomedical industries due to their intrinsic biocompatibility and biodegradability (Gerhardt et al., 2006). Well-tuned architectures of substituted hemilactides lead to the creation of new polylactide materials with regular structures that allow clarification of polymer behaviour at the supramolecular level, as well as achieving new useful properties (Fuoco et al., 2016;Trimaille et al., 2007;Zhang & Song, 2014). Nevertheless, the further development of the field is hampered by the fact that asymmetrically substituted hemilactides still constitute a very limited group of compounds, the structural characterization of most of which remains incomplete. In this context, the goal of the present study was to elaborate a reliable protocol for obtaining 3-methyl-6-[(propynyloxy)methyl]-1,4-dioxane-2,5-dione, 1.

Structural commentary
The molecule of the final product ( Fig. 1) possesses a 1,4-dioxane-2,5-dione six-membered ring, as well as the two different substituents, i.e. methyl and propynyloxymethyl groups, linked to atoms C1 and C3, respectively, determining the aimed architecture of 1. In general, the bond lengths and angles are in normal ranges for organic carbohydrates. The hemilactide heterocycle exhibits a twisted boat conformation, where atoms C1, C2 and O1 are in one plane and atoms C1, C3, C4 and O2 are in another plane; the planes are inclined at a dihedral angle of 27.9 (2) . The values of the observed puckering parameters [ = 84.8 (3) and ' = 308.2 (3) ] deviate slightly from those corresponding to an ideal boat conformation ( = 90 and ' = 300 ). Two stereocentres represented by the C1 and C3 atoms have opposite chirality, i.e. R,S (and S,R in the centrosymmetric counterpart), the substituents at which adopt a trans configuration with respect to the ring, by minimizing repulsive interactions. The bulkier propynyloxymethyl group is located above the ring, i.e. in the axial position with a gauche conformation for the C6-O5-C7-C8 segment, at a dihedral angle of 71.3 (2) . A similar conformation has been observed in meso-3,6-dipropargyloxymethyl-1,4-dioxane-2,5dione (Zhang et al., 2015).

Figure 1
The atom-numbering diagram of the molecule of 1. C and O atoms are shown as displacement ellipsoids at the 50% probability level and H atoms are shown as spheres of arbitrary radius.

Synthesis and crystallization
The desired product 1 was obtained from the initial rac-1chloropropane-2,3-diol (2) via a three-step pathway (see Fig. 3) inspired partly by general protocols (Bredikhina et al., 2014;Trimaille et al., 2004;Nagase et al., 2008), comprising the oxidation of 2 to rac-3-chloro-2-hydroxypropanoic acid (3) followed by the etherification with propargyl alcohol to 2-hydroxy-1-(propynyloxymethyl)propanoic acid (4) and the final double esterification of 4 with bromopropyonyl bromide. The final purification of 1 was performed by auto-flash-chromatography on silica, using chloroform as eluent to give, after evaporation under reduced pressure, a white crystalline solid (see supporting information for more details on the synthesis and structural characterization of the intermediate and final products).

Special details
Experimental. X-ray crystallographic data for I were collected from a single crystal sample, which was mounted on a loop fiber. Data were collected using a Bruker Venture diffractometer equipped with a Photon 100 CMOS Detector, a Helios MX optics and a Kappa goniometer. The crystal-to-detector distance was 4.0 cm, and the data collection was carried out in 1024 x 1024 pixel mode. 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.