apo-Milbemycin A3 oxime

Milbemycin oxime (MO) drug substance is a 16-membered macrocyclic lactone that exhibits a broad spectrum of biological activity and high potency towards parasites. In this study, a comprehensive forced degradation study was carried out on MO drug substance to identify and characterize its major degradation products (DPs). MO drug substance was subjected to acid, base, oxidation (H2O2), heat (solid and solution state), and photolytic (solid and solution state) stress degradation as per the ICH guidelines. Chromatographic separation of the drug substance (MO A3 and MO A4) and its DPs was achieved using a gradient elution on a HALO C18 column (100 × 4.6 mm, 2.7 µm). Mobile phase A consisted of water/acetonitrile (60/40, v/v) and mobile phase B consisted of ethanol/isopropanol (50/50, v/v). A total of twelve major DPs were observed for MO drug substance under various stress conditions. These DPs were further identified and characterized using liquid chromatography-high resolution mass spectrometry and comparison of their fragmentation profile with MO A4 and MO A3 using tandem mass spectrometry. Of these, H2O2 induced oxidative degradation product (3,4-dihydroperoxide MO A4) was isolated using semi-preparative HPLC and characterized by comparison of its nuclear magnetic resonance spectroscopy data with MO A4. The proposed structures of the DPs have been rationalized by appropriate degradation pathways for MO A4 and MO A3.

We describe here an enantioselective synthesis of (+)-EBC-23, a potent anticancer agent from the Australian rainforest. Our convergent synthesis features a [3+2] dipolar cycloaddition of an olefin-bearing 1,3-syn diol unit and an oxime segment containing 1,2-syn diol functionality as the key step. The segments were synthesized in a highly enantioselective manner using Noyori asymmetric hydrogenation of a β-keto ester and Sharpless asymmetric dihydroxylation of an α,β-unsaturated ester. Cycloaddition provided isoxazoline derivative which upon hydrogenolysis furnished the β-hydroxy ketone expediently. A one-pot, acid-catalyzed reaction removed the isopropylidene group, promoted spirocyclization, constructed the complex spiroketal lactone core, and furnished EBC-23 and its C11 epimer. The C11 epimer was also converted to EBC-23 by chemoselective oxidation and reduction sequence. The present synthesis provides convenient access to this family of natural products in an efficient manner.

The synthesis and crystal structure for the title compound, hexa-aqua-hexa-kis(μ-2-hy-droxy-benzene-carbo-hydrox-a-mato)bis-(2-hy-droxy-benzene-carbo-hydrox-a-m-ato)tetra-indium(III) tetra-nitrate 8.57-hydrate + unknown solvent, [In4(H2shi)8(H2O)6](NO3)4·8.57H2O·solvent, where H2shi- is salicylhydrox-imate (C7H5NO3), are reported. The complex cation of the structure, [In4(H2shi)8(H2O)6]4+, is a dimer with a step-like topology and possesses an inversion center that relates each [In2(H2shi)4(H2O)3]2+ side of the complex cation. Each InIII ion is seven-coordinate with a penta-gonal-bipyramidal geometry, and the salicyl-hydroximate ligands have a 1- charge as only the oxime oxygen of the ligand is deprotonated. Four inter-stitial nitrate anions maintain the charge balance of the compound. One of the nitrate anions (and its symmetry equivalent) is disordered over two different orientations with an occupancy ratio of 0.557 (7) to 0.443 (7). The inter-stitial solvent water mol-ecules show substantial disorder. Approximately 8.57 water mol-ecules per formula unit were refined as disordered and partially occupied, while a suitable model could not be devised for the other extensively disordered solvent mol-ecules (water and possibly methanol as this was the synthesis solvent). Thus, these latter solvent mol-ecules were instead treated with the SQUEEZE routine [Spek (2015). Acta Cryst. C71, 9-18.] as implemented in the program PLATON, and the procedure corrected for 151 electrons within solvent-accessible voids of 367 Å3.