Rigid and concave, 2,4-cis-substituted azetidine derivatives: A platform for asymmetric catalysis

A series of single enantiomer, 2,4-<i>cis</i>-disubstituted amino azetidines were synthesised and used as ligands for copper-catalysed Henry reactions of aldehydes with nitromethane. Optimisation of ligand substituents and the reaction conditions was conducted. The enantiomeric excess of the formed products was highest when alkyl aldehydes were employed in the reaction (>99% e.e.). The absolute stereochemistry of one representative azetidine derivative salt was determined by analysis of the Flack parameter of an XRD single crystal structure. The origin of selectivity in catalysis was investigated computationally, revealing the importance of the amino-substituent in determining the stereochemical outcome. A racemic platinum complex of a <i>cis</i>-disubstituted azetidine is examined by XRD single crystal structure analysis with reference to its steric parameters, and analogies to the computationally determined copper complex catalyst are drawn.<br

Palladium and platinum 2,4-cis-amino azetidine and related complexes

Crystal structures and structural interpretation of complexes of azetidine (and related) ligands coordinated to palladium(II) and platinum(II)

Data_Sheet_2_Palladium and Platinum 2,4-cis-amino Azetidine and Related Complexes.ZIP

<p>Seven N,N'-palladium(II) chloride complexes, one N,N'-palladium(II) acetate complex of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Two platinum(II) chloride N,N'-complexes of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Computational analysis and determination of the %Vbur was examined conducted. A CNN' metallocyclic complex was prepared by oxidative addition of palladium(0) to an ortho bromo 2,4-cis-disubstituted azetidine and its crystal structure displays a slightly pyramidalized metal-ligand orientation.</p

Data_Sheet_3_Palladium and Platinum 2,4-cis-amino Azetidine and Related Complexes.ZIP

<p>Seven N,N'-palladium(II) chloride complexes, one N,N'-palladium(II) acetate complex of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Two platinum(II) chloride N,N'-complexes of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Computational analysis and determination of the %Vbur was examined conducted. A CNN' metallocyclic complex was prepared by oxidative addition of palladium(0) to an ortho bromo 2,4-cis-disubstituted azetidine and its crystal structure displays a slightly pyramidalized metal-ligand orientation.</p

Data_Sheet_1_Palladium and Platinum 2,4-cis-amino Azetidine and Related Complexes.PDF

<p>Seven N,N'-palladium(II) chloride complexes, one N,N'-palladium(II) acetate complex of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Two platinum(II) chloride N,N'-complexes of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Computational analysis and determination of the %Vbur was examined conducted. A CNN' metallocyclic complex was prepared by oxidative addition of palladium(0) to an ortho bromo 2,4-cis-disubstituted azetidine and its crystal structure displays a slightly pyramidalized metal-ligand orientation.</p

Azetidines Kill Multidrug-Resistant <i>Mycobacterium tuberculosis</i> without Detectable Resistance by Blocking Mycolate Assembly

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies

Azetidines Kill Multidrug-Resistant <i>Mycobacterium tuberculosis</i> without Detectable Resistance by Blocking Mycolate Assembly

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies