Synthesis of C-glycosyl phosphonate derivatives of 4-amino-4-deoxy-α-ʟ-arabinose.

The incorporation of basic substituents into the structurally conserved domains of cell wall lipopolysaccharides has been identified as a major mechanism contributing to antimicrobial resistance of Gram-negative pathogenic bacteria. Inhibition of the corresponding enzymatic steps, specifically the transfer of 4-amino-4-deoxy-ʟ-arabinose, would thus restore the activity of cationic antimicrobial peptides and several antimicrobial drugs. C-glycosidically-linked phospholipid derivatives of 4-amino-4-deoxy-ʟ-arabinose have been prepared as hydrolytically stable and chain-shortened analogues of the native undecaprenyl donor. The C-phosphonate unit was installed via a Wittig reaction of benzyl-protected 1,5-arabinonic acid lactone with the lithium salt of dimethyl methylphosphonate followed by an elimination step of the resulting hemiketal, leading to the corresponding exo- and endo-glycal derivatives. The ensuing selective monodemethylation and hydrogenolysis of the benzyl groups and reduction of the 4-azido group gave the α-ʟ-anomeric arabino- and ribo-configured methyl phosphonate esters. In addition, the monomethyl phosphonate glycal intermediates were converted into n-octyl derivatives followed by subsequent selective removal of the methyl phosphonate ester group and hydrogenation to give the octylphosphono derivatives. These intermediates will be of value for their future conversion into transition state analogues as well as for the introduction of various lipid extensions at the anomeric phosphonate moiety.

Elucidation of Photoisomerization-Related Structural Changes in an Acrylamide-Bridged Binaphthalene-Diazene Macrocyclic Chiroptical Switch by Experimental Electronic Circular Dichroism Spectra Simulation: Role of Dispersion Corrections.

Nondestructive readout of light-driven molecular memory devices can be achieved by monitoring the alterations in the chiroptical properties of 1,1'-binaphthalene as a conformationally responsive chiral group. In our system, this signaling unit is connected via acrylamide linkers to the receiving diphenyldiazene fragment, which undergoes significant geometrical changes upon (E)/(Z)-photoisomerization. The compound functions as a stable photochromic switch by alternating irradiation at 365/465 nm, with fully reversible modulation of circular dichroism (CD) signal intensity (up to 1:3) and extended thermal stability of the (Z)-isomer. According to molecular modeling, the acrylamide spacers are due to the imposed cyclic strain upon photoisomerization forced to switch amide conformations, which is markedly reflected in the CD spectra, whereas binaphthalene conformational changes are mostly neglected both by theory and by experiment. In CD simulation by TD-DFT, CAM-B3LYP outperforms B3LYP and M06 by means of similarity analysis, whereas the last mentioned functional also delivers satisfactory performance qualitatively. The inclusion of dispersion corrections during geometry optimization was crucial to retain consistency with the measured spectra. By carefully considering all relevant conformations of this 20-membered macrocycle, reasonable agreement with the experiment is reached not only for the CD simulation of the individual conformers but also of the photoisomerization process of their admixture.