Planar chiral 5,11-disubstiuted dibenzo[a,e]cyclo-octatetraenes (dbCOTs) have been developed as the first useful chiral homologs to dbCOT-ligands for asymmetric applications. Methods enabling the preparation of such compounds on a gram-scale in enantiomerically pure form are described. Evaluated as ligands in rhodium(I)-catalyzed 1,4- and 1,2-arylation reactions, tertiary and quarternary stereogenic centers were formed with excellent yields and selectivities of up to >99 % ee. A catalytic asymmetric synthesis of a key cyclization precursor to (-)-penifulvin A highlights the system in an applied context.
Abstract4‐Amino‐4‐deoxy‐l‐arabinopyranose (Ara4N) residues have been linked to antibiotic resistance due to reduction of the negative charge in the lipid A and core regions of the bacterial lipopolysaccharide (LPS). To study the enzymatic transfer of Ara4N onto lipid A, which is catalysed by the ArnT transferase, we chemically synthesised a series of anomeric phosphodiester‐linked lipid Ara4N derivatives containing linear aliphatic chains as well as E‐ and Z‐configured monoterpene units. Coupling reactions were based on sugar‐derived H‐phosphonates, followed by oxidation and global deprotection. The enzymatic Ara4N transfer was performed in vitro with crude membranes from a deep‐rough mutant from Escherichia coli as acceptor. Product formation was detected by TLC and LC‐ESI‐QTOF mass spectrometry. Out of seven analogues tested, only the α‐neryl derivative was accepted by the Burkholderia cenocepacia ArnT protein, leading to substitution of the Kdo2‐lipid A acceptor and thus affording evidence that ArnT is an inverting glycosyl transferase that requires the Z‐configured double bond next to the anomeric phosphate moiety. This approach provides an easily accessible donor substrate for biochemical studies relating to modifications of bacterial LPS that modulate antibiotic resistance and immune recognition.
The chirality of 5,11‐disubstituted dibenzo[a,e]cyclooctatetraene ligands is represented by a two‐fold axis of symmetry in molecular monarch‐butterflies searching for flowers (metal centers). A flap of the butterfly wings will interconvert enantiomeric insects in the same way as dissymmetric cyclooctatetraenes racemize. The symmetry of the butterflies is broken both by the pattern of the wings and through a single antenna on each head. The latter represents the 5,11‐pattern of substitution that gives rise to exceptionally efficient asymmetric catalysis. More information can be found in the Communication by D. Strand et al. on page 2344.
The action of a membrane‐embedded lipid‐to‐lipid glycosyltransferase (ArnT) on a synthetic lipid‐shortened phosphodiester derivative of 4‐amino‐4‐deoxy‐L‐arabinose (Ara4N) forms a new phosphodiester linkage to the lipid A part of bacterial lipopolysaccharides. The substitution by Ara4N is a major mechanism contributing to the antimicrobial resistance of Gram‐negative bacteria. The Burkholderia cenocepacia enzyme shows exquisite specificity concerning the stereochemistry at the anomeric center and the double bond of the prenyl chain. Models have been generated with PyMOL (Schrödinger Software) from PDB entries 6DFE and 5EZM. More information can be found in the full paper by P. Kosma et al. on page 2936 in Issue 23, 2019 (DOI: 10.1002/cbic.201900349).
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