Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS

Selectively methylated analogues of naturally occurring 2-heptyl-4(1H)-quinolones, which are alkaloids common within the Rutaceae family and moreover are associated with quorum sensing and virulence of the human pathogen Pseudomonas aeruginosa, have been prepared. While the synthesis by direct methylation was successful for 3-unsubstituted 2-heptyl-4(1H)-quinolones, methylated derivatives of the Pseudomonas quinolone signal (PQS) were synthesized from 3-iodinated quinolones by methylation and iodine–metal exchange/oxidation. The two N- and O-methylated derivatives of the PQS showed strong quorum sensing activity comparable to that of PQS itself. Staphylococcus aureus, another pathogenic bacterium often co-occurring with P. aeruginosa especially in the lung of cystic fibrosis patients, was inhibited in planktonic growth and cellular respiration by the 4-O-methylated derivatives of HQNO and HHQ, respectively

Boron-Enabled Geometric Isomerization of Small Alkene Fragments via Selective Energy Transfer Catalysis

The mammalian visual cycle epitomizes the importance of complex polyenes in biology. However, isomerization-based strategies to enable the sterodivergent construction of these important biomolecules from geometrically defined alkene linchpins remain conspicuously underdeveloped. Mitigating the thermodynamic constraints inherent to isomerization is further frustrated by the considerations of atom efficiency in idealized low molecular precursors. Herein, we report a general ambiphilic C3 scaffold that can be isomerized and bi-directionally extended. Predicated on highly efficient triplet energy transfer, the selective isomerization of β-15 borylacrylates is contingent on the participation of the boron p-orbital in the substrate chromophore. Rotation of the C(sp2)-B bond by 90° in the product renders re-excitation inefficient and endows directionality. This subtle stereoelectronic gating mechanism enables the stereocontrolled syntheses of well-defined retinoic acid derivatives.<br /

Direct Observation of Triplet States in the Isomerization of Alkenylboronates by Energy Transfer Catalysis

Alkenylboronates are versatile building blocks for stereocontrolled synthesis owing to the traceless nature of the boron group that can be leveraged to achieve highly selective geometric isomerization. Using thioxanthone as an inexpensive photocatalyst, the photoisomerization of these species continues to provide an expansive platform for stereodivergent synthesis, particularly in the construction of bioactive polyenes. Although mechanistic investigations are consistent with light-driven energy transfer, direct experimental evidence remains conspicuously absent. Herein, we report a rigorous mechanistic investigation using two widely used alkenylboronates alongside relevant reference compounds. Through the combination of irradiation experiments, transient absorption spectroscopic studies, kinetic modeling, and DFT calculations with all isomers of the model compounds, it has been possible to unequivocally detect and characterize the perpendicular triplet generated by energy transfer. Our results serve not only as a blueprint for mechanistic studies that are challenging with organic sensitizers, but these guidelines delineated have also enabled the development of more sustainable reaction conditions: for the first time, efficient organocatalytic isomerization under sunlight irradiation has become feasible

A desilylative approach to alkyl substituted C(1)-ammonium enolates : application in enantioselective [2+2] cycloadditions

Funding: The research leading to these results has received funding from the CSC-St Andrews PhD Scholarship Scheme (Y.W.), the Newton Fellowship Programme (H.L.) and the Engineering and Physical Sciences Research Council, University of St Andrews, and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT) for financial support [Ph.D. studentship to W. H.; Grant code: EP/L016419/1].The catalytic generation of C(1)-ammonium enolates from the corresponding α-silyl-α-alkyl substituted carboxylic acids using the isothiourea HyperBTM is reported. This desilylative approach grants access to α-unsubstituted and α-alkyl substituted C(1)-ammonium enolates, which are typically difficult to access through traditional methods reliant upon deprotonation. The scope and limitations of this process is established in enantioselective [2+2]-cycloaddition processes with perfluoroalkylketones (31 examples, up to 96% yield and >99:1 er), as well as selective [2+2]-cycloaddition with trifluoromethyl enones (4 examples, up to 75% yield and >99:1 er). Preliminary mechanistic studies indicate this process proceeds through an initial kinetic resolution of an in situ prepared (±)-α-silyl-α-alkyl substituted anhydride, while the reaction process exhibits overall pseudo zero-order kinetics.Publisher PDFPeer reviewe