Molecular design strategies that profit from the intrinsic stereoelectronic and electrostatic effects of fluorinated organic molecules have mainly been restricted to bio-organic chemistry. Indeed, many fluorine conformational effects remain academic curiosities with no immediate application. However, the renaissance of organocatalysis offers the possibility to exploit many of these well-described phenomena for molecular preorganization. In this minireview, we highlight examples of catalyst refinement by introduction of an aliphatic C-F bond which functions as a chemically inert steering group for conformational control.
The cycloaddition of aromatic azomethine imines to 1,1-cyclopropane diesters was achieved using Ni(ClO4)2 as catalyst. The methodology gives access to unique tricyclic dihydroquinoline derivatives with dr up to 6.6:1. A nonconcerted mechanism is proposed on the basis of stereochemical analysis of the reaction.
A critical requirement toward the clinical use of nanocarriers in drug delivery applications is the development of optimal biointerfacial engineering procedures designed to resist biologically nonspecific adsorption events. Minimization of opsonization increases blood residence time and improves the ability to target solid tumors. We report the electrostatic self-assembly of polyethyleneimine-polyethylene glycol (PEI-PEG) copolymers onto porous silica nanoparticles. PEI-PEG copolymers were synthesized and their adsorption by self-assembly onto silica surfaces were investigated to achieve a better understanding of structure-activity relationships. Quartz-crystal microbalance (QCM) study confirmed the rapid and stable adsorption of the copolymers onto silica-coated QCM sensors driven by strong electrostatic interactions. XPS and FT-IR spectroscopy were used to analyze the coated surfaces, which indicated the presence of dense PEG layers on the silica nanoparticles. Dynamic light scattering was used to optimize the coating procedure. Monodisperse dispersions of the PEGylated nanoparticles were obtained in high yields and the thin PEG layers provided excellent colloidal stability. In vitro protein adsorption tests using 5% serum demonstrated the ability of the self-assembled copolymer layers to resist biologically nonspecific fouling and to prevent aggregation of the nanoparticles in physiological environments. These results demonstrate that the electrostatic self-assembly of PEG copolymers onto silica nanoparticles used as drug nanocarriers is a robust and efficient procedure, providing excellent control of their biointerfacial properties.
Herein, we report the enantio- and diastereoselective formation of trans-iodo- and trans-chlorocyclopropanes from α-iodo- and α-chlorozinc carbenoids by using a dioxaborolane-derived chiral ligand. The synthetically useful iodocyclopropane building blocks were derivatized by an electrophilic trapping of the corresponding cyclopropyl lithium species or a Negishi coupling to give access to a variety of enantioenriched 1,2,3-substituted cyclopropanes. The synthetic utility of this method was demonstrated by the formal synthesis of an HIV-1 protease inhibitor. In addition, the related stereoselective bromocyclopropanation was also investigated. New insights about the relative electrophilicity of haloiodomethylzinc carbenoids are also presented.
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