While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation.
Herein we report that under mild solvolytic conditions, enantioenriched bromochlorides can be ionized, stereospecifically cyclized to an array of complex bromocyclic scaffolds, or intermolecularly trapped by exogenous nucleophiles. Mechanistic investigations support an ionic mechanism wherein the bromochloride serves as an enantioenriched bromonium surrogate. Several natural product-relevant motifs are accessed in enantioenriched form for the first time with high levels of stereocontrol, and this technology is applied to the scalable synthesis of a polycyclic brominated natural product. An array of nucleophiles including olefins, alkynes, heterocycles, and epoxides are competent traps in the bromonium-induced cyclizations, leading to the formation of enantioenriched mono-, bi-, and tricyclic products. This strategy is further amenable to intermolecular coupling between cinnamyl bromochlorides and a diverse set of commercially available nucleophiles. Collectively this work demonstrates that enantioenriched bromonium chlorides are confiugurationally stable under solvolytic conditions in the presence of a variety of functional groups.
Archaeal glycerol dibiphytanyl glycerol tetraethers (GDGT) are some of the most unusual membrane lipids identified in nature.T hese amphiphiles are the major constituents of the membranes of numerous Archaea, some of which are extremophilic organisms.D ue to their unique structures, there has been significant interest in studying both the biophysical properties and the biosynthesis of these molecules. However,these studies have thus far been hampered by limited access to chemically pure samples.Herein, we report aconcise and stereoselective synthesis of the archaealt etraether lipid parallel GDGT-0 and the synthesis and self-assembly of derivatives bearing different polar groups.
Archaeal glycerol dibiphytanyl glycerol tetraethers (GDGT) are some of the most unusual membrane lipids identified in nature.T hese amphiphiles are the major constituents of the membranes of numerous Archaea, some of which are extremophilic organisms.D ue to their unique structures, there has been significant interest in studying both the biophysical properties and the biosynthesis of these molecules. However,these studies have thus far been hampered by limited access to chemically pure samples.Herein, we report aconcise and stereoselective synthesis of the archaealt etraether lipid parallel GDGT-0 and the synthesis and self-assembly of derivatives bearing different polar groups.
Archaeal glycerol dibiphytanyl glycerol tetraethers (GDGT) are some of the most unusual membrane lipids identified in nature. These amphiphiles are the major constituents of the membranes of numerous <i>Archaea</i>, some of which are extremophilic organisms. Due to their unique structures, there has been significant interest in studying both the biophysical properties and the biosynthesis of these molecules. However, these studies have thus far been hampered by limited access to chemically pure samples. Herein, we report a concise and stereoselective synthesis of the archaeal tetraether lipid GDGT-0 and the synthesis and self-assembly of derivatives bearing different polar groups.
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