Chiral Alkyl Halides: Underexplored Motifs in Medicine

Abstract

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.

Stereochemistry and biological activity of chlorinated lipids: a study of danicalipin A and selected diastereomers

“… 4 , 5 Halogenation is known to influence electronic properties, lipophilicity, and metabolic stability of bioactive molecules. 6 , 7 Additional subtle effects may be manifest in conformational preferences 8 especially in aliphatic systems as notably highlighted by Hoffmann, 8 b O'Hagan, 8 c and more recently by Gademann. 8 d We were interested in the question: Do configurational isomers 2 and 3 ( Fig.…”

Site Selective Chlorination of C(sp3)−H Bonds Suitable for Late‐Stage Functionalization

“…Derivatives of leucine (7) and a Leu-Glu dipeptide (8) also underwent chlorination at the tertiary C(sp 3 ) À H bond on the side-chain without epimerization of any of the stereocenters, indicating the potential utility of this method for the chlorination of leucine residues in polypeptides. Substrates containing a free carboxylic acid (9), a primary amide (10), a phthalimide-protected amine (11), and a cyclohexyl group (12), all underwent chlorination in excellent yields, further demonstrating the tolerance of this method for common functional groups. The reaction of dihydrocitronellyl acetate, which contains two sterically similar but electronically differentiated tertiary C(sp 3 )ÀH bonds formed the 7-and 3chlorinated products in a 4.0:1 mixture (only major isomer 13 shown).…”

“…[10] Interest in the development of C(sp 3 ) À H bond chlorination reactions has been driven by the high value of alkyl chlorides. C(sp 3 )ÀCl bonds are present in numerous natural products [11] and can imbue beneficial properties to biologically-active molecules, [12] such as increased lipophilicity, modulation of the electronic properties of nearby functional groups, and the prevention of metabolic oxidation at the site of chlorination (for some selected examples of biologically active molecules containing C(sp 3 )ÀCl bonds, see Scheme 1 C). Furthermore, alkyl chlorides can be used as a site for diversification by substitution at the C(sp 3 )ÀCl bond.…”

1H-NMR Determination of Organic Compounds in Municipal Wastewaters and the Receiving Surface Waters in Eastern Cape Province of South Africa

“…Brominated alkanes are water disinfectants [37], but reports show that some bromides (e.g., brominated trihalomethane) are environmental carcinogens [38]. Alkyl halides are common in industries for the production of refrigerants, propellants, fire retardants and drugs, from where they enter the environment [39]. Proton shifts of amino bonded alkanes were observed in wastewater and treated effluents samples while 1 H-NMR shifts of triethylamine at 2.5 ppm were restricted to wastewater samples.…”