Expanding organofluorine chemical space: the design of chiral fluorinated isosteres enabled by I(i)/I(iii) catalysis

Abstract

Short aliphatic groups are prevalent in bioactive small molecules and play an essential role in regulating physicochemistry and molecular recognition phenomena. Delineating their biological origins and significance have resulted in...

Effect of gem‐Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes

“…[8][9][10][11][12] It would not be exaggerating to say that most current medicinal chemistry projects involve manipulations with fluorine atoms or fluorinated substituents to finetune the key parameters of the molecule of interest. [12][13][14][15][16] Typically, the introduction of fluorine-containing moieties has been aimed at optimization of physicochemical properties and metabolism. [12,13,17] Recently, opportunities provided by weak interactions improving binding to biological targets have also received much attention.…”

“…The outstanding role of fluorine in drug discovery is difficult to overestimate [8–12] . It would not be exaggerating to say that most current medicinal chemistry projects involve manipulations with fluorine atoms or fluorinated substituents to fine‐tune the key parameters of the molecule of interest [12–16] . Typically, the introduction of fluorine‐containing moieties has been aimed at optimization of physicochemical properties and metabolism [12,13,17] .…”

Carbodefluorination of fluoroalkyl ketones via a carbene-initiated rearrangement strategy

“…Compounds 86 and 127 were readily reduced to alcohols in the presence of NaBH 4 , which enabled monofluorination of products 200 and 205 with DAST to afford the trifluoroalkylated products 201 and 206 in high yield. These conversions enable the synthesis of products with tuneable multivicinal fluorination 77 – 79 . This platform is attractive for the site-specific introduction of fluorine in aliphatic chains.…”

Catalytic alkene skeletal modification for the construction of fluorinated tertiary stereocenters

“…The latter results highlight an added-value of our methodology in accessing an interesting and useful subset of organofluorine compounds increasingly observed in newly approved drug molecules. 24 Phenyl or alkyne groups did not provide the expected branched fluorides, and instead, the corresponding linear derivatives were obtained ( 3z , aa ). These results indicate that these substituents may provoke a delocalization of the charge in the allylic π system; however, we do not have a clear explanation for the excellent linear selectivity observed.…”