Diastereoselective Mannich Reactions Using Fluorinated Ketones: Synthesis of Stereogenic Carbon–Fluorine Units

Abstract

A diastereoselective Mannich reaction of simple α-fluoro ketones with N-tert-butylsulfinylimines was developed. This method provides a concise route to a variety of structurally diverse α-fluoro-β-amino ketones containing fluorinated stereogenic carbon centers; good yields and high diastereoselectivities were achieved. This method uses readily accessible starting materials and has a broad substrate scope: cyclic and linear α-fluoro ketones and fluoromethyl ketones are all suitable substrates.

Modern Approaches for Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

“…Comparing with the reactions on α-fluoro esters, , this reaction used NaHDMS as a strong base and ether as asolvent (Scheme ). Cyclic α-fluoro ketones could react with a wide range of sulfinylimines bearing varieties of substituents, including aryl, alkyl, and vinyl groups. Also, obviously improved diastereoselectivities were obtained, and usually two diastereomers were detected for most cases.…”

Kitamura Electrophilic Fluorination Using HF as a Source of Fluorine

“…Synthesis of fluorinated derivatives of monocarbonyl compounds, such as ketones and aldehydes, are of high importance in fluoro-organic chemistry [110][111][112][113][114][115][116][117][118][119][120][121]. These types of fluorinated derivatives are of proven synthetic value as building blocks for the preparation of a variety of polyfunctional fluorine-containing compounds of biological interest [30,[122][123][124][125][126][127][128].…”

N-[(1R,2S)-1-(4-Bromophenyl)-2-fluoro-3-(2-methylphenyl)-3-oxopropyl]-4-nitrobenzamide

“…The introduction of fluorine into a bioactive molecule often improves the binding affinity, metabolic stability, and bioavailability (Purser et al, 2008). In this context, the -fluoroamine motif is an important structural motif and has been found in a number of drug candidates (Murray et al, 2003;Li et al, 2016). It is generally believed that a -fluoro substitution lowers the pK a value of the neighboring amines, and can thus modulate many pharmacological properties (Morgenthaler et al, 2007).…”