Catalytic Asymmetric Fluorination Comes of Age

Abstract

asymmetric catalysis · electrophilic substitution · fluorinated substituents · fluorinationThe CÀF bond is a fundamental unit of organic chemistry, and its introduction into organic compounds has been widely deployed to optimize the properties of performance materials.[1] Important contemporary applications are in organic materials such as liquid crystals for display technologies, [2] the refinement of catalysts for asymmetric transformations, [3] as well as the important role of strategic fluorination for lead optimization in the pharmaceuticals sector.[4] Although fluorine is very often found on aromatic rings in, for example, pharmaceutical and agrochemical products, the enantioselective introduction of the C À F bond at a stereogenic center has emerged as a clear goal in organic chemistry ever since the first asymmetric fluorination reagents, N-fluorocamphorsultams 1 a, b, were reported by Differding and Lang [5] in 1988 (Scheme 1).There are obvious advantages in medicinal chemistry in replacing hydrogen with fluorine at metabolically vunerable carbon atoms and at enolizable centers in drugs, to lengthen in vivo half-lives. The quest for methods to mediate the introduction of the C À F bond with high enantioselectivity and with catalytic efficiency has been intense, and successes have been emerging rapidly as illustrated by related Highlights in 2006 [6,7] and in other recent reviews. [8][9][10] The major focus in asymmetric C À F bond formation has involved catalytic enolate/a-carbonyl fluorination of amides, b-cyano-, b-nitro-, and b-keto esters, as well as malonates. In 2005 there were a flurry of papers reporting the successful asymmetric fluorination of aldehydes using pyrrolidine or imidazolidinone organocatalysts in combination with electrophilic fluorinating reagents.[11] This progress has recently been reviewed in a Highlight.[6] Developments in asymmetric fluorination were slow for a decade after the discovery of the N-fluorosultams 1 a, b, [5] but subsequent progress has been rapid and impressive, particularly in using selectfluor (2) and N-fluorodibenzenesulfonimide (NFSI, 3) as electrophilic fluorine-transfer reagents for catalytic processes. The first efficient enantioselective fluorinations used reagents derived from cinchona alkaloid, which were independently discovered in 2000 in the laboratories of Cahard [12] and Shibata.[13] These protocols demonstrated high enantioselectivities (up to 91 % ee) but with stochiometric reagents. Catalytic fluorinations using selectfluor/NFSI as transfer reagents were demonstrated; however, they were not efficient.Asymmetric Lewis acid based catalysts also emerged in 2000.[13] Hintermann and Togni were the first to demonstrate such fluorination reactions, [14] using taddol-titanium complexes in combination with selectfluor to mediate the afluorination of b-keto esters. Such an approach has evolved to the present, in that chiral ligand-metal complexes have been discovered which can now mediate catalytic and highly enantioselective fluorination protocols. This ...

Ruthenium(II) complex catalysts bearing a pyridyl-supported pyrazolyl-imine ligand for transfer hydrogenation of ketones

“…Planar tridentate NNN ligands have recently been paid much attention due to their potential applications in homogeneous catalysis, organic synthesis, materials and physical chemistry [13][14][15]. However, examples of unsymmetrical planar tridentate NNN ligands and their transition metal complexes have only been scattered [16][17][18][19][20]. Recently, we found that phosphinefree unsymmetrical pyridyl-supported 2,6-(mixed N-heterocycles) ligands can demonstrate a dynamic ''on and off" chelating effect for the metal center during catalysis, and their transition metal complexes usually exhibit enhanced catalytic activity and selectivity [21][22][23][24][25][26].…”

Optimized synthesis of a pentafluoro- gem -diol and conversion to a CF2Br -glucopyranose through trifluoroacetate-release and halogenation

“…1,2 The incorporation of fluorine can improve the pharmacokinetic properties of lead molecules, as it is known to increase metabolic stability and lipophilicity. Although there are many methods to introduce fluorine 3 and trifluoromethyl groups, 4 there are substantially fewer strategies to install a difluoromethylene group. 5–7 The most common synthetic protocols for installing a difluoromethylene group are through the use of a difluoroenol 8 or a difluoroenolate.…”

A combination of directing groups and chiral anion phase-transfer catalysis for enantioselective fluorination of alkenes

“…Recently reported general methods for the enantioselective synthesis of allylic fluorides include the reaction of allylic chlorides with palladium catalysts (24,25) as well as the fluorination of allylsilanes using cinchona alkaloid catalysis (26,27). Furthermore, we envisioned that, upon removal of the amide directing group, this method would provide access to enantioenriched β-fluoroamines bearing a fluorinated quaternary center, a privileged bioactive motif and longstanding synthetic challenge (28)(29)(30)(31)(32)(33).…”