Fluorination diastereoselectivity

The key step to this first reported case of the highly diastereoselective addition of a fluorinated enolate in an aldol process is the selective formation of the enolate a,a-Difluonnated enolates prepared by a metallation process employing either a zinc-copper couple [S] or reduced titanium species [9] undergo aldol condensation smoothly (equation 9) (Table 5)... 

Ketene acetals prepared from fluorinated esters by trimethylsilylation undergo Lewis acid-promoted aldol condensations giving satisfactory yields but low diastereoselectivity [27] (equation 22). 

It was shown (801) that the diastereoselectivity of a-fluoroalkyl nitrones is reversed to that of the corresponding a-alkyl nitrones. This fact supports the conclusion that the conformation, due to the relief of the dipole repulsion between the fluorine atom and the oxygen atom of the nitrone is preferred in a-fluoroalkyl nitrones. 

Hydroxypiperidine alkaloids have been synthesized via anodic methoxylation that allowed the regio- and stereoselective introduction of substituents [213]. A highly diastereoselective fluorination was achieved with chiral l,3-oxathiolan-5-ones derived from camphorsulfonamide. In dimethoxyethane containing Et4NF-4HF, the monofluorinated product (9) was obtained as a single diastereomer [214]. 

M. Essers, C. Muck-Lichtenfeld, G. Flaufe, Diastereoselective diels-alder reactions of a-Fluorinated a, -unsaturated carbonyl compounds Chemical consequences of fluorine substitution, J. Crg. Chem. 67 (2002) 4715-4721. 

The fluorination of enolates of ketone, amide, or hydrazone bearing a chiral auxiliary (SAMP, Evans oxazolidine) with nonchiral fluorination reagent (A-fluoro sulfonimides, A-fluoropyridine) occurs with excellent diastereoselectivities. ... 

Syntheses of amido- and peptido-fluoroketones have been reviewed (Figure 7.46). The main problems concern enantio- and diastereoselectivity, and also the oxidation step of a fluorinated amino alcohol, which is generally required. Indeed, the peptidic couplings required for the edification of parts Pi, P2, etc. cannot be... 

The biotransformation of organofluorine materials into optically active functionalized fluo-rinated materials along with a discussion on the effect of fluorine atom(s) during enantio-selective and/or diastereoselective transformations is described. The ability of microorganisms to discriminate between enantiomers is particularly important regarding resolution and asymmetric synthesis. Furthermore, the use of chiral fluorinated materials in the design and preparation of new types of biologically active materials is discussed. 

Chiral fluorinated allylic alcohols obtained by enzymatic resolution (Table 5, Runs 13 and 14) were employed in diastereoselective cyclopropanation using the carbenoid from samarium and di-iodomethane [32]. This reaction proceeded smoothly at -78 °C to 0 °C, but not as smoothly as the case of non-fluorinated allylic alcohols at -78 °C. 

Diastereoselective fluorination of the benzylic position has also been studied by these same workers [30]. 

Electron-withdrawing fluorine atoms are introduced on the methylenic a-carbon by the Reformatsky reaction of Boc-leucinal with ethyl bromodifluoroacetate in the presence of activated zinc dust with no diastereoselection. Under thermodynamic control, the y -isomer is obtained almost exclusively (Scheme 16)J15 The use of additives such as diethylaluminium chloride-silver(II) acetate enhances the chemical yield of the reaction, but also presents the disadvantage of being nonstereoselectiveJ78 ... 

The Pummerer rearrangement has also been used to transform the 4-tolylsulfinyl group, which is an effective chiral auxiliary, into other functionalities via the aldehyde. Thus, chiral /> -(ben-7yloxy)-/J-(fluoroalkyl) sulfoxides 11 have been transformed into aldehydes 12 in a two-step process.7,8 The 3,3-difluoro-substituted aldehydes 12 can be converted directly into a variety of other functional groups without isolation. The chiral center at C2 is derived from the corresponding chiral / -oxo sulfoxide, which can be reduced diastereoselectively due to the presence of the chiral 4-tolylsulfinyl group.7,8 Diastereoselective reduction of fluorine-free fi-oxo sulfoxides has been intensively studied, especially in the laboratories of Solladie.9... 

The same sequence of diastereoselective reduction of a /i-oxo-y-fluoro sulfoxide followed by Pummerer rearrangement and hydrolysis to the aldehyde has been used successfully in the synthesis of fluorine-containing carbohydrates.10... 

A wide range of fluorinated compounds are applied as pharmaceuticals and agrochemicals. Several stereoselective methods are used for synthesis of optically active molecules bearing a C-F bond at the stereogenic carbon atom [72, 73]. These are mainly based on diastereoselective fluorination of chiral molecules or enantioselective alkylation of fluoroorganic compounds. Asymmetric introduction of a fluorine... 

At about the same time of the work on diastereoselective fluorination, chiral non-racemic N-fluoro compounds for direct enantioselective fluorination of C H acidic substrates were developed. 

Enders D, Faure S, Potthoff M, Runsink J (2001) Diastereoselective electrophilic fluorination of enantiopure a-silylketones using N-fluoro-benzosulfoni-mide regio- and enantioselective synthesis of a-fluoroketones. Synthesis 2001 2307-2319... 

In contrast, fluorinated ketones have been used as both nucleophilic and electrophilic reaction constituents. The lithium (Z)-enolate of l-fluoro-3,3-dimethylbutan-2-one can be selectively prepared and undergoes highly diastereoselective aldol condensation with aldehydes to give products 17. ... 

The acetoxy group was hydrolyzed using hydrazine to give (46). Nucleophilic substitution of the fluorine atom produced the tricyclic /3 lactam (47). A diastereoselective aza-Diels-Alder reaction was used in a synthesis of (-)-lasubine (I). Tin tetrachloride mediated reaction of complex (48) with Danishefsky s diene afford 2,3-dihydro-4-pyridone (49) as a single diastereomer (Scheme 86). Chiral benzaldehyde imines can be aUylated with high diastereoselectivity to give optically active homoaUyhc amines (Scheme 87). 

Diastereoselective anodic fluorination of phenylacetate having a chiral auxiliary has also been reported [Eq. (6)] [32]. 

The diastereoselective anodic fluorination of a-phenylsulfenyl acetates has been studied using various chiral auxiliaries [Eq. (15)] [49]. The diastereoselectivity is affected by supporting fluoride salts, and Et4NF-3HF leads to better selectivity relative to Et3N-3HF or Et3N-2HF. 

---