Enantioselective fluorinations

Catalytic enantioselective fluorination has recently emerged. Both organocatalysis and metal catalysis have been successfully developed. Chiral N-F reagents have been prepared or formed in situ starting form a chiral amine derivative and a classical N-F reagent vide supra)P These reagents allow the enantioselective fluorination of... 

Oppolzefs chiral auxiliary,6 (-)-2,10-camphorsultam, is useful in the asymmetric Diels-Alder reaction,3 4 and for the preparation of enantiomerically pure p-substituted carboxylic acids7 and diols,8 in the stereoselective synthesis of A2-isoxazolines,9 and in the preparation of N-fluoro (-)-2,10-camphorsultam, an enantioselective fluorinating reagent.10... 

In addition to the synthesis of enantiomerically pure (camphorylsulfonyl)oxaziridine7 and its derivatives,8 the (camphorsulfonyl)imine has been used in the preparation of (-)-2,10-camphorsultam (Oppolzers auxiliary),6-9 (+)-(3-oxocamphorysulfonyl)oxaziridine10 and the N-fluoro-2,10-camphorsultam, an enantioselective fluorinating reagent.11... 

An enantioselective fluorination method with catalytic potential has not been realized until recently, when Takeuchi and Shibata and co-workers and the Cahard group independently demonstrated that asymmetric organocatalysis might be a suitable tool for catalytic enantioselective construction of C-F bonds [78-80]. This agent-controlled enantioselective fluorination concept, which requires the use of silyl enol ethers, 63, or active esters, e.g. 65, as starting material, is shown in Scheme 3.25. Cinchona alkaloids were found to be useful, re-usable organocata-lysts, although stoichiometric amounts were required. 

This method is also useful for enantioselective fluorination of alkyl esters of type 65 (Scheme 3.27, Eq. 1) [78, 79]. The resulting fluoro-organic products 66 are use-... 

Catalytic enantioselective fluorination using chiral Pd complexes (59) and (60) has been reported.166,167 This method has provided various fluorinated compounds, includ- ing /3-keto phosphonates, oxindoles, and phenylacetate derivatives, in a highly enantioselective manner (75-96% ee). 

Improving Enantioselective Fluorination Reactions Chiral N-Fluoro Ammonium Salts and Transition Metal Catalysts... 

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. 

Scheme 1. Substrate mediated dia- and enantioselective fluorination with an achiral quaternary N-F ammonium salt.

Scheme 2. Representative enantioselective fluorinations with chiral quaternary N-F ammonium salts. The absolute configuration of product 22 is unknown.

Scheme 3. Synthesis of fluorinated amino acids via enantioselective fluorination. The absolute configuration of the product is unknown.

To summarise, the development of novel enantioselective fluorination methods with the aid of either chiral N-fluoro ammonium salts or transition metal catalysts has established truely practical routes towards chiral fluorinated compounds. Despite the current mechanistic uncertaincies it appears that a door has been opened for exciting and promising further development of asymmetric (catalytic) fluorination reactions in the near future [31, 32]. 

Organocatalysis has led to the development of new methods for the asymmetric a-halogenation of carbonyl compounds leading to the formation of stereogenic C-X centers. Hence, details of direct enantioselective fluorination, chlorination, and bromination reactions will be presented in the following sections. 

Enantioselective fluorination. The N-fluoro sultams 1 and 2 are prepared from the imine available from ( + )-camphor-10-sulfonyl chloride. 

These are the first reagents known to effect enantioselective fluorination of enolates of carbonyl compounds. The highest enantioselectivity is observed in the reaction of (-)-l with a p-keto ester (equation I). 

Muniz K (2003) Improving enantioselective fluorination reactions chiral N-fluoro ammonium salts and transition metal catalysts. In Schmalz HG, Wirth T (eds) Organic synthesis highlights. Wiley-VCH, Weinheim... 

Enantioselective fluorination is commonly conducted with chiral agents such as quinine-based [N-F]+ compounds, and these have been successfully utilised in ionic liquids.115,161 Very good yields and selectivities have been obtained in the enantioselective fluorination of /Nkctoesters catalysed by the chiral palladium complex 57, see Scheme 9.2. l l Depending on the substrate employed, substantial acceleration of the reaction rate relative to that in ethanol was observed with yields and selectivities comparable to those obtained in water or ethanol. The reaction rate was found to depend on both the length of the alkyl substituent of the imidazolium cation as, well as on the type of anion present, whereas the selectivity was not affected by such variations. The products were extracted from the ionic liquid phase with diethyl ether, and in that manner catalytic activity was maintained for up to ten cycles. 

Scheme 9.2 Palladium-catalysed enantioselective fluorination of / -ketoesters...

Enantioselective fluorination reactions catalyzed by chiral palladium enolate complexes have been the subject of considerable research . For instance, the fluorination of acyclic /S-ketoester (88, equation 24) using Af-fluorobenzenesulfonimide (NFSI) gave product 89 in high yields and with excellent enantioselectivity (ee up to 94%) . This reaction can be carried out in environmentally benign alcoholic solvents and provides valuable synthetic building blocks that find applications in medicinal chemistry, chemical biology and material sciences. 

A variety of highly enantioselective chiral N-F fluorinating reagents derived from Cinchona alkaloids were developed for the direct enantioselective fluorination of C—H acidic substrates (for details, see Chapter 6). Simultaneously, metal-catalyzed... 

Table 4.8 Cinchona alkaloids and their derivatives promoted the enantioselective fluorination of 2-oxo-cyclopentanecarboxylic acid tert-butyl ester.

Scheme 2.93 Enantioselective electrophilic fluorination of silyl enol ethers by N-fluorodihydro-quinine 4-chlorobenzoate. The enantioselective fluorination reagent is generated in situ from F-TEDA-BF4 (Selectfluor) and dihydroquinine 4-chlorobenzoate [206].

Electrophilic substitution. Enantioselective fluorination by (PhS02)2NF is carried out with the aid of a Pd complex of 16A. ... 

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