This review deals with general and significant developments in the area of building block chemistry of lightly-fluorinated aliphatic compounds, that is, those that contain one, two, or three, fluorine atoms. For the purposes of the review, building blocks are small readily-available materials that already contain fluorine atoms. They are classified according to the number of carbon atoms supplied to the target molecule, rather than according to the number of fluorine atoms. Finally, certain fluorinated motifs which may be generated easily, and are then transformable in useful ways, are discussed.

Building Block Approaches to Aliphatic Organofluorine Compounds

Enantioselective aldol reactions with fluoroacetate would enable access to numerous fluorinated analogues of therapeutically important compounds but have been a long-standing unsolved challenge. Now, bioinspired fluoromalonic acid half thioesters (F-MAHTs) have been devised and allow for highly stereoselective reactions with aldehydes under mild organocatalytic conditions.

Enantioselective aldol reactions with masked fluoroacetates

Chlorodifluoromethyl ketones CF2ClCOR, where R is an alkyl, aryl, and 1-alkynyl group, underwent the Reformatsky-type aldol reaction with a wide variety of aldehydes or ketones in the presence of acid-washed zinc dust and copper(I) chloride or silver acetate to give the corresponding α,α-difluoro-β-hydroxy ketones in good to excellent yields. Specific activation of zinc metal with the metal salt is essential to achieve high efficiency of the reaction, depending upon the structures of the chlorodifluoromethyl ketones and the carbonyl compounds employed. In-situ formed intermediates in these reactions were successfully detected by 19F NMR spectroscopy, which suggests that their structure is not an α-metallo ketone but an oxygen-metallated species possessing the zinc(II) metal as counter cation.

An efficient and general method for the Reformatsky-type reaction of chlorodifluoromethyl ketones with carbonyl compounds giving α,α-difluoro-β-hydroxy ketones

Regio- and stereoselective synthesis of vicinal fluorohydrins

The synthesis of carbohydrate derivatives from acyclic precursors

The ester enolate Claisen rearrangement of allyl α-fluoroacetates 1 forms 2-fluoroalkenoic acids 2 in good to excellent yield with good internal asymmetric induction. This selectivity was unexpected as stereoselective deprotonation of fluoroacetates is not normally possible. The selective formation of the required α-fluoro silyl ketene acetal 3 was found to result from the stereoselective rearrangement of the allyl α-fluoro-α-silylacetate isomer. Although silyl ketene acetals derived from α-fluoropropanoates 7 also rearranged, control of internal asymmetric induction was not possible

Ester enolate Claisen rearrangements of allyl .alpha.-fluoroacetates and .alpha.-fluoropropanoates

The Stereoselective Aldol Condensation of α-Fluoroacetates

2,6-Di-t-butyl-4-methylphenyl(BHT) and benzyl α-fluoroacetates were converted to their lithium enolates and were utilized in the aldol condensation. The improved diastereoselectivity found with the BHT esters is thought to arise from of equilibration of the aldol product rather than stereoselective enolate formation.

Janet S. Plummer

Papers

Ester enolate Claisen rearrangements of allyl .alpha.-fluoroacetates and .alpha.-fluoropropanoates

The Stereoselective Aldol Condensation of α-Fluoroacetates

The Stereoselective Aldol Condensation of α-Fluoroacetates.