[Fluorine, an essential element for medicinal chemistry]. / Le fluor: un élément essentiel en chimie médicinale.

Because of the intrinsic properties of the fluorine atom, organic fluoride compounds have unique properties of particular importance in the pharmaceutical industry. The effect of fluorine is illustrated by selected examples of medicinal chemistry.

Fluoro artemisinins: difluoromethylene ketones.

The reactions of the ring-contracted aldehydes, derived from anhydrodihydroartemisinin, with gem-difluoroenoxysilanes in the presence of BF(3).Et(2)O afforded the corresponding difluoromethylene ketol adducts in good yields. Similar Lewis acid catalyzed reactions of dihydroartemisinin acetate with the difluoroenoxysilanes provided the 10-substituted difluoromethylene ketones in good to moderate yields. Interestingly enough, the course and the stereochemistry of these reactions are highly dependent on the nature of the Lewis acids used; the addition reaction was accompanied by epimerization at C-9, and the stereochemistry at C-10 depends on the difluoroenoxysilane used. The best results were obtained using SnCl(4) to give the 9alpha,10beta-stereoisomer in high stereoselectivity. When 0.4 equiv of SnCl(4) was used for the reaction with the alpha-(4-methoxyphenylenoxysilane)-beta,beta-difluoroenoxysilane, however, a rearrangement of the endoperoxide was observed.

Novel [1,2]- and [2,3]-Wittig rearrangements of alpha-benzyloxy beta-CF(3)-beta-lactam enolates.

[reaction: see text] alpha-Benzyloxy alpha-CF(3)-beta-lactams are shown to offer the first examples of the enolate [1,2]- and enolate ortho-[2,3]-Wittig rearrangements which provide a unique entry to the alpha-benzyl-alpha-hydroxy lactams and the alpha-aryl-alpha-hydroxy lactams, respectively. Both products are potential precursors of new trifluoromethyl isoserines, and the latter is not accessible via the usual alkylation methodology.

1-Trifluoromethyl epoxy ethers. Effect of hexafluoro-2-propanol on reactions with secondary aromatic amines: synthesis of 3-trifluoromethyl indole derivatives.

Trifluoromethyl epoxy ethers 1 and 2 reacted with aromatic amines in hexafluoro-2-propanol at room temperature providing trifluoromethyl indolinols 3 and 4 in excellent isolated yields. 3-Trifluoromethyl indoles 9 and 10 could be prepared by treatment of indolinols with SOCl(2).

Cobalt-Induced C-N and C-C Bond Formation via Metal-Stabilized alpha-CF(3) Carbenium Ion.

An alpha-CF(3)-carbenium ion stabilized by a bimetallic [Co-Co] cluster was prepared and isolated in good yield, starting from the corresponding alcohol by action of HBF(4)/Et(2)O. C-N and C-C bonds with nitrogen and carbon nucleophiles could be easily formed. Subsequent decomplexation gave the free substituted beta-CF(3) alkynes in good yields.

Short stereoselective route to gamma-CF3 allylic alcohols: rearrangements with creation of quaternary CF3-substituted carbons

A concise preparation of tetrasubstituted hindered functionalized CF3-olefins 2-7 from corresponding enol ether 3 is described. Geometrically pure gamma-CF3, gamma-alkyl allylic alcohols thus prepared could undergo Claisen-type rearrangements and provide, in good yields, carboxylic esters and amides containing a beta- quaternary CF3-substituted carbon.

Synthesis and antimalarial activities of fluoroalkyl derivatives of dihydroartemisinin.

Fluoroalkyl ethers (4) of dihydroartemisinin (2) have been prepared by reaction of fluoroalkyl alcohols with dihydroartemisinin by different methods (BF3,Et2O or TMSCl catalysis or Mitsunobu reaction). Ethers 4a-d derived from primary fluoroalkyl alcohols were obtained in moderate to good yields by these methods. Ethers 4e-j have been prepared from fluoroalkyl secondary and tertiary alcohols and phenol using the Mitsunobu reaction. Although in vitro antimalarial activities of ethers toward Plasmodium falciparum W-2 asiatic strain are moderate, in vivo activities against Plasmodium berghei (NT 173) are excellent.

Stereoselective synthesis of peptidyl trifluoromethyl alcohols and ketones: inhibitory potency against human leucocyte elastase, cathepsin G, porcine pancreatic elastase and HIV-1 protease.

New fluorinated inhibitors have been designed to target two major proteases-human leucocyte elastase and HIV-1 protease. Two series of beta-peptidyl trifluoromethyl alcohols (TFMAs) Z-L-Val-NH-*CH(Y)*CH(OH)-CF3, where *C is the chiral centre, varied in the nature of the substituent Y, a phenylethyl [-(CH2)2-C6H5] or an isopropyl [-CH(CH3)2] group. These TFMAs were first synthesized as two pairs of the syn and anti diastereoisomers. The inhibitory effects of these mixtures were then assessed on three serine proteases chosen on the basis of the aromatic and aliphatic nature of the substituents-human leucocyte elastase (HLE), human cathepsin G (HCG) and porcine pancreatic elastase (PPE). In the presence of detectable inhibition, each epimer at C2 was separated to determine its inhibition constant (Ki) towards HLE, HCG and PPE. The stereoisomerically pure TFMAs were then oxidized into peptidyl trifluoromethyl ketones (TFMKs) for similar inhibition assays. The absolute configuration of the compounds remained unknown. One epimer at C2 of each syn and anti TFMA with the phenylethyl substituent behaved as a competitive inhibitor towards HLE and HCG with inhibition constants below the millimolar range, whereas their TFMK counterparts were non-inhibitors. In the second series, the two ketones inhibited both elastases with Ki values in the micromolar range, whereas only the syn TFMA was active towards HLE (Ki = 5.65 x 10(-4)M). The tested compounds also had structural properties compatible with recognition by HIV-1 protease. The inhibition of the enzyme was observed with TFMK only (IC50 = 15-200 microM). The phenylethyl substituent promoted inhibition by a factor of 10 (IC50 = 15 microM) compared with the isopropyl substituent (IC50 = 200 microM) leading to selective inhibition of HIV-1 protease. Isomerically pure TFMKs were more potent towards HLE than the alcohols from which they were obtained. However, an enantiomerically pure TFMA selectively inhibited HLE unlike its TFMK analogue which also inhibited PPE. This last result together with the selective inhibition of HIV-1 protease by TFMK with a phenylethyl substituent might be relevant to the design of specific HLE and HIV-1 inhibitors as therapeutic agents.