Fluorine substituents in organic molecules do dramatically influence the electronic structure of neighbouring functional groups and the conformation of molecules. Hence the presence of fluorine in a compound changes its chemical reactivity and biological activity. On the basis of MP2 and SCS-MP2 calculations, we discuss the conformational preferences and basicity of the diastereoisomeric 2-fluorocyclopropylamines (cis-2 and trans-2) in comparison to those of cyclopropylamine (1) and 2-fluoroethylamine (3). 1 and 2 are viewed as model compounds for the antidepressant drug tranylcypromine (trans-2-phenylcyclopropylamine, 1a) and its fluorinated derivatives 2. The potential energy profile for the rotation of the amino group in cis-2 differs from that of trans-2 and 1 which have very similar rotational curves. For 2 the global minimum conformer is trans-2a and the lowest energy cis-conformer 2c is less stable by 2.57 kcal mol(-1). The calculated enthalpy differences between the conformers gauche-1b and s-trans-1a (2.0 kcal mol(-1)) as well as between gauche-3b and gauche-4a (0.2 kcal mol(-1)) agree well with the available experimental data of 2.0 kcal mol(-1) and 0.1 +/- 0.3 kcal mol(-1), respectively. The calculated gas phase proton affinities (PA) of 1 (217.6 kcal mol(-1)), cis-2c (215.6 kcal mol(-1)), and trans-2a (209.3 kcal mol(-1)) follow the trends of the pKa values measured in solution for the diastereomeric 2-phenylcyclopropylamines 1a and 1b and their fluorinated derivatives cis-2 and trans-2. It is shown that the conformational preferences and basicity of the investigated molecules are due to stereoelectronic effects from hyperconjugative interactions which lead to different local charge distributions and different hybridization of the nitrogen lone-pair. The basicity of gauche-3a (PA = 215.3 kcal mol(-1)) and anti-3b (PA = 210.1 kcal mol(-1)) is controlled by the charge of the nitrogen atom, while that of cis-2c and trans-2a is overlap controlled as a result of different hybridization of the nitrogen lone-pair [sp4.34 (cis-2c), sp4.07 (trans-2a)].

A series of racemic, diastereoisomeric aryl cyclopropylamines substituted with fluorine in the 2-position and electron-donating and electron-withdrawing groups on the aromatic ring have been prepared. These represent analogues of the classic MAO inhibitor tranylcypromine (trans-2-phenylcyclopropylamine, 1). Their activities as inhibitors of recombinant human liver monoamine oxidases A (MAO A) and B (MAO B) were determined. The trans-compounds were low micromolar inhibitors of both MAO A and MAO B with moderate MAO A selectivity while the less active cis-analogues were MAO B selective. In the trans-series, electron-withdrawing para-substituents increased the potency of MAO A inhibition while electron-donating groups such as methyl or methoxy had no influence on this activity. In contrast, aromatic ring substitution in the trans-series had essentially no effect on the inhibition of MAO B. The corresponding cis-compounds were shown to be 10-100 times less active against MAO A, while trans- and cis-compounds were quite similar in terms of inhibition of MAO B. The best MAO A/MAO B selectivity (7:1) in the trans-series was found for trans-2-fluoro-2-(para-trifluoromethylphenyl)cyclopropylamine (7d), while a 1:27 selectivity was found for cis-2-fluoro-2-(para-fluorophenyl)cyclopropylamine (10c). These results are discussed in connection with the pK(a) and logD values, the mechanism of action of tranylcypromines, and the geometry of the active site of the enzymes.

The reaction of α-fluorostyrene (1a) with methyl phenyldiazoacetate in the presence of Rh 2 (OAc) 4 gave a 64:36 mixture of diastereomeric monofluorinated cyclopropanes 5a and 6a. When using chiral Rh II catalysts Rh 2 (TBSP) 4 (7) and Rh 2 (DOSP) 4 (8), the products were obtained enantioselecti-

Diastereomeric arylcyclopropylamines substituted with fluorine in the 2-position and with electron donating or electron withdrawing groups at the aromatic ring were evaluated as inhibitors of microbial tyramine oxidase. The trans-isomers were consistently more potent inhibitors of the enzyme than the cis-isomers. Electron donating substituents increased the potency of tyramine oxidase inhibition, while electron withdrawing substituents decreased the activity. The results obtained are discussed in terms of pK a and log D values of the inhibitors as well as the mechanism of action of tranylcypromines and the geometry of the active site of the enzyme.

No abstract