a b s t r a c tA new 4-hydroxy-a,a-diphenyl-L-prolinol containing polymethacrylate, prepared without chromatography by a large scale adaptable synthesis, has been evaluated as a catalyst in the asymmetric reduction of 1-arylethanones. Using 1-(4-bromophenyl)ethanone as the model substance, the reduction was tested with various borane sources and solvents. The best swellings of the polymer and reactivity were observed in THF using N,N-diethylaniline borane complex as the hydride source. The selectivity in the reduction of 1-(4-bromophenyl)ethanone was found to depend on the substrate concentration and catalyst loading. Using the best conditions identified, a series of 1-arylethanones was reduced to their corresponding enantioenriched secondary alcohols. High rates and ee-values were obtained in the reduction of acetophenones containing electron withdrawing groups in the aromatic ring, whereas a moderate selectivity was the result for products containing electron donating aromatic substituents. Upon recovery of the polymer beads, it was found that vacuum drying led to extensive rupturing, while the bead structure was intact if washed with methanol and air dried at atmospheric pressure. Repeated use of the polymer catalyst gave the product alcohol with a lower 90% ee. Elemental analysis showed this to be due to the loss of the chiral prolinol unit.
In the search for new antifungal compounds and to explore structure activity relationships, a series of 24 chiral benzyl amine type antifungals was synthesised and characterised. In vitro testing against the human pathogen Cryptococcus neoformans revealed that several derivatives had MIC50 values similar to that of the commercial drug Butenafine. All of these contained a bulky group in the para position of the benzyl fragment. Eighteen compounds were also tested for activity against the dermatophytes Trichophyton mentagrophytes and Trichophyton rubrum. Of these (R)-N-(4-tert-butylbenzyl)-N-methyl-1-(naphthalen-1-yl)ethanamine (MIC50: 0.06 μg/mL) and a para-benzyloxy substituted derivative (MIC50: 0.125 μg/mL) possessed high activity. Testing of derivatives with a stereocentre at the benzylic carbon, revealed that (S)-stereochemistry was required for potency: a MIC50 value of 1 μg/mL was obtained for (S)-1-(4-tert-butylphenyl)-N-methyl-N-(naphthalen-1-ylmethyl)ethanamine. Preparation of the corresponding fluoromethyl compound was achieved employing lipase B from Candida antarctica as catalyst in the key step. A low antifungal activity was observed for the fluorinated derivative indicating the importance of the amine basicity for the antifungal potency of these compounds.
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