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Synthesis and antinociceptive activity of 9-phenyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine

The synthesis of 9-alkyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine is reported. A potent antinociceptive activity was confirmed for the 9-phenyl-9-propionyl-oxy derivative bearing an oxygen or sulfur atom in the heteroaromatic structure.Abstract The synthesis of 9-alkyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine is reported. A potent antinociceptive activity was confirmed for the 9-phenyl-9-propionyl-oxy derivative bearing an oxygen or sulfur atom in the heteroaromatic structure.

Preparation of halohydrin β-blocker precursors using yeast-catalysed reduction

Abstract The preparation of halohydrin β-blocker precursors using yeast-catalysed reduction of α-haloketones was performed. The influence in the yield and e.e. of several process variables was analysed. The (S)-enantioselectivity observed with Saccharomyces cerevisiae can be changed to (R)-enantioselectivity using methyl vinyl ketone as selective inhibitor (25 mM). Using resting fresh cells better yields and e.e.s are observed than using growing cells. Yarrowia lipolytica 1240 resting cells gave 87% yield of (S)-1-chloro-3(1-naphthyloxy)propan-2-ol (99% e.e.). Pichia mexicana 11105 resting cells gave 85% yield of (R)-1-chloro-3(1-naphthyloxy)propan-2-ol (precursor of propranolol) (95% e.e). The reduction process is applied to other α-haloketones, a lower e.e. being obtained the closer the size of the ketone substituents.

Original paperSynthesis and antinociceptive activity of 9-phenyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridineSynthèse et activité antinociceptive de dérivés phényl-9-alkoxy-9 ou acyl-oxy-9 de xanthène, thioxanthène et acridine

The synthesis of 9-alkyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine is reported. A potent antinociceptive activity was confirmed for the 9-phenyl-9-propionyl-oxy derivative bearing an oxygen or sulfur atom in the heteroaromatic structure.Abstract The synthesis of 9-alkyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine is reported. A potent antinociceptive activity was confirmed for the 9-phenyl-9-propionyl-oxy derivative bearing an oxygen or sulfur atom in the heteroaromatic structure.

Chemoenzymatic synthesis of pure enantiomeric 2-aryl propionic acids

Abstract A new chemoenzymatic procedure to obtain pure enantiomeric 2-arylpropionic acids is described. The one pot synthesis of (±)-2-arylpropionic acids is carried out by addition of dichlorocarbene to the O bond of arylmethylketones and hydrogenolysis of the addition product. The racemic mixture is resolved by enantiospecific hydrolysis of the racemic ethyl esters using native lipase from Candida rugosa . The good yields, the accessibility of the starting arylmethylketones and the stereospecificity of the enzymatic hydrolysis make the process interesting in order to obtain the same non steroidal antiinflammatory drugs such as Ibuprofen or Naproxen.

New yeast strains for enantioselective production of halohydrin precursor of (S)-Propranolol

Abstract The synthesis of ( R ) or ( S ) 1-chloro-3-(1-naphthyloxy)propan-2-ol, (2-Propranolol precursor) using yeast-catalysed reduction of 1-chloro-3-(1-naphthyloxy)propan-2-one, 1 is described. Several yeast strains have been used. The best strains were selected using the reduction of cyclohexanone, as the reaction test. These selected strains were more active and productive than the commercial strain of S. cerevisiae from Sigma. The stereoselective reduction of 1 was performed using actively fermenting cells or fresh resting cells. The last experimental conditions were the best to achieve good yields and e.e. in 1. Pichia mexicana 11015 resting cells gave 85% yield in ( R ) 1 (e.e. = 95%) (precursor of ( S )-Propranolol). Yarrowia lipolytica 1240 resting cells gave 87% yield in ( S ) 1 (e.e. = 99%).

Organic reactions catalyzed by immobilized lipases. Part I. Hydrolysis of 2-aryl propionic and 2-aryl butyric esters with immobilized Candida cylindracea lipase

Abstract The alteration of the selectivity of enzymes due to the immobilization methodology is discussed. The hydrolysis of esters of ( R,S ) 2-phenyl propionic and 2-phenyl butyric acids has been used as a reaction test. Lipases from Candida cylindracea immobilized on agarose and alumina have been used as enzymatic derivatives. The stirring speed, [Substrate]/[Enzyme] ratio and pH are the main variables that control the process. An increase in the stirring speed, a diminution of the [Substrate]/[Enzyme] ratio and pH = 7.0 favours the hydrolysis of esters. The effect of the support on the enzymatic activity is discussed. Inorganic supports such as Al 2 O 3 or SiO 2 stabilize the oil/water interface acting in the same way as Na(I) or Ca(II) in the case of native enzyme. Enzymatic derivative on Al 2 O 3 is the most interesting biocatalyst. The effect of the alkyl chain of the ester is not related to the steric hindrance but to the stability of the microemulsion. The butyl ester is the most interesting ester for carrying out the hydrolysis. A model of the ester-active site interaction is proposed to explain the increase observed in the stereoselectivity of the hydrolysis of ( R,S )-ester. High enantioselective hydrolysis of the racemates (yielding S (+) isomer; ee ≤ 98%) can be achieved using the immobilized derivatives.

A new application of Candida antarctica lipase for obtaining natural homochiral BBAs aryloxypropanolamine

Abstract CAL offers increased ee, together with broad substrate structural tolerance that makes it a firm candidate for the resolution of BBAs of type 1 .

Synthesis of α,α-disubstituted acetic acids using low-valent titanium

Dihalogenocarbenes generated using low-valent titanium (LVT) undergo a one-pot cycloaddition to diaryl, aryl alkyl or dialkyl ketones to give α,α-disubstituted acetic acids such as (R,S)-2-arylpropanoic acids. TiI4 proved most effective in this reaction for which the product yield was optimized by use of an excess of reducing agent.

Stereoselectivity of chemically modified α-chymotrypsin and immobilized lipases

The chemical modification of α-chymotrypsin by monomethoxypolyethylene glycol and the immobilization of lipases from Candida rugosa and C. antarctica on several supports changes the enantioselectivity of the enzymatic derivatives compared with the behaviour of the native enzymes. Hydrolysis and synthesis of esters have been used as reaction tests. This alteration could be related to the rigidification of the ‘h’ subsite of the enzyme by the effect of those processes. Technical variables such as time, temperature, stirring speed etc. do not alter the observed enantioselectivity. The presence or absence of water changes slightly the enantioselectivity in the synthesis of esters catalysed by immobilized lipases in dry isooctane.

New heteroaryl derivatives of fentanyl

Abstract— The preparation of analogues of fentanyl with N‐phenyl replaced with a heterocyclic aromatic ring, and with N‐alkyl/arylalkyl N‐acyl substituents is reported. Only those compounds carrying an N‐phenylethyl substituent were active in the rat tail‐withdrawal test. Fentanyl (1) is the prototype of the 4‐anilido‐piperidine class of opioid analgesics (Casy & Parfitt 1986). Several recent publications (Casy & Huckstep 1988; Bagley et al 1989) on this series have dealt with heterocyclic and aromatic modifications of the fentanyl molecule. Although the antinociceptive potency of most novel derivatives was greater than that of morphine, they had reduced activity when compared with fentanyl itself. To acquire further information on the structure‐reactivity relationships of the series, new heteroaryl derivatives have been prepared and tested for antinociceptive activity.