Lilias Rees

Selective functionalisatlon: Part 10. The nitration of phenols by pyridine derivatives carrying a transferable nitro group

Abstract Pyridinium salts bearing carboxylate side chains and pyridones are shown to react with nitronium tetrafluoroborate or nitrogen dioxide to yield activated intermediates capable of selectively nitrating phenol ortho to the hydroxyl group with virtually complete selectivity and in quantitative yield in aprotic solvents. Although the nitration of phenol itself is exceptionally selective, the nitration of some substituted phenols lead to mixtures of mononitrated products and in especially reactive cases such as 4-methoxyphenol and naphthols, to dinitrated products also. The reactions can be most conveniently carried out on a polymeric support. Spectroscopic evidence is presented to show that intermolecular association between pyridinium salts and the phenols takes place under conditions similar to the reaction conditions and that hydrogen bonding between the phenolic hydroxyl group and acceptor groups on the pyridine ring can also occur. It is suggested that the combination of these two effects leads to the observed selectivity. Attempts to extend the scope of the reaction to other electrophiles and substrates are outlined.

Asymmetric reduction of dihydrofolate using dihydrofolate reductase and chiral boron-containing compounds

Abstract The reduction of dihydrofolic acid to chiral tetrahydrofolic acid has been investigated by enzymic and non-enzymic means. With dihydrofolate reductase from E.coli as catalyst and recycling systems for NADPH, up to 1 g of optically pure stable tetrahydrofolate derivatives was obtained. The technique makes the possibility of synthesising chiral 5-formyltetrahydrofolate (leucovorin) for use in cancer rescue therapy attainable. In contrast, although dihydrofolate was reduced by a number of chiral boranes and borates built from amino acids and amino alcohols, enantiomeric excesses were minimal.

Latent inhibitors. Part 9. Substrate activated time-dependent inhibition of carboxypeptidase A by aminocyclopropanecarboxylic acid derivatives and analogues

A series of 1-aminocyclopropanecarboxylic acid derivatives and analogues have been synthesised as potential inhibitors of carboxypeptidase A. Whereas simple cyclopropylcarboxamido derivatives of Gly, Phe and Pro showed no indications of time-dependent, irreversible inhibition, benzamido-1-aminocyclopropane carboxamido-Phe and Pro were characterised as latent inhibitors. The former was also a substrate for carboxypeptidase A but the latter was purely an inhibitor. This behaviour suggested that cyclopropylketones should also be inhibitors of carboxypeptidase A; this suggestion was confirmed experimentally. Kinetic experiments showed surprisingly that the rate of inhibition is increased in the presence of substrate, hippurylphenylalanine. Related secondary alcohols also acted as time-dependent inhibitors. The results are evaluated in the context of current views on the mechanism of action of carboxypeptidase A.

Latent inhibitors. Part 8. Synthesis and evaluation of some mechanism-based inhibitors of dihydrofolate reductase

The synthesis of two new pteridine-7-spirocyclopropanes that are time-dependent irreversible inhibitors of dihydrofolate reductase is described. Several related compounds including a cyclopropyl substituted quinoxaline and 2-aminopteridine-4(3H),6(5H)-dione were also prepared but these compounds were not found to be time-dependent inhibitors. The inhibitors were assessed using several dihydrofolate reductases, Escherichia coli RT/39, two mutants of the E. coli enzyme, Lactobacillus casei, and chicken liver. Activity was found against all enzymes tested but most strongly against E. coli wild type enzyme.

Novel reactivity of 2-(chloromethoxy)ethyl acetate

Abstract 2-(Chloromethoxy)ethyl acetate reacts with alcohols in the presence of silver carbonate to produce 2-(alkoxymethoxy)ethyl acetates and bis(alkoxy)methanes. A mechanism which involves neighbouring group participation of a chloromethyl ether oxygen atom is proposed to account for the formation of the latter products.

Selective nitration of phenol

Activated nitro derivatives of pyridinium salts have been shown to mediate in the highly selective ortho nitration of phenol in high yield.

The preparation of the (6R)- and (6S)-diastereoisomers of 5-formyltetrahydrofolate (leucovorin)

The separation of the (6R)- and (6S)-diastereoisomers of tetrahydrofolic acid by derivatisation on N-5 with chiral auxiliary reagents followed by fractional crystallisation or extraction is described. Chloroformates of chiral alcohols were used as chiral auxiliaries and those derived from cyclic terpene alcohols were found to be most effective for the separation. The cleavage of the derivative and conversion in situ into 5,10-methenyltetrahydrofolic acid which was subsequently hydrolysed to afford 5-formyltetrahydrofolate (leucovorin) was investigated for the derivatised tetrahydrofolates; that from (–)-menthol was the only one that combined satisfactory separation with sufficient lability for efficient conversion into 5-formyltetrahydrofolate. The characterisation and optical purity of the products is described.

A simple and effective method for preparation of the 6(R)- and 6(S)-diastereoisomers of 5-formyltetrahydrofolate (leucovorin)

Acylation of 6(RS)-tetrahydrofolate with (–)-menthyl chloroformate afforded an N-5 derivative which was separable into its diastereoisomers by extraction with n-butanol; these derivatives were converted separately into the 6(R)- and 6(S)-diastereoisomers of 5-formyltetrahydrofolate by treatment with a mixture of formic acid and hydrogen bromide in acetic acid followed by hydrolysis.