Tjoe B.R.A. Chen

Dealkylation of quaternary ammonium salts by thiolate anions: A model of the cobalamin-independent methionine synthase reaction.

Abstract The reactions of thiolate ions derived from thiophenol and homocysteine with substituted quaternary ammonium salts result in alkyl transfer from nitrogen to sulfur. A radical mechanism for this transalkylation, accounts for the reactivity pattern of the substrate salts. In a model study of the cobalamin-independent methionine synthase reaction, 5,5,6,7-tetramethyl-5,6,7,8-tetrahydropteridinium salt (25), which can be considered as a model for the natural coenzyme 5-CH3H4-folate (1), was allowed to react with the thiolate of homocysteine, whereupon the formation of methionine was observed in good yield. These results suggest that in the enzymatic process the N(5)-CH3 bond may be activated for the methyl transfer step, by coordination of the N(5) with an electrophile or a proton at the active site.

The michael induced ramberg-bäcklund homologation to conjugated isoprenoids

Abstract Treatment of the sulfones 1 or 2 with sodium phenylsulfinate in DMSO affords the head-to-tail coupled conjugated monoterpenoids 5–8 in comparable amounts. The corresponding reaction of 3 gives the isomers 16 and 17 . The tail-to-tail homologation of 4 furnishes chiefly a 2 E ,4 E/Z -mixture of the conjugated isoprenoids 18 and 19 . The various isoprenoid mixtures are separated into their components and the configuration of the isomers is established by 1 H NMR double resonance and the NMR/NOE technique. The head-to-tail and tail-to-tail coupled isoprenoid mixtures 5–8 and 18–21 , respectively, are isomerized to 2 E/Z , 4 E -mixtures in a 2:1 ratio. The C 15 -sulfones 11 and 13 are obtained by treatment of 1 with the head-functionalized isoprene synthon 10 . Some speculations on the stereochemical course of the MIRB-homologation are presented.

Alkyl transfer from quaternary ammonium salts to cobalt (I): Model for the cobalamin-dependent methionine synthase reaction

Abstract The reaction of cobaloxime(I) with diverse quaternary ammonium salts leads, in general, to a group transfer from nitrogen to cobalt. The behaviour of the salts in these transalkylations is consistent with an S N 2 mechanism, involving Co(I) as a nucleophile. In a model study of the cobalamin-dependent methionine synthase reaction, 5- 13 CH 3 -methyl labelled 5,5,6,7-tetramethyl-5,6.7,8-tetrahydropteridinium salt( 23 ) -a model of the natural coenzyme 5-CH 3 H 4 -folate ( 1 )- was allowed to react with cobaloxime(I) and cobalamin(I). In each case the formation of the methyl transfer product, namely, methylcobaloxime and mothylcobalamin, respectively, was shown by 13 C-NMR spectroscopy.

Models of folate cofactors 17. Methylation of 1,3-dimethyl-6-methylamino-uracil by a 5,10-CH2-H4folate model. the first mimic of the overall dTMP synthase reaction

Abstract 2-Tosyl-1,2,3,12b-tetrahydroimidazo[1,5-f]lphenanthridine ( 6 ) was prepared in five steps from 6-chloromethylphenanthridine ( 1 ) in an overall yield of 50%. The reaction of 6 with 1,3-dimethyl-6-methylaminouracll ( 8 ) in CH 3 CN/TFA (100:1) at 50-80°C, gave a mixture of products from which 1,3-dimethyl-6-methylaminothymine ( 9a ) could be isolated. This constitutes a mimic of the overall dTMP synthase reaction in transferring both a methylene unit and a hydride equivalent from the cofactor model 6 to the 5-position of a uracil derivative. The other products which are formed in the reaction of 6 with 8 are derived from the reaction of the exocyclic intermediate C , formed in the carbon transfer step, with nucleophiles present in the reaction mixture.

Models of folate coenzymes 16: Chemical modelling of the thymidylate synthase reaction. Evidence for an “exocyclic methylene intermediate” analogue, which is reducible to a thymine derivative, in the reaction of 6-aminouracils with a 5,10-methylenetetrahydrofolate model

Abstract Reactions of 6-amino-, 6-alkylamino- and 6-anilino-l,3-dimethyluracils ( 1a - e ) with 3,4-diphenyl-1-tosylimidazolidine ( 2 ), in the presence of acid, lead to the formation of products which are derived from an “exocyclic methylene intermediate” analogous to the one formed in the thymidylate synthase reaction. The intermediate has been identified by (a) spectral studies, (b) formation of adducts with dihydropyridine and dihydroquinonline derivatives and (c) its reduction to the corresponding thymine derivative. These results provide chemical precedence for the carbon transfer step of the thymidylate synthase reaction in a reaction between models of both the apoenzyme-substrate complex and the coenzyme 5,10-methylenetetrahydrofolate.Abstract Reactions of 6-amino-, 6-alkylamino- and 6-anilino-l,3-dimethyluracils ( 1a - e ) with 3,4-diphenyl-1-tosylimidazolidine ( 2 ), in the presence of acid, lead to the formation of products which are derived from an “exocyclic methylene intermediate” analogous to the one formed in the thymidylate synthase reaction. The intermediate has been identified by (a) spectral studies, (b) formation of adducts with dihydropyridine and dihydroquinonline derivatives and (c) its reduction to the corresponding thymine derivative. These results provide chemical precedence for the carbon transfer step of the thymidylate synthase reaction in a reaction between models of both the apoenzyme-substrate complex and the coenzyme 5,10-methylenetetrahydrofolate.

Model studies of the cobalamin-dependent methionine synthase reaction

Abstract The cobalt atom of cobaloxime(I) and cobalamin(I) is methylated by a 5-methylpterinium salt acting as a model of the activated 5-methyltetrahydrofolate cofactor.

A model of the cobalamin-independent methionine synthase reaction

Homocysteine is converted to methionine via a nonenzymatic methyl transfer from a 5-methyitetrahydrofolate model bearing a positive charge at N(5).

The first example of a mimic of the overall thymidylate synthase reaction

2-Tosyl-1,2,3,12b-tetrahydroimidazo[1,5-f]phenanthridine functions as a mimic of the cofactor 5,10-methylenetetrahydrofolate in transferring both a methylene moiety and a hydride equivalent (i.e. an overall methyl group) to the C-5 position of a uracil derivative.

A chemical model of thymidylate synthetase. Formation of a thymine derivative via an exocylic methylene intermediate

Reaction of 6-aminouracil derivatives with imidazolidines (methylenetetrahydrofolate models), in the presence of acid, gives an exocyclic methylene intermediate which reacts with nucleophiles present in the mixture or can be reduced to a thymine derivative.