Model studies related to the cofactor of oxomolybdoenzymes. Part 4. Reduction of the pyrazine ring in quinoxalines and pteridines

Abstract

Reduction of quinoxalines and pteridines with sodium borohydride or sodium cyanoborohydride in the presence of benzyl chloroformate gives Nbenzyloxycarbonyl-or N,N'bisbenzyloxycarbonyl tetrahydro derivatives. BackgroundAll the oxomolybdoenzymes except nitrogenase, including xanthine oxidase, aldehyde oxidase, sulfite oxidase and nitrate reductase, contain a common cofactor, Moco which has been shown to have molybdenum coordinated via two sulfurs in an organic portion which includes a pterin, the complete organic unit being termed molybdopterin. There is evidence' that the pyrazine ring in the pterin is in a reduced state, earlier views being that it is at a tetrahydro level but the most recent work3 suggesting that molybdopterin is a dihydropterin, has a quinonoid tautomeric form, and that therefore partial structure 1 represents Moco. It is relevant to note that a tetrahydropterin is the cofactor for monoamine-synthesising monooxygena~es.~The absolute configuration of the side-chain hydroxy-bearing carbon has been deduced to be that shown in 1, on the basis of a CD comparison between samples of alkyne 2 produced in homochiral form by total synthesis,' and by degradation of the enzyme, respectively.6 which regioselective reductions are carried out to produce 1,2,3,4-tetrahydroquinoxalines and 5,6,7,8-tetrahydropteridines, stabilised by (removable) protection in such a way as to facilitate our synthetic work towards molybdopterin and Moco.Other workers have shown that catalytic reductions "-14 of pteridines give 5,6,7,8-tetrahydro derivatives, which are oxygenlabile; ' sodium dithionite treatment leads to 7,8-dihydro derivatives. '' Acylation of tetrahydropteridines at N-5 produces air-stable compound^,'^ but care is needed, for N-5ethylation has been observed under vigorous acetylation conditions.'2 An elegant method for the partial reduction of pyridines, which also allows isolation of unstable dihydro products in protected/stabilised form, was introduced by Fowler,16 who found that treatment of pyridine with sodium borohydride in the presence of methyl chloroformate gave a mixture of 1methoxycarbonyl-1,2-and -1,4-dihydropyridines thus stabilised as urethanes. 1 2Since it is likely that the mode of action of Moco involves redox processes at the metal centre, possibly linked to changes in the pyrazine ring oxidation level, we have previously reported synthetic studies on quinoxalines carrying 1,2-disulfur-substituted side-chains at C-2,1.798 the complexation9 of some of these products with molybdenum, tungsten, vanadium and cobalt as models for the situation in Moco, and electrochemical studies l o on [Co(q5-C5H,)(S2CRH)] (where R = quinoxalin-2-yl).

Multiple States of the Molybdenum Centre of Dimethylsulphoxide Reductase from Rhodobacter Capsulatus Revealed by EPR Spectroscopy

“…It is tempting to postulate, therefore, that the molybdenum centre of dimethylsulphoxide reductase, normally in the High-g, nitrate-reductase-like conformation, can adopt a desulpho xanthine-oxidase-like conformation on reduction by dithionite of the pteridine from the dihydro to the tetrahydro form, as in the Low-g type-1 species. Such a proposal has important implications concerning possible roles (Rajagoplan 1991 ; Russell et al, 1992) of the pteridine in the cofactor. In particular, it would be consistent with the suggestion (one of the many put forward by Rajagopalan, 1991) that the pterin oxidation state might control the redox potentials of molybdenum in molybdoenzymes.…”

“…Such a proposal has important implications concerning possible roles (Rajagoplan 1991 ; Russell et al, 1992) of the pteridine in the cofactor. In particular, it would be consistent with the suggestion (one of the many put forward by Rajagopalan, 1991) that the pterin oxidation state might control the redox potentials of molybdenum in molybdoenzymes.…”

Synthesis and oxidative behaviour of reduced indeno[1,2-b]quinoxalines and benzo[b]phenazines

“…2,3-Dihydroindene-l,2-dione (0.73 g, 5.0 mmol) and 4,5dimethylbenzene-l,2-diamine (0.73 g, 5.4 mmol) were heated at reflux in ethanol (25 an3, 95%) for 1.25 h. The reaction mixture was cooled and the title compound separated as colourless needles (1.10 g, 89%), mp 200-201 "C; ~5 ~2 . 5 The reaction mixture became maroon coloured and, after 0.75 h, was treated with methyl iodide (0.2 g, 1.4 mmol) whereupon the colour was discharged. The solvent and excess methyl iodide were removed and the residue was chromatographed eluting with 6% ethyl acetate in light petroleum to give an oil (1 8 mg), which consisted of the isomeric title compounds in the ratio 10 :.7 respectively; these components could not be separated.…”

A concise treatment of pterins: some recent synthetic and methodology aspects and their applications in molecular sensors

“…7,8 Sodium dithionite will partially reduce oxidized pterin to 7, 8-H2pterins. 9 Borohydride reductants of the general type M[BHR3] (M= Li, Na, K; R =H, alkyl, CN) can be selected to partially reduce oxidized pterins to the semi-reduced state, usually obtained as the stable 7,8-dihydropterin tautomer. Combining a borohydride reductant with an alkylating reagent (benzylchloroformate or FMOC) accomplishes reduction of pterins to the 5, 6, 7, 8-tetrahydro reduced state with mono-alkylation while di-alkyl protection at N5 and N8 is required for quinoxaline reduction.…”