Oxidation from pteridines

Pterins — These are pigments derived from pteridine skeletons. All natural pterins are 2-amino-4-hydroxypteridines bearing various substituents at Cg and C7 and having different oxidation states of N5 and Ng. 

The primary syntheses of pyrazine JV-oxides from aliphatic components only are described in this chapter. The preparations of pyrazine JV-oxides by oxidation of pyrazines are dealt with under the reactions of the appropriately substituted pyrazines for example, those of pyrazine and alkylpyrazine TV-oxides are described in Chapter IV, and of halogenopyrazine JV-oxides in Chapter V. The cleavage of JV-oxides of pteridines and related systems to aminopyrazine JV-oxides is described in Section VIII.3A(2). 

TABLE VIII.2 AMINOPYRAZINE A -OXIDES FROM CLEAVAGE OF V-OXIDES OF PTERIDINES AND RELATED RING SYSTEMS... 

Oxidations in the pteridine series comprise (i) replacement of hydrogen by hydroxyl, (ii) glycol formation at the central C=C bond (iii) the removal of hydrogen atoms from dihydro and tetrahydro derivatives. 

Leucovorin, since it is totally reduced, is polarographically inert in a pH 9 buffered solution.63 After acid treatment, three polarographic waves are generated, corresponding to an anodic oxidation of a tet-rahydro compound and two cathodic reductions of unreduced pteridines presumably at least one of these three is a dihydro species. Polarography is useful as a technique in structural elucidation, but analytical data would be difficult to obtain from an acid-treated solution containing several species, each with its own polarographic behavior. 

Reductive sequences involving flavoproteins may be represented as the reverse reaction, where hydride is transferred from the coenzyme, and a proton is obtained from the medium. The reaction mechanism shown here is in many ways similar to that in NAD+ oxidations, i.e. a combination of hydride and a proton (see Box 11.2) it is less easy to explain adequately why it occurs, and we do not consider any detailed explanation advantageous to our studies. We should register only that the reaction involves the N=C-C=N function that spans both rings of the pteridine system. 

The ready alkylation of heterocyclic thiols lends this link to applications in solid-phase synthesis. Although much more work has been done in other heterocyclic systems, a prototype solid-phase synthesis has been described in which the pteridine is built from a 2- or 4-alkylthiopyrimidine attached to a cross-linked polystyrene support <20030BG1909, 2003TL1267> Oxidative cleavage was preferred using DMDO to avoid unwanted by-products... 

An alternative route to such 6-(l-hydroxyalkyl)-substituted pteridines including 106 is from 2,4,5-triamino-6-butoxypyrimidine 107 and 2-formyloxiranes 108 in which the stereochemical properties are emphasized by the inclusion of the 17-steroidal ester <1992S303>. L-Biopterin 106 was synthesized from the oxirane 108 and 107 via a 5,6-dihydropteridine intermediate which was oxidized in situ to afford the product (Scheme 21). Syntheses of oxiranes and the condensation mechanism in the context of molecular orbital calculations were discussed. The field has been reviewed <1998H(48)1255>. 

In modern medicinal chemistry, the creation of diversity on a structural framework is important. In principle, diversity at positions 2, 4, 6, 7, and 8 of pteridines can be achieved using such solid-phase chemistry. This prototype solid-phase synthesis involved nitrosation of the resin-bound pyrimidine, reduction of nitroso group with sodium dithionite, and subsequent cyclization with biacetyl to afford pteridines 114 and 115. Cleavage from the resin by nucleophilic substitution of the oxidized sulfur linker using w-chloroperbenzoic acid or DMDO led to the pteridine products 116 and 117 (Scheme 23). 

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