Dihydropyrimidines, reduction

The aerobic degradation of several azaarenes involves reduction of the rings at some stage, and are discussed in Chapter 10, Part 1. Illustrative examples include the degradation of pyridines (3-alkyl-pyridine, pyridoxal) and pyrimidines (catalyzed by dihydropyrimidine dehydrogenases). Reductions are involved in both the aerobic and the anaerobic degradation of uracil and orotic acid. 

Figure 11.3 shows spectra from a cubane pair in an enzyme called DPD, dihydropyrimidine dehydrogenase (Hagen et al. 2000). It catalyzes the first step in the breakdown of pyrimidine bases. The two cubanes have unusually low reduction potentials, and so they are reduced to the [4Fe-4S]1+ form with S = 1/2 ground state by means of... 

In a study of the catabolic pathway of pyrimidines, it was found that the reduction of uracil was blocked almost completely by 5-cyanouracil (XXXV) in an in vitro test with the rat enzyme dihydropyrimidine dehydrogenase [303]. 5-Halogenated uracils and thymine are weakly active in this regard, and 5-acetyluracil and 5-trifluoromethyluracil are completely inert. 

Although sodium borohydride cannot reduce unactivated pyrimidines, it can reduce the polarized C=N bonds in dihydropyrimidines to their tetrahydro derivatives. For example, the reduction of the dihydropyrimidinone 537 can be performed enantioselectively with sodium borohydride to give the tetrahydropyrimidinone 538 in 85% yield <199608201 >. 

From the yields of 5,6-dihydropyrimidine radicals, we predict reduction product yields of 0.04-0.06 pmol/J for 5,6-dihydrouracil and 0.03-0.05 pmol/J for 5,6-dihydro-thymine for B-form DNA hydrated to 9 waters per nucleotide. With respect to oxidation products, we predict strand-break yields —0.10 pmol/J. A very surprising prediction of this model is that the yield of damaged guanine is nil. Half the damage is oxidized sugar products and the other half is reduced pyrimidines. 

The behavior of pyrimidine during polarographic reduction depends on the pH of the aqueous solution. In acidic solution two one-electron waves are observed, while in neutral solution two two-electron waves result. In alkaline solution four-electron reduction is effected via 1,6-dihydropyrimidine to give tetrahydropyrimidine (84AHC(36)235). 

Reduction of dihydropyrimidines by the use of excess sodium borohydride in methanol, at 60 °C, has been used as a route to substituted polyamines (equation 76). The reaction occurs in a stereocontrolled fashion and gives reasonable yields. These latter molecules are synthetic targets due to their potential in chemotherapy. 

In aprotic medium, on the other hand, pyrimidine gives a reversible diffusion-controlled le wave at a very negative potential, with formation of a radical anion which is deactivated via two pathways rapid formation of the anionic, probably 4,4 -, dimer, with a rate constant of 8 x 105 L mol-1 sec-1, and proton abstraction from residual water in the medium at a much lower rate constant, 7 L mol-1 sec-1 98). This is rapidly followed by a further le reduction to produce, ultimately, 3,4-dihydropyrimidine 98). In the presence of acid there is also a le reduction wave corresponding to formation of a free radical which, as in aqueous medium, dimerizes, most likely to 4,4 -Z w-(3,4-dihydropyrimidine). Examination of the mechanism of reduction in acetonitrile in the presence of acids supported the conclusion that reduction of pyrimidine in aqueous medium is preceded by its protonation98). 

Following initial studies by Cavalieri Lowy 96), it was shown by Smith Elving74) that the polarographic behaviour of 2-aminopyrimidine in acid medium is similar to that for the parent pyrimidine, which exhibits three waves at the dropping mercury electrode 74). The initial le step involves formation of a free radical which dimerizes and, at the potential of the second le reduction step, 2-amino-3,4-dihydropyrimidine is formed. But, unlike pyrimidine, 2-aminopyrimidines do not undergo a second 2e reduction to tetrahydro derivatives. Wave III (pH 7-9) involves two electrons and two protons, and is due to the combined processes responsible for waves I and II at lower pH. Both Smith Elving 74), and Sugino 104>, found that reduction of 2-aminopyrimi-dine on a mercury electrode 74) and lead cathode 104) resulted in the formation of unstable products. 

In view of the earlier demonstration that pyrimidone-2 undergoes one-electron reduction, with formation of a dimer identified as 6,6 -6ij-3,6-dihydropyrimidine-2, which is suceptible to quantitative photodissociation to the parent pyrimidone-2, and bearing in mind that 2-oxopurine may be considered a formal analogue of a 5,6-disubstitut-ed pyrimidone-2, it appeared of interest to examine whether an analogous reaction sequence occurs with 2-oxopurine. 

The reduction of substituted 4-hydroxy-5,6-dihydropyrimidins such as VIII/ 114 is a reaction used several times as key step in the syntheses of polyamine alkaloids, Scheme VIII/21. In the presence of NaCNBH3/AcOH at 50°, ring enlarged azalactams of type VIII/115 are obtained in yields of about 90 %. Aza-lactams, prepared by this method, are nine- [65], thirteen- [66], and seventeen-membered [67] [68] [69]. 

In mammalian systems, catabolism of uracil and thymine proceeds in parallel steps, catalyzed by the same enzymes (Figure 27-31). The rate-determining step is reduction to a 5,6-dihydroderivative by dihydropyrimidine dehydrogenase. In the second step, dihydropyrimidinase hydrolyzes cleavage of the dihydropyrimidine rings to -ureido compounds. In the third step, /1-ureidopropionase hydrolyzes the j3-ureido compounds to -alanine or fi-aminoisobutyrate (BAIB), with release of ammonia and carbon dioxide. Thus, the major end product of the catabolism of cytosine and uracil is /i-alanine, whereas that of thymine is BAIB. 

The mechanism of this LiAlH4 reduction of pyrimidine-2-ones should be similar to that of amides (Scheme 7). Therefore, we supposed that one should also be able to obtain 1,2-dihydropyrimidine (21a) by reduction of the corresponding 4,6-diphenylpyrimidine (106), and, indeed, LiAlH4 reduction of 106 in tetrahydrofuran gives 30-70% (depending on conditions) transformation of 106 to 21a. The reaction is very clean and only unchanged 106 was isolated. The reason for incomplete transformation of 106 is still unclear.184... 

This reaction was extended to other derivatives. Thus 2-phenyl-1,6-dihydropyrimidine was prepared by LiAlH4 reduction of 2-phenylpyrimidin-4-one or 2-phenylpyrimidine. Undoubtedly, there is great potential in the reduction of pyrimidines with complex hydrides, and this approach should attract wide attention in the future. 

Dihydropyrimidines by catalytic hydrogenation Dihydro- and tetrahydropyrimidines by metal hydride reductions Dihydropyrimidines by electrochemical reduction Dihydropyrimidines by adduct formation with organometallics Dihydropyrimidines by photochemical adduct formation Dihydropyrimidines by adduct formation with -nucleophiles Dihydropyrimidines by adduct formation with P-nucleophiles Dihydropyrimidines by adduct formation with O-nucleophiles Dihydropyrimidines by adduct formation with S-nucleophiles... 

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