Uracil ring synthesis

Researchers at FMC Corporation have synthesized 3-(4,6-substituted benzoheterocy-clyl)uracil herbicides. The uracil ring synthesis is based on conversion of aryl amines into isocyanates68. A useful fluorinated aniline herbicide is fluometuron. Chlorination of 2-methylpyridine (102), followed by animation at the 4-position, and hydrolysis, yields the hormone-weedkiller Picloram (103) (Scheme 22). 

Low-molecular-mass thiols such as coenzyme A and protein-bound thiol cofactors such as phospho-pantetheine are present in all cells. Their SH groups can also be oxidized to disulfides and it is of interest that in resting bacterial spores these compounds exist largely as disulfides or mixed disulfides. Upon germination of the spores special enzymes reduce the disulfides.136 Some proteins involved in control of protein synthesis contain SH groups that add covalently to C-6 atoms of a uracil ring in specific mRNA molecules. Control of their state of reduction may also be important.137... 

Hydroxymethyluracil 30, a component of the present-day DNA of Bacillus subtilis bacteriophages [103], was obtained by electrophilic addition of formaldehyde to the C5-C6 double bond of a preformed uracil ring (which is probably the reason for the absence of uracil in the reaction mixture). Thymine was then obtained from 5-hydroxymethyluracil by the hydride shift mechanism shown in Scheme 18 involving formic acid as a product of formaldehyde oxidation. This is the only prebiotic synthesis of thymine so far described starting from one-carbon atom precursors as simple as formamide and formaldehyde. 

Fluorouracil [flure oh YOOR a sil] (5-FU), a pyrimidine analog, has a stable fluorine atom in place of a hydrogen atom at position 5 of the uracil ring. The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic acid, thus depriving the cell of one of the essential precursors for DNA synthesis. 

The hydrolytic lability of N.O-acetals varies widely. One extreme is exemplified by a synthesis of the cyanobacterial hepatotoxin Cylindrospermopsin [Scheme 8.157]345 in which hydrolysis of the oxazolidine ring in 157.1 required HCI in aqueous THF at 85 °C The penultimate step in the synthesis required hydrolysis of two N-MOM groups on the uracil ring but the positively charged guanidi-nium salt 157.3 thwarted a second protonation required for the hydrolysis hence, 12 M HCI at 95 °C was required to secure the product 157 4. 

Mertes investigated the coupling of the 5-mercuriuridines with styrenes in aqueous media resulting in alkylation of the uracil nucleotides. Carbon alkylation of C-5 on the uracil ring in the ribo- and deoxyri-bonucleosides and nucleotides was obtained in high yields by this method. A similar reaction was used by Langer et al. in the synthesis of 5-(3-amino)allyluridine and deoxyuridine-5 -triphosphates (AA-UTP and AA-dUTP) (6.12) ... 

The required functionality is introduced into the 5 position of the uracil ring by hydroxymethylation of 2, 3 -isopropylideneuridine followed by oxidation of the hydroxymethyl derivative with active Mn02 to yield 5-formyl-2, 3 -isopropylideneuridine. The latter is converted into the mono- and triphosphate by conventional procedures. During the synthesis of the monophosphate by the method of Tener, a base-catalyzed anomerization occurs so that a mixture of the a- and j8-anomers of 5-formyluridine monophosphate is produced. After conversion to the triphosphate, the two anomeric triphosphates may be separated. 

Partly saturated pyrazino[l,2-r-]pyrimidines were prepared by formation of the pyrazine ring. 2-Substituted-8-hydroxy-3,4-dihydro-177,277-pyrazino[l,2-r-]pyrimidin-l-ones were prepared by a [6+0] synthesis involving cyclization of 6-hydroxy-pyrimidine-4-(fV-hydroxyethyl)carboxamides <2005W02005/087766>. The 2/7-pyra-zino[l,2-c]pyrimidine-3-carboxamide 164 (Y = NH) was formed from [5+1] atom fragments via the uracil derivative 163 (Y = NH) and DMF-dimethyl acetal. Compounds 163 were prepared from 6-chloromethyluracil and glycine methyl ester 162 (Y = NH) (Scheme 20) <2004W02004/014354>. 

In the course of their studies of pseudouridine,164 Asbun and S. B. Binkley183 reported the synthesis of 5-/3-D-arabinofuranosyl- and 5-/3-D-xylofuranosyl-uracil (258 and 259) by the acid-catalyzed ring-closure of the corresponding alditol derivatives. The configuration at the anomeric carbon atom was determined on the basis of optical rotatory dispersion studies. 

The common pyrimidine ribonucleotides are cytidine 5 -monophosphate (CMP cytidylate) and uridine 5 -monophosphate (UMP uridylate), which contain the pyrimidines cytosine and uracil. De novo pyrimidine nucleotide biosynthesis (Fig. 22-36) proceeds in a somewhat different manner from purine nucleotide synthesis the six-membered pyrimidine ring is made first and then attached to ribose 5-phosphate. Required in this process is carbamoyl phosphate, also an intermediate in the urea cycle (see Fig. 18-10). However, as we noted... 

Uracil is removed from the DNA by a uracil glycosidase which excises the base from the sugar ring. This activity is analogous to the hydrolytic activity of the isoleucyl-tRNA synthetase toward Val-tRNAIle. In both cases the hydrolytic site is too small by the size of one methylene group to accommodate the substrate that is to be left intact. In DNA synthesis, the editing is performed by a separate enzyme, since the editing can wait until after polymerization. As this luxury is not permitted in protein synthesis, the hydrolytic function is on the synthetase, so that correction can occur before the misacylated tRNA leaves the enzyme. 

The key step in the synthesis was bromination of ketone 59, followed by hydrogenation to liberate the free guanidine, which underwent an intramolecular Sn2 reaction to form the tetrahydropyrimidine ring B. Further hydrogenation reduced the ketone to yield 42% of 63 containing the fully functionalized tricyclic system and protected hydroxymethyl-uracil side chain of cylindrospermopsin. Hydrolysis of the pyrimidine of 63 in concentrated hydrochloric acid at reflux and selective monosulfation completed the synthesis of cylindrospermopsin. 

More complex, but still feasible, is the synthesis of pyrimidine bases from simple prebiotic substrates, although the reported yields of these reactions are relatively low. In this context, two main prebiotic precursors have been identified cyanoethine and a primary product of its hydrolysis, cyanoacetaldehyde. These compounds contain a preformed C-C bond which is incorporated in the C5-C6 position of the pyrimidine ring. In 1968 Ferris and co-workers reported that the reaction of cyanoethine with cyanate at 30 °C yields cytosine and, after its hydrolysis, uracil in acceptable yield [27]. trans-Cyanovinylurea was recovered as a key intermediate for this transformation. However, this reaction requires relatively high concentrations of cyanate (>0.1 mol/1), unlikely to occur in aqueous media due to its rapid degradation to carbon dioxide and ammonia. Cyanoethine also reacts with cyanate and yields cytosine and uracil at elevated temperatures. In this reaction urea or guanidine (also considered as prebiotic organic compounds) can easily replace cyanate (Figure 8.8) [26]. 

From both a biochemical and a synthetical point of view the synthesis of hydrogenated uracils by direct reduction of the pyrimidine ring is a reaction of considerable importance. These reduced uracils bear a similar relationship to /3-aminoacids as the hydantoins do to a-aminoacids. A practical method of reducing uracil combinations, therefore, opens up a new method of synthesizing representatives of this important class of... 

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