Pterins, substituted synthesis

The evidence for a pterin-substituted 1,2-enedithiolate was first reported by Raja-gopalan, Johnson, and coworkers, who isolated pterins from the oxidative decomposition of molybdenum-bound MPT, Figure 4 [7,49,55,56], In complementary work, Taylor and coworkers confirmed the structure of several of the pterin decomposition products by direct synthesis (see Section V. A) [30,57-59], Urothi-one, first isolated in 1940 from human urine [60], was shown to be a metabolic degradation product of MPT [37], Other isolated pterin-containing decomposition and/or derivatized products from molybdenum enzymes include Form A, Form B (a urothione-like product), and camMPT (Figure 4) [7], Two other pterins, Form Z and the MPT precursor, can be obtained from molybdenum deprived organisms, N. crassa Nit-1, and oxidase-deficient children, neither of which pro-... 

A new, versatile and selective synthesis of 6- and 7-substituted pteridines was reported by Rosowsky (73JOC2073). /3-Keto sulfoxides, which can be viewed as latent a keto aldehydes, react with (251) to give 6-substituted pterins, and the use of a-keto aldehyde hemithioacetals leads in a regiospecific synthesis to the isomeric 7-substituted pterins (equation 85). 

Pterin, 4-amino — see Folic acid, 4-amino-4-deoxy-Pterin, 6-amino-structure, 3, 276 Pterin, 7-amino-structure, 3, 276 Pterin, 6-arylthio-reactivity, 3, 299 Pterin, 6-(l-carboxyethoxy)-synthesis, 3, 309 Pterin, 6-carboxy-7-hydroxy-properties, 3, 277 Pterin, 7-carboxy-6-hydroxy-properties, 3, 277 Pterin, 6-chloro-nucleophilic substitution, 3, 292 synthesis, 3, 290... 

A new synthesis of pterins based on the acylation of 4-amino-5-nitrosopyrimidines with dienoic acid chlorides, followed by a high-yielding intramolecular hetero DA cycloaddition and cleavage of the N—O bond has been reported <06HCA1140>. Several new substituted pterins have been obtained in an efficient one-pot procedure using N,N dimethyldichloromethyleniminium chloride (phosgeniminium chloride) and a suitable pyrazine <06H933>. 

A major recent growth point in substitution reactions has been the synthesis of pteridine glycosides, especially ribosides for study as probes in DNA chemistry taking advantage of the fluorescent properties of pteridines (see Section 10.18.12.4). Typically these reactions are developments of standard methods of glycosylation used with purines and pyrimidines as nucleophiles. In these and in other cases, the ambident nucleophiles within the pterin... 

Despite all of the activity in pyrimidine-based synthesis, only one study has emerged of solid-phase versions of these reactions <2003TL1267, 20030BC1909>. This chemistry was based upon condensation of dicarbonyl compounds with resin-bound pyrimidine-5,6-diamines through a 2-alkylthio link and oxidative cleavage as described in Section 10.18.7.2. The value of alkylthio substituents in the synthesis of complex substituted pterins has also been demonstrated in the synthesis of nucleic acid conjugates <2004OBC3588> (see Section 10.18.12.4). 

The above problems of concomitant formation of regioisomers (as well as products resulting from disproportionation of various dihydro intermediates) have been successfully surmounted by an unequivocal synthesis of 2-amino-3-cyano-5-halomethylpyrazines (16a,b) and their corresponding 1-oxides (28a,b), which can then be utilized for the construction of isomer-free 6-substituted pteridines and pterins (Scheme 3.3a). Thus, condensation of / -chloropyruval-doxime or / -bromopyruvaldoxime, derived from diketene by chlorination or bromination, respectively, with aminomalononitrile tosylate in 2-propanol gives the 2-amino-3-cyano-5-halomethylpyrazine 1-oxides (28a) and (28b). Deoxygenation to (16a) and (16b) is readily accomplished with phosphorus trichloride [47]. 

PCD deficient patients excrete 7-biopterin (137), called primaterin, in their urine [152-154], which had not been observed in normal mammals. The mechanism of the 7-substituted pterin synthesis from 6-substitute has been proposed [155,156] (Scheme 33). When 95 is rapidly dehydrated to 45 via PCD, the dihydroxypropyl side chain of 95 is retained at its 6-position. However, in the absence of PCD activity, the rate of conversion of unstable 95 is slow. Therefore, its pyrazine ring is opened to give 98, and recyclization of 98 to the 7-substituted pterin derivative proceeds via spiro intermediate 138 [89,156]. 

The modeling and ultimate total synthesis of molybdopterin and Mo-co have been hampered by difficulties associated with the pterin chemistry involved. However, synthetic assaults on molybdopterin, the molybdenum cofactor, and the degradation products of the molybdenum cofactor are now well underway. The total chemical synthesis of urothi-one (7), the postulated metabolic excretory product of Mo-co (25), has recently been reported (4 7). Compound 7 is a naturally occurring substituted thiophene that is found in the urine of normal humans. It is absent (25) from the urine of children who lack the molybdenum cofactor due to a genetic defect and who are unable to metabolize sulfite (48). The absolute configuration of Form A (8), another degradation product of... 

The condensation of 2,5,6-triaminopyrimidin-4-one (76) vith unsymmetrical dicarbonyl compounds 77 led to the substituted pterins, vith preferential formation of the un vanted 7-isomer rather than the 6-isomer. A one-pot synthesis of 6-methylpterin 78 involved condensation vith methylglyoxal (77) at a controlled temperature (0-5 °C). Sodium bisulfate vas used to mask the more reactive aldehyde function. Under the action of micro vave irradiation, however, the 6-isomer can be obtained with total regioselectivity without addition of sodium bisulfate or hydrazine hydrate (Scheme 5.22) [66]. 

In 2002 Isay-type condensations for synthesis of 6-substituted pterins, including pterin sugar derivatives and 2-substituted quinoxalines, were developed under microwave irradiation conditions [103]. Interestingly, the isomer-free 6-substituted pterins desired were obtained in moderate to good yields whereas mixtures of both 6- and 7-isomers (major) are usually formed when conventional Isay type condensations are used. 

A regioselective synthesis of 6-substituted pterins 729, 730, and 731 was achieved using an MW-assisted direct Isay-type condensation of triamine 728 with methyl-glyoxal or aldohexoses to give under MWI, without addition of sodium bisulfate or hydrazine hydrate, 729 in 70% yield within 62 s and the sugar derivatives 730 and 731 in 40% and 38% yields, respectively, within 270 s (Scheme 141) (02TL8371). 

Treatment of pterin 8-oxide (15) with a mixture of trifluoroacetic acid and its anhydride under mild conditions provides a facile synthesis of xanthopterin (16) (95—100 %) (see Scheme 11). Analogous rearrangement of 2,4-diaminopteridine 8-oxide (17) takes place under more forcing conditions, but methyl substitution in the 6-position of compounds (15) and (17) effectively blocks the rearrangement,... 

In Table 5 the five antimalarials are arranged in order of increasing potency with respect to inhibition of the synthesis of thymidylate (plus signs). The most potent compound contains a pyrido (2, 3 d) pyrimidine nucleus and somewhat resembles a pterin derivate. The others are substituted pyrimidines. 

An Amadori rearrangement was also found to take place as the first step in the reaction of o-glucose (1) with 2,4,5-triamino-6-hydroxypyrimidine (41) to give substituted pterine derivatives 42 (Scheme 11) [42]. Such compounds are important intermediates for the synthesis of folic acids and hydroxyalkylpterine and are of interest in context with the biogenesis of pterines 43 [43]. 

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