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An unusually facile ring opening of 5-alkoxyoxazoles. Application to the synthesis of dimethoxy-.alpha.-methyldopa J. Org. Chem. 1979, 44, 2042.

In the presence of BuLi, 5-alkoxyoxazoles undergo a ring-opening reaction leading to lithiated isocyanoacetic acid derivs., which are intermediates for the prepn. of a variety of heterocyclic systems and amino acid derivs. Thus, 4-methyl-5-ethoxyoxazole gave LiOC(OEt)CMeN+.tplbond.C-, which was alkylated with alkyl iodides and bromides. Alkylation with 3,4-(MeO)2C6H3CH2Br, and subsequent base hydrolysis gave dimethoxy-.alpha.-methyldopa [3,4-(MeO)2C6H3CH2CMe(NH2)CO2H], which has been converted to .alpha.-methyldopa.

Bis heteroannulation. 1. Model studies in the synthesis of highly oxygenated sesquiterpenes J. Am. Chem. Soc. 1978, 100, 7748.

Acetylenic oxazole I, prepd. in 5 steps from MeCH(NH2)CO2Et, was refluxed for .apprx.72 h in PhEt contg. hydroquinone to give 80-90% II which could be cleaved under mild acid catalysis to give 85-90% III (R = Et). Refluxing II with 1N H2SO4 30-6 h gave 60-5% lactone IV apparently by cyclization of the intermediate III (R = H).

Pteridines. XXXVII. A total synthesis of L-erythro-biopterin and some related 6-(polyhydroxyalkyl)pterins J. Am. Chem. Soc. 1976, 98, 2301.

6-(1-Erythro-1',2'-dihydroxypropyl)pterin was prepd. by cupric acetate oxidn. of 5-deoxy-L-arabinose to its osone, transoximation with acetone oxime to the .alpha.-ketoaldoxime, condensation with benzyl .alpha.-aminocyanoacetate methanesulfate to give II, cyclization with guanidine to biopterin 8-oxide, and deoxygenation with sodium dithionite. The overall yield was 12%. In analogous fashion, 6-(D-arabino-tetrahydroxybutyl)pterin and 6-D-threo-trihydroxypropyl)pterin were prepd. from D-glucose and D-xylose, resp.

Pteridines. XXXV. Total synthesis of asperopterin B J. Org. Chem. 1975, 40, 2336.

Asperopterin B (I) is found in the culture broth of Aspergillus oryzae. Two independent routes to 2,4-diamino-6-hydroxymethyl-7(8H)-pteridinone (II) were described. II was hydrolyzed to isoxanthopterin III which was regiospecifically methylated to give I. Both syntheses of II use the authors' synthetic approach to pteridines.

Pteridines. XXXVI. Syntheses of xanthopterin and isoxanthopterin. Application of N-oxide chemistry to highly functionalized pyrazines and pteridines J. Org. Chem. 1975, 40, 2341.

New synthetic routes to xanthopterin (I) and isoxanthopterin (II) are described. Thus, II was prepd. from 2-amino-3-cyanopyrazine 1-oxide by POCl3 chlorination-deoxygenation to 2-amino-3-cyano-6-chloropyrazine, condensation with guanidine to give 2,4-diamino-7-methoxypteridine, and alk. hydrolysis. Alternatively, II was prepd. from 2-amino-3-(ethoxycarbonyl)pyrazine 1-oxide by Ac2O-AcOH rearrangement to 2-amino-3-ethoxycarbonyl-6(1H)-pyrazinone followed by annelation of the pyrimidine ring with guanidine. Also, II was prepd. from 2,4-diaminopteridine 8-oxide by reaction with pyrrolidine to give 2,4-diamino-7-(1-pyrrolidinyl)pteridine, followed by alk. hydrolysis. I was also prepd. by a no. of new routes which use the N-oxide functionality for the selective positioning of appropriate substituents in the pyrazine ring. Thus, 2-amino-3-cyanopyrazine 4-oxide (prepd. from the isomeric 1-oxide by oxidn. to the 1,4-dioxide followed by selective monodeoxygenation with PCl3) was converted to I by POCl3-DMF deoxygenation-chlorination to give 2-amino-3-cyano-5-chloropyrazine, cyclization with guanidine to 2,4-diamino-6-methoxypteridine, and alk. hydrolysis. The method of choice for the synthesis of pure I involves the selective, quant. isomerization of pterin 8-oxide with (F3CCO)2O-F3CCO2H. The mechanism of this N-oxide rearrangement is discussed, and expts. with model pyrazines and pteridines are described.

Pteridines. XXXIV. Synthesis of 8-hydroxy-7(8H)-pteridinones (pteridine hydroxamic acids) J. Org. Chem. 1975, 40, 2332.

A series of 2,4-diamino-6-alkyl-substituted 8-hydroxy-7(8H)-pteridinones (pteridinehydroxamic acids) (I) was prepd. from 2,4-diamino-6-substituted pteridine 8-oxides by chlorination in glacial AcOH, followed by cleavage of the resulting pteridinehydroxamic acid anhydrides II with ethanolic HCl. An alternative but less satisfactory route to 2,4-diamino-6-methyl-8-hydroxy-7(8H)-pteridinone involved condensation of pyruvohydroxamoyl chloride with aminomalononitrile tosylate to give 2-amino-3-cyano-5-methyl-6-chloropyrazine 1-oxide, hydrolysis to the pyrazinehydroxamic acid III, and cyclization with guanidine.

Pteridines. XXXIII. Unequivocal total synthesis of L-erythro-Biopterin J. Am. Chem. Soc. 1974, 96, 6781.

L-erythro-Biopterin (I) [2-amino-6-(L-erythro-1,2-dihydroxypropyl)-4(3H)-pteridinone] was totally synthesized via: (1) Cu(OAc)2 oxidn. of 5-deoxy-L-arabinose to its osone, (2) trans-oximination with acetone oxime to the .alpha.-oxo aldoxime, (3) condensation with benzyl .alpha.-aminocyanoacetate MeSO3H salt to give 2-amino-3-benzyloxycarbonyl-5-(L-erythro-1,2-dihydroxypropyl)pyrazine 1-oxide, (4) cyclization with guanidine to biopterin 8-oxide, and (5) deoxygenation with Na dithionite. An improved synthesis of 5-deoxy-L-arabinose from L-rhamnose is also described.

Pteridines. XXX. Facile synthesis of xanthopterin J. Am. Chem. Soc. 1973, 95, 4455.

Pterin 8-oxide (I) rearranges quant. to xanthopterin (II) upon dissoln. in a mixt. of CF3CO2H/(CF3CO)2O at 50.degree.

Pteridines. XXVIII. New, general, and unequivocal pterin synthesis J. Am. Chem. Soc. 1973, 95, 6407.

Pterins are prepd. Reaction of an .alpha.-oxoaldoxime or a .alpha.-oxoketoxime with esters of .alpha.-aminocyanoacetic acid gives 2-amino-3-alkoxycarbonyl-pyrazine 1-oxides (I) which cyclized with guanidine to pterin 8-oxides (II). Deoxygenation of the I and II, and the conversion of II to 7,8-dihydropterins, are described.

Pteridines. XXIX. Unequivocal route to 2,4-diamino-6-substituted pteridines J. Am. Chem. Soc. 1973, 95, 6413.

2,4-Diamino-6-substituted pteridines (I) are prepd. Reaction of an .alpha.-keto-aldoxime with aminomalononitrile gives 2-amino-3-cyano-5-substituted pyrazine 1-oxides which yield 2,4-diamino-6-substituted pteridine 8-oxides upon cyclization with guanidine. 2,4-Diaminopteridines are then obtained by deoxygenation of the corresponding 8-oxides, or alternately by prior deoxygenation of these pyrazine 1-oxides, followed by cyclization with guanidine. The conversion of 2-amino-3-cyano-5-methylpyrazine 1-oxide to the corresponding 1,4-dioxide, and a no. of chem. transformations of this latter intermediate, are also described.