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This review highlights the first total synthesis of (alpha S, beta S)-beta-hydroxywybutosine, the identity of which was established with fluorescent nucleoside isolated from rat liver tRNA(Phe). Three general prerequisites for the synthesis of the target are emphasized: construction of new 9-beta-D-ribofuranosyl-3-methylpurines; the first syntheses of optically active gamma-aryl-alpha,beta-unsaturated amino acids; and a new method for hydrogenolysis of glycols through their cyclic carbonates to give the gamma-aryl-beta-hydroxy amino acid derivatives. The mechanism for the formation of cyclic carbonates from reactions of glycols with (COCl)2 and highly selective preparation of the cyclic oxalates are also described.

1-Benzylwye (8) underwent electrophilic substitution at the 7-position in the presence of phosgene and pyridine in tetrahydrofuran (THF) to afford the 1,4-dihydropyridines (11, 10, and 14) together with the carboxylic acid 6 and its methyl ester 2 after short treatment of the reaction mixture with methanol and then with water. When triethylamine was used instead of pyridine, phosgene reacted with triethylamine rather than 8, producing (E)-3-(diethylamino)propenoyl chloride (17) and diethylcarbamoyl chloride (18).

An improved synthesis of 3-beta-D-ribofuranosylwybutine (2) has been achieved by the Wittig reaction between 4,6-dimethyl-9-oxo-3-[2,3,5-tris-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-4,9-dihydro-3H-imidazo[1,2-a]-purine-7-carbaldehyde (8) and the phosphorane derived from (R)-2-[(methoxycarbonyl)amino]-3-(triphenylphosphonio)propanoate (9), followed successively by methylation, hydrogenation, and deprotection. On the other hand, the minor nucleoside wybutosine of yeast tRNA(Phe) was isolated on a scale of 80 microg by partial digestion of unfractionated tRNA (1 g) with nuclease P1, followed successively by reversed-phase column chromatography, complete digestion with nuclease P1/alkaline phosphatase, and reversed-phase HPLC. Comparison of this nucleoside with 2 has unambiguously established that the structure of wybutosine is (alphaS)-alpha-[(methoxycarbonyl)-amino]-4,6-dimethyl-9-oxo-3-beta-D-ribofuranosyl-4,9-dihydro-3H-imidazo[1,2-a]purine-7-butanoic acid methyl ester (2).

The first synthesis of (alphaS,betaS)-beta-hydroxy-alpha-[(methoxycarbonyl)amino]-4,6-dimethyl-9-oxo-3-beta-D-ribofuranosyl-4,9-dihydro-3H-imidazo[1,2-a]purine-7-butanoic acid methyl ester [(alphaS,betaS)-11] has been achieved by OsO(4) oxidation of [S-(E)]-4-[4,6-dimethyl-9-oxo-3-[2,3,5-tris-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-4,9-dihydro-3H-imidazo[1,2-a]purin-7-yl]-2-[(methoxycarbonyl)amino]-3-butenoic acid methyl ester (13) followed by successive gamma-deoxygenation through the cyclocarbonates, separation from the (alphaS,betaR)-isomer by means of flash chromatography, and deprotection. On the other hand, the minor nucleoside of rat liver tRNA(Phe) was isolated on a scale of 100 microg by partial digestion of unfractionated tRNA (1 g) with nuclease P(1), followed by reverse-phase column chromatography, complete digestion with nuclease P(1)/alkaline phosphatase, and reverse-phase HPLC. Comparison of this nucleoside with the synthetic one has unambiguously established its structure to be (alphaS,betaS)-11.

The unstable minor nucleosides, wyosine, wybutosine, and β-hydroxywybutosine, were isolated from tRNAs in sufficient amounts for determination of their structures.

Alkylation of 8-oxoadenosine (13) with 4-benzyloxy-3, 5-dibromobenzyl bromide (20), followed by Dimroth rearrangement and acid hydrolysis, provided N-(3, 5-dibromo-4-hydroxybenzyl)-8-oxoadenosine (15). The 2'-deoxy version of this reaction sequence accomplished the first synthesis of N-(3, 5-dibromo-4-hydroxybenzyl)-8-oxodenine (16), which is the correct expression for marine ascidian purine aplidiamine.

1-Benzyl-4, 6-dimethyl-4, 9-dihydro-1H-imidazo[1, 2-α]purin-9-one bearing an alkyl, a 1-alkenyl, a hydroxymethyl, a methoxymethyl, or a formyl group at the 7-position (3a-e) underwent rearrangement through fission and recyclization of the pyrimidine ring, attaining equilibrium with the corresponding positional isomer 4a-e in MeONa-MeOH at 25°C, whereas 7-methoxycarbonyl and 7-halogeno compounds 3f-i were irreversibly converted into the rearranged products 4f-i under identical conditions. The position of equilibrium appears to be affected by the electronic factor of the substitutent rather than the steric one. The pseudo-first-order rate constants measured for the reactions of 3a, b, d, f-i suggest that the reaction is accelerated by the electron-withdrawing substituent. However, the reactions of this series of compounds do not always obey the Hammett equation.On the other hand, a linear free energy relationship (ρ=+3.2) was observed for the rates of rearrangement of a 6-demethyl series of compounds 9a, b, d, f, g, when σ0P values were employed. The deviations from this relationship for the reactions with the 7-hydroxymethyl compound 9c and the 7-carbamoyl compound 9e are explicable in terms of the accelerative effect through intramolecular hydrogen bonding with the carbonyl oxygen at the 9-position.

Phenyl, tolyl, anisyl, and 1-naphthyl iodides (7a-g, n) smoothly reacted with (S)-N-(benzyloxycarbonyl)-vinylglycine (6) in H2O in the presence of Pd(OAc)2, Bu4NCl, and NaHCO3 at 45°C, producing [S-(E)]-(2-arylvinyl)glycine derivatives 8a-g, n of high enantiomeric purity. The yields of the reactions of 3- (7f), 2- (7e), and 4-iodoanisoles (7g) increased in this order. This relationship between the yield and the position of substitution has been found to hold for bromophenyl iodides (7i-k), although somewhat lower chemical and optical yields were realized in these cases. Phenyl iodide 7l carrying an electron-withdrawing 4-acetyl group gave an unsatisfactory result, and more electron-deficient 4-nitrophenyl iodide (7m) did not provide the desired product. All these results suggest that the reaction is advantageous with electron-sufficient substrates 7. However, this was not the case for 4-iodophenol (7h), as well as some heterocyclic iodides.

The synthesis of the title compounds started with the Vilsmeier reaction of 3-[2,3,5- tris -O-(tert- butyldimethylsilyl)-β- d - ribofuranosyl]wye ( 5b ) and proceeded through the Wittig reaction with ( R )- N -(methoxycarbonyl)-3-(triphenylphosphonio)alaninate ( 4 ), methylation with trimethylsilyldiazomethane, OsO 4 oxidation, cyclocondensation with triphosgene, and catalytic hydrogenolysis. Chromatographic separation of the resulting diastereomeric mixture and subsequent deprotection afforded the two desired nucleoside [ [R-(R ∗ ,S ∗ )]- and [S-(R ∗ ,R ∗ )]- 2b ] for the first time.

3-Alkyl-8-hydroxyadenines (5) have been shown to undergo regioselective methylation at the 7- or 9-position depending on the reaction conditions. Thus, treatment of 5a, c with dimetyl sulfate in aqueous NaOH provided 3-alkyl-7-methyl-8-oxoadenines (6b, h) in 48-60% yields, together with 3-alkyl-8-methoxyadenines 4d, h), whereas treatment of 5a-c with MeI in AcNMe2 at 40°C for 48h and subsequent anion exchange afforded 3-alkyl-9-methyl-8-oxoadenine hydrochlorides (7d, g, h·HCl) in 50-59% yieds. However, the reactions of 5a, c with EtI or PhCH2Br took place slowly, giving complex mixtures of products.Compounds 6d, h were alternatively prepared in 51% and 31% yields, respectively, together with 3-alkyl-7, 9-dimethyl-8-oxoadenine hydrochlorides (11d, h·HCl), by treatment of 3-alkyl-8-methoxyadenines (4d, h) with MeI in AcNMe2 at room temperature for 6 h, followed by hydrolysis with boiling aqueous HCl. This method was applicable to ethylation with EtI, and 7-ethyl-3-methyl-8-oxoadenine (6e) was obtained in 70% yield from 8-ethoxy-3-methyladenine (4e). Compound 11h was shown to be obtainable through futher methylation of 6h. Thus, 11d, h were prepared in good yields by treatment of 6d, h with MeI in AcNMe2.Compounds 7, to which zwitterionic structures were assigned, were stable in 0.1 N aqueous NaOH at room temperature, whereas 11d, h were no longer stable under such conditions.

1-Methyl-5-(methylamino)imidazole-4-carbonitrile (4a) afforded three minor ring-opened products (5a, 6a, 10a) besides its 2-oxo derivative 3a on treatment with ethyl chloroformate in aqueous sodium bicarbonate. The geometrical isomers of these trisubstituted propenenitriles (5a, 6a, 10a) can be separated from each other by means of TLC, but equilibrate rapidly in solution. Because these compounds were converted into 3a in aqueous sodium hydroxide, alkaline treatment of the reaction mixture of 4a afforded a higher yield of 3a; although 3a also rapidly changed into other compounds in 0.1 N aqueous sodium hydroxide at room temperature, it could be recovered from the solution in high yield.5-Alkylamino homologues 3b, c were also prepared in 64% and 46% yields, respectively, by similar treatment of the substrates 4b, c having the 5-alkylamino substituents. The same products 3b, c were obtainable from the positional isomers 4d, e in 83% and 51% yields, respectively. These outcomes are interpretable by supposing that the reactions proceed through common intermediates, equilibrated mixtures of (E)- and (Z)-[2-(alkylamino)-1-cyano-2-(methylamino)ethenyl]carbamic acid ethyl esters (7).

On treatment with boiling H2O for 5-6h, 1-alkoxy-7-alkyladenines (13) underwent hydrolytic cleavage at the N(1)-C(2) and the N(1)-C(6) bonds to produce the imidazole-5-carboxamidines (14) in 53-60% yields and the imidazole-5-carboxamides (18) in 5-7% yields, respectively. The Dimroth rearrangement of 13 to N6-alkoxy-7-alkyladenine (15) was found to proceed through 14 more slowly than that of the 9-alkyl analogues 1 at pH 7 and above, being accompanied by hydrolysis to give the deformylated product (16) and by deamination through 18 leading to 7-alkylhypoxanthine (12), 1-alkoxy-7-alkylhypoxanthine (19), and 1-alkyl-4-aminoimidazole-5-carboxamide (20). Interestingly, the N(1)-C(6) bond fission product 17a was obtained from 13a by treatment with 0.01N aqueous NaOH at 4°C for 35d, but in only 2% yield, or more efficiently (in 56% yield) by pyrolysis at 150°C for 1h. On the other hand, 13 underwent acid hydrolysis faster than 1, providing the deformylated product 16 in 85-96% yields on treatment with 1-2N aqueous HCl at room temperature for 2-5h. 4-amino-N'-methoxy-1-methyl-5-carboxamidine (16a) was alternatively obtained in 59% yield by treatment of 1-methoxy-7-methyladenine (13a) with boiling 2N aqueous NaOH for 10min. Efficient preparations of the rearranged products 15 (80-86%) were accomplished by treating 13 with boiling 0.1N aqueous NaOH for 20-30min.

An alternative synthesis of 3, 9-dimethyl-8-oxoadenine (N6-demethylcaissarone) hydrochloride (5a·HCl) starting from 9-methyl-8-oxoadenine (17) is described. The synthesis proceeded through N(7)-benzylation, N(1)-oxidation, and O-benzylation to afford the 1-benzyloxy derivative 25, which afforded the ring-opened formamide derivative 26 on treatment with dilute aqueous NaOH. Methylation of the monocycle 26 with MeI in the presence of K2CO3, followed by acid-catalyzed cyclization and subsequent catalytic hydrogenolysis afforded 5a·HCl. The key intermediate 25 was alternatively prepared from 17 by N-oxidation and subsequent O, N(7)-dibenzylation with PhCH2Br in the presence of K2CO3.

7-Methyladenine (6a) and 7-ethyladenine (6b) afforded the N(1)-oxides 7a, b in 78% yield each on treatment with m-chloroperoxybenzoic acid at room temperature; this is analogous to the previously reported N-oxidation of 7-benzyladenine (6c) to give the N(1)-oxide 7c. When treated with an excess of methyl iodide, ethyl iodide, or benzyl bromide in N, N-dimethylacetamide at room temperature, each of the 1-oxides 7a-c underwent alkylation almost exculsively at the oxygen atom of the N-oxide group. The products, isolated in good yields, were the salts 8d-l·HX of the nine 1-alkoxy-7-alkyladenines, in which either the O-alkyl or the N(7)-alkyl group is any one of methyl, ethyl, and benzyl. The UV and 1H-NMR spectral data for 8·HX and some of their free bases 8 are presented.

7-Alkoxy-3-alkyladenine perchlorates (9) were prepared from 3-alkyladenines (4) by N-oxidation followed by alkylation with alkyl halides in N, N-dimethylacetamide. The 7-methoxy derivatives 9d, g, j thus obtained afforded 3-methyl-8-hydroxyadenine (7a), 3-ethyl-8-hydroxyadenine (7b), and 3-benzyl-8-hydroxyadenine (7c) in 74%, 72%, and 39% yields, respectively, on treatment with boiling 0.1 N aqueous sodium hydroxide, whereas treatment of 9d, g, j with sodium methoxide in methanol at room temperature afforded 3-alkyl-8-methoxyadenines (10m, p, q) in 91%-98% yields. Similar treatment of 9d with sodium ethoxide in ethanol afforded 8-ethoxy-3-methyladenine (10n) in 89% yield. Compounds 10m, q were alternatively prepared from 9d, j in 77% and 84% yields, respectively, by treatment with 0.1 N aqueous sodium hydroxide in the presence of methanol. This method was suitable for the synthesis of the 8-benzyloxy compound 10o : it was obtained in 60% yield by treating 7-benzyloxy-3-methyladenine perchlorate (9f) with a mixture of aqueous sodium hydroxide and benzyl alcohol. Compounds 7 were alternatively prepared from 9 through 10. For example, 7c was obtained in 84% overall yield by treatment of 9j with sodium methoxide, followed by hydrolysis of the resulting 10q with boiling 1 N hydrochloric acid.On the other hand, methylation of 3-methyladenine 7-oxide (8a) with dimethyl sulfate in 0.1 N aqueous sodium hydroxide in the absence or presence of added methanol afforded N6, 3-dimethyladenine 7-oxide (14) in 13% or 14% yield, together with 7a (4% yield) or 10m (11%).

On treatment with boiling 2 N hydrochloric acid for 48 h, N6-methyl-8-oxoadenosine (1), 1-methyl-8-oxoadenosine (5), and 7-methyl-8-oxoadenosine (8) underwent glycosidic hydrolysis, though much more slowly than the corresponding 8-unsubstituted compounds, furniching the aglycons (2, 6, and 9) in 45%-63% yields. Under these conditions, N6-methyl-8-oxoadenine (2) rearranged to 9-methyl-8-oxoadenine (3) (8% yield), presumably through fission and reclosure of the imidazole ring. Apparent methyl migration also occurred with 3-methyl-8-hydroxyadenine (7), which afforded 1-methyl-8-oxoadenine (6) in 9% yield on treatment with hydrochloric acid under similar conditions.

Oxidations of N6-methyladenine (8a) and N6-benzyladenine (8b) with m-chloroperoxybenzoic acid (MCPBA) in methanol have been found to afford the N(1)-oxides 7a, b in 36% and 35% yields, respectively. The structure of 7b has been established by leading it to N6-methoxyadenine (10) through O-methylation, Dimroth rearrangement, and nonreductive debenzylation. On the other hand, N6, N6-dimethyladenine (16) afforded the N(3)-oxide 17 in 40% yield on treatment with MCPBA in methanol. On the basis of these findings, together with data accumulated for N-oxidations of adenine, Nx-monosubstituted adenines, and 6-substituted purines, the formation of hydrogen bonding between the 6-amino NH and the carbonyl oxygen of a peroxycarboxylic acid may account for regioselective N(1)- and N(7)-oxidations of adenine and Nx-monosubstituted adenines.

Deoxygenation of the 1,2-glycol (±)-5 was achieved at the position adjacent to the heterocycle through the cyclic carbonate (±)-14, providing the monohydroxy compound 6. This new method of regioselective deoxygenation was employed for the first synthesis of β-hydroxywybutines [[R-(R ∗ ,S ∗ )]- and [S-(R ∗ ,R ∗ )]-2] : oxidation of the methyl butenoate 7 with osmium tetroxide, followed by deoxygenation through the cyclic carbonates (19 and 20), afforded the two diastereomers of 2.

A detailed account is given of the first unequivocal synthesis of adenine 7-oxide (8). The synthesis started with peroxycarboxylic acid oxidation of 3-benzyladenine (6), readily obtainable from adenine (1) by benzylation, and proceeded through nonreductive debenzylation of the resulting 3-benzyladenine 7-oxide (7). The location of the oxygen function in 7 and 8 was confirmed by their chemical reactions including deamination and methylation and by X-ray crystallographic analysis. A UV spectroscopic approach suggested that the neutral species of 8 exists in H2O as an equilibrated mixture of the N(7)-oxide (8) and N(7)-OH (21) tautomers. Treatment of 6 with 30% aqueous H2O2 in MeOH in the presence of MeCN and KHCO3 at 30°C produced the N(7)-oxide 7 and 7-acetamido-3-benzyladenine (15) in 12% and 1% yields, respectively.

In contrast to the N(3)-selectivity in N-alkylation, N-oxidation of 7-benzyladenine (17) with m-chloroperoxybenzoic acid in MeOH has been found to give 7-benzyladenine 1-oxide (18) in 76% yield. Alternatively, the same N-oxide (18) has been synthesized in 81% yield from 1-benzyl-4-(ethoxymethyleneamino)imidazole-5-carbonitrile(19) and hydroxylamine. Treatment of 1-benzyl-4-(hydroxyamino)imidazole-5-carbonitrile (24), obtained in 63% yield from the corresponding 4-nitro drivative (20) by catalytic hydrogenation (Pt/H2), with formamidine acetate in boiling EtOH furnished 7-benzyladenine 3-oxyde (23) in 78% yield. A UV spectroscopic approach indicated that the neutral species of 18 exists in H2O in the N(1)-oxide form rather than the N(1)-OH form (27).

A full account is given of the first syntheses of 6-mercaptopurine 7-N-oxide (4) and 6-methylthiopurine 7-N-oxide (5). The synthesis of 4 followed a "phenacylamine route", which started from condensation of 4, 6-dichloro-5-nitropyrimidine (15) with N-(4-methoxybenzyl)phenacylamine to form the phenacylaminopyrimidine derivative (11) and proceeded through conversion into the mercapto derivative, intramolecular cyclization between the NO2 nitrogen atom and the phenacyl carbanion to give 6-mercapto-9-(4-methoxybenzyl)purine 7-N-oxide (12), and removal of the 4-methoxybenzyl group. S-Methylation of 12 and removal of the 4-methoxybenzyl group afforded 5. The location of the oxygen function in 4, 5, and 12 was confirmed by X-ray crystallographic analysis of 5·H2O, which was shown to exist in the N(7)-OH form (19). A UV spectroscopic approach suggested that the neutral species of 4 exists in HO as the N(7)-OH tautomer (21), whereas that of 5 exists as an equilibrated mixture of the N(7)-oxide (5) and the N(7)-OH (19) tautomers. In the in vitro bioassay of antileukemic activity against murine L5178Y cells, the N-oxides 4 and 12 were found to be weakly cytotoxic.

Oxidation of 1-benzyladenine (12) with m-chloroperoxybenzoic acid in MeOH or in MeOH-0.5 M phosphate buffer (pH 6.6) has been found to afford 1-benzyladenine 7-oxide (13) as the main product. Nonreductive debenzylation of 13 gave adenine 7-oxide (14) in 63% yield. The structure of 13 was unequivocally established by an X-ray crystallographic analysis.

Among N-protected and unprotected vinylglycines tested, N-(benzyloxycarbonyl)vinylglycine (1c) provided the highest yield of the coupling product 3c in the reaction with 1-iodo-4-methoxybenzene (2) in N, N-dimethylformamide in the presence of palladium acetate, sodium bicarbonate, and tetrabutylammonium chloride, whereas none of the desired product was obtained in the reaction with 4-methoxyphenyl trifluoromethanesulfonate (7). The stereoselectivity of the reaction was reversed by employing triethylamine instead of sodium bicarbonate to furnish (Z)-3c predominantly. In the presene of sodium bicarbonate, replacement of the solvent by water improved not only the chemical yield and stereoselectivity but also the optical purity : geometrically pure (E)-3c of 96% ee was formed in a good yield.

An alternative synthesis of the key intermediate 8 for the synthesis of wybutine 1 has been attained through the Heck reaction between (S)-N-(methoxycarbonyl)vinylglycine 13 and 1-benzyl-7-iodowye 7. The nucleoside version of this method using 7-iodo-3-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)wye 19, followed by catalytic hydrogenation, afforded a mixture of diastereoisomers 22 and 23. Separation of isomer 22 by means of high-performance liquid chromatography, followed successively by esterification and deprotection has accomplished the first synthesis of 3-(β-D-ribofuranosyl)wybutine 3, which is the most probable structure for wybutosine isolated from phenylalanine transfer ribonucleic acids.

Oxalyl chloride reacts with a wide range of acyclic 1,2-glycols 1 in the presence of triethylamine to produce 1,3-dioxolan-2-ones 3 together with 1,4-dioxane-2,3-diones 2. Ethylene glycol (1d), monosubstituted ethylene glycols 1e, j—l, and erythro-1,2-disubstituted ethylene glycols 1f, m, o provide the cyclic carbonates 3 as the minor products, while the threo-compounds 1g, i, n, p, q and pinacol (1h) afford 3 as the main products. The formation of 3 may be rationalized in terms of stereoelectronically controlled cleavage of the conjugate base 17− of the tetrahedral intermediates. The rate for the conformational change of 17− into 18− and the equilibrium constant between these conformers are proposed to be the major factors affecting the reaction pattern.

(R)-[2-Carboxy-2-[(methoxycarbonyl)amino]ethyl]triphenylphosphonium chloride (1) was converted by treatment with anion exchange resin (HCO-3) into the inner salt 13h, which gave a better yield (43%) than 1 in the Wittig reaction with benzaldehyde to afford the [S-(E)]-(2-phenylvinyl)glycine derivative 24. The inner salt 13i bearing an N-benzyloxycarbonyl group was prepared by hydrogenolysis of (R)-[3-benzyloxy-2-[(benzyloxycarbonyl)amino]-3-oxopropyl]triphenylphosphonium chloride (11e) over palladium on carbon, followed by dehydrochlorination. Hydrogenolysis of 11e over Pearlman's catalyst afforded the unprotected phosphonium chloride 12 (X=Cl). N-tert-Butoxycarbonylation of 12 followed by dehydrochlorination afforded 13j, which was more efficiently prepared through hydrogenolysis of (R)-[3-benzyloxy-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]triphenylphosphonium chloride (11f).The usefulness of 13h-j as building blocks for the synthesis of configurationally labile (2-arylvinyl)glycine derivatives was exemplified by the Wittig reactions with piperonal, which exclusively afforded the (E)-isomers 18h-j with high optical purity in 28-39% yield.

Dehydration of 5-(cyanomethylamino)-1-methyl-1H-imidazole-4-carboxamide (14a) with a combination of phosphorus oxychloride and triethylamine afforded the nitrile 17a. This compound underwent selective hydration at the cyanamide moiety to furnish the urea 18a followed by cyclization to 3, 9-dimethylisaguaninae (19a) under alkaline conditions. Similar dehydration of the nucleoside analog 14b followed by treatment with 0.1 N aqueous sodium hydroxide led to the first access to 3-methylisoguanosine (19c). Although 3-methylisoguanosine (19c) proved to undergo hydrolysis at the N-glycosidic bond most slowly among the known 3-methyl-9-β-D-ribofuranosylpurines in 0.1 N hydrochloric acid at 25°C, the rate was 650 times faster than that for the unmethylated isoguanosine (3).

The phosphonium chloride 6 having an optically active amino acid moiety was synthesized from (S)-serine benzylester tosylate (2b) through a six-step route. The utility of 6 as a reagent for the Witting reaction was exemplified in the olefination with benzaldehyde, affording the (E)-β, γ-unsaturated amino acid derivative 11 as a sole geometrical ispmer. This new method of amino acid homologation was successuflly employed for the first chiral synthesis of wybutine (1c), the minor base isolated from yeast phenylalanine transfer ribonucleic acids : the Wittig reaction between 6 and the tricyclic aldehyde 16 followed successively by methylation and catalytic reduction afforded 1c. Comparison of wybutine with synthetic 1c has unequivocally established that wybutine has an S configuration.

Oxidation of 7-benzyladenine (9) with m-chloroperoxy-benzoic acid in MeOH has been found to yield 7-benzyladenine 1-oxide (11) as the main product. Alternatively, the same N-oxide (11) has been synthesized in 81% yield from 1-benzyl-4-(ethoxymethyleneamino)imidazole-5-carbonitrile (12) and hydroxylamine. Treatment of 1-benzyl-4-(hydroxyamino)imida- zole-5-carbonitrile (17), prepared in 63% yield from the corresponding 4-nitro derivative (13) by catalytic reduction (Pt/H 2 ), with formamidine acetate in boiling EtOH gave 7-benzyladenine 3-oxide (16) in 83% yield

The first unequivocal synthetic route to adenine 7-oxide (7) has been established. The route started with peroxycarboxylic acid oxidation of 3-benzyladenine (5), readily obtainable from adenine (2) by benzylation, and proceeded through nonreductive debenzylation of the resulting 3-benzyladenine 7-oxide (6)

Oxalyl chloride reacts with a wide range of acyclic 1,2-glycols 1 in the presence of triethylamine to produce 1,3-dioxolan-2-ones 3 together with 1,4-dioxane-2,3-diones 2. Ethylene glycol (1d), monosubstituted ethylene glycols 1e, j—l, and erythro-1,2-disubstituted ethylene glycols 1f, m, o provide the cyclic carbonates 3 as the minor products, while the threo-compounds 1g, i, n, p, q and pinacol (1h) afford 3 as the main products. The formation of 3 may be rationalized in terms of stereoelectronically controlled cleavage of the conjugate base 17− of the tetrahedral intermediates. The rate for the conformational change of 17− into 18− and the equilibrium constant between these conformers are proposed to be the major factors affecting the reaction pattern.

(R)-[2-Carboxy-2-[(methoxycarbonyl)amino]ethyl]triphenylphosphonium chloride (1) was converted by treatment with anion exchange resin (HCO-3) into the inner salt 13h, which gave a better yield (43%) than 1 in the Wittig reaction with benzaldehyde to afford the [S-(E)]-(2-phenylvinyl)glycine derivative 24. The inner salt 13i bearing an N-benzyloxycarbonyl group was prepared by hydrogenolysis of (R)-[3-benzyloxy-2-[(benzyloxycarbonyl)amino]-3-oxopropyl]triphenylphosphonium chloride (11e) over palladium on carbon, followed by dehydrochlorination. Hydrogenolysis of 11e over Pearlman's catalyst afforded the unprotected phosphonium chloride 12 (X=Cl). N-tert-Butoxycarbonylation of 12 followed by dehydrochlorination afforded 13j, which was more efficiently prepared through hydrogenolysis of (R)-[3-benzyloxy-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]triphenylphosphonium chloride (11f).The usefulness of 13h-j as building blocks for the synthesis of configurationally labile (2-arylvinyl)glycine derivatives was exemplified by the Wittig reactions with piperonal, which exclusively afforded the (E)-isomers 18h-j with high optical purity in 28-39% yield.

6-Mercaptopurine 7-N-oxide (6) has been synthesized for the first time from 4,6-dichloro-5-nitropyrimidine (12) by following a «phenacylamine route» through the intermediates (8) and (9). Methylation of (9) and removal of the p-methoxybenzyl group provided 6-methylthiopurine 7-N- oxide (7)

Vinylglycine (2) has been shown to undergo racemization under acidic conditions. Optically pure 2 was obtained from 2.HCl by enzymatic hydrolysis through N-acetylvinylglycine (5), followed by recrystallization. (S)-N-(Methoxycarbonyl)vinylglycine (6) was configurationally so unstable under acidic conditions that 6 could not be obtained from 2 in an optically pure form. On the other hand, configurationally stable (S)-N-(9-phenylfluoren-9-yl)vinylglycine methyl ester (9) was synthesized from (S)-homoserine; 9 was hydrolyzed with sodium hydroxide to afford the carboxylic acid 10 of more than 99% ee.

Cyclic oxalates 2 have been efficiently synthesized by the reaction of 1,2-glycols 1 with oxalyl chloride in the presence of pyridine or 2,4,6-trimethylpyridine, rather than triethylamine, or by reaction with 1,1′-oxalyldiimidazole.

Among N-protected and unprotected vinylglycines tested, N-(benzyloxycarbonyl)vinylglycine (1c) provided the highest yield of the coupling product 3c in the reaction with 1-iodo-4-methoxybenzene (2) in N, N-dimethylformamide in the presence of palladium acetate, sodium bicarbonate, and tetrabutylammonium chloride, whereas none of the desired product was obtained in the reaction with 4-methoxyphenyl trifluoromethanesulfonate (7). The stereoselectivity of the reaction was reversed by employing triethylamine instead of sodium bicarbonate to furnish (Z)-3c predominantly. In the presene of sodium bicarbonate, replacement of the solvent by water improved not only the chemical yield and stereoselectivity but also the optical purity : geometrically pure (E)-3c of 96% ee was formed in a good yield.

Deoxygenation of the 1,2-glycol (±)-5 was achieved at the position adjacent to the heterocycle through the cyclic carbonate (±)-14, providing the monohydroxy compound 6. This new method of regioselective deoxygenation was employed for the first synthesis of β-hydroxywybutines [[R-(R ∗ ,S ∗ )]- and [S-(R ∗ ,R ∗ )]-2] : oxidation of the methyl butenoate 7 with osmium tetroxide, followed by deoxygenation through the cyclic carbonates (19 and 20), afforded the two diastereomers of 2.

1-Methyl-5-(methylamino)imidazole-4-carbonitrile (4a) afforded three minor ring-opened products (5a, 6a, 10a) besides its 2-oxo derivative 3a on treatment with ethyl chloroformate in aqueous sodium bicarbonate. The geometrical isomers of these trisubstituted propenenitriles (5a, 6a, 10a) can be separated from each other by means of TLC, but equilibrate rapidly in solution. Because these compounds were converted into 3a in aqueous sodium hydroxide, alkaline treatment of the reaction mixture of 4a afforded a higher yield of 3a; although 3a also rapidly changed into other compounds in 0.1 N aqueous sodium hydroxide at room temperature, it could be recovered from the solution in high yield.5-Alkylamino homologues 3b, c were also prepared in 64% and 46% yields, respectively, by similar treatment of the substrates 4b, c having the 5-alkylamino substituents. The same products 3b, c were obtainable from the positional isomers 4d, e in 83% and 51% yields, respectively. These outcomes are interpretable by supposing that the reactions proceed through common intermediates, equilibrated mixtures of (E)- and (Z)-[2-(alkylamino)-1-cyano-2-(methylamino)ethenyl]carbamic acid ethyl esters (7).