Nucleosides from glycals

Besides the conventional methods, the metallo-carbene route to access cyclic compounds has become a versatile tool in sugar chemistry. Synthesis of stavudine 112, an antiviral nucleoside, from an allyl alcohol [101] is realized by a Mo(CO)5-mediated cyclization reaction (O Scheme 26). Molybdenum hexacarbonyl smoothly reacts with the triple bond of 113 to generate the intermediate Mo-carbene, which undergoes a clean cyclorearrangement to yield the furanoid glycal 114. Alkynol isomerization is effected by group-6 transition metal carbonyl complexes [102]. 

As illustrated in Schemes 4.1.4 through 4.1.9, the use of pyrimidinyl mercuric acetates have been instrumental in the development of C-nucleosides. Although the comparison in Scheme 4.1.9 illustrates the utility of aryl iodides in addition to aryl mercury compounds, the nature of the specific reagents were quite different. As shown in Scheme 4.1.11, Zhang, etal.,10 utilized pyrimidinyl iodides in the preparation of C-nucleosides from furanose glycals. As illustrated, the product mixture composition was highly susceptible to the specific reaction conditions used. Thus, of the two products shown, either is available in comparable yields. 

The cycloadducts formed from glycals and dibenzyl azodicarboxyl-ate, anomalously linked nucleosides from 2-deoxy-D-ribose, and certain other heterocyclic derivatives are covered in Chapter 9. 

Several stereoselective syntheses of 4-(ribofuranosyl)imidazole nucleosides were reported. Imidazole 53 was obtained from 50 by a Mitsunobu cyclization [95TL3165]. Treatment of a suitably protected ribofuranosyl chloride with two equivalents of a lithioimidazole afforded the 1-(5-imidazolyl)ribofuranoid glycal (54) directly which undergoes elimination to the furylimidazole (55) [95CPB152]. 

Nucleosides based upon monocyclic, fused and spirocyclic oxepines have been synthesised via nitrone cycloaddition reactions <07JOC7427>, while oxepine nucleic acids were synthesised from the ring expansion of cyclopropanated glycals <07JACS8259>. 

A two-step synthesis of modified 2 -C-nucleoside precursor, ethyl [2-(5-methyl-2,4-dioxo-3,4-dihydro-2i/-pyrimidin-l-yl)-4-hydroxyl-5-hydroxymethyltetra-hydrofuran-3-yl]fluoro-acetate 172, from protected glycal 170 and xanthate has been developed following the same idea, and a diastereomeric 1 1 mixture of 2,3-trans product 171 was obtained in 57% yield (O Scheme 46). The use of triethylborane as a free-radical initiator was less successful and a longer reaction time was also required. Interestingly, introducing th)miine at C-1 in the presence of silver triflate at 0°C was highly stereoselective, and only a C, C2-trans linked product was detected. 

A brand-new methodology for synthesizing glycals from noncarbohydrate precursors, one based on cyclization of acetylenic alcohols, has emerged from the field of metalorganics. Molybdenum pentacarbonyl-trialkylamine complexes have been found to efficiently catalyze cyclization of l-alkyn-4-ols to substituted dihydrofurans [233,234]. This same transformation has been successfully carried out on asymmetrically substituted alcohols the furanoid glycals 132, 134, and 135 (O Scheme 45) so obtained have in turn been used as intermediates in the synthesis of nucleosides [235]. 

The observation that, under acidic conditions, 2,3-dihydro-4if-pyran will substitute at position 9 of purine derivatives led to the suggestion that nucleosides might be prepared directly from glycals. Although the conditions employed during synthesis of the tetrahydropyranyl derivatives were unsuitable for interaction between 6-chloropurine and 3,4-di-O-acetyl-D-arabinal, when these two compoimds were fused together in the presence of p-toluenesulfonic acid, a mixture of 6-chloro-9-(3,4-di-0-acetyl-2-deoxy-a- and -/3-D-er2/iAro-pentopyranosyl)purines resulted, from which the known a-D anomer was isolated in pure form. Alternatively, an unsaturated nucleoside was obtained from tri-O-acetyl-D-glucal by this method (see p. 91). 

In the area of 2, 3 -didehydro-2, 3 -dideoxynucleosides, a new route to compounds of this type in the pyrimidine series is outlined in Scheme 4. The thioglycoside 54 was produced directly from deoxyribose and thiophenol in acidic conditions, and the condensations to form the nucleoside derivatives were P-selective by about 2 l/ A full account has been given of the formation of 2, 3 -didehydro-2, 3 -dideoxy systems from 2, 3 -dimesylates, protected at 0-5, by treatment with telluride anion (see Vol. 27, p. 247)7 Treatment of the furanoid glycal 55, made by cyclization of an acetylenic alcohol (Chapter 13), with silylated thymine in the presence of iodine, followed by sodium methoxide, provides a new route to d4T (56)7 A new synthesis of d4T (56) from 5-methyluridine has also been described, as has a route to d4T labelled with at C-1, which starts from [l- C]-ribose and proceeds via [r- C]-5-methyluridine, convertible in very high yield to [l - C]-d4T. ... 

There has been a full account of the synthesis of the 2 -stannylated alkene 135 (X = SnBua) by base-induced stannyl migration from C-6 (see Vol. 32, p. 275), and the application of this compound to the preparation of the alkenyl halides 135 (X = Cl, Br, I), and products with carbon substituents at C-2 through Stille couplings. Reaction of di-O-acetyl-L-rhamnal with silylated thjmiine gave the 2 -enopyranosyl nucleoside by allylic rearrangement, as a mixture of anomers. A paper discussing a glycal substituted at C-3 with a nucleobase is mentioned in Chapter 10, and a 3 -ene derived from thymidine is mentioned in Section 17. 

Kawakami H, Ebata T, Koseki K, Okano K, Matsushita H, Ebata T, Koseki K, Okano K, Matsumoto K, Matsushita H (1993) Nucleoside synthesis from furanoid glycals. Heterocycles 36 665-669... 

Reference is made in Chapter 3 to the synthesis of C-glycosides from glycal derivatives by use of palladium adducts, and related work leading to 2,3-unsaturated C-nucleosides is reported in Chapter 20. 

The 5-deoxy-fluoro-sugar derivatives (15) and (16) have been synthesised from D-glucose for incorporation into potential chemotherapeutic nucleosides. Improvements to Ogawa s method for the synthesis of 2-deoxy- -glycosides, involving addition of arylsulphenyl esters of the desired aglycon to glycals, with... 

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