Nucleosides with Branched-chain Sugars

The 2 -deoxy-2 -methylene nucleoside 92 has been prepared using a Wittig reaction, and a number of other 4-amino-5-oxo-pyrido[2,3-d]pyrimidine ribonucleosides with chain branches at C-2, C-3 and C-4 were also reported.  

Reagents i, (Tms)2NH, (NH4)2S04 ii, base, HMDS, TmsCI, TmsOTf, MeCN 

A route to 2, 3 -dideoxy-2 -trifluoromethylpyrimidine nucleosides involves the synthesis of the lactone 99, and its separable cis-isomer, from isopropylidene-D-glyceraldehyde, which provides C-3 to C-5. Reduction of 99 and glycosylation gave, with moderate stereoselectivity, the nucleosides 100 (B = Ura, Thy, Cyt), and the cis-isomer of 99 could also be converted to r,2 -tru 5-nucleosides. An alternative route to 100 (B = Ura) proceeds through the difluoromethylene 

Reagents i, BuaSnH, AIBN ii. H2O2. KF. KHCO3 iij, (Me3Sn)2. AIBN iv. TBAF v, TbdmsCI 

A review on HIV-1 specific reverse transcriptase inhibitors has appeared, with special emphasis on TSAO-T (109) and related compounds. Some new analogues of TSAO-T and its TV -methyl derivative have been reported, with ethers and esters replacing the Tbdms group at 0-5, and also with aminogroups at C-5, and some of the ethers and amines had moderate activity.  

The Z-alkene 106, produced by a Wittig reaction, could be isomerized to the E-isomer 107 by Michael addition of thiophenol (selectively from the a-face), followed by oxidation to the sulfoxide and thermal elimination.  

The fused isoxazolidine 108 was made by regioselective and diastereoselective [3+2] cycloaddition, and has been converted to the nucleosides 109.  

A full and extended account has been given of the synthesis of 2, 3 -dideoxy-3 -C-hydroxymethyl purine nucleosides by a photochemical method (see Vol. 28, p. 278).  

The branched glycosyl acetate 110 has been prepared from diisopropylidene-D-glucose and used to make the branched adenine nucleosides 111 -114. Various fluorinated, branched nucleosides 115 (X=H, Me, Hal) have been described, whilst 116 has been made by hydroboration-oxidation of the 3 -C-methylene compound and converted into the bicyclic species 117.  

Acetolysis of the anhydrosugar 118 gave a mixture of pyranosyl and furanosyl glycosyl acetates, which could be converted to the 3 -hydroxymethyl nucleosides 119 and, after a deacetylation-periodate-borohydride sequence, 120 respectively.  

Reagents i, Sml2, HMPA ii, silica gel iii, (Tms)2Thy, Pd2(dba)3, PPhs iv, NH3, MeOH 

Previously reported intermediates (Vol.27, p.253-4) have been converted into other nucleoside analogues with two-carbon chains at C-2, such as the selectively-protected triol 87, prepared by reduction of the lactone 86. 2 -C-Methyl ribonucleosides have been made by Vorbriiggen-type coupling of the appropriate base to a sugar unit (see Chapter 14). 

It has been found that the anti-tumour agent CNDAC (88) (see Vol.27, p.254 and earlier volumes) undergoes equilibration in base to the vt-ribo- epimer 89, degradation to the glycal being a slower process. The arabino-isovast has the 

Chattopadhyaya s laboratory has reported further on systems with extensive modification at C-2 and C-3. The unsaturated bromide 99 was made from a known seconucleoside (Vol.28, p.277) and converted to 100 by treatment with tributylstannane followed by deprotection. In related fashion, 101 was prepared by intramolecular Diels-Alder reaction. 

The doubly-branched pyrimidine nucleosides 102 have been prepared by coupling of silylated uracil with a sugar unit (Chapter 14), and branched pyranosyl systems 103 have been reported. 

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A. Rosenthal and S. N. Mikhailov, Branched-chain sugars. Modifications in the reaction of l,2 5,6-di-0-isopropylidene-oi-D-ribo-hexofuranos-3-ulose with Giignard and oiganolithium reagents, J. Carbohydr. Nucleosides Nucleotides 6 237 (1979). 

The reaction of 2-formylglycals with malononitrile afforded push-pull butadienes with a sugar moiety. The treatment of these branched-chain sugars with ammonia yielded nicotinonitrile acyclo-C-nucleosides. Furthermore, a one-step ring transformation of 2(3)-formylglycals with Af-aryl-acetoacetanilides gave pyridone acyclo-C-nucleosides [140-142]. 

The preparation of the branched-chain sugar found in the naturally occurring nucleoside antibiotic amipurimycin is depicted in Scheme 1. The synthesis involved deoxygenation at C-4 of a 3-ulose derivative with triphenyphosphine-iodine-imidazole in the first step. ... 

C-methyl-a-L-threofuranosyl)adenine has been accomplished by a standard route from the branched-chain sugar. The deamination of this nucleoside with adenosine deaminase was found to be about two hundred times slower than is the case with adenosine itself. ... 

A general review has been published on silicon-tethered reactions with parts devoted to the preparation of branched-chain sugars (including nucleosides), through the addition of radicals generated from (bromomethyl)silyl ether tethers to double bonds or by the addition of radicals generated from phenyl selenides onto allylsilyl ether tethers. ... 

E xides and oxetanes react readily with lithiodithiane to give derivatives of 3- or y-hydroxy aldehydes or ketones. The method has been used for the multistep synthesis of an inomycin fragment, thietane prostaglandin analogs, branched-chain nucleoside sugars, the southern hexahydrobenzctfu-ran unit avermectin, the anti-Gram-positive bacterial elaiphylin andsyn-l,3-polyols. ... 

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