C-branched nucleosides

Z. Xi, J. Rong, and J. Chattopadhyaya, Diastereospecific synthesis of 2 - or 3 -C-branched nucleosides through intramolecular free-radical capture by silicon-tethered acetylene, Tetrahedron 50 5255 (1994). 

Rozner published a synthesis of 3, 5 -C-branched nucleosides and used the addition of protected propargyl alcohol to an a-siloxyaldehyde to control absolute stereochemistry at C2 [25], He noted that use of the bulky trityl and TBDPS protecting groups were essential for the reaction. In this respect the corresponding product could be isolated in only low yield (>10%) when changing to MOM-pro-tected propargyl alcohol and TBS-protected oxyaldehyde (Eq. 20). 

The most representative examples of intramolecular free radical cyclization in carbohydrate chemistry are the syntheses of C-branched nucleosides derivatives. The key step in C-branched nucleoside preparation is the regio- and stereo-controlled formation of a new C-C bond at the branching point of the ribofuranose ring [58]. Among published reports, a temporary silicon connection is becoming a growing interest in the syntheses of C-branched nucleosides by intramolecular radical cyclization. 

C-branched nucleosides have been found to possess a number of biological properties, including antibacterial, antitumour, and antiviral activity. This has fueled a drive for preparing novel analogs of such molecules. Chattopadhyaya and co-workers have published extensively on the manipulation of nucleosides using intramolecular radical cyclizations [76], which are carried out under mild and, importantly, neutral conditions, making them compatible with a range of functionality. 

The 4 -acyl nucleosides 77, 78, 4 -C-branched nucleosides such as 79, and l-A -[(2 -deoxy-P-D-n7>o-pentofuranosyl)methyl] thymine, cytosine and adenosine. A number of carbocyclic nucleosides cis-l-[(2-hydroxymethyl)cyclo-pentyl]uridine, 4,4-dihydroxymethyl-(l-thymin-l-yl)cyclohexane, and the cyclopropyl-fused carbocylic analogue 81. ... 

Plavec J, Garg N, Chattopadhyaya J (1993) How does the steric effect drive the sugar crarformation in the 3-C-branched nucleosides J Chem Soc Chem Coirunun 1011-1014... 

Vinyltins were used for synthetic purpose in radical addition/elimination sequences. The main limitation comes from the necessity to functionalize the olefin by suitable groups, such as phenyl [307] or esters [308], in order to stabilize the transient carbon-stereoselective preparation of I -C branched nucleosides (Scheme 6.36) [309]. An intramolecular version was also developed, giving access to methylene cyclopentane units [310]. 

M. Nomura, S. Shuto, M. Tanaka, T. Sasaki, S. Mori, S. Shigeta, and A. Matsuda, Nucleosides and Nucleotides. 185. Synthesis and biological activities of 4 -a-C-branched-chain sugar pyrimidine nucleosides, J. Med. Chem., 42 (1999) 2901-2908. 

X. Zhen, P. Agback, J. Plavec, A. Sandstrom, and J. Chattopadhyaya, New stereocontrolled synthesis of isomeric C-branched-p-D-nucleosides by intramolecular free-radical cyclization— opening reactions based on temporary siiicon connection. Tetrahedron 45 349 (1992). 

In this chapter, synthetic methodologies for the preparation of C-branched carbohydrates, and nucleosides will be summarized and discussed. 

A number of nucleoside analogues, either used clinically as anticancer dmgs or evaluated in clinical studies, are of C-branched structures which can be prepared by introducing methyl [12], allyl [13], ethynyl [12a,14], trifluoromethyl [15], and the other groups [16] through addition of organometallics to sugar moieties. This will not be discussed in detail here. 

Zinc-mediated Barbier-t) e addition of 238, followed by Luche s procedure obtained a mixture of the homoallylic alcohol diastereomers 239 and 240. Alcohol 239 was carried through benzoylation, deketalization, silylation, and ozonolysis, to produce C-branched y-lactone 241. Benzoylation of 240 followed by hydroboration, PCC oxidation, debenzoylation, and alkaline-promoted cyclization directly formed C3-branching 2-deoxyfuranose 242 [87] (O Scheme 63). A novel method for stereoselective synthesis of 4 -a-carbon-substituted nucleosides, through epoxidation of 4, 5 -unsaturated nucleosides and SnCU-promoted epoxy ring opening, was... 

Hossain, N. and Herdewijn, P. (1998) Facile synthesis of 3 -C-branched 1,5-anhydrohexitol nuclesides. Nucleosides Nucleotides, 17, 1781-1786 Hossain, N., van Halbeek, H., De Clercq, E. and Herdewijn, P. (1998) Synthesis of 3 -C-branched l, 5 -anhydromannitol nucleosides as new antiherpes agents. Tetrahedron, 54, 2209-2226 Ishikawa, T., Shimizu,... 

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. ... 

The condensation of 3 -oxo-2, 5 -di-0-trityluridine with Wittig and related reagents which produces 3-C-branched unsaturated nucleosides is mentioned in Chapter 20... 

Application of the reaction sequence periodate oxidation - cyclization with nitromethane hydrogenation to rt6o-nucleosides provides a general synthetic entry to 3-aminohexosyl p5nimidines i7-20) and purines 21-as) which otherwise are not readily accessible. That this sequence can be extended to nitroethane to give 3 -C-methyl branched aminosugar nucleosides, has been demonstrated, starting from uridine 4.10,26)... 

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