Nucleoside Cyclic Pyrophosphates

3 Nucleoside Cyclic Pyrophosphates. Extensive work has been carried out by Matsuda et al. in their efforts to synthesise chemically stable cyclic adenosine diphosphate ribose (cADPR) analogues. The carbocyclic inosine analogue (83) was first prepared through an efficient cyclisation of an 8-bromo-A-1 -[5 -(phosphoryl)carbocyclic-ribosyl]inosine 5 -phenylthiophos- 

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When AMP is heated under reflux in DMF, the 2, 3 -cyclic phosphate is formed, and cyclic phosphates can also be obtained from nucleosides and ortho-, pyro-, or poly-phosphoric acids under the same conditions. Promotion of phosphorylation by DMF is well known and the reaction with AMP is probably intermolecular as no 3, 5 -cyclic AMP can be detected. Minor products in the latter reaction are the 2, 3 -cyclic 5 -diphosphate and the 2 (30,5 -diphosphate. The synthesis of adenosine 2 (3 )-phosphate 5 -pyrophosphate has been achieved by the phosphoromorpholidate method used in a synthesis of Co A. ... 

If 8-mercaptoadenosine-2, 3/-cyclic phosphate is treated with a phosphateactivating agent, e.g. diphenyl phosphorochloridate or tetraphenyl pyrophosphate, an oligomer is formed in which each phosphate is esterified by the 2 - and 3 -hydroxy-groups of one nucleoside residue and the 5 -hydroxy-group of the next. On... 

In the 1,3,2-dioxaphosphole method a bis(2-butene-2,3-diyl) pyrophosphate is used as the condensing agent. It allows two successive esterifications of one phosphate group to be performed without additional activation. First a 5 -O-protected nucleoside is added in methylene chloride in the second reaction an unprotected nucleoside can be used, since only the 3 OH group is able to attack the cyclic enediol 3 -nucleosidyl phosphotriester. Protected dinucleoside triesters are obtained in 80% yield. Removals of protective groups, methoxytrityl by means of trifluoroacetic acid in methylene chloride and 1-methylacetonyl by aqueous triethyl-amine, also give about 80% yield (F. Ramirez, 1975, 1977). 

Treatment of nucleoside 5-phosphates 526 with DCC at high dilution affords the cyclic phosphates 527. Without the high dilution the expected pyrophosphates are obtained. 

The nucleotide anhydride, adenosine 5 -triphosphate (24), when digested with aqueous barium hydroxide, gives a complex mixture containing such products as adenine, adenosine, adenosine 2 -, 3 -, and 5 -phosphates, adenosine 5 -pyrophosphate, and adenosine 2 (or 3 ),5 -diphosphate. - In addition, a nucleotide was foimd in this digest whose structure proved - to be that of adenosine 3 5 -cyclic phosphate (25). This component did not consume metaperiodate, and was degraded enzymically to adenosine 5 -phosphate (26) and adenosine 3 -phosphate (27), without the formation of adenosine 2 -phosphate. Hydrolysis of (25) with an acidic ion-exchange resin did, however, produce the 2 - and 3 -phosphates of adenosine. Compound (25) possessed only one phosphoryl dissociation, and showed a ratio of nucleoside to phosphate of 1 1, which, along with a molecular-... 

However, Borden and Smithi have found that treatment of the p-nitro-phenyl esters of 2 -deoxyribonucleoside 3 - and 5 -phosphates and of ribo-nucleoside 5 -phosphates with potassium fert-butoxide in methyl sulfoxide affords the corresponding nucleoside 3 5 -cyclic phosphates in excellent yields. Other phosphorus-activated nucleotides, such as nucleoside 5 -phosphorofluoridates, 5 -(2,4-dinitrophenyl phosphate)s and 5 -(PS-P " diphenyl pyrophosphate) s, were also cyclized to nucleoside 3 5 -cyclic... 

This may be overcome by forming the imidazolidate of the pyrophosphate and reacting this with the nucleoside monophosphate. Alternatively, the cyclic carbonate may be hydrolyzed by treatment with aqueous triethylamine. The imidazolidate method is presently the method of choice for the synthesis of ATP and GTP analogues modified at the base and/or sugar portion. One... 

The commonly used syntheses of nucleoside triphosphates are the Yoshikawa method and the Ludwig-Eckstein method. The Yoshikawa method , the simplest one, is shown in the upper reaction in Scheme 6. The ehemistry involves first the S -monophosphotylation of an un-proteeted nucleoside with phosphorous o)ychloride (POCI3), which affords a highly reactive intermediate (76). This intermediate is then reaeted with pyrophosphate to yield the cyclic triphosphate (77), followed by hydrolysis to the target (80). This method allows the selective... 

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