Adenosine displacement reaction

A one-pot procedure for the transformation of 6-thiopurine nucleosides to 6-aminopurines was developed using DMDO as the oxidant in the presence of a stoichiometric amount of various amines <1996T6759>. For example, 6-thio-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)purine was readily converted to the 6-alkylamino derivatives (6-amino, 75% yield 6-methylamino, 55% yield). Similarly, A -6-acetyl-8-thio-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)adenosine was converted to A -6-acetyl-8-methylamino-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)adenosine (DMDO, methylamine, CH2CI2, 25 °C, 83% yield). Less nucleophilic 2-mercaptopurine derivatives did not undergo the displacement reaction, however, and only the products of dithiane formation and desulfurization were isolated. 

As is known for other nucleoside kinases, the steady-state kinetics of the adenosine kinase reaction is complex owing to regulatory effects. Adenosine and AMP apparently bind at a regulatory site, where they modulate activity, as well as at the active site, where they act as substrates. These interactions complicate the kinetics, but a careful analysis shows that the basic kinetic pathway is sequential and involves the compulsory formation of ternary complexes (79). Thus, the kinetics is consistent with the stereochemistry and suggests that the phospho transfer is a direct, one-step displacement between substrates bound at the active site in a ternary complex. Complications introduced into the mechanistic analysis of this enzyme by the adventitious phosphorylation of the protein by ATP have been discussed elsewhere (7). 

The initial step in cytokinin (adenine derivatives with an isoprenoid side chain) biosynthesis is Al-prenylation of adenosine 5-phosphate, a reaction catalyzed by adenosine phosphate-isopentenyltransferases (PTs). PTs catalyze the isopropene unit transfer reaction to an acceptor (adenosine monophosphate, AMP) which serves as a nucleophile. The latter is alkylated by DMAPP to form, by an Sivf2-nucleophilic displacement reaction, a prenylated AMP and pyrophosphate (PP) as products [14, 15]. 

Vitamin B12s reacts rapidly with alkyl iodides (e.g., methyl iodide or a 5 -chloro derivative of adenosine) via nucleophilic displacement to form the alkyl cobalt forms of vitamin B12 (Eq. 16-31). These reactions provide a convenient way of preparing isotopically labeled alkyl cobalamins, including those selectively... 

The reaction probably proceeds through the formation of an imino analogue of mixed anhydrides by nucleophilic displacement of cyanide during the phosphate activation. Cyanogen bromide was found to be more effective than DISN in this transformation. Since higher yields were obtained in the preparation of the cyclic phosphate from 3 -adenosinc phosphate than from 2/-adenosine phosphate, the authors suggested the formation of an activated... 

Figure 29.32 Spliceosome assembly and action. U1 binds the 5 splice site and U2 binds to the branch point. A preformed U4-US-U6 complex then joins the assembly to form the complete spliceosome. The U6 snRNA re-folds and binds the 5 splice site, displacing Ul, Extensive Interactions between U6 and U2 displace U4. Then, in the first transesterification step, the branch-site adenosine attacks the S splice site, making a lariat Intermediate. US holds the two exons in close proximity, and the second transesterification takes place, with the S splice-site hydroxyl group attacking the 3 splice site. These reactions result in the mature spliced mRNA and a lariat form of the intron bound by U2. US. and U6. After T. Villa, j. A. Pletss. and C, Guthrie. Cell 109(2002) H9-1S2.]...

The drug most commonly used to treat Trichomonas vaginalis and some entamoebal infections, l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole [Flagyl, (3)] can also produce an aversion to ethanol in patients. It has now been shown that while (3) will displace the nicotinamide moiety of NAD+ or NADP+ in the presence of pyridine transglycosidase to produce new nucleotides, there is no reaction between (3) and NADH. It is not, however, believed that the toxicity towards anaerobic organisms is due to the new adenosine pyrophosphates derived from (3). 

Leucine aminopeptidase is interesting in that its active site contains two zinc atoms which together bind and activate the water molecule [74]. Despite this enzyme containing a dinuclear metal center at its active site, its mechanism, and specifically its mode of proton transfers reactions, appear to follow the general theme established by thermolysin and carboxypeptidase Adenosine deaminase and other members of the family of nucleoside and nucleotide deaminases utilize zinc-bound water as the catalytic nucleophile to displace ammonia from the 6-position of purines or the 4-position of pyrimidines and in all cases display inverse solvent deuterium isotope effects ranging from 0.3 to 0.8 on fec/Kni [75-80]. These effects are reminiscent of those observed for metallopro-teases and have their origins, like those of the proteases, in fractionation factors for the protons of the bound water that are less than one. 

Adenine gives mainly 3-alkylated products under neutral conditions, but 7/9-substitution when there is a base present. Adenosine derivatives on the other hand usually give 1-alkylated products, presumably due to hindrance to N-3-attack by the pen-9-ribose substituent. That attack can still occur at C-3 is shown by the intramolecular quatemisation of N-3, which is an important side reaction when 5 -halides are subjected to displacement conditions. 

Nitration of 6-substituted purines at C-2, using a mixture of tetra-n-butylammonium nitrate and trifluo-roacetic anhydride, is an exceptionally useful functionalisation of the purine ring system. The reaction works for both electron-rich (adenosine), 6-alkoxypurines and electron-poor (6-chloropurine) substrates, but full protection of all OH and NH groups is required. This is not a simple electrophihc substitution - the mechanism has been shown, using 6-chloro-9-Boc purine, to involve sequential nitration of N-7, addition of trifluoroacetoxy at C-8 and then migration of the nitro group to C-2. The final, re-aromatisation, step involves elimination of trifluoroacetic acid. Displacement of a 2-nitro group, thus introduced, by fluoride as nucleophile (see 27.5 for nucleophilic substitutions) can be made the means to synthesise 2-fluoroadenosine. ... 

A useful conversion of a nucleoside 2,6-dithione into a 6-methylamino-adenosine via oxidation with dimethyldioxirane, illustrates several instructive points. The presumed intermediates are sulfinic acids the 2-sulfinic acid loses sulfur dioxide to leave hydrogen at C-2, and nucleophilic displacement of the 6-sulfinic acid (or possibly the sulfonic acid after further oxidation) introduces the amino group. Similar reactions can be carried out on pyrimidine thiones. The scheme shows intermediates derived from a disulfinic acid - it is not clear in what order oxidations/loss of sulfur dioxide/displacements take place. 

The formation of a quaternary salt (7) upon heating 2,3-0-isopropylidene-5-0-(p-tolylsulfonyl)adenosine, observed by Clark, Todd, and Zussman and referred to elsewhere in this review, accounts for the low yield, since this monomolecular quaterni-zation takes place much more rapidly than bimolecular displacement of the p-tolyl-sulfonyloxy group by the methyl mercaptide ion. Recently, this difficulty has been overcome and a good yield of L-2-amino-4-(5-thioaden-5-yl)butyric acid obtained by the reaction of (9b) with the disodium salt of homocysteine in liquid ammonia. This compound had also been prepared enzymically. ... 

---