Adenine, 9- displacement reactions

As in the case of pyrimidine bases discussed previously, adenine and guanine are subject to nucleophilic displacement reactions at particular sites on their ring structures (Figure 1.50). Both compounds are reactive with nucleophiles at C-2, C-6, and C-8, with C-8 being the most common target for modification. However, the purines are much less reactive to nucleophiles than the pyrimidines. Hydrazine, hydroxylamine, and bisulfite—all important reactive species with cytosine, thymine, and uracil—are almost unreactive with guanine and adenine. 

It was shown that the 2-methylsulfanyl group of 2-(methylsulfanyl)adenine could not be replaced successfully by ammonia under a variety of conditions and this experience was duplicated using allcylamines." However, in the case of 2-(methylsulfanyl)purin-6-ol it is possible to perform the displacement reaction in alcoholic amine solution to give, for example, the 2-dimethylamino derivative 3. ... 

A comparison was made of the displacement reaction occurring on 2-(mcthylsulfinyl)-adeninc and its 1-oxide. 2-(Mclhylsulfinyl)adenine 1-oxide was readily converted to isoguanine 1-oxidc (10) in 4% aqueous sodium hydroxide (rt) while 2-(methyIsulfinyI)adcnine remained unchanged in this strength of alkali even at 90 C. ... 

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]. 

The reactions outlined in Scheme 96 have been used to prepare 3 -thioadenosine and 9-(3-thio-P-D-xylofuranosyl)adenine. The 0,S-dibenzoate (627), one of the products formed in the displacement reaction with sodium thiobenzoate, arises from an S 0 benzoyl migration and benzoylation of the liberated 3 -thiol group. The other product isolated from this displacement reaction was 9-(2-0-benzoyl-3-deoxy-P-D- /ycero-pent-3-enofuranosyl)adenine. Hydrogenolysis of the dibenzoate (627) and a related 2 -thiobenzoate [prepared from 5, /V -dipivaloyl-9-(2-deoxy-2-iodo-P-D-arabinofuranosyl)adenine] gave 3 - and 2 -deoxyadenosine after removal of the protecting groups. 

Cleavage at A or G If the DNA is first treated with acid, dimethyl sulfate methylates adenine at the 3-position as well as guanine at the 7-position (not shown). Subsequent reaction with OH and piperidine triggers degradation and displacement of the methylated A or G purine base and strand scission, essentially as indicated here for reaction of dimethyl sulfate with guanine. 

Methyl oxetane-2-carboxylate derivatives (e.g., 284), obtained by ring contraction of aldonolactones, have been employed for the synthesis (279) of the nucleoside / -noroxetanocin [9-(/ -D-eryt/iro-oxetanosyl)adenine, 304] and its a-anomer via an a-chloride obtained by a modified Hunsdiecker reaction. Displacement of chloride by adenine and debenzylation gave 304. The threo isomer of304, /J-epinoroxetanocin (305), was likewise synthesized from D-lyxono-1,4-lactone. The oxetane nucleosides display potent antiviral activity against the human immunodeficiency virus (HIV). 

With oxygen-free atmospheres, attack at the 8-position is followed by degradation to 5-formamidopyrimidines (71).126,127 The complexity of this reaction is shown by the fact that adenine gives, in addition to the 5-formamidopyrimidine, some 8-oxoadenine128 and small amounts of hypoxanthine, produced by oxo displacement of the amino group. 

The reaction of an epoxide containing molecule with a nucleophile is typically an excellent manner in which to open the epoxide ring. A recent synthesis of carbocyclic nucleoside analogues provides an excellent example of reaction conditions that epoxides can sometimes withstand <07T5050>. Treatment of epoxide 18 with chloropurine under Mitsunobu conditions provides a good yield of epoxy purine derivative 19. This derivative was then converted to adenine derivative 20 by ester hydrolysis and subsequent chloride displacement with cyclopropylamine. 

A nucleoside derivative of 4-acetamido-4-deoxy-D-xyIofuranose was synthesized by a series of reactions. Partial benzoylation of methyl )8-L-arabinopyranoside produces " methyl 2,3-di-0-benzoyl-j3-L-arabinopyranoside. p-Toluenesulfonylation at 0-4, followed by displacement with sodium azide, gives methyl 4-azido-2,3-di-0-benzoyl-4-deoxy-a-D-xylopyranoside. Hydrogenation, debenzoylation, N-acetylation, and acetolysis yield 4-acetamido-l,2,3,5-tetra-0-acetyl-4-deoxy-D-xylofuranose (D-enantiomorph of 191), which reacts in the presence of titanium tetrachloride in chloroform with chloromercuri-(6-benzoyladenine), giving, after deacylation, 9-(4-acetamido-4-deoxy-)8-D-xylofuranosyl)adenine. ... 

Coenzymes - Many enzymes require nonprotein coenzymes for catalytic activity.8 These are cosubstrates, and must be constantly reconverted into their active form for catalysis to continue. This is not a problem for growing microorganisms since the normal metabolic processes ensure an adequate supply of coenzymes. However, with purified, or immobilized enzymes, maintaining a sufficient concentration of coenzyme can pose a major problem. Coenzymes are expensive and it is seldom economically feasible to add them in stoichiometric amounts. This is often undesirable for chemical reasons, e.g., the coenzyme may be unstable, or the eventual build-up of high concentrations of its inactive form may Induce displacement of an equilibrium reaction in the opposite direction to that desired.3 It is therefore necessary to use catalytic amounts of coenzymes and to ensure that the active forms are continuously regenerated. Some coenzymes present little or no problem in this regard since they are automatically reformed under the normal aqueous reaction conditions or in the presence of oxygen. These include biotin, pyrldoxal phosphate (PLP), thiamine pyrophosphate, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD).1 ... 

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. 

It is quite often most convenient to prepare a desired purine nucleoside by transformations at the purine moiety of another purine nucleoside. Perhaps the most useful and frequently employed transformation is the nucleophilic displacement of a chlorine atom or an alkylthio group attached to C-2, C-6, or C-8 of the purine nucleus. In his early work, Fischer established that the order of reactivity of the chlorine atoms attached to a purine is Cl-6 > Cl-2 Cl-8, so that, by choosing the proper sequence of reactions, a variety of products can be obtained. Thus, as already described, Fischer was able to prepare the n-glucosyl analogs of adenine and guanosine by the appropriate transformations of 2,8-dichloro-9- -D-glucopyranosyladenine. 

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