Reductive denitration

The Michael addition of nitro compounds is a useful method for the preparation of various natural products. The Michael addition of nitroalkanes to dehydroalanines gives y-nitro-a-amino acids, which provides a convenient synthesis of side-chain modified a-amino acids (Eq. 4.114).152 Transformations of y-nitro-a-amino acid derivatives into a-amino acids occur by reductive denitration (see Section 7.2) into y-oxygenated a-amino acids by the Nef reaction (Eq. 

Purified mtALDH catalysed the stoichiometric formation of 1,2-GDN and nitrite from GTN, in a reaction that was shown to be dependent on the presence of thiols. It was argued that reductive denitration of GTN involves interaction of one of two adjacent active site thiols with GTN to yield an -SNO2 group, which then reacts with the other thiol to yield nitrite and a disulfide. In a final, essential step the inactive disulfide is converted back to two thiols by external thiol compounds (Scheme 2.2). It is interesting to note that this mechanism is essentially that foreseen by Needleman and colleagues in their proposed nitrate receptor (see earlier). 

Scheme 2.2 Mechanism of reductive denitration of organic nitrates (RONO2) to nitrite, catalysed by mtALDH. Adapted from Chen et al. [95].

The in vivo metabolism of nitrovasodilators, as exemplified above, can result from a number of pathways and mechanisms. The obvious pathways that come to mind first are enzymatic and nonenzymatic hydrolysis. As discussed below, the former pathway does not appear to occur, while the latter should play a limited role in vivo. The two other pathways to be discussed are hemoprotein-catalyzed and thiol-mediated reductive denitrations. 

Fig. 9.6. Postulated mechanisms in the cytochrome P450 catalyzed reductive denitration of organic nitrates. Pathway a shows the hypothetical mechanism for the reduction of organic nitrates to organic nitrites, whereas Pathway b presents the same reaction for organic nitrites.

Further work by Baum and co-workers showed that the nitration of l,l-diamino-2,2-dinitroethylenes with trifluoroacetic anhydride and nitric acid in methylene chloride yields 1,1,1-trinitromethyl derivatives via addition of nitronium ion to the double bond of the enamine such treatment also resulting in the A-nitration of the products. In this way, trini-tromethyl derivatives like (185) and (188) are obtained. Further treatment of these trinitromethyl derivatives with aqueous potassium iodide results in reductive denitration and the formation... 

As discussed above, the nitro groups of tetranitromethane and trinitromethyl compounds are susceptible to nucleophilic attack. Both potassium iodide and alkaline hydrogen peroxide affect the reductive denitration of trinitromethyl groups to em-nitronitronates 1,1,1-trinitroethane (33) is quantitatively reduced to potassium 1,1-dinitroethane (24) on treatment with alkaline hydrogen peroxide. Nucleophiles such as potassium fluoride in DMF can displace nitrite anion from tetranitromethane. Various nucleophiles, including azide, chloride, fluoride and ethoxide have been used to displace one of the nitro groups from fluorotrinitromethane. 

Sugar nitric acid esters are also subject to reductive denitration (see p. 9) and to the chemical reactions typical of sugar nitrates. 

F. Baumberger and A. Vasella, Deoxynitrosugars—stereoelectronic control in the reductive denitration of tertiary nitro ethers. A synthesis of C-glycosides, Helv. Chim. Acta <56 221C (1983). 

The comparatively slow rate of reaction of the 2,3,6-isomer with sulfite ion and with hydrazine has been used as the basis of a method of separating it from other isomers (Ref 1). The comparatively rapid reaction of the 2,4,5-isomer with piperidine forms the basis for a procedure for its colorimetric determination, as noted below The 2,3,4- and 2,4,5-isomers undergo reductive denitration to 2,4-DNT at room temp in good yield with aq Na borohydride (Ref 20) ... 

Reductive denitration was also investigated in the furanose series,45,252 using diethyl (2,3 5,6-di-0-isopropylidene-l-nitro-a-D-mannofuranosyl)phosphonate (158), an anomeric mixture of the analogous phenyl sulfone (159), (4R)-4,7-anhydro-2,3,4-trideoxy-5,6 8,9-di-0-isopropylidene-4-C-nitro-D-manno-nono-... 

Sometimes special structural features render possible a reduction of the porphyrin 7r-system. Chlorins 98a were obtained from the Cu complex 97 by nucleophilic addition to a peripheral double bond activated by a nitro group. Reductive denitration occurred on treatment of 98a with tributylstannane. The chlorins 98b can be easily transformed into alkoxyporphyrins 99, which are enol ethers of oxohydroporphyrins and are treated in Section IV,C (84CC1537). 

Recently, Baum and coworkers154 reported the nitration of 1,1-diamino-2,2-dini-troethylene. On treatment with nitric acid and trifluoroacetic anhydride in methylene chloride at 0 °C, 1,1-enediamines 42 are converted to 3-nitro-2-(trinitromethyl)-l,3-diazacyclic compounds 192 in good yields (equation 79). Compounds 192 have also been prepared from the nitration of 7, although the yields are lower (16-22%). Denitration of 192 to 193 includes a reductive denitration of 192 with potassium iodide and acidification of initially formed salts of 193. Nitration of 193 regenerates 192 (equation 79). 

Reaction of the nitromethyl derivative 77 obtained in four steps from cellobiose peracetate, with the glucose-derived aldehyde 78 and potassium fluoride/18-crown-6 leads to the expected condensation product 79. The acetylation-elimination-reduction sequence (— 80) followed by reductive denitration and total deprotection affords the 0,C-trimer mimic 81. 

CYP177A1 (XplAjjp) Rhodococcus sp. strllY 2WIV, 2WIY, 4EP6 Imidazole Reductive denitration of hexa-hydro-1,3,5-trinitro-1,3,5-triazine (royal demolition explosive, RDX) [135,137]... 

Denitration can be effected by chemical reducing agents (134)- For monomolecular nitrates, reductive denitration with hydrogen and Raney nickel (135) is preferable. Ammonium hydrogen sulfide effectively denitrates the nitrated polysaccharides. 

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