0-Hydroxynitrosamines

Scheme L A mechanism for the formaldehyde catalyzed dehydration of p-hydroxynitrosamines.

Scheme 5. Transformation expected to spontaneously follow enzymatic a -hydroxylation of a p-hydroxynitrosamine.

Scheme 6, A summary of some data on the biochemical retroaldoUlike fragment tation of four p-hydroxynitrosamines.

These results support our hypothesis that there is a retroaldol like cleavage of 3-hydroxynitrosamines which occurs in biological systems. Our results agree with the data of Kruger, Preussmann, and Blattmann. The fact that the tertiary nitros-aminoalcohols undergo the cleavage as well as their secondary counterparts demonstrates that oxidation to a ketone is not a... 

It has been demonstrated that beta-hydroxynitrosamines such as NDE1A may undergo retroaldol-type reactions in strongly alkaline medium to form nitrosamlnes of lower molecular weight (19, 20). In some cases the nitrosamlnes formed from the retroaldol reaction are more potent animal carcinogens than is NDE1A. 

These epoxides are very reactive and are excellent alkylating agents. They may be the primary metabolic products of vinyl nitrosamines. One interesting reaction of the epoxides demands the intermediacy of long sought-after a-hydroxynitrosamine. 

The base-catalyzed cleavage of B-hydroxynitrosamines occurs as is shown in equation 4 to produce a smaller fragment nitrosamine and the carbonyl compound. This reaction is formally analogous to the retroaldol cleavage of a B-hydroxyaldehyde or ketone and as we will see below, appears to be mechanistically related to this transformation. We have demonstrated that this reaction occurs with a wide range of structurally variant B-hydroxynitrosamines 5). Table 1 lists the structure, yield, and reactivity estimate of the compounds that we have studied so far under the same conditions. A variety of conditions have been used to in-... 

Hydroxynitrosamine Base Induced Fragmentation Products, Yields, Reaction Times, and Half-Lives. 

In Table 1, we have recorded the yields of fragment nitrosamine produced when the B-hydroxynitrosamine is treated with potassium t-butoxide in tetrahydrofuran (THF) at 70° (5). Reported yields are by no means maximal and the conditions were chosen so that we could compare the rates of cleavage of a number of different B-hydroxynitrosamines. By using an appropriate alkoxide-alcohol system, a nearly quantitative yield of fragment nitrosamine can be produced in this retroaldol type cleavage reaction. 

It is important to recognize that one of the factors which may affect the yield of these transformations is that the reaction is reversible (in theory). Seebach and Enders have developed an excellent synthesis for B-hydroxynitrosamines that is effectively the reverse of the transformation discussed here (7 ). The first step of this transformation, shown in equation 5, involves the re-... 

Although our investigation of the mechanism of this transformation is incomplete at present, our data are consistent with the view that the fragmentation is an example of the retroaldol cleavage of a B-hydroxynitrosamine as depicted in Scheme 2. Such a hypothesis requires that the a-nitrosamino carbanion possess a stability similar to that of an enolate ion. Keefer and Fodor s discovery of the acidity of the a-hydrogen of the nitrosamino function ( ) and Seebach and Ender s extensive utilization of this fact in organic synthesis (7 ) adequately substantiate this point. 

If the fragmentation of the alkoxide is rate-determining and endothermic, one would expect the transition state structure to resemble the products and thence be influenced by the relative stability of the carbonyl fragment. A transformation similar to the retroaldol cleavage of B-hydroxynitrosamines has been observed. Kruger reported that the treatment of 2-ketopropylpropylnitrosa-mine with refluxing potassium hydroxide in alcohol led to the production of methyl propylnitrosamine as is illustrated in equation 6 (10). This transformation is also under study in our laboratory. 

Several other 8-hydroxynitrosamines have been or are likely to be found in environmental samples. Among these are N-nitroso-3-hydroxypyrrolidine X (l ) (found in bacon), N-nitrosobis(2-hy-droxypropyl)amine XI (a potent pancreatic carcinogen in hamsters, the amino progenitor of which is used in many of the same applications as diethanolamine) (16), and the N-nitroso derivatives of the common drugs ephedrine XII (17) and ethambutol XIII (18), both of which have been shown to be carcinogenic. 

The a-oxidation pathway ofTV-nitrosodiethanolamine metabolism (Figure 2) leads to the formation of an a-hydroxynitrosamine that rapidly decomposes, producing glycol aldehyde, acetaldehyde, ethylene glycol and molecular nitrogen. The latter is assumed to arise from a reactive (2-hydroxyethyl)diazonium ion, which probably is responsible for the formation of 2-hydroxyethylated adducts in DNA (Scherer et al., 1991 Loeppky etal., 1998 Loeppky, 1999). 

The formation of ether derivatives of hydroxynitrosamines converts these nonvolatile A-nitroso derivatives into volatile compounds suitable for analysis by GC and their sensitive detection by TEA or In this sense, the trimethylsilylation using A-methyl trimethylsilyl... 

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