Isonitramine synthesis

The structure of these compounds remained obscure for a long time. Traube originally assigned the structure —N—N—OH to the isonitramino group, but in further researches he found that isonitramines and the derivatives of nitrosohydro-xylamine which he prepared by the action of nitrous acid on -derivatives of hydro-xylamine were identical. He did not, however, draw from this any definite conclusions as to the structure of isonitramines in spite of the fact that by the synthesis of isonitraminoisobutyric acid, Gomberg [63] had confirmed the nitrosohydro-xylamine structure of the isonitramino group. 

A recent synthesis of (+)-nitramine (275) and (-)-isonitramine (276) has been reported [611]. Resolution of an a-substituted p-ketoester with pig liver esterase was the key improvement to provide the required chiral quaternary carbon. Subsequent cyclization of the piperidine ring gave 275 and 276. In a recent synthesis of sibirine (277), a-deprotonation/alkylation of an imine gave an intermediate having the required quaternary carbon,... 

Esterification. The lipase-mediated esterification is promoted by microwave (90°, 15 min.). Four lipases immobilized in microemulsion-based gels retain their activity in catalyzing esterification. Resolution by selective acetylation of ethyl 6-hydroxy-1-cyclohexenecarboxylate gives access to a chiral intermediate for a synthesis of the spirocyclic alkaloids (+)-nitramine, (+)-isonitramine, and (-)-sibirine. 

The basis of this old method is the addition of nitric oxide to alcoholic solutions of sodium salts of C-alkyl derivatives of ethyl ace-toacetate (54) 128,129) (Scheme 17). Salts of alkyl derivatives of diethyl malonate (55) were used in Neelakantan s modification (79). In both cases sodium salts of isonitramine (56), stable only in alkaline solution, were formed initially and subsequently transformed into N-hydroxyamino acids (1) by means of concentrated hydrochloric acid. This method using common substrates is quite general and may be used for the synthesis of N-hydroxyamino acids (1) of different types 36, 79). Usually it has been used for the synthesis of N-hydroxyglycine (28) 129) and N-hydroxyphenylalanine (35) (79, 94,129). 

Park et al. also reported an analogous strategy for the synthesis of (+)-isonitramine (107) [61], A phase-transfer catalyzed enantioselective ot-alkylation of lactam 108, followed by subsequent manipulations, was employed for the successful total synthesis of the Nitraria alkaloid (+)-isonitramine (107) (Scheme 21). 

Scheme 12.16 Asymmetric total synthesis of (—)-paroxetine and (—)-isonitramine by phase-transfer catalytic alkylations of 1,3-dicarbonyl compounds 90a and 90b.

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