Synthesis of (±)-Nitramine and (±)-Isonitramine by Utilizing Stereoselective Reduction of Ethyl 1-(3-Bromopropyl)-2-oxocyclohexanecarboxylate

Abstract

Abstmct -Formal synthesis of (*)-nitramhe (1) and (%)-isonitramhe (2) was achieved. Thus, the reduction of ethyl 1-(3-bromopropy1)-2-oxocyclohexanecarboxylate (6) with NaBH, in MeOH gave the wrresponding cyclohexanol (7) having cis geometry between hydroxyl and ester groups, predominantly. On the other hand, the nrms located isomer (8) was preferentially obtained by reduction with LiAI(OBul),H in THF. Treatment of the former reduction product (7) having cis geomehy with benzylamine at 60 "C gave cis located ethyl 1-(3-(N-benzylamino)-propy1)-2-hydroxycyclohexanecarboxylate (9), which was further treated with BuLi to give a spirolactam, 2-benzyl-7-hydroxy-2-azaspiro[5,5]undec~-l-one (11) in 84 % yield. Reduction of the lactam (11) with BH3SMe, in THF gave N-benzylnitramine (13). In a similar manner, N-benzylisonitramine (14) was synthesized from Pans located hydroxyaminoester (10).Piperidine alkaloids nihamine (1) and isonitramine (2), isolated £rom plants of the genus Nitwuia,' are of interest due to their unique structure of a 2-azaspiro[5.5]undecan-7-ol skeleton, which resembles that of neurotoxic alkaloids histrioni~toxins.~ Various strategies and approaches to the synthesis of azaspiroalkaloids have been reported: via Michael additi~n,~&~.' Man nlch ' reaction,3d Diels-Alder ~eaction,~Virch reductive alkylati~n,~' int~amolecular addition of nitrile oxide," intramolecular addition of nitr~ne,'~ S,2' inhamolecular alkylation of ladam en~late,~' radical cyclization," inham0kUlar ring-opening of the chiral epoxy sulfone," and othem3'" We were able to achieve a synthesis of the 2-azaspiro[5S]undecane skeleton by means of an intramolecular spirolactam formation between m i n e and ester functions. We describe herein a new and stereoselective formal synthesis of nitramine (1) and isonitramine (2).