Solid-Phase Synthesis of New Heterocyclic Azoniaspiro Ring Systems

Significance

The solid-phase synthesis of tri- and tetrasubstituted 10-oxo-3,9-diaza-6-azoniaspiro[5.5]undecanes 5 and 6 was demonstrated. The p-methylbenzhydrylamine resin-bound 2,3-diketopiperazines 2 prepared from corresponding dipeptide 1 (using Ala, Val, Phe, and Leu) were reduced by BH₃·THF to give piperazine-tethered secondary amine 3. After acylation of 3 with bromoacetic acid, the intramolecular attack of tertiary amino nitrogen on bromomethylene produced azoniaspiro cationic compounds 4. Cleavage from the resin by HF/anisole gave the desired 1,8,9-trisubstituted 10-oxo-3,9-diaza-6-azoniaspiro[5.5]undecanes 5 in moderate yields. Treatment of 5 with acyl chlorides or isocyanates gave 3-acyl- or 3-aminocarbonyl compounds 6 in 43-52% yield.