TRANS-3,4-DIAMINOPIPERIDINES - AZACYCLOHEXANE CONGENERS OF KAPPA AGONIST U-50488

A variety of trans-3,4-diaminopiperidines were synthesized regio- and stereoselectively from 1-(carbobenzyloxy)-1,2,3,6-tetrahydropyridine. These compounds are structurally related to the selective kappa agonist U-50488. The two key reactions which determine the stereo- and regiochemistry of the final products involve the S(N)2 ring opening of an epoxide and an aziridinium species. Reaction of secondary amines with epoxide 3 led to ca. 1.5:1 mixtures of amino alcohols 4 and 5, while S(N)2 attack by methylamine on aziridinium intermediate 6 occurs diastereoselectively at C-4 to give diamines 7. Depending upon the isolation procedure, trimethylsilyl iodide cleavage of the carbobenzyloxy group in compounds 8 and 9 provides either N-benzyl compounds 12 and 13 or the unsubstituted piperidines 10 and 11.