Protecting-group strategies for the synthesis of N4-substituted and N1,N8-disubstituted spermidines, exemplified by hirudonine

Abstract

Methods are described for the preparation of derivatives of the polyamines 1,4-diaminobutane (putrescine) and N-(3-aminopropyl)-1,4-diaminobutane (spermidine) in which a particular amino group is modified with, e.g., a guanidino function. Specific amino groups in these polyamines were protected as N-trifluoroacetyl and N-4-azidobenzyloxycarbonyl derivatives, which were unmasked chemoselectively using methanolic ammonia and dithiothreitol–triethylamine, respectively. Guanidino functions were introduced by an improved procedure in which an amino group was treated with 3,5-dimethyl-N-nitro-1H-pyrazole-1-carboximidamide in methanol to give a nitroguanidine derivative, from which the nitro group was removed by catalytic transfer hydrogenation. The methodology is exemplified by the development of efficient preparative routes to agmatine and hirudonine. The integrity of the sequence of protection/deprotection leading to hirudonine was confirmed by a crystal-structure analysis of its sulfate. The effect of selected compounds on the uptake of putrescine into rat lung cells was determined and showed that N ⁴-(4-azidobenzyloxycarbonyl)spermidine was the best inhibitor (K_i = 3.4 µM).