Protecting-group strategies for the synthesis of N-4-substituted and N-1,N-8-disubstituted spermidines, exemplified by hirudonine

Methods are described for the preparation of derivatives of the polyamines 1,4-diaminobutane (putrescine) and N-(3-aminopropyl)-1,4-diaminobutane (spe rmidine) in which a particular amino group is modified with, e.g., guanidin o function. Specific amino groups in these polyamines were protected as N-t rifluoroacetyl and N-4-azidobenzyloxycarbonyl derivatives, which were unmas ked chemoselectively using methanolic ammonia and dithiothreitol-triethylam ine, respectively. Guanidino functions were introduced by an improved proce dure in which an amino group was treated with 3,5-dimethyl-N-nitro-1H-pyraz ole-1-carboximidamide in methanol to give a nitroguanidine derivative, from which the nitro group was removed by catalytic transfer hydrogenation, Te methodology is exemplified by the development of efficient preparative rout es to agmatine and hirudonine. The integrity of the sequence of protection/ deprotection leading to hirudonine was confirmed by a crystal-structure ana lysis of its sulfate. The effect of selected compounds on the uptake of put rescine into rat lung cells was determined and showed that N-4-(4-azidobenz yloxycarbonyl)spermidine was the best-inhibitor (K-i = 3.4 mu M).