Practical Synthesis of Spermine, Thermospermine and Norspermine

Abstract

Polyamines, such as spermine (1), thermospermine (2) and norspermine (3), are widely distributed in nature, and have multiple biological activities. In addition, many of their conjugates have potential for pharmacological use. Here, we present a solid-phase synthesis using our nitrobenzenesulfonyl (Ns) strategy, which can provide 1, 2 and 3 on a gram scale. This approach should be suitable for facile construction of a diverse library of polyamines.

Solid-Phase Synthesis of Selectively Mono-Fluorobenz(o)ylated Polyamines as a Basis for the Development of 18F-Labeled Radiotracers

“…A further approach used N 1 -Boc, N 4 -tosyl-protected putrescine as a building block, in which the tosyl group acts both as protecting and activating group towards N-alkylation with 3-aminoalkyl synthons [34]. A similar approach involving N-nosyl-protected diaminoalkane precursors was pursued in the synthesis of spermine, thermospermine and norspermine [36]. The drawback of handling the polar amino compounds in solution can be overcome by solid-phase synthesis, as it enables the separation of excessive educts by simple and fast filtration and washing, which has revealed to be a major breakthrough in the synthetic access to the polyamine skeletons [37].…”

General Approach for the Liquid-Phase Fragment Synthesis of Orthogonally Protected Naturally Occurring Polyamines and Applications Thereof

“…21 Quite recently, the fragment synthesis of Tsm as well as Spm and Nsm was reported on a polymer support of the o-chlorotrityl-type and using the nosyl (Ns) protecting group for amino protection and activation and the base induced alkylation of the N-nosylated amines by suitable halides as the key-step for the assembly of the skeleton. 22 The Mitsunobu reaction has been also indicated by the same research group as an alternative for the alkylation of Ns-activated amines with alcohols 23,24 and was used on a solid support for the synthesis of the spider toxin Agel 416. 25 Based on our long-standing experience in the use of the triphenylmethyl (trityl, Trt) group for the protection of amino functions of PAs, we reasoned that the Tsm skeleton incorporating orthogonally protected amino functionalities (7) could be assembled from readily available N-tritylated building blocks like the N-trityl-γaminobutyric acid (Trt-GABA) or N-tritylputrescine (Trt-Put, 9) as N-C4 and N-C4-N synthons, respectively, and either 1,3-diaminopropane (Dap) or the corresponding Dde-protected 3-aminopropanol (10a) 25 as N-C3-N or N-C3 synthons, respectively.…”

“…Tsm has been first prepared by Ganem et al from Spd through a five-step sequence . Quite recently, the fragment synthesis of Tsm as well as Spm and Nsm was reported on a polymer support of the o -chlorotrityl-type and using the nosyl (Ns) protecting group for amino protection and activation and the base-induced alkylation of the N-nosylated amines by suitable halides as the key step for the assembly of the skeleton . The Mitsunobu reaction has been also indicated by the same research group as an alternative for the alkylation of Ns-activated amines with alcohols , and was used on a solid support for the synthesis of the spider toxin Agel 416 …”