The Use of Fukuyama ’ s Sulfonamide in the Synthesis of Selectively Protected Spermidines

A diferenciação dos grupos amino terminais de poliaminas freqüentemente envolve uma série de etapas de proteção e desproteção, resultando em rotas sintéticas longas e de baixo rendimento global. Tendo em vista o relevante papel biológico atribuído a estas substâncias, torna-se necessário o desenvolvimento de sínteses mais eficientes para poliaminas. Neste artigo descrevemos uma síntese de duas espermidinas seletivamente protegidas, empregando a sulfonamida de Fukuyama. As duas sínteses foram executadas em três etapas a partir da 1,3-propanodiamina, com um rendimento global superior a 40%.


Introduction
In the past decades a great deal of attention has been given to polyamines, especially because of their involvement in the regulation of cellular functions, such as cell proliferation and differentiation. 1 Additionally, a wide range of biological activities have been attributed to polyamines conjugates and derivatives, such as antianigogenic, anticancer, and neurotoxins, to name a few. 2 The metabolism of polyamines in prokaryotes has also gained increased importance. 3In fact, the inhibition of enzymes involved in the metabolism of parasitic protozoa has been recognized as a promising strategy for the chemotherapy of tropical diseases. 4For instance, the inhibition of ornithine descaboxylase by a-difluoromethylornithine, a drug candidate against African sleeping sickness and malaria, 4,5 blocks the first step of polyamine biosynthetic pathway. 6Trypanothione, structurally characterized as N 1 ,N 8 -bis(glutathionyl)spermidine, is a polyamine derivative used by trypanosomatids as a defense against reactive oxygen species during their infective cycle. 7The metabolism of trypanothione is another target for drug development against trypanosomiases and leishmanioses. 8s part of a research program aiming the synthesis of peptide-polyamine conjugates, we became interested in the preparation of selectively protected spermidines. 9owever, the synthesis of unsymmetrical polyamines usually requires several protection and deprotection steps, making such approaches unnatractive due to the long reaction sequences involved. 10More straighforward alternatives to acess polyamine backbones are needed.
The dual role of Fukuyama's sulfonamide, 11 which not only masks the amino group, but also activates it to grow the polyamine chain, meet the requirements to solve those issues. 12Herein, we wish to describe a versatile route for two orthogonally protected spermidines using Fukuyama's sulfonamide.

Results and Discussion
The first synthesis starts with the monoprotection of 1,3-propanediamine with 2-nitrobenzenosulfonyl chloride (NBS-Cl) in 70% yield, using a modification of the protocol described by Haemers. 13,14The remaining amino group was protected with 1,3-dimethyl-5-acetyl-barbituric acid (DAB) to give 1 in 70% yield. 14Selective N-alkylation with 4-bromobutylphthalimide using K 2 CO 3 as base in refluxing acetonitrile afforded the protected spermidine 2, in good yield. 15ince both phthalimide and DAB groups of spermidine 2 can be removed with hydrazine, we decided to proof that under controlled conditions a selective deprotection may be achieved. 14While the removal of the phthalimide group is usually carried out in refluxing ethanol over 3-5h, the DAB group can be cleaved at 0 o C. Thus, by treatting 2 with aqueous hydrazine in THF at 0 o C, selective removal of DAB was performed, affording spermidine 3 in 82% yield.
A similar strategy was employed to prepare spermidine 5. Accordingly, the monoprotection of 1,3-propanediamine with (Boc) 2 O 16 followed by reaction with NBS-Cl, afforded the known sulfonamide 4, in 62% yield (two steps).Reaction of 4 with 4-bromobutylphthalimide using K 2 CO 3 in refluxing acetonitrile over 12 h provided the orthogonally protected spermidine 5, in 71% yield.End-group differentiation of a parent spermidine has already been demonstrated by us. 9n conclusion, our methodology provides an efficient alternative for the synthesis of orthogonally protected spermidines in a short sequence of steps with good overall yields, from inexpensive starting materials.The Fukuyama's sulfonamide can be introduced at different stages, and acts both as an activating group for N-alkylation and as an orthogonal protective group.Additionally, depending on the temperature, DAB and phtalimide groups can show orthogonal behavior.

Experimental
Melting points were determined with a Thomas-Hoover apparatus and are uncorrected. 1H and 13 C-NMR were recorded on Brucker AC 200 spetrometer.Infrared spectra were obtained with a Nicolet-550 Magna spectrophotometer.The mass spectra (MS) were obtained by electron impact (70 eV) with a GC/VG Micromass 12 spectrometer.
The reactions were monitored by TLC analyses, on 2.0 cm x 6.0 cm aluminium sheets precoated with silica gel 60 (HF-254, Merck) to a thickness of 0.25 mm, using an ultraviolet light for visualization.For column chromatography, Merck silica gel (230-400 mesh) was used.Solvents used in the reactions were generally redistilled prior to use.The 2-nitrobenzenesulfonamides and tertbutoxycarbonyl-aminopropylamine were prepared as described for Amssoms 8 and Boturyn, 16 respectively.