Synthesis of N-Methyl-N-formyltyramine, a new beta-phenethylamide derivative isolated from Cyathobasis fruticulosa (Bunge) Aellen

Abstract

Este trabalho descreve a síntese da N-metil-N-formiltiramina, um novo derivado β-fenetilamídico isolado de Cyathobasis fructiculosa (Bunge) Aellen. O produto natural foi preparado em seis etapas com bom rendimento, partindo-se do 4-hidroxibenzaldeído.The synthesis of N-methyl-N-formyltyramine, a novel β-phenethylamide derivative isolated from Cyathobasis fructiculosa (Bunge) Aellen, is reported. The natural product was prepared in six steps and good overall yield from 4-hydroxybenzaldehyde.Keywords: synthesis, β-phenethylamide derivative, Cyathobasis fructiculosa, natural product Introduction β-Phenethylamides, exemplified by compounds 1 and 2, 1 constitute a relatively widespread family of natural products, the members of which have been found mainly as soluble constituents of cell-wall fractions of higher plants. 2 Several amides, structurally related to them, have been found in different plant species, 3 and N-transferuloyltyramine (3) has demonstrated to have an ubiquitous occurrence. 4,5 There is no definite conclusion yet about the functions of the β-phenethylamides; however, it has been discussed their possible role in plant growth processes, as well as their participation in self defense, due to their antimicrobial and antiviral effects. 6 In addition, β-phenethylamides such as 4-7 have been informed to display interesting biological activities, ranging from DNA strand scission 7 to antimutagenic and anticarcinogenic, 8 and including inhibition of the lipopolysaccharide-induced nitric oxide production in macrophages, 9 as well as inhibition of acetylcholinesterase. 10 Noteworthy, N-acetyl tyramine (8) is an inducible phytoalexin found in soybean seeds, 11 while Paik and coworkers reported the isolation of the unusual compounds 9-11 from Xenorhabdus nematophilus, a bacterial strain which grows symbiotic with a nematode. These β-phenethylamides were shown to be cytotoxic against five human cancer cell lines. 12 Very recently, Topçu and coworkers 13 isolated Nmethyl-N-formyltyramine (12) from the aerial parts and roots of Cyathobasis fruticulosa (Bunge) Aellen (Chenopodiaceae), the only species of the genus Cyathobasis of the Turkish flora, which grows most commonly in Central Anatolia. In view of the potential interest of this type of compounds, we decided to prepare 12, and herein we disclose a short synthesis of the natural product from commercial 4-hydroxybenzaldehyde (13). Results and DiscussionWilliamson etherification of 13 with benzyl chloride provided 99% of aldehyde 14 (Scheme), which was subjected to a Henry condensation with nitromethane in the presence of ethylenediammonium diacetate as base, 14 furnishing 90% of nitrostyrene 15. In turn, this was submitted to reduction with lithium aluminum hydride, giving β-phenethylamine 16, as an oil which easily darkened upon contact with air; therefore, this was immediately amidated in refluxing ethyl formate, providing formamide 17 in 44% overall yield. Noteworthy, the 1 H and 13 C NMR spectra of 17 exhibited signals of two conformers, even at 70 ºC in ...

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