Syntese av noen 5-okso-derivater av (all-Z)-5,8,11,14,17-eicosapentaensyre (EPA) og forsøk på asymmetrisk reduksjon av ketogruppen

Abstract

Synthesis of methyl (6E,8Z,11Z,14Z,17Z)-5-hydroxy-6,8,11,14,17-eicosapentaenate (methyl-5-HEPE) (5), methyl (6E,8Z,11Z,14Z,17Z)-5-oxo-6,8,11,14,17-eicosapentaenate(methyl-5-oxo-EPE) (6) and methyl 4-(3-((2Z,5Z,8Z,11Z)-tetradeca-2,5,8,11-tetraen-1-yl)ocsirane-2-yl)butanate (3) was performed without any significant problems, and with satisfactory yields.

We found no good method for the synthesis of methyl (9Z,12Z,15Z,18Z)-5-hydroxyhenicosa-9,12,15,18-tetraenoate (8) and methyl (9Z,12Z,15Z,18Z)-5-oxohenicosa-9,12,15,18-tetraenoate (9), and future work is needed. There was no time to prepare a separation method for the racemic mixture of compound 5 with HPLC.

Formation of the chiral ligand (S)-3-etoxy-4-(2-(hydroxydiphenylmethyl)pyrrolidine-1-yl) cyclobut-3-ene-1,2-dione (12) from squaric acid and prolinole was successful and gave satisfactory yields. The use of this ligand in the asymmetric reduction of ketone 6 into respectively 5R or 5S gave ambiguous results and need further exploration.

A commercially available model substance for the ketomethyl ester 6 available as methyl-5-oxooctadecanoate (42) was obtained and reduced into methyl-5-hydroksyoktadekanoat (43). Derivatization of compound 43 with Mosher’s acid chloride to make a diastereomeric mixture for use in analysis (HPLC and 1H NMR) were attempted, but gave the product only in enantiomeric form.

Studies during the last years have shown that oxygenated PUFAs holds interesting biological activities. The biological activity of compound 5 and 6 will further be characterized pharmacologically at the OXE receptor in a calcium mobilization assay ( Tyagi et al. , 2012) . This test will be indicative of the anti-inflammatory properties of these compounds "in vitro". We had also hoped to carry out this test for compound 5 in its pure enantiomeric form (5R or 5S) and for compound 8 and 9, but since these syntheses were not as successful as we hoped for, this will have to be done as future work.