Synthesis of Fluoro Analogues of Unsaturated Fatty Acids and Corresponding Acyclic Metabolites

Abstract

Polyunsaturated fatty acids, in particular arachidonic acid and its metabolites, the so‐called eicosanoids, play a major role in human health. Many of them have been involved as potent mediators for various diseases such as inflammation and asthma. Therefore, numerous modifications in the structures of these natural products have been incorporated to study the structure‐activity relationship, monitor the biosynthetic pathway and also to understand the biological activities as well as the mechanisms of action. The modifications include introduction of labelled elements, fluorine atoms, heteroelements, carbo‐ and heterocycles etc. Of all these studies, the introduction of fluorine, which has a unique role as the smallest atom in the periodic table after hydrogen and also as the most electronegative element, provided very useful information. Thus, the present microreview highlights the synthetic efforts of various research groups in the last two decades on bioactive fluorinated fatty acids and corresponding acyclic metabolites. It also presents the most relevant bioactivity data obtained from the fluorinated analogues. The data corresponding to naturally occurring fluorinated fatty acids have been added, as well as the use of fluorinated probes for some biosynthetic studies in fatty acid chemistry (desaturation and methylenation). In addition, it is important to point out that the methods and strategies which have been developed to selectively introduce a single fluorine atom, as well as CF2 or CF3 groups, on such very challenging molecules could also be of much use in many other areas of chemistry. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Preparation of 9α‐Fluorinated Sesquiterpenic Drimanes and Evaluation of Their Antifeedant Activities

“…As substituent it is rarely boring, always good for a surprise, but often completely unpredictable". [5] Over the last few years there has been a growing interest in the synthesis of fluorine-containing analogues of natural products and a large number of fluorinated natural products with biological significance such as amino acids, [6] peptides, [7] glycosides, [8] nucleosides, [9] lipids, [10] oligosaccharides, [11] steroids, [12] prostaglandins, [13] vitamins, [14] antibiotics, [15] pheromones [16] alkaloids [17] and others [18] have been synthesized and some have subsequently been developed as pharmaceuticals and are marketed, registered or at the clinical development stage. [19] Also, a relatively significant number of fluoro derivatives of bioactive terpene-type compounds have bee reported and in many cases these show an increase in activity with respect to the corresponding hydrogen analogue.…”

Stereoselective Synthesis of the 5,5‐Difluoro‐(12R)‐ and ‐(12S)‐Leukotrienes B3

“…The spectral and analytical data are in full agreement with the indicated structure: the E,E stereochemistry of the dienic moiety is maintained, as indicated by the 1 H NMR spectroscopic data (J 8,9 = 15.7 Hz; J 10,11 = 15.2 Hz). The analysis by NMR spectroscopy in the presence of Eu(hfc) 3 indicates a high enantioselectivity (Ͼ80 % ee) for this compound. This was confirmed by the chiral HPLC analysis affording an 87 % ee for (+)-2a.…”

“…In particular, the leukotriene B 4 is strongly implicated as a mediator in inflammation and allergic diseases. [4] It has been demonstrated that the leukotriene B 3 , lacking the terminal 14-15 double bond, has a very similar biological profile [5] (Figure 1). A few fluorinated analogues of LTB 4 have been prepared by total synthesis: they include the 13,13-diF-LTB 4 and the [a] derivative having a CF 3 group in terminal position (i.e.…”

“…[2] In the family of lipids these properties have also been used, and a number of fluorinated analogues of fatty acids and corresponding metabolites have been prepared. [3] The leukotrienes are important arachidonic metabolites with very potent biological properties. In particular, the leukotriene B 4 is strongly implicated as a mediator in inflammation and allergic diseases.…”

“…20-CF 3 LTB 4 ). [3] Several years ago we started a programme dealing with the development of new methodologies to introduce selectively one or two fluorine atoms in positions vicinal to π systems. [6] A particularly challenging case was the fluorination vicinal to polyunsaturated systems, and in this context the fluorinated LTB 3 analogues appeared as very attractive target molecules.…”