title: A versatile and stereocontrolled total synthesis of dihydroxylated docosatrienes containing a conjugated E,E,Z-triene.
abstract: A versatile strategy featuring a Colvin rearrangement, hydrozirconation, a Sonogashira cross-coupling reaction and a Z-selective Wittig olefination, was successfully developed for the construction of a conjugated E,E,Z-triene subunit, flanked on both sides by two Z-allylic hydroxyl groups. This chemical pattern is found in many endogenous lipid metabolites such as maresin 1 (MaR1), neuroprotectin D1 (NPD1), and its aspirin triggered-isomer AT-NPD1, which not only counter-regulate inflammation but also actively orchestrate (at nanomolar doses) the resolution and termination program of acute inflammation while promoting wound healing, return to homeostasis and neuroprotection. Unlike previous approaches, the advantages of the present strategy are obvious, as it allows us to modify the nonpolar tail, the carboxylated head or both ends of the molecule without repeating the whole synthetic sequence (about 26-34 steps according to the literature). Thus, the first total syntheses of NPD1 methyl ester epimer (which can also be considered as an enantiomer of AT-NPD1) and its n-3 docosapentaenoic acid derived analogue were achieved from a highly functionalized and late advanced pivotal intermediate. This innovative route may be easily adapted to gain access to other dihydroxylated metabolites and analogues of polyunsaturated fatty acids containing a conjugated E,E,Z-triene subunit. Different epimers/diastereoisomers may be obtained by purchasing the suitable optically pure (S)- and/or (R)-1,2,4-butanetriol(s) as a chiral pool for both stereogenic centers.
authors: Institut des Biomolécules Max Mousseron (IBMM,UMR5247 CNRS-UM1-UM2-ENSCM), Faculté de Pharmacie, 15 avenue C. Flahault, BP 14491, 34093 Montpellier Cedex 5 (France), Fax: (+33) 4-11-75-96-53.
authors: Gandrath
authors: G
authors: Dayaker
authors: Thierry
authors: T
authors: Durand
authors: Laurence
authors: L
authors: Balas
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D004281:Docosahexaenoic Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; D005231:Fatty Acids, Unsaturated; D008055:Lipids; C487679:protectin D1; D004281:Docosahexaenoic Acids; C026219:docosapentaenoic acid
keywords: lipids; medicinal chemistry; neuroprotectin D1; total synthesis; trienes