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.

An efficient stereoselective synthesis of a sulfur-bridged analogue of bosseopentaenoic acid as a potential antioxidant agent

“…17,18 A Z-stereoselective semireduction of triyne 7, was carried out via a modified Boland protocol using Zn(Cu/Ag) in presence of trimethylsilyl chloride (TMSCl) 19,20 at room temperature, to produce compound 6b in 65% yield. The modified Boland protocol, using Zn(Cu/Ag) in presence of TMSCl, proved to be important for this reaction 12,[20][21][22][23] (Scheme 1); the same reduction carried out with a Lindlar catalyst resulted in a complex mixture of products. 24 © ARKAT USA, Inc Scheme 1.…”

Ultra‐Performance Liquid Chromatography‐Mass Spectrometry Analysis of Free and Esterified Oxygenated Derivatives from Docosahexaenoic Acid in Rat Brain

“…PDX was synthesized by us as previously described (Chen et al, ). PD1 was synthesized by Durand and Colleagues at the Institute of Biomolecules Max Mousseron (Montpellier, France) (Dayaker, Durand, & Balas, ; Jonasdottir et al, ). 2′,7′‐Dichlorofluorescein, PFB‐Br, and DIPE were purchased from Sigma‐Aldrich (Oakville, Ontario, Canada).…”

Recent Developments and Synthetic Applications of Nucleophilic Zirconocene Complexes from Schwartz's Reagent

“…The hydrozirconation/iodination sequence has been an important tool in organic synthesis. For example, in 2014, Balas and co‐workers described the total synthesis of the dihydroxylated docosatrienes, bearing a conjugated E , E , Z ‐triene moiety . In this work, the iodination of alkynes ( 136 and 138 ) was obtained in two steps by using a hydrozirconation/iodination sequence (Scheme ), with excellent yields (ranging from 92 % to quantitative).…”