Total Syntheses of Two bis‐Allylic‐Deuterated DHA Analogues

Abstract

The deuteration of polyunsaturated fatty acids (PUFAs) at their bis-allylic positions is known to limit harmful lipid peroxidation, which leads to the damage of cell membranes. Therefore, to impede toxic lipid peroxidationi n retina tissue, we have designed and synthesized two deuterated analogues of docosahexaenoic acid (DHA;C 22:6, n-3), which is the main lipid constituent of retina membranes. To avoid its oxidative degradation into toxic carboxyethylpyrrole (CEP) adducts,w hilst preserving enzymatic metaboliza-tion into ah ealthyn europrotectine derivative (NPD1), deuterium was incorporated at specific 6-and6 ,9-bis-allylic positions. Aconvergent synthetic strategy,based on aWittig olefination, was developed to obtain both deuterated DHA species. Common aldehyde intermediates were synthesized from another PUFA,e icosapentaenoic acid (EPA; C20:5, n-3). Deuterium atoms were introduced through either the reduction of an ester with ad euterated reagent or an ucleophilic reactionwith deuterated paraformaldehyde.Supportinginformation for this article can be found under: http://dx.

Threshold protective effect of deuterated polyunsaturated fatty acids on peroxidation of lipid bilayers

“…D2‐Lin, D4‐Lnn , and D6‐Ara were prepared as described previously by assembling corresponding polyyne chains and subjecting them to catalytic hydrogenation. Although a similar convergent synthetic strategy, based on a Wittig olefination, was developed to obtain selectively deuterated DHA species , D10‐DHA could be prepared using the less laborious approach of catalytic H/D exchange . D8‐EPA was synthesized according to a newly developed procedure (Scheme 2A) based on the polyacetylene approach followed by partial hydrogenation.…”

Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells

“…Deuterated DHAs, (6,6-D 2 )-DHA and (6,6,9,9-D 4 )-DHA (simplified respectively as D 2 -DHA and D 4 -DHA) were synthesized as previously described by Rosell et al [35] Deuterated lipophenol, phloroglucinol-OiPr-O-(6,6-D 2 )-DHA and phloroglucinol-OiPr-O-(6,6,9,9-D 4 )-DHA (simplified respectively as IP-D 2 -DHA and IP-D 4 -DHA) were synthesized using the methodology described by Crauste et al [21] Briefly, the coupling reactions between the protected silylated isopropylated-phloroglucinol and the deuterated DHAs were initiated using dicyclohexylcarbodiimide and dimethylaminopyridine (DCC/DMAP) as coupling reagents to access protected lipophenols. Final deprotection of triisopropylsilyl (TIPS) protecting groups by Et 3 N-3HF in dry tetrahydrofuran (THF) yielded deuterated lipophenols, IP-D 2 -DHA and IP-D 4 -DHA.…”

“…In the present work, we hypothesized that specific chemical modulations of DHA will preserve its pro-resolving beneficial effect (protectin NPD1 formation, Scheme 1), while reducing its potentially toxic properties under oxidative conditions. A chemical modulation of DHA designed to reduce its radical oxidation vulnerability without affecting its enzymatic metabolism into beneficial protectins, was carried out in our previous synthetic efforts [35]. The developed deuterated DHA analogues were obtained by the introduction of deuterium selectively at the bis -allylic positions C-6 and C-9 (Scheme 2).…”

Acetalization of Enol Ethers with Alcohols under Visible Light Irradiation Using BINOLs as Photoacid Catalysts

“…For comparison, Eosin Y as a photoacid catalyst [5,12] was also tested in this reaction, but only a small amount of product was detected by 1 H NMR analysis after irradiated under blue LEDs for the same time (Table 1, entry 2). Encouraged by the result with simple BINOL, a series of BINOL derives (A-H) were synthesized and examined (entries [3][4][5][6][7][8][9][10][11]. Introducing bromine at the 6,6' positions (A) afforded obvious improvement on the yield (53%, Table 1, entry 3).…”

“…However, its potential as photocatalyst was rarely explored. It is well known that, aromatic alcohols such as 2-naphthol can become a strong acid upon excitation by light, a phenomenon that is defined as excited state proton transfer (ESPT) [7]. Such properties have been successfully applied to light-induced alcohol deprotection [8], activation/inhibition of enzymes [9], and protonation of enol silyl ethers [10].…”