•The first total synthesis of pro-resolving and tissue-regenerative resolvin sulfido conjugates has been achieved.•Chiral centers at C-7 and C-8 were obtained using a chiral pool strategy starting from 2-deoxy-d-ribose.•The chiral center at C-17 was generated by an enzymatic hydroxylation with lipoxidase in the first approach.•The chiral center at C-17 was obtained using a chiral pool strategy starting from d-(−)-arabinose in the second approach.The first total synthesis of the pro-resolving and tissue-regenerative resolvin sulfido-conjugates: 7S,8R,17S-RCTR1, 7S,8R,17S-RCTR2 and 7S,8R,17S-RCTR3, derived from docosahexaenoic acid, has been achieved. Two synthetic approaches are described. Chiral centers 7S and 8R were introduced in both approaches via a chiral pool strategy starting from 2-deoxy-d-ribose. The 17S chiral center was introduced either by a chiral pool strategy or by an enzymatic hydroxylation with lipoxidase. Wittig reactions, selective epoxide formation and epoxide opening with glutathione, l-cysteinylglycine and l-cysteine respectively, were the key steps in the synthesis.Download high-res image (48KB)Download full-size image

The stereospecific total synthesis of the pro-resolving and tissue-regenerative Protectin sulfido-conjugates: 16R,17S-PCTR1, 16R,17S-PCTR2, and 16R,17S-PCTR3, derived from docosahexaenoic acid, has been achieved. The key intermediate 16S,17S-epoxy-Protectin methyl ester was synthesized using the Sharpless catalytic asymmetric epoxidation to generate the chiral centers at C16 and C17. A Cs2CO3 promoted coupling provided the skipped diyne intermediate. Wittig reactions and epoxide opening with glutathione, l-cysteinylglycine, and l-cysteine methyl ester hydrochloride, respectively, were the key steps in the synthesis.

The first stereospecific total synthesis of the pro-resolving and tissue-regenerative Maresin sulfido-conjugates: 13R,14S-MCTR1, 13R,14S-MCTR2 and 13R,14S-MCTR3, derived from docosahexaenoic acid, has been achieved. The key intermediate 13S,14S-epoxy-Maresin methyl ester was synthesized using a chiral pool strategy starting from 2-deoxy-d-ribose. Wittig reactions, selective epoxide formation and epoxide opening with glutathione, l-cysteinylglycine and l-cysteine methyl ester hydrochloride respectively, were the key steps in the synthesis.

The first total synthesis of the potent anti-inflammatory lipid mediator Maresin 2 derived from docosahexaenoic acid, has been achieved. The chiral hydroxy-groups at C13 and C14 were obtained via a chiral pool strategy from 3,4-O-isopropylidene-2-deoxy-d-ribose. Wittig reactions and acetonide cleavage followed by mild ester hydrolysis afforded Maresin 2.

The total synthesis of the potent anti-inflammatory lipid mediator Protectin D1 derived from docosahexaenoic acid, has been achieved. The chiral hydroxy-groups at C10 and C17 were obtained via a chiral pool strategy from (4R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane and 3,4-O-isopropylidene-2-deoxy-d-ribose, respectively. Wittig reactions, Takai olefination, Pd0/CuI Sonogashira coupling, and Zn(Cu/Ag) reduction completed the total synthesis of Protectin D1.