Stereoselective synthesis of protectin D1: a potent anti-inflammatory and proresolving lipid mediator

Abstract

A convergent stereoselective synthesis of the potent anti-inflammatory, proresolving and neuroprotective lipid mediator protectin D1 (2) has been achieved in 15% yield over eight steps. The key features were a stereocontrolled Evans-aldol reaction with Nagao’s chiral auxiliary and a highly selective Lindlar reduction of internal alkyne 23, allowing the sensitive conjugated E,E,Z-triene to be introduced late in the preparation of 2. The UV and LC/MS-MS data of synthetic protectin D1 (2) matched those obtained from endogenously produced material

The novel lipid mediator PD1n-3 DPA: An overview of the structural elucidation, synthesis, biosynthesis and bioactions

“…3 were then performed. The results from these experiments support the proposed pathway [39]. Soybean lipoxygenase-15 (50 U/100 mL) was incubated with n-3 DPA (0.2 μM in 200 μL) in borate buffer (pH = 8.2) at ambient temperature.…”

“…The key steps in the total synthesis are two highly Z-selective Lindlar reductions of internal alkynes, a stereocontrolled Evans-acetate aldol reaction with Nagao’s chiral auxiliary, a Wittig reaction and the use of a chiral pool derived glycidol-ether. The chirality of the alcohols at C10 and C17 as well as the double bond geometry of the triene were assured using these synthetic protocols, see reference [39] for details.…”

“…The role of the 16,17 S -PD n-3 DPA epoxide as a true intermediate, generated from the immediate 17 S -hydroperoxy-DPA precursor, in the biosynthesis was supported by results obtained from LC/MS-MS assisted experiments. The product mixture was subjected to lipid mediator metabololipidomics analysis with m / z values in the 375–277 range [39]. These efforts allowed the structural assignment of four methyl-ether products, see Fig.…”

“…Towards such aims, Dalli, Colas and Serhan reported in 2013 the isolation, structural elucidation and biological evaluations of several novel SPMs biosynthesized from n-3 DPA [38]. Herein, a review of the structural elucidation, the total organic synthesis and the identified biosynthetic pathway of one of these novel SPMs, namely PD1 n-3 DPA is provided [38, 39]. In addition, the potent in vivo anti-inflammatory and pro-resolving properties are also presented.…”

First total synthesis of pro-resolving and tissue-regenerative Maresin sulfido-conjugates

“…7,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] In this Letter we wish to report the first total synthesis of the 14- The chiral centers of the epoxy-aldehyde 7 were generated using a chiral pool strategy starting from 2-deoxy-D-ribose (8).…”