General Strategy for the Synthesis of B₁ and L₁ Prostanoids: Synthesis of Phytoprostanes (RS)-9-L₁-PhytoP, (R)-9-L₁-PhytoP, (RS)-16-B₁-PhytoP, and (RS)-16-L₁-PhytoP

Abstract

In this paper we describe a novel general synthetic approach to B1- and L1-type phytoprostanes, which are formed in vivo from free-radical-catalyzed nonenzymatic peroxidation of α-linolenic acid (1). The synthesis of phytoprostanes (RS)-9-L1-PhytoP (5), (R)-9-L1-PhytoP (5a), (RS)-16-B1-PhytoP (6), and (RS)-16-L1-PhytoP (7) exemplifies this strategy. The common starting compound 8 has been proved to be synthetically equivalent to a cyclopent-2-en-1-one synthon having opposite donor and acceptor properties at carbons α and β, respectively. Key steps include the chemoselective lithiation of a 1-iodo-2-bromoolefin, the introduction of the side chains by transition-metal catalysis following Heck- or Suzuki-type protocols, the construction of an enone moiety by a mild Au(I)-catalyzed Meyer Schuster rearrangement, and a lipase-mediated hydrolysis of methyl esters to deliver the phytoprostanes as free carboxylic acids.

Recent Developments in the Meyer‐Schuster Rearrangement

“…A similar strategy was followed for the synthesis of one of the important metabolites of α‐linoleic acid, called phytoprostanes (Scheme 47). [100] The reaction of cyclopentylaldehyde 191 with the lithium salt of 1‐butyne gave the propargylic alcohol 192 in 96 % yield. By reaction with the gold catalyst 28 h (at 6 mol%) in a methanol‐water mixture, the desired enone 193 was obtained in 76 % yield as a pure E isomer.…”

Synthesis of Chiral Cyclopentenones

“…In 2015, a novel strategy for the synthesis of (R,S)-16-B 1 -PhytoP (phytoprostane B 1 types I), (R,S)-9-L 1 -PtytoP and (R)-9-L 1 -PhytoP (phytoprostane B 1 types II), and (R,S)-16-L 1 -PhytoP was reported by Vidari and co-workers. 630 The retrosynthesis of these PhytoPs is presented in Scheme 332. The starting material, O-TBS-protected 2-iodo-3-bromocyclopentenol (R,S)-1410, is synthetically equivalent to cyclopent-2enone, displaying a donor at carbon α (d) and acceptor properties at carbon β (a).…”

Total syntheses of all tri-oxygenated 16-phytoprostane classes via a common precursor constructed by oxidative cyclization and alkyl–alkyl coupling reactions as the key steps

“…40 An individual total synthesis of 16-E 1 -PhytoP was also published, based on the Friedel-Crafts acylation of furan, followed by a Piancatelli rearrangement and attachment of the ω-chain by 1,4-conjugate addition after enzymatic resolution. 41 The total syntheses of ring-isomeric cyclopentenone PhytoP, namely 9-and 16-B 1 -and L 1 -PhytoP as well as 9-A 1 -and 9-J 1 -PhytoP, were accomplished by the Vidari-Zanoni group, 42,43 whereas Riera's group developed an individual approach to 16-B 1 -and 9-L 1 -PhytoPs. 44 A total synthesis of 16-D 1t -PhytoP was never accomplished.…”