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

Abstract

A unified strategy for the total synthesis of the methyl esters of all phytoprostane (PhytoP) classes bearing two ring-oxygen atoms based on an orthogonally protected common precursor is described. Racemic 16-F-, 16-E-PhytoP and their C-16 epimers, which also occur as racemates in Nature, were successfully obtained. The first total synthesis of very sensitive 16-D-PhytoP succeeded, however, it quickly isomerized to more stable, but so far also unknown Δ-16-D-PhytoP, which may serve as a more reliable biomarker for D-type PhytoP. The dioxygenated cyclopentane ring carrying the ω-chain with the oxygen functionality in the 16-position was approached by a radical oxidative cyclization mediated by ferrocenium hexafluorophosphate and TEMPO. The α-chain was introduced by a new copper-catalyzed alkyl-alkyl coupling of a 6-heptenyl Grignard reagent with a functionalized cyclopentylmethyl triflate.

Direct Catalytic Asymmetric Synthesis of Oxindole-Derived δ-Hydroxy-β-ketoesters by Aldol Reactions

“…δ-Hydroxy-β-ketoesters are useful building blocks for the synthesis of biologically important natural products and pharmaceutical leads. − Common methods to access δ-hydroxy-β-ketoesters include reactions of dianions generated from β-ketoesters by using two or more equivalents of strong base(s) or reactions of preformed silyl dienol ethers or alkyl dienol ether derivatives with carbonyl compounds (Scheme a and b). These methods require either severe conditions or tedious protection and deprotection procedures.…”

First Total Syntheses of Novel Non‐Enzymatic Polyunsaturated Fatty Acid Metabolites and Their Identification in Edible Oils

“…The retrosynthetic analysis of racemic 18( RS )‐18‐F 3t ‐IsoP ( rac ‐ 1 , approach I) leads to protected skipped diyne 4 , which can be further simplified by twofold C(sp3)‐C(sp) disconnection to oxygenated cyclopentanecarboxylate 5 a , propargylic unit 7 and methyl hex‐5‐ynoate 8 (Scheme ). The cyclic intermediate 5 a can be further disconnected to protected 3,5‐dihydroxy ester 6 …”

“…The synthesis commenced with cyclization precursor 6 readily available in three steps in high yield, which was deprotonated by excess LDA in the presence of 8.5 equiv LiCl, followed by oxidative cyclization of the resulting alkoxide enolate triggered by ferrocenium hexafluorophosphate and oxygenation by stable free radical TEMPO (Scheme ). Hydroxycyclopentane carboxylates 11 a and 11 b were isolated in 63 % yield and slightly improved 2.3:1 diastereoselectivity compared to our previous cyclization conditions …”

“…Our two groups have been working on the synthesis of these non‐enzymatic PUFA metabolites for many years and developed diverse individual synthetic strategies but we decided to work together to target new metabolite families. Racemic IsoPs are accessible by Jahn's oxidative cyclization/α‐chain attachment strategy (Approach I) . Since potential specific biological activity is likely inherent to individual enantiomers, asymmetric approach based on enzymatic deracemization of bicyclo[3.3.0]octenes developed in the Durand group will serve to access them for in depth study (Approach II) .…”

History of Chemical Routes towards Cyclic Non-Enzymatic Oxygenated Metabolites of Polyunsaturated Fatty Acids

“…Note, both C15 epimers of the 15-F 2t -IsoP were obtained after oxidative cleavage of the TMP group, reduction of the resulting enone (dr = 1.7:1), and separation of both epimers. This strategy also allowed, for example, the preparation of 15-E 2t -IsoP 33 and F-and E-type of phytoprostanes 34 albeit as their methyl esters (which could be problematic for a final-step saponification because of known epimerization next to the ketone).…”