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Cite this: DOI: 10.1039/x0xx00000x 

Stereoselective Synthesis of Epoxyisoprostanes: An Organocatalytic and “Pot-economy” Approach

Jiang Weng,*,a,‡ Sheng Wang,a,‡ Lin-Jie Huang,a Zhang-Yi Luo,a and Gui Lu*,a,b 

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Received 00th February 2015,  Accepted 00th February 2015 


DOI: 10.1039/x0xx00000x 

  An efficient and direct synthetic route to the epoxyisoprostane EC methyl ester has been accomplished in 8 steps (10% overall yield) from readily available starting materials by using a series of asymmetric organocatalytic reactions and one-pot operations. The oxidized phospholipids (OxPLs) are an important family of endogenous compounds generated in humans and other higher organisms under conditions of oxidative stress.1 There have been accumulating evidences from both in vivo and in vitro studies suggesting potential relevance of OxPLs in different pathologies, such as atherosclerosis,2 inflammation,3 lung injury,4 and many other conditions. Among the family, as shown in Scheme 1, the epoxyisoprostane phospholipids 1-palmitoyl-2-(5,6)epoxyisoprostane E2-sn-glycero-3-phosphocholine (PEIPC, 1) and its dehydration product PECPC (2) are the in vitro oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3phosphocholine (PAPC), which have been isolated from atherosclerotic lesions and other sites of chronic inflammation.5 PEIPC and PECPC have been identified as the most active lipids involving with several important inflammatory responses through increasing the production of proinflammatory mediators interleukin8 (IL-8) and monocyte chemotactic protein-1 (MCP-1).6 Previous studies have also demonstrated that phospholipases (PLA2) can hydrolyze PEIPC and PECPC to release free acid EI (3) and EC (4), respectively.7 Recently, Egger et al. have evaluated the activity of EI and EC in reducing secretion of proinflammatory cytokines IL-6 and IL-12 by dendritic cells in response to a TLR4 agonist and EC was identified as the most active compound.8 In the meantime, Jung et al. demonstrated that EI has potent anti-inflammatory effects on human aortic endothelial cells (HAEC) and strongly down-regulates the inflammatory effects of IL-1β.9 These data suggest that the epoxyisoprostanes EI, EC and their derivatives have many functions in common with PEIPC and PECPC and may be useful antiinflammatory agents.10 To support these in-depth biological research, the development of efficient synthesis of epoxyisoprostanes has been the subject of organic synthesis. In 2005, the groups of Jung11 and Kobayashi12

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have disclosed the total synthesis of PEIPC and PECPC in 20 steps (0.19% yield) and 14 steps (0.13% yield) respectively using chiral cyclopentadiene (CpH) as the starting material. In 2013, Carreira and co-workers completed the enantioselective synthesis of PECPC and PEIPC employing a highly diastereoselective intramolecular C–H insertion cyclization reaction as the key step. This route provided PECPC and PEIPC in 11 steps (5.4% yield) and 13 steps (1.8% yield). Meanwhile, EC and EI could also be conveniently accessed in 10 steps (7.8% yield) and 12 steps (2.7% yield), respectively.8 Considering that EC and EI were the precursors and analogues of PECPC and PEIPC, and all the previous routes required more than ten steps for their preparation, thus a more efficient and short entry to these epoxyisoprostanes and related derivatives would be highly desirable.


Scheme 1. Evolution of the phospholipid oxidation products.

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Scheme 2. Retrosynthetic analysis of epoxyisopeostanes

In recent years, organocatalytic domino reactions13 and “poteconomy”14 have become powerful strategies for the efficient and stereoselective construction of complex molecules. These reactions allow the formation of multiple new bonds and stereocenters in a single vessel under mild conditions, thereby minimizing the timeand cost-consuming purification operations and reducing the generation of wastes. As a part of our ongoing research on the application of organocatalysis for the preparation of biologically active compounds,15 we set out to develop a highly efficient synthesis of epoxyisopeostanes via organocatalytic and “poteconomy” strategy. Our retrosynthetic analysis was shown in Scheme 2. Disconnection of the ∆7-olefinic bond of EC through an intermolecular aldol/dehydration sequence led to epoxyaldehyde 5 and chiral cyclopentenone 6. The intermediate 5 could be obtained from α,β-unsaturated aldehyde 7 via asymmetric epoxidation reaction, while key intermediate 6 could be assembled through an intramolecular aldol reaction from precursor 8. Compound 8 could be accessed through asymmetric Michael reaction of methyl acetoacetate 11 with fumaraldehyde dimethyl acetal 12 and subsequent Wittig olefination. Herein 12 was used as the C4 unit for the construction of core structure, which provided two aldehyde groups for the introduction of ω-side chain and the formation of cyclopentenone skeleton respectively. It is worthy to note that our synthetic approach is completely different from any previous synthesis of epoxylisoprostanes and prostaglandins, especially the method for the construction of 4-substituted 2-cyclopentenone core. Moreover, to realize green synthesis and to avoid the use of toxic transition metal, we envisaged that all key steps for the construction of chiral centers, such as Michael addition, epoxidation, and intramolecular aldol reactions, should be catalyzed by organocatalysts under mild conditions through different activation modes (including enamine, iminium and phase-transfer catalysis). The study was initiated through the investigation of the organocatalytic Michael reaction of methyl acetoacetate 11 with fumaraldehyde dimethyl acetal 12.16 The success of this key reaction relied on the use of diarylprolinol silyl ether, an effective organocatalyst developed by Hayashi and Jørgensen independently.17 In the presence of 10 mol% of diarylprolinol silyl ether (I, Ar = 3,5-bis(trifluoromethyl)phenyl), the desired Michael adduct 10 was obtained in 86% yield with 96% ee (determined by

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chiral HPLC analysis after derivatization), while 32% yield and lower enantioselectivity was achieved with diphenylprolinol silyl ether catalyst. Further solvent screening with H2O, CHCl3 and THF † didn’t afford better results than toluene (see ESI ). The next transformation was the introduction of ω-side chain through Wittig olefination with good control on the Z-alkene. This reaction can be successfully realized by treating aldehyde 10 with in situ generated phosphorus ylid from hexyltriphenylphosphonium bromide to afford the Z-alkene 9 in 72% yield. The above two steps can also be performed in one pot as follows to minimize the purification operation: After the mixture of methyl acetoacetate 11 and fumaraldehyde dimethyl acetal 12 in toluene was treated with organocatalyst I (10 mol%) and PhCO2H (10 mol%) for 16 h, toluene was evaporated in vacuo to give crude aldehyde 10. Then 10 was dissolved in THF and reacted with phosphorus ylid at 20 oC for 1 h and at room temperature for another 10 h. This one-pot two-step sequence significantly improved the yield of Z-alkene 9 to 69% with simpler operation. The subsequent transformation was the construction of the cyclopentenone skeleton. We initially planned to form the cyclopentenone via the intramolecular aldehyde-ketone aldol reaction of 8 (in Scheme 2). When acetal 9 was treated with CF3CO2H, dihydrofuran 13 was isolated in 95% yield instead of the desired aldehyde 8. Although 13 itself is the cyclic analogue of levuglandin,18 here the formation of 13 was due to the enolization and acetalization of 8. Hence we tried to remove the ester group of 9 before the intramolecular aldol reaction to avoid the undesired transformation. After the hydrolysis of the methyl ester 9 in aqueous lithium hydroxide solution and the subsequent decarboxylation of in situ formed β-ketoacid under acidic condition, acetal 14 was obtained quantitatively. Without additional purification, 14 was deprotected via the treatment of Amberlyst-15 ion exchange resin in acetone/H2O to provide ketoaldehyde 15. The above two steps can also be performed in one-pot to give ketoaldehyde 15 in 77% yield with 90% ee. Next the intramolecular aldol condensation of 4-ketoaldehyde 15 † was studied (for details, see ESI ). To the best of our knowledge, through this kind of asymmetric intramolecular aldol condensation to form 4-mono-substituted 2-cyclopentenone has less been developed.19 The difficulty lies in the fact that optical active

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DOI: 10.1039/C5CC01077B

  Scheme 3. Synthesis of epoxyisopeostanes aldehyde 15 is prone to racemize under basic conditions, leading to a loss in the optical purity of the ketoaldehyde before undergoing the expected cyclization step.20 In our preliminary experiment, the treatment of 15 in aqueous NaOH solution gave the desired product 6 in 63% yield with only 3% ee value. Other inorganic bases as Ba(OH)2 and NaOMe provided the product in even lower yields and enantioselectivities. Some basic conditions (e.g., DBU, LDA, LiHMDS etc.) only gave complicated products. These results suggest that the deprotonation at the α-carbon of the aldehyde occurs much easier than the enolization of the terminal ketone. We envisioned that some highly crowded phase-transfer catalyst might benefit the cyclization rather than the racemization. After screening of several phase-transfer catalysts, we found that when the reaction was carried out in KOH (aq.)/CH2Cl2 solution in the presence of Nbenzylcinchoninium chloride (2.5 equiv.), the cyclopentenone 6 could be isolated in 30% yield with a slight loss of optical purity (87% ee of 6 versus 90% ee of 4-ketoaldehyde 15). It is worthy to note that the major by-product 16 (33% yield), which was formed via the enone enolization and double-bond shift, is also the subunit of biologically active prostaglandin B21. Moreover, several neutral and amine based organocatalytic conditions20,22 were also screened, albeit no desired cyclopentenone or cyclopentanone derivatives were obtained. The next step was to assemble the α-side chain of epoxyisoprostane using cyclopentenone 6 and epoxyaldehydes 5. Herein 5 was synthesized beforehead through an asymmetric organocatalytic epoxidation reaction developed by Jørgensen and Córdova.23 Treatment of α,β-unsaturated aldehyde 7 (in Scheme 2) with hydrogen peroxide in the presence of (S)-2(diphenyl(trimethylsilyloxy)methyl)pyrrolidine catalyst, the epoxyaldehyde 5 can readily be obtained in 51% yield with 92% ee (determined by HPLC analysis after derivatization). Then the C8 side chain of epoxyisoprostane was introduced via a procedure

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developed by Kobayashi12a and Carreira8, involving the intermolecular aldol reaction of cyclopentenone 6 with epoxyaldehyde 5, followed by the mesylation and trans-selective elimination to afford the target compound 18 in 63% yield (one-pot, three steps from 6). The spectral data (1H NMR, 13C NMR, HRMS, and optical rotation) of 18 were in excellent agreements with the published data.8


In summary, an enantioselective total synthesis of EC methyl ester was completed from readily available starting materials. The present route is not only short and efficient but also featured the use of multiple kinds of organocatalytic reactions including aminocatalysis (for Michael addition and epoxidation reaction) and phase-transfer catalysis (for intramolecular aldol reaction). Besides, within the principle of pot-economy, several transformations were carried out in one pot, which reduced the purification operations, protecting-group manipulations and the generation of wastes. Moreover, the present total synthesis will also benefit the preparation of a wide variety of prostaglandins and other natural products with cyclopentane or cyclopentene skeletons. Further refinement of the synthetic protocol and biological investigations of the epoxyisoprostanes are also underway in our laboratory.


This work was financially supported by The National High-tech R&D Program of China (No.2013AA092903), the Introduction of Innovative R&D Team Program of Guangdong Province (No. 2009010058), the Guangdong Natural Science Foundation (No. S2013040012409), the Fundamental Research Funds for the

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Journal Name 

2013, 52, 3450; (c) P. A. Clarke, S. Santos, W. H. C. Martin, Green

Institute of Medicinal Chemistry, School of Pharmaceutical Sciences,

Sun Yat-sen University, Guangzhou 510006, People’s Republic of China; Fax:



[email protected];

[email protected] b


C NMR spectra and HPLC

profiles for novel compounds. See DOI: 10.1039/c000000x/

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Stereoselective synthesis of epoxyisoprostanes: an organocatalytic and "pot-economy" approach.

An efficient and direct synthetic route to epoxyisoprostane EC methyl ester has been accomplished in 8 steps (10% overall yield) from readily availabl...
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