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CC BY 4.0 · Pharmaceutical Fronts 2023; 05(03): e168-e174
DOI: 10.1055/s-0043-1772224
Original Article

A Short and Facile [2 + 2] Photocycloaddition Protocol Toward Construction of a Levuglandin Skeleton

Pradeep T. Deota
1   Department of Applied Chemistry, Faculty of Technology and Engineering, The Maharaja Sayajirao University of Baroda, Baroda, Gujarat, India
,
Deepak Singh
2   Department of Chemical Sciences, University of Padova, Padova, Italy
,
Gaurang J. Bhatt
1   Department of Applied Chemistry, Faculty of Technology and Engineering, The Maharaja Sayajirao University of Baroda, Baroda, Gujarat, India
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Abstract

The γ-ketoaldehyde functionality of levuglandins (LGs) has a great propensity for various diseases such as Alzheimer's, atherosclerosis, and renal diseases. The synthesis of LGs constitutes a challenge for synthetic organic chemists due to their complex structures and low abundance in nature which has prompted us to develop its quick synthesis. This study aimed to explore a novel route for the construction of a levuglandin skeleton. We envisaged that the photocycloaddition of an appropriate alkene with equivalent propyne would give the cyclobutene adduct. The oxidative cleavage of the photocycloadduct can lead to the formation of the keto-aldehyde functionality. In this study, the readily available isopropenyl acetate (5) and methyl oleate (6) were used as starting materials to synthesize the target compound 13. The key step involves photocycloaddition of compounds 5 and 6, a regio-controlled elimination of the hydroxy group of compound 10, forming a cyclobutene derivative, as well as an oxidative cleavage of the cyclobutene derivative gives the framework of levuglandin. The intriguing chemistry of elimination resulting in the inseparable mixture of regioisomeric cyclobutenes has also been discussed. The route was simple and economical and helped for the creation of γ-ketoaldehyde functionality which is vital for the activity of levuglandins and can be extended for the construction of prostanoid skeleton through aldol condensation of the γ-ketoaldehydes.

Keywords

levuglandins - photocycloaddition - γ-ketoaldehydes

Supporting Information

1H NMR, 13C NMR, mass, and IR spectra of compounds 7 (or 8), 9, 10, 11, and 14 (mixed), 12, and 13 are available in the Supporting Information (Figs. S1–S28 [online only])002E


Supplementary Material



Publication History

Received: 03 February 2023

Accepted: 11 July 2023

Article published online:
24 August 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Rossy J, Ma Y, Gaus K. The organisation of the cell membrane: do proteins rule lipids?. Curr Opin Chem Biol 2014; 20: 54-59
    CrossrefPubMedGoogle Scholar
  • 2 Nicolaou KC, Ramphal JY, Petasis NA, Serhan CN. Lipoxins and related eicosanoids: biosynthesis, biological properties, and chemical synthesis. Angew Chem Int Ed Engl 1991; 30 (09) 1100-1116
    CrossrefGoogle Scholar
  • 3 Das UN. Essential fatty acids: biochemistry, physiology and pathology. Biotechnol J 2006; 1 (04) 420-439
    CrossrefPubMedGoogle Scholar
  • 4 Montine TJ, Neely MD, Quinn JF. et al. Lipid peroxidation in aging brain and Alzheimer's disease. Free Radic Biol Med 2002; 33 (05) 620-626
    PubMedGoogle Scholar
  • 5 Salomon RG, Miller DB, Zagorski MG, Coughlin DJ. Prostaglandin endoperoxides. 14. Solvent-induced fragmentation of prostaglandin endoperoxides. New aldehyde products from PGH2 and a novel intramolecular 1,2-hydride shift during endoperoxide fragmentation in aqueous solution. J Am Chem Soc 1984; 106 (20) 6049-6060
    CrossrefGoogle Scholar
  • 6 Hamberg M, Samuelsson B. Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc Natl Acad Sci U S A 1974; 71 (09) 3400-3404
    CrossrefPubMedGoogle Scholar
  • 7 Coughlin DJ, Salomon RG. Synthesis of thermal reactivity of some 2,3-dioxabicyclo[2.2.1]heptane models of prostaglandin endoperoxides. J Am Chem Soc 1977; 99 (02) 655-657
    CrossrefPubMedGoogle Scholar
  • 8 Salomon RG, Salomon MF. 2,3-Dioxabicyclo [2.2.1] heptane. The strained bicyclic peroxide nucleus of prostaglandin endoperoxides. J Am Chem Soc 1977; 99 (10) 3501-3503
    CrossrefPubMedGoogle Scholar
  • 9 Miller DB, Raychaudhuri SR, Avasthi K, Lal K, Levison B, Salomon RG. Prostaglandin endoperoxides. 25. Levuglandin E2: enantiocontrolled total synthesis of a biologically active rearrangement product from the prostaglandin endoperoxide PGH2. J Org Chem 1990; 55 (10) 3164-3175
    CrossrefGoogle Scholar
  • 10 Salomon RG, Bi W. Isolevuglandin adducts in disease. Antioxid Redox Signal 2015; 22 (18) 1703-1718
    CrossrefPubMedGoogle Scholar
  • 11 Poliakov E, Meer SG, Roy SC, Mesaros C, Salomon RG. Iso[7]LGD2-protein adducts are abundant in vivo and free radical-induced oxidation of an arachidonyl phospholipid generates this D series isolevuglandin in vitro. Chem Res Toxicol 2004; 17 (05) 613-622
    CrossrefPubMedGoogle Scholar
  • 12 Salomon RG, Batyreva E, Kaur K. et al. Isolevuglandin-protein adducts in humans: products of free radical-induced lipid oxidation through the isoprostane pathway. Biochim Biophys Acta 2000; 1485 (2–3): 225-235
    CrossrefPubMedGoogle Scholar
  • 13 Li W, Laird JM, Lu L. et al. Isolevuglandins covalently modify phosphatidylethanolamines in vivo: detection and quantitative analysis of hydroxylactam adducts. Free Radic Biol Med 2009; 47 (11) 1539-1552
    CrossrefPubMedGoogle Scholar
  • 14 Salomon RG, Miller DB, Raychaudhuri SR, Avasthi K, Lal K, Levison BS. Prostaglandin endoperoxides. 15. Asymmetric total synthesis of levuglandin E2. J Am Chem Soc 1984; 106 (26) 8296-8298
    CrossrefGoogle Scholar
  • 15 Amarnath V, Amarnath K, Masterson T, Davies S, Roberts LJ. A simplified synthesis of the diastereomers of levuglandin E2. Synth Commun 2005; 35 (03) 397-408
    CrossrefGoogle Scholar
  • 16 Roy SC, Nagarajan L, Salomon RG. Total synthesis of iso[7]-levuglandin D2. J Org Chem 1999; 64 (04) 1218-1224
    CrossrefGoogle Scholar
  • 17 Cheng YS, Yu W, Xu Y, Salomon RG. Total Synthesis Confirms the Molecular Structure Proposed for Oxidized Levuglandin D2 . J Nat Prod 2017; 80 (02) 488-498
    CrossrefPubMedGoogle Scholar
  • 18 Pappo R, Allen JD, Lemieux R, Johnson W. Notes - osmium tetroxide-catalyzed periodate oxidation of olefinic bonds. J Org Chem 1956; 21 (04) 478-479
    CrossrefGoogle Scholar
  • 19 Gao X, Lin J, Zhang L. et al. Iodine-initiated dioxygenation of aryl alkenes using tert-butylhydroperoxides and water: a route to vicinal diols and bisperoxides. J Org Chem 2021; 86 (21) 15469-15480
    CrossrefPubMedGoogle Scholar
  • 20 Huang H, Lambert TH. Electrophotocatalytic acetoxyhydroxylation of aryl olefins. J Am Chem Soc 2021; 143 (19) 7247-7252
    CrossrefPubMedGoogle Scholar
  • 21 Plietker B, Niggemann M. RuCl3/CeCl3/NaIO4: a new bimetallic oxidation system for the mild and efficient dihydroxylation of unreactive olefins. J Org Chem 2005; 70 (06) 2402-2405
    CrossrefPubMedGoogle Scholar
  • 22 Ranganathan SM, Muraleedharan K, Bharadwaj PP, Madhusudanan K. One step transformation of tricyclopentabenzene (trindane) [C15H18] to 4-[1R,2S,4R,5S)-1,2,5-trihydroxy-3-oxabicyclo[3.3.0]octane-4 spiro-1′-(2′-oxocyclopentan)-2-yl]butanoic acid [C15H22O7]. Chem Commun (Camb) 1998; (20) 2239-2240
    CrossrefGoogle Scholar
  • 23 Bhatt GJ, Deota PT, Upadhyay D, Jha PK. Site-selective unidirectional benzylic sp3 C-H oxidation of dodecahydrotriphenylene with RuCl3-NaIO4: formation of benzylic ketones. RSC Advances 2021; 11 (55) 34498-34502
    CrossrefPubMedGoogle Scholar
  • 24 Yun D, Ayla EZ, Bregante DT, Flaherty DW. Reactive species and reaction pathways for the oxidative cleavage of 4-octene and oleic acid with H2O2 over tungsten oxide catalysts. ACS Catal 2021; 11 (05) 3137-3152
    CrossrefGoogle Scholar
  • 25 Pan L, Ke Z, Yeung YY. Lewis base catalyzed dioxygenation of olefins with hypervalent iodine reagents. Org Lett 2021; 23 (21) 8174-8178
    CrossrefPubMedGoogle Scholar
  • 26 Mecozzi F, Dong JJ, Angelone D, Browne WR, Eisink NNHM. Oxidative cleavage of alkene C=C bonds using a manganese catalyzed oxidation with H2O2 combined with periodate oxidation. Eur J Org Chem 2019; 2019 (42) 7151-7158
    CrossrefPubMedGoogle Scholar
  • 27 Viski P, Szeverenyi Z, Simandi LI. A novel procedure for the cleavage of olefin derivatives to aldehydes using potassium permanganate. J Org Chem 1986; 51 (16) 3213-3214
    CrossrefGoogle Scholar