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Article

Preparation and Chiral HPLC Separation of the Enantiomeric Forms of Natural Prostaglandins

by
Márton Enesei
1,2,
László Takács
2,
Enikő Tormási
3,
Adrienn Tóthné Rácz
3,
Zita Róka
3,
Mihály Kádár
3 and
Zsuzsanna Kardos
2,*
1
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Műegyetem rakpart 3, 1111 Budapest, Hungary
2
CHINOIN, a member of Sanofi Group, PG Development, Tó utca 1-5, 1045 Budapest, Hungary
3
CHINOIN, a member of Sanofi Group, PG Analytics, Tó utca 1-5, 1045 Budapest, Hungary
*
Author to whom correspondence should be addressed.
Chemistry 2020, 2(3), 727-741; https://doi.org/10.3390/chemistry2030047
Submission received: 15 June 2020 / Revised: 5 August 2020 / Accepted: 10 August 2020 / Published: 18 August 2020
(This article belongs to the Special Issue Organic Chemistry Research in Hungary)
Browse Figures
Versions Notes

Abstract

:
Four enantiomeric forms of natural prostaglandins, ent-PGF2α ((−)-1), ent-PGE2 ((+)-2) ent-PGF1α ((−)-3), and ent-PGE1 ((+)-4) have been synthetized in gram scale by Corey synthesis used in the prostaglandin plants of CHINOIN, Budapest. Chiral HPLC methods have been developed to separate the enantiomeric pairs. Enantiomers of natural prostaglandins can be used as analytical standards to verify the enantiopurity of synthetic prostaglandins, or as biomarkers to study oxidation processes in vivo.

1. Introduction

Interest in the field of prostaglandins has been steadily growing since the basic work of Bergström Samuelsson, and Vane [1,2,3]. Their discoveries revealed the structure, the enzyme-controlled biochemical synthesis from arachidonic acid, and the main physiological effects of prostaglandins as well as their related substances. The biological behavior of prostaglandins, namely the regulation of the functions of all key organs in mammals including humans, has opened promising prospects for their therapeutic use. The request for systematic studies of natural prostaglandins and their synthetic derivatives has forced researchers all over the world to develop economical and scalable syntheses to produce these substances that were previously available only from natural sources [4,5,6].
The first generally applicable prostaglandin synthesis was a linear one, developed by Corey [7]. The key intermediate in the synthesis is lactone (−)-5, commonly referred to as Corey lactone, from which the omega and the alpha side chains of prostaglandins can be constructed [8,9,10]. The linear approach was followed by convergent syntheses, a more versatile one, a two-component coupling was first applied by Sih [11,12]. Noyori developed the idea of the shortest, highly convergent synthesis, the three-component coupling reaction. Noyori’s process provides the prostaglandins or derivatives in a one-pot reaction. The starting material is a chiral cyclopentenone; the omega side chain is introduced by an organo copper-mediated conjugate addition of the optically pure omega side chain. The enolate formed is trapped by the alfa side chain containing alkyl halide [13,14,15]. Recently, Aggarwal has developed a short, stereocontrolled organocatalytic synthesis starting with the double aldol reaction of succinaldehyde in the presence of a chiral auxiliary. The key intermediate is a methoxy acetal from which the omega side chain, which is constructed by a conjugate coupling reaction, then the alpha side chain is formed by a Wittig reaction [16,17,18]. For reviews of prostaglandin syntheses see refs. [19,20,21]. Scheme 1 shows the structures of the key intermediates of the prostaglandin synthesis and the structures of PGF2α and an isoprostane, IPF2α.
Versatile chemical syntheses from widely available starting materials have removed barriers from the use of natural prostaglandins and synthetic derivatives in human [19] and veterinary therapies [22,23]. The main uses in human therapy are treatments of ocular hypertension and glaucoma [24,25], pulmonary arterial hypertension (PAH) [26,27], lumbar spinal stenosis [28], gastric and duodenal ulcer [29], labor induction [30], congenital heart disease in infants [31,32], and chronic idiopathic constipation [33].
The selection of successful drug candidates required the preparation of thousands of prostaglandin derivatives, among them the enantiomers and epimers of natural prostaglandins as well. The idea that enantiomers of natural prostaglandins retain their biological activity but metabolize in vivo more slowly has led to contradicting results; therefore, no drugs have been developed from the prostaglandin enantiomers and the interest in these derivatives has been pushed to the periphery [34,35,36,37,38,39,40,41,42]. The situation changed when Morrow and Roberts reported that prostaglandin-like compounds are generated in vivo from arachidonic acid by the peroxidation of free radicals independently of the cyclooxygenase pathway [43,44,45,46,47]. Unbalanced free radicals, reactive oxygen or nitrogen species (ROS or RNS), can cause oxidative stress in the body, contributing to the development of cardiovascular, neurological, respiratory, and kidney disease, and even cancer [48].
Once discovered, isoprostanes are used as important biomarkers to study the oxidative processes in humans. Prostaglandin enantiomers, which, unlike natural prostaglandins, are also formed from arachidonic acid by free radical reactions, are in the spotlight again as promising biomarkers.

2. Aim of the Work

Evaluation of the literature data revealed that syntheses providing enantiomers of natural prostaglandins in a larger quantity are still missing. The aim of our work is to prepare prostaglandin enantiomers in a practical way using our processes that yield numerous prostaglandin active pharmaceutical ingredients in our prostaglandin plants.
The enantiomeric forms of natural prostaglandins can be used for scientific purposes as reference standards for studying oxidative processes in the body. Natural prostaglandins are synthesized from arachidonic acid by COX-1/COX-2 enzymes. In contrast, enantiomers of the natural prostaglandins can be formed by free radical oxidation.
Another important application of enantiomeric forms is in the analytical tests of the prostaglandin active ingredients. The enantiomeric forms can be used as analytical standards to verify the optical purity of the active ingredients to ensure the quality that meets the requirements of the pharmaceutical authorities.
We plan to prepare the enantiomeric forms of all prostaglandins that are in our portfolio. This work has been started by synthetizing the enantiomeric forms of the natural prostaglandins that are manufactured in our plants, because they can be used for two different purposes. Hereinafter, enantiomeric forms of the modified prostaglandin derivatives will be prepared. The latter can only be used for analytical purposes, as they are not synthesized in the human body. In the present study, the synthesis of ent-PGF1α, ent-PGF2α, ent-PGE2 and ent-PGE1, starting from ent-Corey lactone, and methods for the separation of the enantiomeric pairs by chiral analytical HPLC are presented. See structures of the Corey lactone enantiomers ((−)-5 and (+)-5)) and the prepared ent-prostaglandins in Scheme 2.

3. Material and Methods

The commercially available reagents and analytical grade solvents were purchased from Merck (Darmstadt, Germany). Merck DC Fertigplatten 60 silicagel TLC plates with fluorescence indicator 254 nm was used for TLC chromatography, and Merck silica gel 60 (0.063–230 mm) for column chromatography.
Waters HPLC system equipped with a PDA detector and Empower V3 electronic data processing system was used for the HPLC method development.
1H and 13C NMR spectra were recorded on Bruker AvanceIII (Billerica, MA, USA) instrument at 500.15 MHz and 125.8 MHz, respectively, in the DMSO-d6 solvents. Chemical shifts (δ) are given in parts per million (ppm) relative to TMS, coupling constants (J) in hertz (Hz). The solvent signals were used as references and the chemical shifts converted to the TMS scale (deuterated dimethyl sulfoxide (DMSO-d6): δC 39.52 ppm (sep) in DMSO-d6, δH 2.50 ppm (m), residual peak in DMSO-d6) [49]. In the report, the full assignment of the 1H and 13C NMR spectra have been achieved by utilizing the attached proton test (APT) and the two-dimensional HSQC, ed-HSQC, HMBC, COSY, NOESY and ROESY measurements.

4. Results and Discussions

4.1. Synthesis of Mirror Images of Natural Prostaglandins

In our prostaglandin plant, we use modified version of Corey synthesis [48] to produce a variety of natural and structurally modified prostaglandins as active pharmaceutical ingredients (PG API-s) [50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69]. This versatile synthesis allows the production of different types of prostaglandins from a common intermediate, the Corey lactone ((−)-5). The same strategy was used to design the synthesis of enantiomeric forms of natural prostaglandins. Logically, in this case, the starting material was the mirror image of the Corey lactone, called ent-Corey lactone ((+)-5), from which each of the four enantiomeric prostaglandins could be prepared. The ent-Corey lactone can be synthetized by known methods from (+)-bicyclic lactone, the “wrong” enantiomer of the resolution step of the prostaglandin synthesis [48,70,71]. Preparation and resolution of rac-bicyclic lactone is shown in Scheme 3. The ent-Corey lactone and Corey lactone are also commercially available [72].
The initial reaction steps in the synthesis of ent-prostaglandins, were the transformation of the ent-Corey lactone ((+)-5) to the unprotected lactol (11). First, the primary hydroxyl-group in the ent-Corey lactone ((+)-5) was oxidized by Anelli oxidation [73]. Dichloromethane solution of the crude aldehyde (6) was reacted with the sodium salt dimethyl (2-oxo)heptylphosphonate (7) to form the omega side chain under the conditions of Horner–Wadsworth–Emmons (HWE) reaction [74,75,76]. Protected enone (8) was purified by crystallization. Then, the 15-oxo-group was stereoselectively reduced with in situ prepared catecholborane in the presence of (S)-2-Methyl-CBS catalyst [77]. After work-up, the lactone group of protected enol (9) was reduced to the lactol (10). The undesired diastereomer, the derivatized side-product of 15-oxo-reduction, (S)-10 was removed by chromatography and crystallization. The methanolysis of PPB-protecting group provided the unprotected lactol (11), which was purified by crystallization. Reaction steps are shown in Scheme 4.
The unprotected lactol (11), containing a masked aldehyde functionality, is a common building block of all four enantiomeric prostaglandins. The alpha side chain for ent-PGF2α ((−)-1) was prepared by Wittig reaction with the phosphorane liberated from 4-carboxybutyl triphenylphosphonium bromide (CBP-Br) (12) by the strong base, KOBut. We have not crystallized yet the oily crude ent-PGF2α (1), instead it was converted to its stable, crystalline tromethamine salt.
For the preparation of the remaining three derivatives ent-PGE2 ((+)-2), ent-PGF1α ((−)-3), ent-PGE1 ((+)-4), the lactol group of 11 was reoxidized to lactone (13) with iodine in an aqueous medium containing KI and KHCO3. This reoxidation is required for the selective formation of the 9-oxo group in the PGE derivatives. Free hydroxyl groups were protected with dihydropyran by an acid catalyzed reaction, supplying the bis-THP lactone (14). To form the alpha side chain of the prostaglandin structure, the lactone group was reduced to lactol to make the molecule suitable for the Wittig reaction. The alpha side chain was built again with the phosphorane prepared from CBF-Br (12) with KOBut as the base in THF solution, giving the ent-THP2-PGF2α (16), that is the last common intermediate for the preparation of ent-PGE2 ((+)-2), ent-PGF1α ((−)-3) and ent-PGE1 ((+)-4).
Preparation of ent-PGE2 ((+)-2), happened by the oxidation of the free 9-hydroxyl group of acid (16) with pyridinium chlorochromate (PCC) in ethyl acetate. The pH of the reaction mixture was buffered by sodium acetate and acetic acid. The crude ent-THP2-PGE2 (17) was filtered through silica gel to remove the residue of the oxidant. In the last step of this series, the THP-protecting groups were removed in isopropanol. The reaction was catalyzed by 1 mol/L hydrochloric acid. Crude ent-PGE2 ((+)-2) was purified by chromatography using hexane-ethyl acetate eluent, and crystallization from ether-diisopropyl ether.
To prepare ent-PGF1α ((−)-3) and ent-PGE1 ((+)-4) the cis double bound in the alpha side chain of 16 must be selectively reduced. This selective reduction is a key step because it allows derivatives containing either one or two double bonds to be prepared from a common intermediate. This transformation is performed by catalytic hydrogenation in diisopropyl ethylamine-dichloromethane solution using 10% Pd/C catalyst. The quantity of crude ent-THP2-PGF1α (18) was divided into two parts. One part was dissolved in isopropanol containing 1 mol/L hydrochloric acid to remove the THP-protecting groups, giving ent-PGF1α. Crude ent-PGF1α ((−)-3) was purified by double crystallization from ethyl acetate followed by ethyl acetate-hexane.
The 9-hydroxyl group of the remaining quantity of 18 was oxidized with PCC to the 9-oxo derivative, ent-THP2-PGE1 (19). Crude 19 was purified by column chromatography. The evaporated main fraction was dissolved in isopropanol containing 1 mol/L hydrochloric acid to remove the protecting groups. Crude ent-PGE1 ((+)-4) was crystallized from diisopropyl ether-hexane. Reaction steps for the preparation of ent-prostaglandins are shown in Scheme 5.

4.2. Separation of Natural Prostglandin Enantiomers by Chiral HPLC

Having the optically pure mirror images of four natural prostaglandins in our hands (chemical purities are given in the Supplementary Material), the next goal was to develop chiral HPLC methods for the separation of the enantiomeric pairs. To date, only one scientific article has reported the chiral reversed phase HPLC separation of PGE2 enantiomers. According to the article, various chiral HPLC columns were tested, but the enantiomeric separation was only successful when the Phenomenex Lux Amylose2 column was used. Elution of the Lux Amylose2 column with methanol:water or 2-propanol:water did not resolve the enantiomers. When a low concentration of acetonitrile (25% in water with 0.1% formic acid) and a slow flow rate (50 µL/min) were used, the enantiomers separated, but the peaks were broadened. The best results were obtained when two columns, connected in series were used for the enantiomeric separation [78].
As the known procedure presented a rather sophisticated method and that method was only applied for the separation of PGE2 enantiomers, we have decided to work out a simplified procedure which is suitable for routine tests of the prostaglandins manufactured in our plant.
Reverse phase methods are promising for the chromatographic analysis of acidic compounds, including prostaglandin acids, so we have been looking for a reverse phase chiral column. Based on literature data and our previous experience, we have chosen Chiracel OJ-RH as the chiral HPLC column. This type of column has been successfully applied for the enantiomeric separation of chemically distinct racemic organic acids [79].
In selecting the values of the test parameters, we partly took into account the column supplier’s recommendation [80], and partly our chromatographic experience. The reversed phase HPLC conditions are summarized in Table 1.
Based our preliminary experiments, sample solutions were prepared by dissolving equal amounts of the pure enantiomers in the sample solvent (acetonitrile:methanol:water = 30:10:60) and aliquots from the solution of the corresponding enantiomeric pairs were mixed prior to the injection. The eluent was a three-component mixture containing acetonitrile:methanol:water (pH = 4). It is noted here that pH of the water was adjusted to 4 with phosphoric acid (85 w/w% in H2O) in every case. This pH = 4 value provides an adequate separation and elution rate for the prostaglandin acids, without causing decomposition of their acid-sensitive structure. Phosphoric acid was also recommended for adjusting the pH of Chiracel OJ-RH columns at this pH value to avoid degradation of the column. Composition of the eluents were varied in a wide range to achieve a good resolution. The composition of the eluents is summarized in Table 2.
The results for individual runs were evaluated by comparing the resolution values (R) calculated according to United States Pharmacopeia (USP-NF, < 621 > Chromatography). To achieve at least R = 1.2 resolution the composition of the eluent and column temperature were varied. When optimizing the method, not only the resolution, but also the time and eluent consumption were taken into account. The effect of the variable parameters on the resolution of enantiomers of PGE2 is shown in Figure 1.
By varying the indicated parameters, we performed the chiral separation of all four enantiomeric pairs with excellent resolution, R ≥ 1.5. The best resolutions are shown in Figure 2, Figure 3, Figure 4 and Figure 5.
Enantiopurity of the individual pure ent-prostaglandins has been also determined by the developed chiral methods. HPLC area percentages and enantiomeric excesses are summarized in Table 3.

5. Conclusions

Four mirror images of the natural prostaglandins, ent-PGF2α ((−)-1), ent-PGE2 ((+)-2), ent-PGF1α ((−)-3), and ent-PGE1 ((+)-4) were synthesized by the modified Corey synthesis. The starting material was the ent-Corey lactone ((+)-5), which is a side-product of our prostaglandin production. Using ent-Corey lactone ((+)-5) the mirror images of natural prostaglandins and numerous modified derivatives can be synthesized. The mirror images of prostaglandins can be used as reference standards to justify the optical purity of the pharmaceutical active ingredients. In addition, enantiomeric forms of natural prostaglandins may be important biomarkers to study the oxidative stress of the human body to better understand the mechanism of development of many serious, or even fatal, diseases.
Chiral HPLC methods have been also developed for the analytical separation of the enantiomeric pairs. Enantiopurity of the pure ent-prostaglandins has been determined. The HPLC method developed proved to be quite general. The Chiracel OJ-RH column was suitable for the separation of all four enantiomeric pairs. The eluent mixture contained acetonitrile:methanol:water (pH = 4) in each case, but the solvents were mixed in different proportions. The column temperature was 25 °C for the separation of the enantiomeric pairs of PGF2α, PGF1α and PGE1, but adequate resolution of the PGE2 enantiomers was achieved at a higher column temperature, at 40 °C.
In contrast to the known method, the procedure developed is suitable for the routine analytical tests to check the enantiopurity of the prostaglandins produced in our plants.
Our long-term goal is to synthesize the mirror images of all prostaglandins that are in our portfolio in order to test the enantiopurity of the active ingredients of the prostaglandin drugs.

Supplementary Materials

Preparation of ent-PGF2α ((−)-1), ent-PGE2 ((+)-2) ent-PGF1α ((−)-3), and ent-PGE1 ((+)-4) is available online at https://www.mdpi.com/2624-8549/2/3/47/s1.

Author Contributions

Conceptualization, Z.K., L.T. and E.T.; methodology, L.T.; E.T.; Z.R.; M.E.; A.T.R.; formal analysis, M.K.; investigation, M.E.; A.T.R.; writing—original draft preparation, Z.K., E.T.; writing—review and editing, L.T., Z.R.; visualization, E.T.; supervision, Z.K.; project administration, Z.K.; All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

The authors thank Zoltán Szeverényi and Klára Ősapay for reviewing the manuscript before submission.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Bergström, S. The prostaglandins: From the Laboratory to the Clinic (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 1983, 22, 858–866. [Google Scholar] [CrossRef]
  2. Samuelsson, B. From studies of biochemical mechanism to novel biological mediators: Prostaglandin endoperoxides, thromboxanes, and leukotrienes (Nobel lecture). Angew. Chem. Int. Ed. Engl. 1983, 22, 805–815. [Google Scholar] [CrossRef]
  3. Vane, J.R. Adventures and Excursions in bioassay: The steppingstones to prostacyclin (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 1983, 22, 741–752. [Google Scholar] [CrossRef]
  4. Kurzok, R.C.; Lieb, C. Biochemical studies of human semen. II. The action of semen on the human uterus. Proc. Soc. Exp. Biol. Med. 1930, 28, 268–272. [Google Scholar] [CrossRef]
  5. Goldblatt, M.W. Properties of human seminal plasma. J. Phisyol. 1935, 84, 208–218. [Google Scholar] [CrossRef] [PubMed]
  6. von Euler, U.S. On the specific vasodilating and plain muscle stimulating substances from accessory genital glands in man and certain animals (prostaglandin and vesiglandin). J. Phisyol. 1937, 88, 213–234. [Google Scholar]
  7. Corey, E.J. The logic of chemical synthesis: Multistep synthesis of complex carbogenic molecules (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 1991, 30, 455–465. [Google Scholar] [CrossRef]
  8. Corey, E.J.; Weinshenker, N.M.; Schaaf, T.K.; Huber, W. Stereo-controlled synthesis of prostaglandins F2a and E2 (dl). J. Am. Chem. Soc. 1969, 91, 5675–5677. [Google Scholar] [CrossRef]
  9. Corey, E.J.; Schaaf, T.K.; Huber, W.; Koelliker, U.; Weinshenker, N.M. Total synthesis of prostaglandins F2a and E2 as the naturally occurring forms. J. Am. Chem. Soc. 1970, 92, 397–398. [Google Scholar] [CrossRef]
  10. Corey, E.J.; Noyori, R.; Schaaf, T.K. Total synthesis of prostaglandins F1a, E1, F2a, and E2 (Natural forms) from a common synthetic intermediate. J. Am. Chem. Soc. 1970, 92, 2586–2587. [Google Scholar] [CrossRef]
  11. Sih, C.J.; Salomon, R.G.; Price, P.; Peruzzotti, G.; Sood, R.G. Total synthesis of (±)-15-deoxyprostaglandin E1. J. Chem. Soc. Chem. Commun. 1972, 4, 240–241. [Google Scholar] [CrossRef]
  12. Sih, C.J.; Price, P.; Sood, R.; Salomon, R.G.; Peruzzotti, G.; Casey, M. Total synthesis of prostaglandins II. Prostaglandin E1. J. Am. Chem. Soc. 1972, 94, 3643–3644. [Google Scholar] [CrossRef] [PubMed]
  13. Noyori, R.; Suzuki, M. Prostaglandin synthesis by tree-component coupling. Angew. Chem. Int. Ed. Engl. 1984, 23, 847–876. [Google Scholar] [CrossRef]
  14. Suzuki, M.; Morita, Y.; Koyano, H.; Koga, M.; Noyori, R. Three-component coupling synthesis of prostaglandins. A simplified, general procedure. Tetrahedron 1990, 46, 4809–4822. [Google Scholar] [CrossRef]
  15. Noyori, R. Asymmetric catalysis: Science and opportunities (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 2002, 41, 2008–2022. [Google Scholar] [CrossRef]
  16. Coulthard, G.; Erb, W.; Aggarwal, V.K. Stereocontrolled organocatalytic synthesis of prostaglandin PGF2a in seven steps. Nature 2012, 489, 278–281. [Google Scholar] [CrossRef]
  17. Baars, H.; Classen, M.J.; Aggarwal, V.K. Synthesis of Alfaprostol and PGF2a through 1,4-addition of an alkyne to an enal intermediate as the key step. Org. Lett. 2017, 19, 6008–6011. [Google Scholar] [CrossRef] [Green Version]
  18. Pelss, A.; Gandhamsetty, N.; Smith, J.R.; Mailhol, D.; Silvi, M.; Watson, A.J.A.; Perez-Powell, I.; Prévost, S.; Schützenmeister, N.; Moore, P.R.; et al. Reoptimization of the organocatalyzed double aldol domino process to a key enal intermediate and its application to the total synthesis of delta12 prostaglandin J3. Chem. Eur. J. 2018, 24, 9542–9545. [Google Scholar] [CrossRef] [Green Version]
  19. Collins, P.W.; Djuric, S.W. Synthesis of therapeutically useful prostaglandin analogs. Chem. Rev. 1993, 93, 1533–1564. [Google Scholar] [CrossRef]
  20. Das, S.; Chandrasekhar, S.; Yadav, J.S.; Grée, R. Recent developments in the synthesis of prostaglandin analogues. Chem. Rev. 2007, 107, 3286–3337. [Google Scholar] [CrossRef]
  21. Peng, H.; Chen, F.-E. Recent advances in asymmetric total synthesis of prostaglandins. Org. Biomol. Chem. 2017, 15, 6281–6301. [Google Scholar] [CrossRef] [PubMed]
  22. Cooper, M.J. Prostaglandins in veterinary practice. In Pract. 1981, 3, 30–34. [Google Scholar] [CrossRef] [PubMed]
  23. Cooper, M.J.; Hammond, D.; Schultz, R.H. Veterinary uses of prostaglandins. In Practical Applications of Prostaglandins and Their Synthesis Inhibitors, 1st ed.; Kerim, S.M.M., Ed.; Springer: Berlin/Heidelberg, Germany; MPP Press Ltd.: Dordrecht, The Netherlands, 1979; pp. 190–209. [Google Scholar]
  24. Lee, C.W.; Buckley, F.; Costello, S.; Kelly, S. A systematic review of the characteristics of randomised control trials featuring prostaglandins for the treatment of glaucoma. Curr. Med. Res. Opin. 2008, 24, 2265–2270. [Google Scholar] [CrossRef] [PubMed]
  25. Toris, C.; Gulati, V. The biology, pathology and therapeutic use of prostaglandins in the eye. Clin. Lipidol. 2011, 6, 577–591. [Google Scholar] [CrossRef]
  26. Lee, S.H.; Rubin, L.J. Current treatment strategies for pulmonary arterial hypertension. J. Internal Med. 2005, 258, 199–215. [Google Scholar] [CrossRef]
  27. Buckley, M.S.; Berry, A.J.; Kazem, N.H.; Patel, S.A.; Librodo, P.A. Clinical utility of treprostinil in the treatment of pulmonary hypertension: An evidence based review. Core Evid. 2014, 9, 71–80. [Google Scholar] [CrossRef] [Green Version]
  28. Kim, H.J.; Kim, J.H.; Park, Y.S.; Suk, K.S.; Lee, J.H.; Park, M.S.; Moon, S.H. Comparative study of the efficacy of limaprost and pregabalin as single agents and in combination for the treatment of lumbar spinal stenosis: A prospective, double-blind, randomized controlled non-inferiority trial. Spine J. 2016, 16, 756–763. [Google Scholar] [CrossRef]
  29. Satoh, H.; Takeuchi, K. Management of NSAID/Aspirin-Induced Small Intestinal Damage by GI-Sparing NSAIDs, Anti-Ulcer Drugs and Food Constituents. Curr. Med. Chem. 2012, 19, 82–89. [Google Scholar] [CrossRef]
  30. Jozwiak, M.; Oude Rengerink, K.; Ten Eikelder, M.L.G.; van Pampus, M.G.; Dijksterhuis, M.G.K.; de Graaf, I.M.; van der Post, J.A.M.; van der Salm, P.; Scheepers, H.C.J.; Schuitemaker, N.; et al. Foley catheter or prostaglandin E2 inserts for induction of labour at term: An open-label randomized controlled trial (PROBAAT-P trial) and systematic review of literature. Eur. J. Obst. Gynecol. Reprod. Biol. 2013, 170, 137–145. [Google Scholar] [CrossRef]
  31. Distefano, G. The pharmacological manipulation of Botallo’s duct in the duct-dependent congenital cardiopathies and in the preterm infants with respiratory distress. A review and personal findings. Minerva Pediatrica 2005, 57, 21–34. [Google Scholar]
  32. Huang, F.K.; Lin, C.C.; Huang, T.C.; Weng, K.P.; Liu, P.Y.; Chen, Y.Y.; Wang, H.P.; Ger, L.P.; Hsieh, K.S. Reappraisal of the prostaglandin E1 dose for early newborns with patent ductus arteriosus-dependent pulmonary circulation. Pediatr. Neonat. 2013, 54, 102–106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Baker, D.E. Lubiprostone: A new drug for the treatment of chronic idiopathic constipation. Rev. Gastroent. Disord. 2007, 7, 214–222. [Google Scholar]
  34. Corey, E.J.; Andersen, N.H.; Carlson, R.M.; Paust, J.; Vedejs, E.; Vlattas, I.; Winter, R.E.K. Total synthesis of prostaglandins. Synthesis of the pure dl-E1, -F1a, F1b, -A1 and -B1. J. Am. Chem. Soc. 1968, 90, 3247. [Google Scholar] [CrossRef] [PubMed]
  35. Corey, E.J.; Vlattas, I.; Harding, K. Total synthesis of natural (levo) and enantiomeric (dextro) forms of prostaglandin E1. J. Am. Chem. Soc. 1969, 91, 535–536. [Google Scholar] [CrossRef]
  36. Slaters, H.L.; Zelawski, Z.S.; Taub, D.; Wendler, N.L. A new stereoselective total synthesis of prostaglandin E1 and its optical antipodes. J. Chem. Soc. Chem. Commun. 1972, 6, 304–305. [Google Scholar] [CrossRef]
  37. Slaters, H.L.; Zelawski, Z.S.; Taub, D.; Wendler, N.F. A stereoselective total synthesis of nat(−)-prostaglandin E1 and its optical antipode. Tetrahedron 1974, 30, 819–830. [Google Scholar] [CrossRef]
  38. Taub, D.; Hoffsommer, R.D.; Kuo, C.H.; Zelaeski, Z.S.; Wendler, N.L. A stereoselective total synthesis of PGE1. Chem. Comm. 1970, 1258–1259. [Google Scholar]
  39. Cooper, E.L.; Yankee, E.W. Enantiomeric prostaglandins. J. Am. Chem. Soc. 1974, 96, 5876–5894. [Google Scholar] [CrossRef]
  40. Andersen, N.H.; Imamoto, S.; Picker, D.H. Synthesis of bis-unsaturated prostaglandins. Prostaglandins 1977, 14, 61–101. [Google Scholar] [CrossRef]
  41. Ramwell, P.W.; Shaw, J.E.; Corey, E.J.; Andersen, N. Biological activity of synthetic prostaglandins. Nature 1969, 221, 1251–1253. [Google Scholar] [CrossRef]
  42. Miller, W.L.; Sutton, M.J. Relative biological activity of certain prostaglandins and their enantiomers. Prostaglandins 1976, 11, 77–84. [Google Scholar] [CrossRef]
  43. Morrow, J.D.; Harris, T.M.; Roberts, L.J., II. Non-cyclooxygenase oxidative formation of a series of novel prostaglandins: Analytical ramifications for measurement of eicosanoids. Anal. Biochem. 1990, 184, 1–10. [Google Scholar] [CrossRef]
  44. Morrow, J.D.; Hill, K.E.; Burk, R.F.; Nammour, T.M.; Badr, K.F.; Roberts, L.J., II. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc. Natl. Acad. Sci. USA 1990, 87, 9383–9387. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Milne, G.L.; Dai, Q.; Roberts, L.J., II. The isoprostanes 25 years later. Biochim. Biophis. Acta 2015, 1851, 433–445. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Oge, K.; Cuyamendous, C.; de la Torre, A.; Candy, M.; Guy, A.; Bultel-Poncé, V.; Durand, T.; Galano, J.M. History of chemical routes towards cyclic non-enzymatic oxygenated metabolites of polyunsaturated fatty acids. Synthesis 2018, 50, 3257–3280. [Google Scholar]
  47. Antus, B.; Kardos, Z. Oxidative stress in COPD: Molecular background and clinical monitoring. Curr. Med. Chem. 2015, 22, 627–650. [Google Scholar] [CrossRef]
  48. Pizzino, G.; Irrera, N.; Cucinotta, M.; Pallio, G.; Mannino, F.; Arcoraci, V.; Squadrito, F.; Altavilla, D.; Bitto, A. Oxidative stress: Harms and benefits for human health. Oxid. Med. Cell. Longev. 2017, 2017, 1–13. [Google Scholar] [CrossRef]
  49. Gottlieb, H.E.; Kotlyar, V.; Nudelman, A. NMR chemical shifts of common laboratory solvents as trace impurities. J. Org. Chem. 1997, 62, 7512–7515. [Google Scholar] [CrossRef]
  50. Tömösközi, I.; Gruber, L.; Kovács, G.; Székely, I.; Simonidesz, V. Regiospecific Prins reaction, a new way to prostanoids. Tetrahedron Lett. 1976, 50, 4639–4642. [Google Scholar] [CrossRef]
  51. Szabó, T.; Dalmadi, G.; Remport, R.I.; Forró, L.; Hermecz, I.; Sárközi, P.; Nemes, J. Process for the Preparation of PGF2a Tromethamine Salt. Patent HU 56060 A2, 29 July 1991. [Google Scholar]
  52. Ivanics, J.; Szabó, T.; Hermecz, I.; Dalmadi, G.; Kovacs, G.; Resul, B. Chemical Process: Preparation of 13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2a Esters. Patent WO 1993000329 A1, 7 January 1993. [Google Scholar]
  53. Dalmadi, G.; Hajdu, F.; Hermecz, I.; Mozsolits, K.; Szabo, T.; Szeverényi, Z.; Vajda, E. Process for the Preparation of Prostaglandin E1. Patent WO 1997022881 A1, 26 June 1997. [Google Scholar]
  54. Galambos, G.; Benno, N.; Povarny, B.M.; Dalmadi, G.; Ebinger, K.; Forró, L.; Hajdu, F.; Hermecz, I.; Kardos, Z.; Lukacs, G.; et al. Process for the Selective Reduction of α,β-Unsaturated Ketones as Prostaglandin Intermediates. Patent WO 1997022602 A2, 26 June 1997. [Google Scholar]
  55. Szabó, T.; Bódi, J.; Dalmadi, G.; Kardos, Z.; Szeverényi, Z. Process for the Preparation of Beraprost and Its Salts. Patent WO 2003011849 A1, 13 February 2003. [Google Scholar]
  56. Kardos, Z.; Szeverényi, Z.; Dalmadi, G.; Szabó, T.; Bódi, J. Production of Beraprost Ester by Selective reduction. Patent HU 0103088 A2, 28 July 2001. [Google Scholar]
  57. Havasi, G.; Kiss, T.; Hortobágyi, I.; Kardos, Z.; Lászlófi, I.; Bischof, Z.; Bódis, Á. Novel Processes for the Preparation of Prostaglandin Amides. Patent WO 2012164324 A1, 6 December 2012. [Google Scholar]
  58. Kardos, Z.; Kiss, T.; Lászlófi, I.; Hortobágyi, I.; Bischof, Z.; Bódis, Á.; Havasi, G. Process for the Preparation of Travoprost. Patent WO 2013093528 A1, 27 June 2013. [Google Scholar]
  59. Bischof, Z.; Bódis, Á.; Kőműves, M.M. Alternative Process for the Preparation of Travoprost. Patent WO 2014083367 A1, 5 June 2014. [Google Scholar]
  60. Vajda, E.; Hortobágyi, I.; Lászlófi, I.; Buzder-Lantos, P.; Havasi, G.; Takács, L.; Kardos, Z. New Process for the Preparation of High Purity Prostaglandins. Patent WO 2015136317 A1, 17 September 2015. [Google Scholar]
  61. Juhász, I.; Hortobágyi, I.; Altsach, T.; Lászlófi, I.; Borkó, N.Á.; Rozsumberszki, I.; Havasi, G.; Kardos, Z.; Buzder-Lantos, P. Process for the Preparation of Treprostinil and Its Salt Forms. Patent WO 2016055819 A1, 14 April 2016. [Google Scholar]
  62. Buzder-Lantos, P.; Kardos, Z.; Hortobágyi, I.; Lászlófi, I.; Juhász, I.; Fónagy, L.; Váradi, C.; Borkó, N.Á. Process for the Preparation of Carboprost and Its Tromethamine Salt. Patent WO 2017093770 A1, 8 June 2017. [Google Scholar]
  63. Takács, L.; Fekete, I.; Buzder-Lantos, P.; Lászlófi, I.; Hortobábyi, I.; Havasi, G.; Kardos, Z. Preparation of Latanoprostene Bunod of Desired, Pre-Defined Quality by Gravity Chromatography. Patent WO 2017093771 A1, 8 June 2017. [Google Scholar]
  64. Hortobágyi, I.; Lászlófi, I.; Kardos, Z.; Molnár, J.; Takács, L.; Bán, T. Process for the Preparation of Triple-Bond Containing Optically Active Carboxylic Acids, Carboxylate Salts and Carboxylic Acid Derivatives. Patent WO 2017152667 A1, 14 September 2017. [Google Scholar]
  65. Hortobágyi, I.; Lászlófi, I.; Kardos, Z.; Molnár, J.; Takács, L.; Tormási, R. Preparation of Epoprostenol Sodium of Enhanced Stability. Patent WO 2017162668 A1, 28 September 2017. [Google Scholar]
  66. Hortobágyi, I.; Lászlófi, I.; Kardos, Z.; Molnár, J.; Takács, L.; Bán, T. Process for the Optically Active Beraprost. Patent WO 2017174439 A1, 12 October 2017. [Google Scholar]
  67. Hortobágyi, I.; Lászlófi, I.; Kardos, Z.; Molnár, J.; Takács, L.; Horváth, K. Process for the preparation and purification of misoprostol. Patent WO 2019011668 A1, 19 January 2019. [Google Scholar]
  68. Hortobágyi, I.; Lászlófi, I.; Varga, Z.; Juhász, I.; Ritz, I.; Kardos, Z. Process for the preparation of polymorph form B of treprostinil diethanolamine salt. Patent WO 2019170093 A2, 12 September 2019. [Google Scholar]
  69. Rozsumberszki, I.; Váradi, C.; Bán, T.; Kardos, Z.; Hortobágyi, I.; Szabó, T. Process for the preparation of iloprost. Patent WO 2019202345 A2, 24 October 2019. [Google Scholar]
  70. Corey, E.J.; Arnold, Z.; Hutton, J. Total synthesis of prostaglandins E2 and F2a (dl) via a tricarbocylic intermediate. Tetrahedron Lett. 1970, 4, 307–310. [Google Scholar] [CrossRef]
  71. Tőke, L.; Szabó, G.; Fogassy, E.; Ács, M.; Nagy, L.; Árvai, L. Verfahren zur Trennung von racemischen Alkalimatellsalzen und vom Lacton der cis-2-Hydroxy-cyclopent-4-en-1-yl-essigsaure. Patent CH 647 496 A5, 9 January 1979. [Google Scholar]
  72. Sigma-Aldrich Products, Chemical and Biochemical Product. Available online: https://www.sigmaaldrich.com/catalog/search?term=Corey+lactone&interface=All&N=0&mode=match%20partialmax&lang=fr&region=FR&focus=product (accessed on 26 July 2020).
  73. Anelli, P.L.; Biffi, C.; Montanari, F.; Quici, S. Fast and selective oxidation of primary alcohols to aldehydes or to carboxylic acids and of secondary alcohols to ketones mediated by oxoammonium salts under two-phase conditions. J. Org. Chem. 1987, 52, 2559–2562. [Google Scholar] [CrossRef]
  74. Wadsworth, W.S.; Emmons, W.D. The utility of phosphonate carbanion in olefin synthesis. J. Am. Chem. Soc. 1961, 83, 1733–1738. [Google Scholar] [CrossRef]
  75. Horner, L.; Hofmann, H.; Klink, W.; Ertel, H.; Toscano, V.G. PO aktivierte Verbindung als Olefinierungreagentin. Chem. Ber. 1962, 95, 581–601. [Google Scholar] [CrossRef]
  76. Bruckner, R.; Harmata, M. (Eds.) Organic Mechanisms—Reactions, Stereochemistry and Synthesis; Springer: Berlin/Heidelberg, Germany, 2010; pp. 471–475. [Google Scholar]
  77. Corey, E.J.; Bakshi, R.K.; Shibata, S. Highly enantioselective borane reduction of ketones catalyzed by oxazaborolidines. Mechanism and synthetic implications. Am. Chem. Soc. 1987, 109, 5551–5553. [Google Scholar] [CrossRef]
  78. Brose, S.A.; Thuen, B.T.; Golokovo, M.Y. LC/MS/MS method for analysis of E2 series prostaglandins and isoprostanes. J. Lip. Res. 2011, 52, 850–859. [Google Scholar] [CrossRef] [Green Version]
  79. Overbeke, A.V.; Baeyens, W.; Oda, H.; Aboul-Enein, H.Y. Direct enantiomeric HPLC separation of several 2-aryl-propionic acids, barbituric acids and benzodiazepines on Chiracel OJ-R chiral stationary phase. Chromatographia 1996, 43, 599–606. [Google Scholar] [CrossRef]
  80. Chiral Technologies, Daicel-Chromatography Market Leader. Available online: https://mz-at.de/downloads/chiral_chiralcel_oj-rh_instruction_manual.pdf (accessed on 26 July 2020).
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Scheme 1. Key intermediates of prostaglandin syntheses and structures of PGF2α and IPF2α.
Scheme 1. Key intermediates of prostaglandin syntheses and structures of PGF2α and IPF2α.
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Scheme 2. Structure of Corey lactone enantiomers and ent-PGF1α, ent-PGF2α, ent-PGE2 and ent-PGE1.
Scheme 2. Structure of Corey lactone enantiomers and ent-PGF1α, ent-PGF2α, ent-PGE2 and ent-PGE1.
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Scheme 3. Preparation and resolution of rac-bicyclic lactone.
Scheme 3. Preparation and resolution of rac-bicyclic lactone.
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Scheme 4. Preparation of lactone (11) from ent-Corey lactone (+)-5. (a) NaOCl, KBr, NaHCO3, TEMPO catalyst, dichloromethane, water, 0–10 °C; (b) 7, NaOH, dichloromethane, water, 0–10 °C, crystallization from diisopropyl ether-hexane; (c) BH3-DMS, pyrocatechol, (S)-2-Me-CBS, THF, (−15)–(−10) °C; (d) DIBAL-H, THF, toluene, (−75)–(−70) °C, chromatography with toluene-EtOAc, crystallization from toluene-hexane; (e) K2CO3, MeOH, 35–40 °C, crystallization from EtOAc-diisopropyl ether.
Scheme 4. Preparation of lactone (11) from ent-Corey lactone (+)-5. (a) NaOCl, KBr, NaHCO3, TEMPO catalyst, dichloromethane, water, 0–10 °C; (b) 7, NaOH, dichloromethane, water, 0–10 °C, crystallization from diisopropyl ether-hexane; (c) BH3-DMS, pyrocatechol, (S)-2-Me-CBS, THF, (−15)–(−10) °C; (d) DIBAL-H, THF, toluene, (−75)–(−70) °C, chromatography with toluene-EtOAc, crystallization from toluene-hexane; (e) K2CO3, MeOH, 35–40 °C, crystallization from EtOAc-diisopropyl ether.
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Scheme 5. Preparation of ent-prostaglandins from lactol 11. (a) CBP-Br, KOBut, THF, (−10)-(−5) °C; (b) TAM, MeOH, acetone, hexane, 25 °C→ 0 °C; (c) I2, KI, KHCO3, water; (d) Dihydropyran, pTsOH.H2O, toluene, THF, 20–50 °C; (e) DIBAL-H, toluene, THF (−75)–(−70) °C; (f) CBP-Br, KOBut, THF, toluene, (−10)–(−5) °C; (g) PCC, NaOAc, AcOH, EtOAc, 30–40 °C, chromatography with diisopropyl ether-acetone mixture as eluent; (h) 1 mol/L HCl, H2O, i-PrOH, 20 °C, chromatography with hexane-EtOAc mixtures as eluent, crystallization from ether-diisopropyl ether; (i) cat H2, Pd/C, diisopropyl ethylamine, dichloromethane, rt; (j) 1 mol/L HCl, H2O, i-PrOH, 20 °C, crystallization from EtOAc then EtOAc-hexane; (k) PCC, NaOAc, EtOAc, AcOH, 30–40 °C, chromatography with diisopropyl ether-EtOAc mixture as eluent; (l) 1 mol/L HCl, H2O, i-PrOH, 20 °C, crystallization from diisopropyl ether-hexane.
Scheme 5. Preparation of ent-prostaglandins from lactol 11. (a) CBP-Br, KOBut, THF, (−10)-(−5) °C; (b) TAM, MeOH, acetone, hexane, 25 °C→ 0 °C; (c) I2, KI, KHCO3, water; (d) Dihydropyran, pTsOH.H2O, toluene, THF, 20–50 °C; (e) DIBAL-H, toluene, THF (−75)–(−70) °C; (f) CBP-Br, KOBut, THF, toluene, (−10)–(−5) °C; (g) PCC, NaOAc, AcOH, EtOAc, 30–40 °C, chromatography with diisopropyl ether-acetone mixture as eluent; (h) 1 mol/L HCl, H2O, i-PrOH, 20 °C, chromatography with hexane-EtOAc mixtures as eluent, crystallization from ether-diisopropyl ether; (i) cat H2, Pd/C, diisopropyl ethylamine, dichloromethane, rt; (j) 1 mol/L HCl, H2O, i-PrOH, 20 °C, crystallization from EtOAc then EtOAc-hexane; (k) PCC, NaOAc, EtOAc, AcOH, 30–40 °C, chromatography with diisopropyl ether-EtOAc mixture as eluent; (l) 1 mol/L HCl, H2O, i-PrOH, 20 °C, crystallization from diisopropyl ether-hexane.
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Figure 1. Effect of the variable parameters on the resolution of PGE2 enantiomers.
Figure 1. Effect of the variable parameters on the resolution of PGE2 enantiomers.
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Figure 2. Chiral separation of the optical isomers of PGF2α (tested as TAM salt), R = 1.5. Optimized parameters: Eluent: MeCN:MeOH:water (pH = 4) = 30:10:60, column temperature 25 °C, wavelength 200 nm.
Figure 2. Chiral separation of the optical isomers of PGF2α (tested as TAM salt), R = 1.5. Optimized parameters: Eluent: MeCN:MeOH:water (pH = 4) = 30:10:60, column temperature 25 °C, wavelength 200 nm.
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Figure 3. Chiral separation of the optical isomers of PGF1α, R = 1.7. Optimized parameters: Eluent: MeCN:MeOH:water(pH = 4) = 23:10:67, column temperature 25 °C, wavelength 200 nm.
Figure 3. Chiral separation of the optical isomers of PGF1α, R = 1.7. Optimized parameters: Eluent: MeCN:MeOH:water(pH = 4) = 23:10:67, column temperature 25 °C, wavelength 200 nm.
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Figure 4. Chiral separation of the optical isomers of PGE2, R = 1.5. Optimized parameters: Eluent: MeCN:MeOH:water(pH = 4) = 15:20:65, column temperature 40 °C, wavelength 210 nm.
Figure 4. Chiral separation of the optical isomers of PGE2, R = 1.5. Optimized parameters: Eluent: MeCN:MeOH:water(pH = 4) = 15:20:65, column temperature 40 °C, wavelength 210 nm.
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Figure 5. Chiral separation of the optical isomers of PGE1, R = 1.8. Optimized parameters: Eluent: MeCN:MeOH:water(pH = 4) = 30:10:60, column temperature 25 °C, wavelength 200 nm.
Figure 5. Chiral separation of the optical isomers of PGE1, R = 1.8. Optimized parameters: Eluent: MeCN:MeOH:water(pH = 4) = 30:10:60, column temperature 25 °C, wavelength 200 nm.
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Table
Table 1. Reversed phase HPLC conditions.
Table 1. Reversed phase HPLC conditions.
ParameterValue
Apparatus:Waters HPLC system equipped with a PDA detector and Empower V3 electronic data processing system
Column:Chiracel OJ-RH, 150 × 4.6 mm, 5 µm
Column temperature:25 or 40 °C (5–40 °C) *
Flow rate:0.5 mL/min (0.5–1.0 mL) *
Injected volume:5 µL
Concentration of sample:0.25 mg/mL
Composition of eluent:see Table 2
Composition of sample solvent:acetonitrile:methanol:water
30:10:60
Wavelength:200, 210 nm
Run time:20–40 min
* The optimal parameters recommended by the column supplier are shown in the brackets.
Table
Table 2. Eluent composition.
Table 2. Eluent composition.
Run Composition
AcetonitrileMethanolWater (pH = 4)
1301060
2251065
3241066
4231067
5201070
6201565
7152065
8151570
Table
Table 3. Enantiopurity of the ent-prostaglandins.
Table 3. Enantiopurity of the ent-prostaglandins.
ent-PGHPLC Area %Enantiomeric Excess
ent-PGF2a.TAM (−)-1.TAM98.20.964
ent-PGE2 (+)-299.90.998
ent-PGF1α (−)-399.30.986
ent-PGE1 (+)-499.90.998

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Enesei, M.; Takács, L.; Tormási, E.; Tóthné Rácz, A.; Róka, Z.; Kádár, M.; Kardos, Z. Preparation and Chiral HPLC Separation of the Enantiomeric Forms of Natural Prostaglandins. Chemistry 2020, 2, 727-741. https://doi.org/10.3390/chemistry2030047

AMA Style

Enesei M, Takács L, Tormási E, Tóthné Rácz A, Róka Z, Kádár M, Kardos Z. Preparation and Chiral HPLC Separation of the Enantiomeric Forms of Natural Prostaglandins. Chemistry. 2020; 2(3):727-741. https://doi.org/10.3390/chemistry2030047

Chicago/Turabian Style

Enesei, Márton, László Takács, Enikő Tormási, Adrienn Tóthné Rácz, Zita Róka, Mihály Kádár, and Zsuzsanna Kardos. 2020. "Preparation and Chiral HPLC Separation of the Enantiomeric Forms of Natural Prostaglandins" Chemistry 2, no. 3: 727-741. https://doi.org/10.3390/chemistry2030047

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