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    • 专利摘要:
    Procedure for obtaining dialdehyde secoiridoids. This invention relates to a process for the preparation of dialdehyde secoiridoids, such as oleacein and oleocanthal, by the use of DMSO. This procedure allows to double the yield of the Krapcho reaction with which oleaceine is obtained from oleuropein, present in the olive leaf. The oleaceína, a secoiridoide dialdehidico present in the virgin olive oil and extra virgin has very interesting biological properties as anti-inflammatory and anti-asthmatic. The Krapcho reaction is used for the first time to the conversion of the monoaldehyde aglycones of oleuropein and ligstrósido, present in phenolic extracts of EVOO, in the corresponding dialdehyde derivatives oleocanth and oleacein, with which a very efficient method of enriching the extracts is achieved phenolic in the dialdehyde secoiridoide, with high added value. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2693177A2
    申请号:ES201830049
    申请日:2017-03-10
    公开日:2018-12-07
    发明作者:José María FERNÁNDEZ-BOLAÑOS GUZMÁN；Inés MAYA CASTILLA；Alejandro GONZÁLEZ BENJUMEA
    申请人:Universidad de Sevilla；
    IPC主号:
    专利说明:

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    D E S C R I P C I O N
    Method for obtaining dialdehydric secairidoids Object of the invention
    This invention allows doubling the yield of the Krapcho reaction with which oleacema is obtained from oleuropema, present in the olive leaf. Oleacema, a dialdehydric secairidoid present in virgin and extra virgin olive oil, has very interesting biological properties such as anti-inflammatory and anti-asthmatic. The Krapcho reaction to the conversion of the monoaldehydric aglicons of oleuropema and ligstroside, present in phenolic extracts of EVOO, into the corresponding oleocantal dialdehydric derivatives and oleacema, has been extended for the first time, thus achieving a very effective method of enrich phenolic extracts in dialdehydic secairidoids, of high added value. A new procedure for stabilizing and increasing the bioavailability of oleacema and oleocantal by acylation and acetalization reactions is also described.
    This invention is part of the production in the areas of Agriculture, Food, Chemistry and Pharmacy.
    The Activity Sector in which the invention can be used corresponds to the Food and Pharmaceutical Industry area.
    State of the art
    The major components of the phenolic fraction of extra virgin olive oils (EVOO) are the oleacema and oleocantal dialdehydes, the olealpema and ligstroside monoaldehydric aglycones, and the corresponding dialdehydic aglyceons (1).
    It has been described that oleocantal has beneficial properties such as anti-inflammatory (2; 3) and anti-tumor (4; 5) activity. In addition, the oleocantal plays a neuroprotective role in the brain (6; 7), being effective in reducing p-amyloid plaques, which contributes to the prevention of Alzheimer's disease (8).
    On the other hand, oleacema is a potent antioxidant and a good inhibitor of the enzyme 5 lipoxygenase involved in the biosynthesis of leukotrienes, so that oleacema can be useful in the treatment of asthma and allergic rhinitis (9). It has proven to be an effective drug against diseases related to the degradation of atherosclerotic plaques (10), and has antiproliferative properties (11).
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    Recently, a process for transforming oleuropelna, the main phenolic compound present in the olive leaf, into oleacelna has been described using the Krapcho reaction based on heating in DMSO containing NaCl and water. The published yield for this reaction is 20.5%. It has also been described that oleacelna decomposes significantly during chromatographic purification both in silica gel and in the reverse phase (12).
    The oleocantal can be isolated from EVOO (13) or can be prepared from D-lixose (14). Oleacelna can also be synthesized from D-lixose (14).
    References
    (1) Diamantakos P et al. Oleokoronal and oleomissional: new major phenolic ingredients of extra virgin olive oil. Olivae 2015, 122, 23
    (2) Parkinson L & Keast R. Oleocanthal, a phenolic derived from virgin olive oil: a review of the beneficial effects on inflammatory disease. Int J Mol Sci 2014, 15, 12323
    (3) Peyrot Des Gachons C et al. Use of the irritating principal oleocanthal in olive oil, as well as structurally and functionally similar compounds, WO2006122128 A2
    (4) Hodge AM et al. Foods, nutrients and prostate cancer. Cancer Cause Control 2004, 15, 11
    (5) LeGendre O et al. (-) - Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization, Mol Cell Oncol 2015, 2, e1006077-1-8
    (6) Heneka et al. Neuroinflammation in Alzheimer’s disease, Lancet Neurol 2015, 14, 388
    (7) Theoharides TC, Anti-inflammatory compositions for treating neuro-inflammation, US2013115202 A1
    (8) Abuznait et al. Olive oil-derived oleocanthal enhances fi-amyloid clearance as a potential neuroprotective mechanism against Alzheimer’s disease: In vitro and in vivo studies, ACS Chem Neurosci 2013, 4, 973
    (9) Vougogiannopoulou et al. One-step semisynthesis of oleacein and the determination as a 5-lipoxygenase inhibitor, J Nat Prod 2014, 77, 441
    (10) Czerwinska ME et al. Oleacein for treating or preventing diseases resulting from atherosclerotic plaques, US20160008311
    (11) Corona et al. Inhibition of p38 / CREB phosphorylation and COX-2 expression by olive oil polyphenols underlies their anti-proliferative effects. Biochem Biophys Res Commun 2007, 362, 606
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    (12) Karkoula et al. Direct measurement of oleocanthal and oleacein levels in olive oil by quantitative 1H NMR. Establishment of a new index for the characterization of extra virgin olive oils. J Agric Food Chem 2012, 60, 11696
    (13) Fogli S et al. Cytotoxic activity of oleocanthal isolated from virgin olive oil on human melanoma cells. Nutr Cancer 2016, 68, 873
    (14) Smith IIIAB et al. Syntheses of (-) - oleocanthal, a natural NSAID found in extra virgin olive oil, the (-) - deacetoxy-oleuropein aglycone, and related analogues. J Org Chem 2007, 72, 6891.
    Figures
    Figure 1.- Structures of diacilated oleacelna 2 and dehydrated oleuroside aglycone (DOA) diacilated 3.
    Figure 2.- Krapcho demethoxycarbonylation reaction on oleuropelna 1 followed by acylation, chromatographic separation and subsequent deacilation.
    Figure 3.- Krapcho demethoxycarbonylation reaction on the monoaldehyde aglycones of oleuropelna 7 and ligstroside 6 followed by acylation.
    Figure 4.- Chemoselective monoacetalization reactions on the unconjugated carbonyl of the acylated oleocantal 9 and the diacylated oleacelna 2.
    Description of the invention
    An improvement of the original procedure for the transformation of oleuropelna into oleacelna has been carried out by means of the demethoxycarbonylation reaction of Krapcho in wet DMSO. With this invention, based on the absence of alkali halide, we improve the previously described process by substantially decreasing the heating time and increasing the yield of oleacelna by more than double. In the course of the reaction, a second product, the dehydrated oleuroside aglycone (DOA, Dehydrated Oleuroside Aglycone), can be isolated from which there is no background.
    The reaction mixture is acylated in situ, achieving stabilization of both the oleacelna and the DOA and allowing the chromatographic purification of both. There is no history of diacilated oleacelna; (Figure 1, R = Me).
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    Using the same procedure, the conversion of oleuropelna and ligstroside monoaidehydric aglicons to oleacelna and oleocantal, respectively, is achieved by heating in wet DMSO. The transformation can be carried out with the monoaldehyde aglicons separately, or with phenolic mixtures, such as mixtures of isolated olive oil phenols. This procedure allows enriching the mixture of phenols in the oleacelna and oleocantal dialdehyde secairidoids, facilitating chromatographic isolation of both by reducing the number of components of the mixture.
    Then, the object of the present invention is a process for obtaining oleacelna and / or oleocantal dialdehyde secairidoids characterized in that it comprises the treatment of oleuropelna monoaldehyde aglycon and / or ligstroside monoaldehyde aglycon, respectively, with dimethylsulfoxide (DMSO) or hexadeuterated dimethylsulfoxide (DMSO-d6) moistened at temperatures above 90 ° C, using conventional or microwave heating and in the absence of inorganic salt.
    The monoaldehyde aglycone of oleuropelna and / or the monoaldehyde aglicon of ligstroside can be separated or mixed with other phenolic compounds.
    The acylation of this enriched mixture in the phenolic dialdehldos stabilizes both compounds for the chromatographic purification stage. Both diacylated oleacelna 2 and acylated oleocantal 9 can be deacylated using lipase or alcohol-based catalyst.
    Then, the process of the present invention further comprises a step of acylation of the oleacelna and / or the oleocantal obtained to obtain so! diacilated oleacelna (2) and / or acylated oleocantal (9),
    RCOO
    RCOO '
    image 1

    RCOO
    image2
    image3
    where R is selected from hydrogen (H), (C1-C22) alkyl, substituted or unsubstituted phenyl.
    image4
    The diacylated dialdehydric derivatives have also been stabilized by their transformation into monoacetalic-monoaldehyde derivatives by regioselective acetalization with ethylene glycol on the unconjugated formyl group, keeping the acyl groups on phenolic hydroxyls. In this way, more stable and lipophilic derivatives can be obtained, and therefore more bioavailable. The subsequent deacilation leads to the 3-ethylidene acetals of oleacelna and oleocantal.
    Then, the present invention also comprises the regioselective acetalization with ethylene glycol of the diacilated oleacelna (2) and / or the acylated oleocantal (9), obtained to obtain compounds 11 and / or 10.
    RCOO
    ° -V '
    10 or
    RCOO

    eleven
    image5
    where R is selected from hydrogen (H), (C1-C22) alkyl, substituted or unsubstituted phenyl, as well as its subsequent deacylation to obtain compound compounds 13 and / or 12.
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    image6
    image7
    In summary, the present invention describes the process of converting different secairidoid compounds into oleocantal and oleacelna by means of a variant of the demethoxycarbonylation of Krapcho in high temperature wet DMSO in the absence of halide (inorganic salt). This reaction can be carried out on isolated oleuropelna 25, on extracts rich in oleuropelna, on phenolic fractions extracted from extra virgin and extra virgin olive oil, and on monoaldehydic aglicons of oleuropelna and ligstroside isolated.
    This invention makes it possible to enrich phenolic extracts from olive oil in oleacelna and oleocantal at the expense of their monoaldehyde precursors, and facilitate the chromatographic separation of said dialdehydric derivatives.
    Krapcho reaction on oleuropelna
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    The reaction of Krapcho on oleuropelna 1, or extracts rich in oleuropelna, in wet DMSO or DMSO-d6 at a temperature above 140 ° C in the absence of halide (inorganic salt) leads to oleacelna and the dehydrated aglycone of the oleuroside (DOA). The chromatographic purification (silica gel, among other adsorbents) of this mixture only allows DOA to be isolated due to the substantial decomposition of the oleacelna during the process. The acylation of the mixture allows both compounds to stabilize and also can be purified more effectively by chromatographic separation (silica gel, among other adsorbents), which leads to the isolation of the new compounds 2 and 3 (Figure 2). The deacylation of 2 carried out for example with lipase or alcohol base (MeOH, among other aliphatic alcohols) leads to oleacelna 4 whose spectroscopic data coincide with those of natural oleacelna; also, the deacylation of 3 leads to the dehydrated aglycone of the oleuroside (DOA) 5, not previously described. This reaction of Krapcho on the ligstroside leads to the oleocantal 8.
    Krapcho reaction on phenolic mixtures from extra virgin or extra virgin olive oil
    The reaction of Krapcho with phenolic mixtures from extra virgin or virgin olive oil, containing among other phenolic compounds the aglycones
    monoaldehydes of ligstroside 6 and oleuropelna 7, carried out by heating in DMSO or DMSO-d6 at temperatures above 90 ° C leading to the transformation of these monoaldehldos into the corresponding dialdehldos 8 (oleocantal) and 4 (oleacelna), so the mixture is enriched in said dialdehldos (Figure 3). The separation
    Chromatography of both dialdehldos allows obtaining pure oleocantal 8 with good
    performance. The acylation of the mixture of 8 and 4 followed by chromatographic separation allows to obtain acylated oleocantal pure 9 and diacilated oleacelna 2. There are no
    antecedents of 2, nor of the synthesis of 9 by acylation of oleocantal 8, although 9 if it has been prepared by an alternative route (Smith, III et al. J Org Chem 2007, 72, 6891). The deacylation of 9 to regenerate 8 is carried out, for example, with lipase or alcohol base (MeOH, among other aliphatic alcohols).
    The reaction of Krapcho on the isolated monoaldehyde agglon of ligstroside 6, or on the isolated monoaldehydic aglylon of oleuropelna 7, allows us after elimination of the DMSO to obtain directly oleocantal 8 or oleacelna 4, respectively.
    Chemoselective derivatization on unconjugated carbonyl of acylated oleocantal 9 or acylated oleacein 2 by acetalization reaction
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    Treatment of acylated derivatives 2 9 and 9 2 with ethylene glycol in the presence of a strong acid as a catalyst, for example trifluoroacetic acid, leads to 10 and 11, respectively, acetalized in unconjugated carbonyl (Figure 4). The deacylation of these compounds is carried out with the aforementioned methods using, for example, lipase or base as a catalyst in the presence of aliphatic alcohol, which allows obtaining monoacetalized oleacelna 12 and monoacetalized oleocantal 13. Compounds 12 and 13 are also they can be obtained by acetalization of oleocantal 8 and oleacelna 4, respectively, with ethylene glycol and acid catalysis.
    Mode of realization of the invention
    Preparation of diacetylated oleacelna (2, R = Me) and dehydrated aglycone of the acetylated oleuroside (3, R = Me), from oleuropein (1)
    o ^ 9 o
    image8
    image9
    A solution of oleuropein 1 (110 mg, 0.20 mmol) in wet DMSO (3 ml) is heated at 150 ° C for 5 h. The reaction mixture is acetylated without removing the solvent using Ac2O (0.4 ml) and a catalytic amount of DMAP (2 mg). After completion of the reaction (8 h, at room temperature) the excess of Ac2O is hydrolyzed and concentrated to dryness at low pressure. The residue is purified by column chromatography using as eluent AcOEt-cyclohexane (1: 3 ^ 1: 1), obtaining acetylated DOA as a colorless syrup (higher RF) and diacetylated oleacelna (lower RF) as a colorless syrup.
    Data of acetylated oleacelna 2 (R = Me). Yield: 38 mg, 42% RF 0.4 (AcOEt-cyclohexane 1: 1), [aJD4 +103. 1H-NMR (300 MHz, CDCh): 5 9.63 (m, 1H, H-3), 9.21 (d, 1H,
    J = 2.0 Hz, H-1), 7.12 (d, 1H, J = 8.3 Hz, H-7 '), 7.06 (dd, 1H, J = 8.3 Hz, J = 1.9 Hz, H- 8'), 7.02 (d, 1H, J = 1.9 Hz, H-4 '), 6.62 (c, 1H, J = 7.1 Hz, H-8), 4.29D4.19 (m, 2H, H-1'), 3.63D3. 55 (m, 1H, H-5), 2.97 (ddd, 1H, J = 18.7 Hz, J = 8.5 Hz, J = 1.2 Hz, H-4a), 2.89 (t, 2H, J = 6.7 Hz, H- 2 '), 2.74 (ddd, 1H, J = 18.7 Hz, J = 6.3 Hz, J = 0.9 Hz, H-4b), 2.68 (dd, 1H, J = 15.8 Hz, J = 8.5 Hz, H-6a) , 2.60 (dd, 1H, J = 15.8 Hz, J = 6.5 Hz, H-6b), 2.28 and 2.27 (2 s,
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    3H each, 2 Ac), 2.04 (d, 3H, J = 7.1 Hz, H-10). 13C-NMR (125.7 MHz, CDCI3): 5 200.6 (C-3), 195.3 (C-1), 172.0 (C-7), 168.5, 168.4 (2 OCOMe), 154.5 (C-8), 143.3 (C -9), 142.1, 140.9 (C5 ', C-6'), 136.8 (C-3 '), 127.1 (C-8'), 124.0 (C-4 '), 123.5 (C-7'), 64.5 (C-1 '), 46.3 (C-4), 37.0 (C-6), 34.5 (C-2'), 27.4 (C-5), 20.8 (2 OCOMe), 15.4 (C-10). HRLSI-MS: calculated for C21H24NaO8 ([M + Na] +): 427.1363, found: 427.1362.
    Data of acetylated dehydrated oleuroside aglyon (DOA) 3 (R = Me). Performance:
    12.5 mg, 15%, Rf 0.6 (AcOEt-cyclohexane 1: 1), [at £ 4-26. 1H-NMR (500 MHz, CDCl3): 5
    7.49 (s, 1H, H-3), 7.10 (m, 2H, H-7 ', H-8'), 7.04 (m, 1H, H-4 '), 6.53 (s, 1H, H-1) , 6.14 (dd, 1H, J = 17.6 Hz, J = 11.0 Hz, H-8), 5.30 (d, 1H, J = 17.6 Hz, H-10frans), 5.07 (d, 1H, J = 11.0 Hz, H -10c / s), 4.23 (m, 2H, J = 6.9 Hz, H-1 '), 3.93 (t, 1H, J = 4.8 Hz, H-5), 3.73 (s, 3H, COOMe), 2.90 ( t, 2H, J = 6.9 Hz, H-2 '), 2.63 (dd, 1H, J = 14.4 Hz, J = 4.1 Hz, H-6a), 2.54 (dd, 1H, J = 14.4 Hz, J = 5.5 Hz, H-6b), 2.29 and 2.28 (2 s, 3H each, 2 Ac). 13C-NMR (125.7 MHz, CDCl3): 5 171.3 (C-7), 168.5, 168.4 (OCOMe), 166.9 (COOMe), 151.5 (C-3),
    142.1 (C-5 '), 141.2 (C-1), 140.8 (C-6'), 137.1 (C-3 '), 127.2 (C-8), 123.9 (C-8'), 123.4 (C- 4 '), 123.4 (C-7'), 117.7 (C-4), 112.7 (C-10), 108.9 (C-9), 64.5 (C-1 '), 51.7 (COOMe), 39.3 (C- 6), 34.4 (C-2 '), 27.2 (C-5), 20.8 (OCOMe). HRLSI-MS: calculated for C23H24NaO9 ([M + Na] +): 467.1313, found: 467.1310.
    Oleacein (4)
    image10
    OR
    2 R = Me (12 mg, 0.038 mmol) is dissolved in MeOH (1 ml) and lipase from Candida antarctica Novozyme 435 (12 mg) is added. The mixture is heated at 40 ° C for 3 h. Once the reaction is finished, it is microfiltered and concentrated to dryness obtaining the product as an orange syrup. Performance: quant. RF 0.1 (AcOEt-cyclohexane 1: 1). 1H-NMR (300 MHz, CDCh): 5 9.64 (m, 1H, H-3), 9.22 (d, 1H, J = 1.9 Hz, H-1), 6.78 (d, 1H, J = 8.0 Hz, H -7 '), 6.71 (d, 1H, J = 1.9 Hz, H-4'), 6.64 (c, 1H, J = 7.0 Hz, H-8), 6.54 (dd, 1H, J = 8.0 Hz, J = 1.9 Hz, H-8 '), 4.17 (m, 2H, H-1'), 3.69 (m, 1H, H-5), 2.92 (ddd, 1H, J = 19.2 Hz, J = 8.5 Hz, J = 1.2 Hz, H-6a), 2.81D2.62 (m, 5H, H-4, H-2 'and H-6b), 2.05 (d, 3H, J = 7.1 Hz, H-10).
    Dehydrated Oleuroside Aglicon (DOA, 5)
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    3 R = Me (32 mg, 0.072 mmol) is dissolved in MeOH (1 ml) and lipase from Candida antarctica Novozyme 435 (32 mg). The mixture is stirred at room temperature for 4 h. Once the reaction is finished, it is microfiltered and concentrated to dryness obtaining the product as an orange syrup. Performance: quant. RF 0.45 (AcOEt-cyclohexane 1: 1). 1H-NMR (300 MHz, CDCh): 5 7.52 (s, 1H, H-3), 6.78 (d, 1H, J = 8.0 Hz, H-7 '), 6.77 (d, 1H, J = 2.0 Hz, H-4 '), 6.61 (dd, 1H, J = 8.0 Hz, J = 2.0 Hz, H-8'), 6.57 (s, 1H, H-1) 6.15 (dd, 1H, J = 17.6 Hz, J = 11.1 Hz, H-8), 5.35 (d, 1H, J = 17.6 Hz, H-10franS), 5.08 (d, 1H, J = 11.1 Hz, H-10cis), 4.14 (m, 2H, H-1 '), 3.95 (dd, 1H, J = 4.1 Hz, J = 5.5 Hz H-5), 3.77 (s, 3H, COOMe), 2.80 (t, 2H, J = 6.9 Hz, H-2'), 2.58 (dd, 1H, J = 14.4 Hz, J = 4.1 Hz, H-6a), 2.54 (dd, 1H, J = 14.4 Hz, J = 5.5 Hz, H-6b).
    Acetylated Oleocantal (9 R = Me)
    AcO
    image11
    8 (100 mg, 0.33 mmol) is dissolved in a mixture of A ^ O / Py 1: 1 (v / v) cooled to 0 ° C. After 15 min it is left under stirring at room temperature one night. Ac2O is hydrolyzed and concentrated to dryness at low pressure and the residue is purified by column chromatography (AcOEt-cyclohexane 1: 2) to obtain a colorless syrup. Performance: quant. 1H-NMR (300 MHz, CDCh): 5 9.63 (m, 1H, H-3), 9.21 (d 1H, J = 2.0 Hz, H-1), 7.19 (m, 2H, H-4 ', H- 8 '), 7.01 (m, 2H, H-5', H-7 '), 6.61 (c, 1H, J = 7.1 Hz, H-8), 4.24 (m, 2H, H- 1'), 3.61 (m, 1H, H-5), 2.97 (ddd, 1H, J = 18.3 Hz, J = 8.5 Hz, J = 1.1 Hz, H-4a), 2.89 (t, 2H, J = 6.9 Hz, H-2 '), 2.74 (dd, 1H, J = 18.3 Hz, J = 8.5 Hz, H-4b), 2.70 (dd, 1H, J = 15.8 Hz, J = 8.4 Hz, H-6a), 2.60 (dd, 1H , J = 15.8 Hz, J = 6.6 Hz, H-6b), 2.29 (s, 3H, Ac), 2.05 (d, 3H, J =
    7.1 Hz, H-10). 13C-NMR (75.5 MHz, CDCh): 5 200.5 (C-3), 195.3 (C-1), 172.0 (C-7), 169.7 (COOMe), 154.4 (C-8), 149.5 (C-6 ' ), 143.4 (C-9), 135.5 (C-3 '), 130.0 (C-4', C-8 '), 121.8 (C-5', C-7 '), 64.9 (C-1') , 46.4 (C-4), 37.0 (C-6), 34.5 (C-2 '), 27.4 (C-5), 21.3 (COOMe),
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    15.3 (C-10). HRESI: calculated for C19H22O6Na ([M + Na] +): 369.1309, found: 369.1309.
    5,6-Di-O-acetylleacein 3-ethylidene acetal (11 R = Me)
    image12
    2 R = Me (115 mg, 0.28 mmol) is dissolved in CDCl3 (2 ml) and ethylene glycol (31 pl, 0.56 mmol) and TFA (10.7 pl, 0.14 mmol) are added. The mixture is heated at 50 ° C for 3 h, until the disappearance of the starting product monitored by 1 H-NMR. Finally, the medium is neutralized with NaHCO3 and the product is purified by column chromatography (AcOEt-cyclohexane 1: 2). Yield: 86 mg, 68% RF 0.4 (AcOEt-cyclohexane 1: 1). 1H-NMR (300 MHz, CDCh): 5 9.20 (d, 1H, J = 2.0 Hz, H-1), 7.09 (d, 1H, J = 8.2 Hz, H- 7 '), 7.06 (dd, 1H, J = 8.2 Hz, J = 1.9 Hz, H-8 '), 6.99 (d, 1H, J = 1.9 Hz, H-4'), 6.56 (c, 1H, J =
    7.1 Hz, H-8), 4.68 (dd, 1H, J = 6.1 Hz, J = 3.6 Hz, H-3), 4.19 (m, 2H, H-1 '), 3.89 and 3.76 (2 m, 2 H each, OCH2CH2O), 3.28 (m, 1H, H-5), 2.85 (t, 2H, J = 6.8 Hz, H-2 '), 2.81 (dd, 1H, J = 15.6 Hz, J = 9.6 Hz, H-6a), 2.60 (dd, 1H, J = 15.6 Hz, J = 5.5 Hz, H-6b), 2.26 and 2.25 (2 s, 3H each, 2 Ac), 2.10 (m, 1H, H-4a ), 1.96 (d, 3H, J = 7.1 Hz, H-10), 1.83 (dt, 1H, J = 14.0 Hz, J = 5.9 Hz, H-4b). 13C-NMR (75.5 MHz, CDCl3): 5 195.2 (C-1), 172.4 (C-7), 168.3, 168.2 (OCOMe), 153.0 (C-8), 144.1 (C-9), 141.9, 140.7 ( C-5 ', C-6'), 136.8 (C-3 '), 127.0 (C-8'), 123.8 (C-4 '), 123.3 (C-7'), 103.2 (C-3), 64.8 and 64.7 (OCH2CH2O), 64.3 (C-1 '),
    37.5 (C-6), 36.0 (C-4), 34.3 (C-2 ’), 29.3 (C-5), 20.6 (OCOMe), 14.0 (C-10). HRLSI-MS: calculated for C23H28NaO9 ([M + Na] +): 471.1626, found: 471.1613.
    Oleacein 3-ethylidene acetal (13)
    HO
    image13
    11 (87 mg, 0.19 mmol) is dissolved in MeOH (1 ml), Candida antarctica Novzyme 435 lipase (30 mg) is added and stirred at room temperature for 4 h. The
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    The mixture is microfiltered and concentrated to dryness, obtaining the product as an orange syrup. Performance: quant. RF 0.3 (AcOEt-cyclohexane 1: 1)
    1H-NMR (300 MHz, CDCh): 5 9.21 (d, 1H, J = 1.9 Hz, H-1), 6.76 (d, 1H, J = 8.0 Hz, H-7 '), 6.67 (d, 1H, J = 1.5 Hz, H-4 '), 6.57 (c, 1H, J = 7.1 Hz, H-8), 6.50 (dd, 1H, J = 8.0 Hz, J = 1.5 Hz, H-8'), 4.67 (dd, 1H, J = 6.0 Hz, J = 3.6 Hz, H-3), 6.19 (sa, 2H, OH), 4.11 (m, 2H, H-1 '), 3.89 and 3.75 (2 m, 2 H each, OCH2CH2O), 3.31 (m, 1H, H-5), 2.77 (dd, 1H, J = 15.5 Hz, J = 9.4 Hz, H-6a), 2.68 (t, 2H, J = 6.8 Hz, H -2 '), 2.59 (dd, 1H, J = 15.5 Hz, J = 5.6 Hz, H-6b), 2.12 (m, 1H, H-4a), 1.97 (d, 3H, J = 7.1 Hz, H- 10), 1.83 (dt, 1H, J = 14.1 Hz, J = 5.8 Hz, H- 4b). 13C-NMR (75.5 MHz, CDCl3): 5 195.7 (C-1), 172.6 (C-7), 153.8 (C-8), 144.4 (C-5 ’),
    144.1 (C-9), 143.3 (C-6 '), 129.9 (C-3'), 120.7 (C-8 '), 116.4 (C-4'), 116.0 (C-7 '), 103.3 (C - 3), 65.3 (C-1 '), 64.9, 64.8 (OCH2CH2O), 37.7 (C-6), 36.1 (C-4), 34.4 (C-2'), 29.3 (C-5),
    15.1 (C-10). HRLSI-MS: calculated for C ^ H24NaOr ([M + Na] +): 387.1414, found 387.1401.
    Oleocantal 3-ethylidene acetal (12)
    image14
    OR
    8 (33 mg, 0.11 mmol) is dissolved in CDCl3 (1ml) and ethylene glycol (0.22 mmol) and TFA (0.054 mmol) are added. The mixture is heated to 50 ° C and monitored by 1 H-NMR until total conversion. The mixture is neutralized with NaHCO3 and concentrated to dryness. The residue is purified by column chromatography (AcOEt-cyclohexane 1: 2) to obtain a colorless syrup. Yield: 31 mg, 84%. 1H-NMR (300 MHz, CDCl3): 5 9.23 (d, 1H, J = 2.0 Hz, H-1), 7.02 (m, 2H, H-4 ', H-8'), 6.75 (m, 2H, H-5 ', H-7'), 6.57 (c, 1H, J = 7.1 Hz, H-8), 6.04 (sa, 1H, OH), 4.70 (dd 1H, J = 6.0 Hz, J = 3.7 Hz , H-3), 4.16 (m, 2H, H-1 '), 3.86, 3.78 (2 m, 2H each, OCH2CH2O), 3.31 (m, 1H, H-5), 2.79 (t, 2H, J = 7.0 Hz, H-2 '), 2.78 (dd, 1H, J = 15.7 Hz, J = 9.3 Hz, H-6a), 2.62 (dd, 1H, J = 15.7 Hz, J = 5.8 Hz, H-6b ), 2.14 (ddd, 1H, J = 14.0 Hz, J = 9.3 Hz, J = 3.7 Hz, H-4a), 1.98 (d, 3H, J = 7.1 Hz, H- 10), 1.84 (dt, 1H, J = 14.0 Hz, J = 6.0 Hz, H-4b). 13C-NMR (75.5 MHz, CDCh): 5 195.3 (C-1), 172.0 (C-7), 154.8 (C-6 '), 153.5 C-8), 143.2 (C-9), 130.1 (C- 4 ', C-8'), 129.6 (C-3 '),
    115.5 (C-5 ’, C-7’), 103.4 (C-3), 65.3 (C-1 ’), 64.8, 64.9 (OCH2CH2O), 37.7 (C-6), 36.1 (C-
    4), 34.3 (C-2 ’), 29.3 (C-5), 15.1 (C-10). HRCI: calculated for C19H24NaO6 ([M + Na] +): 371.1465, found: 371.1456.
    4-O-Acetylleocantal 3-ethylidene acetal (10 R = Me)
    5
    10
    fifteen
    twenty
    image15
    OR
    12 (31 mg, 0.108 mmol) is dissolved in CH2Cl2 (1 ml) and Ac2O (12.2 pl, 0.16 mmol) and a catalytic amount of DMAP are added. It is stirred at room temperature overnight and hydrolyzed with water. The phases are separated and the organic phase is washed with 2x5 ml of water. The organic phase is dried with Na2SO4 and concentrated to dryness. Performance: quant. 1H-NMR (300 MHz, CDCh): 5 9.23 (d, 1H, J = 2.0 Hz, H-1), 7.17 (m, 2H, H-4 ', H-8'), 7.00 (m, 2H, H-5 ', H-7'), 6.55 (c, 1H, J = 7.1 Hz, H-8), 4.69 (dd, 1H, J = 6.1 Hz, J = 3.6 Hz, H-3), 4.17 ( m, 2H, H-1 '), 3.85, 3.77 (2 m, 2H each, OCH2CH2O), 3.30 (m, 1H, H-5), 2.86 (t, 2H, J = 6.9 Hz, H-2' ), 2.80 (dd, 1H, J = 15.7 Hz, J = 9.5 Hz, H-6a), 2.62 (dd, 1H, J = 15.7 Hz, J = 5.6 Hz, H-6b), 2.28 (s, 3H, Ac), 2.14 (ddd, 1H, J = 13.9 Hz, J = 9.2 Hz, J = 3.6 Hz, H-4a), 1.97 (d, 3H, J = 7.0 Hz, H-10), 1.84 (dt, 1H , J = 14.0 Hz, J = 5.9 Hz, H-4b). 13C-NMR (75.5 MHz, CDCh): 5 195.2 (C-1), 172.5 (C-7), 169.7 (OCOMe), 153.0 (C-8), 149.5 C-6 '), 144.2 (C-9) , 135.6 (C-3 '), 130.0 (C-4', C-8 '), 128.7 (C-5', C-7 '), 103.4 (C-1), 64.9 (OCH2CH2O), 64.8 (C -1 '), 64.7 (OCH2CH2O), 37.6 (C-6), 36.1 (C-4), 34.5 (C-2'), 29.4 (OCOMe), 21.2 (C-5), 15.0 (C-10) . HRESI: calculated for C23H28NaO9 ([M + Na] +): 471.1626, found: 471.1613.
    权利要求:
    Claims (5)
    [1]
    5
    10
    fifteen
    twenty
    25
    30
    1. Procedure for obtaining oleacelna and / or oleocantal dialdehydic secairidoids characterized in that it comprises the treatment of olealpelna monoaldehyde aglylon (7) and / or ligstroside monoaldehyde aglicon (6), respectively, with dimethylsulfoxide (DMSO) or dimethylsulfoxide hexadeuterate (DMSO-d6) humidified at temperatures above 90 ° C, using conventional or microwave heating and in the absence of inorganic salt.
    [2]
    2. Method according to claim 1 wherein the monoaldehyde aglycone of oleuropelna and / or the monoaldehyde aglycone of the starting ligstroside are mixed with other phenolic compounds.
    [3]
    3. Method according to any of claims 1-2 characterized in that it further comprises an acylation stage of the oleacelna and / or the oleocantal obtained to obtain so! diacilated oleacelna (2) and / or acylated oleocantal (9),
    RCOO
    RCOO '
    image 1
    RCOO
    image2
    image3
    where R is selected from hydrogen (H), (C1-C22) alkyl, substituted or unsubstituted phenyl.
    image4
    [4]
    4. Method according to claim 3 characterized in that it comprises the regioselective acetalization with ethylene glycol of the diacilated oleacelna (2) and / or the acylated oleocantal (9), obtained to obtain as! compounds 11 and / or 10,
    RCOO '
    image5
    RCOO ^ / ^ / ^ O.
    RCOO
    XJ
    eleven
    image6
    where R is selected from hydrogen (H), (C1-C22) alkyl, substituted or unsubstituted phenyl.
    [5]
    5. Method according to claim 4 characterized in that it comprises the deacylation of compounds 11 and / or 10 to give compounds 13 and / or 12.
    image7
    or
    xxp
    or
    image8
    image9
    RCOO
    RCOO
    or i 0
    Diacylated oleacein
    OR
    RCOO ^^^^ O
    RCOO '^^
    image10
    Figure 1
    image11
    image12
    image13
    image14
    image15
    image16
    image17
    image18
    RCOO
    RCOO '
    RCOO
    RCOO '
    image19
    Figure 2
    image20
    Figure 3
    image21
    Figure 4
    image22
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    同族专利:
    公开号 | 公开日
    ES2693177B1|2019-12-03|
    ES2693177R1|2019-02-20|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    EP3838885A1|2019-12-16|2021-06-23|National and Kapodistrian University of Athens|Process for the production of oleocanthal, oleacein and their analogues|US20070299129A1|2006-01-05|2007-12-27|Deviris Inc.|Compounds and derivatives for the treatment of medical conditions by modulating hormone-sensitive lipase activity|
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