WO2011069236A1 - Méthode de synthèse de l'hypocrelline - Google Patents

Méthode de synthèse de l'hypocrelline Download PDF

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Publication number
WO2011069236A1
WO2011069236A1 PCT/CA2010/001595 CA2010001595W WO2011069236A1 WO 2011069236 A1 WO2011069236 A1 WO 2011069236A1 CA 2010001595 W CA2010001595 W CA 2010001595W WO 2011069236 A1 WO2011069236 A1 WO 2011069236A1
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WO
WIPO (PCT)
Prior art keywords
hypocrellin
phleichrome
oxidation
dichloromethane
dihydroxy
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Ceased
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PCT/CA2010/001595
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English (en)
Inventor
Minghui Du
Darol Maunder
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Alberta Innovates
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Alberta Innovates
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Publication of WO2011069236A1 publication Critical patent/WO2011069236A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C07C45/66—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/52—Ortho- or ortho- and peri-condensed systems containing five condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/54—Ortho- or ortho- and peri-condensed systems containing more than five condensed rings

Definitions

  • the present invention relates to methods of preparing hypocrellin, more particularly, methods of preparing hypocrellin B from perylenequinones such as phleichrome.
  • hypocrellins are naturally occurring perylenequinones found in various parasitic fungi, including Hypocrella bambusae and Shiraia bambusicola.
  • the photosensitizing activity and chemical structure of hypocrellin B and a related compound hypocrellin A was first described in 1992 (Nenghui et al., 1992, J. Photochem Photobiol B 14(3):207-17).
  • C, D hypocrellins
  • Phleichrome a perylenequinone, is a known natural product initially isolated from the mycelium of C. phlei.
  • hypocrellins and fungal perylenequinones are limited by extraction from the fungi that produce it, or complex multi-step synthetic methods from precursors (PCT Publication WO 98/33470, US 6,936,571, Hauser et al., 1994 J. Org Chem
  • H. bambusae has not been reported as successfully grown in culture, thus its role as a source of hypocrellin is limited to its harvest in China.
  • hypocrellin B is complicated as illustrated by PCT publication WO 98/33470; and extraction from natural sources may not provide sufficient product for widespread use in pharmaceuticals. A more expedient method of obtaining hypocrellin B would be advantageous.
  • the present invention relates to methods of preparing hypocrellin, more particularly, methods of preparing hypocrellin B from perylenequinones such as phleichrome.
  • the present invention provides for a method of preparing hypocrellin B comprising: combining a 4,9-dihydroxy-3,10-perylenequinone with an oxidation reagent to provide an oxidation product of phleichrome; and cyclization of the oxidation product to provide hypocrellin B.
  • the 4,9-dihydroxy-3,10-perylenequinone may be phleichrome.
  • the oxidation reagent may comprise DMSO and acetic anhydride.
  • the cyclization step may occur under basic reaction conditions.
  • the cyclization step comprises combining the oxidation product with an alkali hydroxide; in some embodiments, the alkali hydroxide is LiOH.
  • hypocrellin B It is therefore an advantage of some aspects of the present invention to provide a one-step method of preparing hypocrellin B from phleichrome. Such a method represents an improvement over obtaining hypocrellin B from the tree fungus H. bambusae, which has limited geographical and seasonal availability. Such a method also represents an improvement over a multi-step synthesis of hypocrellin B from precursors by reducing the number of steps and quantity of reagents consumed. [0012]
  • This summary of the invention does not necessarily describe all features of the invention. Other aspects, features and advantages of the present invention will become apparent to those of ordinary skill in the art upon review of the following description of specific embodiments of the invention. DETAILED DESCRIPTION
  • the present invention relates to methods of preparing hypocrellin, more particularly, methods of preparing hypocrellin B from perylenequinones such as phleichrome.
  • hypocrellin B from 4,9-dihydroxy-3,10- perylenequinone is provided.
  • Examples of 4,9-dihydroxy-3,10-perylenequinones include phlei chromes, cercosporin, fagopyrin, altertoxin, hypericin, elsinochromes and the like. These compounds are produced by various fungi or plants - generally the compound is named after the fungi or plant from which it was isolated and studied.
  • cercosporin may be obtained from an extraction of Cercospora spp.; phleichrome may be obtained from an extraction of Cladosporium phlei.; altertoxin may be obtained from an extraction of Alternaria laternata; elsinochrome may be obtained from an extraction of Elsinone spp.; hypericin may be obtained from an extraction of Hypericum perforatum; fagopyrin may be obtained from an extraction of Fagopyrum sagittatum. See, for example, Daub et al. 2000 Annu. Rev Phytopathol 38:461-90; Kim et al., supra; Li et al., 2001 J.
  • C. phlei may be cultured by known methods and the phleichrome pigment obtained by extraction of the mycelial mass, culture medium or both the mycelial mass and culture medium, according to known methods (see, for example Lee et al., 2007, Biotechnology and Bioprocess Engineering 12:505-518; which is incorporated herein by reference).
  • the C. phlei fungus may also be genetically manipulated to alter natural pigment production (see, for example, Kim et al., 2009, Plant Pathol J. 25: 179-183; which is incorporated herein by reference).
  • Phlei chrome may be purified to the desired degree of purity, for example from about 30 to about 99% purity, or any amount therebetween, using known purification techniques.
  • oxidizing reagents include DMSO, Collins' reagent, Corey's reagent, pyridinum dichromate,Na 2 Cr 2 0 7 in water, 2 Cr 2 0 7 in DMF (with heat), Cr0 3 on a silica support (e.g. silica gel) or the like.
  • silica support e.g. silica gel
  • Such reagents and conditions for their use are described in, for example, March 's Advanced Organic Chemistry (MB Smith and J March, eds. Wiley & Sons, 5 th edition 2001 chapter 19-3; which is incorporated herein by reference) and references therein.
  • oxidation of a secondary alcohol may be performed using DMSO in combination with DCC and anhydrous phosphoric acid, oxalyl chloride, acetic anhydride, methanesulfonic anhydride, tosyl chloride, P 2 0s-Et 3 N, trichloromethyl chloroformate, KI and NaHC0 3 , and the like.
  • the oxidation of phleichrome is performed using DMSO in combination with acetic anhydride (Albright-Goldman oxidation) to produce compound (2). Such an oxidation is exemplified in step 1 of Scheme 1 (outlined in Example 1).
  • Acetic anhydride may be used with about 3 to 6 equivalents of acetic anhydride, or about 4, or about 5 equivalents. In some embodiments, acetic anhydride may be used in a significantly greater excess, from about 6 to about 10, to about 20 or more equivalents; for example about 6, 7, 8, 9, 10,11, 12, 13, 11, 15, 16, 17, 18, 19, 20 equivalents.
  • the oxidation may be performed at ambient (room) temperature, or heat may be applied and the oxidation performed at about 20, 25, 30, 25, 40, 45, or 50 degrees Celsius, or any temperature therebetween.
  • the compound (2) is subsequently cyclized to yield the product hypocrellin B (3). In some embodiments this may be via an intramolecular Aldol condensation.
  • the cyclization reaction may comprise combining compound (2) with either LiOH in methanol- water, or 10% NaOH at ambient temperature, for 1-6 hours.
  • step 1 the reaction of step 1 is conducted under conditions sufficient to permit the cyclization to occur spontaneously (see, for example Scheme 2).
  • Hypocrellin B may be used in various applications. For example, it may be used as a starting compound for synthesis of other perylenequinones (WO 98/44470). Derivatives of hypocrellin B, including monomer ruthenium complexes, may be produced for use as
  • Photodynamic agents such as hypocrellin B or a derivative thereof may be coupled to an antibody or another binding agent that specifically binds a tumor or microbe (for example, WO 2001/012217, WO 2004/044191).
  • Hypocrellin B or a derivative thereof may be useful as an as a sonosensitizer and/or a photosensitizer (for example WO 2002/060483, WO 2003/063901 ), and, when activated by light, modulate the activity of an immunotherapeutic agent (for example, WO 2002/060482).
  • hypocrellin B and/or derivatives thereof are for example purposes - other uses for hypocrellin B and/or derivatives thereof will further be apparent to those of skill in the relevant art.
  • Example 1 Two step chemical conversion of Phleichrome to Hypocrellin B [0027] Oxidation by DMSO/acetic anhydride (Albright-Goldman oxidation) followed by cvclization with LiOH or NaOH (Scheme 1)
  • Phleichrome (1) was produced and extracted from C. phlei mycelial mass as described by Lee et al. (2007, Biotechnology and Bioprocess Engineering 12:505-518). Biomass was extracted with ethyl acetate or dicholoromethane. The dark colored residue left upon evaporation of organic solvents was purified on silica gel using 1-5% MeOH-dichloromethane as eluent.
  • hypocrellin B product (3); 81 mg, -40%, two steps
  • the thin layer chromatographic profile methanol- dichloromethane 5%
  • 1H-NMR was identical to that of Hypocrellin B extracted from H. bambusae.
  • the crude product (2) was dissolved in 10% sodium hydroxide (10 mL) and stirred for 1 h.
  • the aqueous solution was extracted with dichloromethane and then acidified with 2M HCl to a pH of approximately 4.
  • the mixture was then extracted with dichloromethane and extract purified on silica gel column (methanol-dichloromethane 1-5%) to provide Hypocrellin B (product (3); 70 mg, -35%).
  • Thin-layer chromatography results and ⁇ -NMR were identical to that obtained from naturally occurring and extracted Hypocrellin B from H. bambusae, and as obtained by cyclization product using LiOH as outlined above.
  • Scheme 1 preparation of hypocrellin B (3).
  • Step 1 DMSO/acetic anhydride, 40°C, 24h.
  • Step 2 LiOH in water, RT 4h, followed by acidification (Lown cyclization) or 10%NaOH, RT lh, followed by acidification
  • Example 2 One step chemical conversion of Phleichrome to Hypocrellin B (Scheme 2)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une méthode de synthèse de l'hypocrelline B à partir de 4,9-dihydroxy-3,10-perylènequinones. Ladite méthode consiste dans un premier temps en l'oxydation de la 4,9-dihydroxy-3,10-perylènequinone, avant la cyclisation du produit d'oxydation en conditions basiques pour obtenir l'hypocrelline B.
PCT/CA2010/001595 2009-12-08 2010-10-05 Méthode de synthèse de l'hypocrelline Ceased WO2011069236A1 (fr)

Applications Claiming Priority (2)

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US12/633,595 2009-12-08
US12/633,595 US7816563B1 (en) 2009-12-08 2009-12-08 Method for preparing hypocrellin

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WO2011069236A1 true WO2011069236A1 (fr) 2011-06-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115851864A (zh) * 2021-03-18 2023-03-28 华南理工大学 一种提高竹黄发酵生产苝醌类次生代谢物产量的方法

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CN113233970B (zh) * 2021-05-18 2022-09-02 山东元核生物工程有限公司 一种高纯度竹红菌素的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998033470A2 (fr) * 1997-01-10 1998-08-06 Altarex Corp. Perylenequinones substituees destinees a la therapie photodynamique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1349965A (zh) * 2000-10-25 2002-05-22 中国科学院感光化学研究所 带有脂肪环或芳香环的脂肪胺基取代去甲氧基竹红菌素及其合成方法和用途
EP1476190B1 (fr) * 2002-01-29 2006-03-29 Altachem Pharma, Ltd. Hypocrellines amino-substituees utilisables en tant qu'agents sonosensibilisants

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998033470A2 (fr) * 1997-01-10 1998-08-06 Altarex Corp. Perylenequinones substituees destinees a la therapie photodynamique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LOWN J.W.: "1996 Hoffman-LaRoche Award Lecture. Photochemistry and photobiology of perylenequinones", CAN.J. CHEM., vol. 75, 1997, pages 99 - 119 *
O'BRIEN E.M. ET AL.: "Perylequinone Natural Products: Total Synthesis of Hypocrellin A", J. ORG. CHEM., vol. 75, 2010, pages 57 - 68 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115851864A (zh) * 2021-03-18 2023-03-28 华南理工大学 一种提高竹黄发酵生产苝醌类次生代谢物产量的方法

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