CN111989318B - Dhpv的新合成方法 - Google Patents
Dhpv的新合成方法 Download PDFInfo
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- CN111989318B CN111989318B CN201980023819.0A CN201980023819A CN111989318B CN 111989318 B CN111989318 B CN 111989318B CN 201980023819 A CN201980023819 A CN 201980023819A CN 111989318 B CN111989318 B CN 111989318B
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- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical group [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
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- 238000007254 oxidation reaction Methods 0.000 claims description 10
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- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 8
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 6
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
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- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
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- ZNXXWTPQHVLMQT-UHFFFAOYSA-N 5-(3',4'-Dihydroxyphenyl)-gamma-valerolactone Chemical compound C1=C(O)C(O)=CC=C1CC1OC(=O)CC1 ZNXXWTPQHVLMQT-UHFFFAOYSA-N 0.000 abstract description 5
- 230000003712 anti-aging effect Effects 0.000 abstract description 4
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- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 8
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
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- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- JHEPBQHNVNUAFL-AATRIKPKSA-N (e)-hex-1-en-1-ol Chemical compound CCCC\C=C\O JHEPBQHNVNUAFL-AATRIKPKSA-N 0.000 description 3
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- 125000000457 gamma-lactone group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
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- 230000003647 oxidation Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
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- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- YBXBQUKPPSYDJY-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)hex-5-en-2-ol Chemical compound COC1=CC=C(CC(O)CCC=C)C=C1OC YBXBQUKPPSYDJY-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- VGXGRYVAJOENGZ-UHFFFAOYSA-N 5-[(3,4-dimethoxyphenyl)methyl]oxolan-2-one Chemical compound C1=C(OC)C(OC)=CC=C1CC1OC(=O)CC1 VGXGRYVAJOENGZ-UHFFFAOYSA-N 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 244000299461 Theobroma cacao Species 0.000 description 2
- 125000004036 acetal group Chemical group 0.000 description 2
- PQLAYKMGZDUDLQ-UHFFFAOYSA-K aluminium bromide Chemical compound Br[Al](Br)Br PQLAYKMGZDUDLQ-UHFFFAOYSA-K 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- YMEKEHSRPZAOGO-UHFFFAOYSA-N boron triiodide Chemical compound IB(I)I YMEKEHSRPZAOGO-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 2
- 150000002206 flavan-3-ols Chemical class 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GEQUYGQAOAAGGO-UHFFFAOYSA-N 4-iodobenzene-1,2-diol Chemical compound OC1=CC=C(I)C=C1O GEQUYGQAOAAGGO-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 208000034162 Primary hypomagnesemia with secondary hypocalcemia Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000001765 catechin Chemical class 0.000 description 1
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 description 1
- 235000005487 catechin Nutrition 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
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- 238000010959 commercial synthesis reaction Methods 0.000 description 1
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- 150000002605 large molecules Chemical class 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 1
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
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- A—HUMAN NECESSITIES
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- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及DHPV的新合成方法，更具体地，涉及可可的主要代谢物5‑(3',4'‑二羟基苯基)‑γ‑戊内酯(DHPV)的新合成方法。该方法的优点不仅在于容易实现大规模合成，而且使得易于选择表现出抗氧化和抗衰老的生理活性的异构体。因此，该方法具有使得DHPV以简单且经济的方式大量生产的效果，使得DHPV作为用于化妆品和药物的功能性材料具有很高的价值。
Description
技术领域
与相关申请的交叉引用
本申请要求于2018年2月8日向韩国知识产权局提交的韩国专利申请No.10-2018-0015474的权益，其全部内容通过引用并入本文。
本发明涉及一种合成DHPV的新方法，更具体地，涉及一种合成可可的主要代谢物DHPV(5-(3',4'-二羟基苯基)-γ-戊内酯)的新方法。
背景技术
DHPV是可可的主要代谢物，已知具有抗氧化作用等。然而，包含衍生自黄烷-3-醇代谢物的低分子量化合物(例如DHPV)作为功能材料的化妆品尚未开发成产品。然而，由于低分子量化合物的膜渗透性高，低分子量化合物作为用于改善皱纹的功能性化妆品材料具有高价值，例如低分子量化合物与大分子相比能够更容易地到达真皮层的优点。
然而，由于DHPV是黄烷-3-醇(例如儿茶素)的体内代谢物，因此仅可以从自然资源中提取并分离出非常少的量。因此，存在的问题是，难以确保足够量的DHPV以进行与生物活性有关的后续研究。因此，国内外著名制造商仅专注于自然资源提取物本身的商业化，而不是天然存在的生物活性物质的衍生物的商业化，并且没有空间去通过药物和化学方法(例如DHPV作为功能性材料的大规模合成)和衍生物开发研究来获取新物质。因此，为了解决上述问题，进行了DHPV的全合成研究，但是它经历了大约七到八步的漫长合成过程，非常复杂(Lambert,Bioorg.Med.Chem.Lett.2005,15,873；Hamada,Synthesis 200,1512)，或难以处理且对环境或人体有害(Curti,Adv.Synth.Catal.2015,357,4082)，或使用苛刻的反应条件来合成(Watanabe,Bull.Agric.Chem.Soc.Japan 1959,23,263)。因此，需要开发一种能够克服上述问题的新合成方法。
发明内容
技术问题
在这些情况下，本发明人进行了广泛的研究以开发DHPV的商业合成方法，结果发现，与传统的合成方法不同，在传统的合成方法中，合成羟基己酸酯，然后通过酯交换反应合成γ-内酯，因此不可避免地要经历漫长的合成步骤，而本发明的合成方法与传统方法相比可以以简单、实用、经济的方式进行，即通过由己烯醇进行氧化裂解，然后进行氧化反应，将现有过程步骤减少为一个步骤，从而完成了本公开。
因此，本公开的一个目的是提供一种以简单、实用和经济的方式制备DHPV的新方法。
技术方案
为了实现以上目的，根据本公开的一个方面，提供了一种合成以下化学式1的DHPV的方法，该方法包括以下步骤：
a)使以下化学式2的芳基卤化物与以下化学式3的环氧化物化合物反应，并进行环氧化物开环反应，以合成以下化学式4的己烯醇化合物；
b)使用一级氧化剂使在步骤a)中合成的化学式4的己烯醇化合物氧化裂解，然后使用二级氧化剂进行氧化反应，得到以下化学式5的γ-内酯化合物；和
c)使步骤b)中获得的化学式5的γ-内酯化合物脱保护。
[化学式1]
[化学式2]
[化学式3]
[化学式4]
[化学式5]
其中，
X是Cl、Br、I或三氟甲磺酸盐(OTf；triflate)，并且
R是甲基(Me)、甲氧基甲基(MOM)、苄基(Bn)、丁基二苯基甲硅烷基(TBDPS)、丁基二甲基甲硅烷基(TBS)、二氢吡喃基(THP)、烯丙基、乙酰基(Ac)或缩醛基。
本公开的制备方法可以由以下反应方案1表示。
[反应方案1]
在下文中，将详细描述制备方法的每个步骤。
根据本公开的制备方法主要包括如上所述的三个步骤。
首先，第一步(步骤a)是使环氧化物与芳基卤化物反应并进行环氧化物开环反应以合成己烯醇的步骤。
芳基卤化物可以优选为二羟基芳基卤化物，并且可以为其中两种类型的羟基被保护基保护的形式。具体地，芳基卤化物的实例可以包括4-溴-1,2-二甲氧基苯或4-碘-1,2-二羟基苯，但是可以适当地选择和使用具有芳基卤化物结构的化合物而没有限制。该保护基可以是甲基(Me)、甲氧基甲基(MOM)、苄基(Bn)、丁基二苯基甲硅烷基(TBDPS)、丁基二甲基甲硅烷基(TBS)、二氢吡喃基(THP)、烯丙基(Allyl)、乙酰基(Ac)、缩醛基，并且该保护基可以优选为甲基。
进一步地，该环氧化物化合物可优选为1,2-环氧-5-己烯。
在优选的实施方式中，基于1当量的环氧化物化合物，芳基卤化物化合物的用量可以为1至10当量。进一步地，作为反应溶剂，可以使用四氢呋喃、二乙醚、二甲氧基乙烷、二噁烷、二甲基亚砜、二甲基甲酰胺等，并且优选以0.01mol至10.0mol的量使用。此外，步骤a)优选在-80℃至25℃下进行。
在根据本公开的具体实施方式的制备方法中，使用4-溴-1,2-二甲氧基苯作为芳基卤化物，使用1,2-环氧-5-己烯作为起始原料，使用n-BuLi、BF3OEt2并在THF中在-78℃下反应，得到己烯醇化合物1-(3,4-二甲氧基苯基)己-5-烯-2-醇(收率：81％)。
第二步骤(步骤b)是进行连续氧化反应的步骤，即，使用一级氧化剂的一级氧化反应和使用二级氧化剂的二级氧化反应以合成γ-内酯。优选地，在一级氧化反应中使用的一级氧化剂可以是OsO4(四氧化锇)、NaIO4(高碘酸钠)、NMO(N-甲基吗啉氧化物)、KHSO5(过氧单硫酸钾盐)或其组合，但不限于此。使用一级氧化剂使步骤b)中制备的具有环氧基的己醇的环氧化物开环以合成内半缩醛(lactol)。随后，二级氧化反应中使用的二级氧化剂可包括氯铬酸吡啶鎓(PCC)、重铬酸吡啶鎓(PDC)、高锰酸钾(KMnO4)、四甲基哌啶基氧基(TEMPO)、四氧化钌(RuO4)、戴斯-马丁高碘烷(DMP)、四丙基高钌酸铵(TPAP)，但不限于此。内半缩醛化合物可以被二级氧化为γ-内酯化合物。
在优选的实施方式中，基于1当量的己烯醇化合物，一级氧化剂的用量可以为0.01至50当量，并且基于1当量的内半缩醛化合物，二级氧化剂的用量可以为1至50当量。
在根据本公开的具体实施方式的制备方法中，步骤a)中制备的己烯醇化合物使用OsO4(四氧化锇)、NaIO4和2,6-二甲基吡啶进行一级氧化，并转化为内半缩醛化合物，所述内半缩醛化合物使用PCC、NaOAc和CH2Cl2进行二级氧化，获得γ-内酯化合物5-(3,4-二甲氧基苄基)二氢呋喃-2(3H)-酮(收率：73％)。
最后的步骤，即第三步骤(步骤c)，是使在步骤b)中制备的γ-内酯化合物的苯基上取代的两个羟基的保护基脱保护的步骤。此时，使用三溴化硼(BBr3)、苯硫酚(PHSH)、碘化锂(LiI)、甲基碘化镁(MeMgI)、氯化锂(LiCl)、三甲基甲硅烷基碘(TMSI)、三溴化铝(AlBr3)、三氯化铝(AlCl3)、三碘化硼(BI3)、三氟化硼(BF3)、三氯化硼(BCl3)，最终获得DHPV。
在优选的实施方式中，基于1当量的内酯化合物，三溴化硼的用量可以为0.1至50当量。此外，步骤c)优选在-80℃至100℃下进行。
在根据本公开的具体实施方式的制备方法中，为了除去与结合在与步骤b)中制备的γ-内酯化合物的苯基上的羟基结合的保护基，在-78℃下使用BBr3在二氯甲烷(CH2Cl2)中进行反应，最终获得DHPV(收率：66％)。
当根据本公开的制备方法合成DHPV时，可以解决以前没有简单的DHPV合成路线并且因此难以在过程步骤中有效地大量生产的问题，可以通过3步或更少步骤的短而有效的合成途径来生产DHPV，并且可以选择性地制备表现出抗氧化和抗衰老生物活性的DHPV异构体。因此，它不仅可以用作抗衰老化妆品的原料，而且可以促进DHPV的大量生产，这在药物化学领域中也是有用的。
有益效果
尽管通过常规研究已显著揭示了DHPV的抗氧化作用，但只能从天然资源中提取并分离出非常少量的DHPV，因此没有任何使用DHPV应用于化妆品和药品的实例。然而，如上所述的本公开的制备方法的优点不仅在于通过可以克服现有缺陷的新合成方法来促进大规模合成，而且使得易于选择表现出抗衰老生物活性的抗氧化剂和异构体。因此，本公开的制备方法有效地使得以简单且经济的方式大量生产作为功能性化妆品和药物材料具有高价值的DHPV成为可能。
具体实施方式
在下文中，参考特定的实施例更详细地描述本公开的配置。然而，对于本领域技术人员显而易见的是，这些实施例仅出于说明性目的而提供，并且本公开的范围不限于此。
实施例1.DHPV的合成
DHPV根据以下合成过程合成。
如图1所示，DHPV的合成主要通过三个步骤进行。
(a)1-(3,4-二甲氧基苯基)己-5-烯-2-醇的制备
将4-溴-1,2-二甲氧基苯(3.0g，13.8mmol)溶解于无水THF(15ml)中并冷却至-78℃，然后逐滴添加正丁基锂(2.5M，6.1ml，15.2mmol)。搅拌40分钟后，添加BF3·OEt2(1.9ml，15.2mmol)和2-(丁-3-烯-1-基)环氧乙烷(1.4g，13.8mmol)。将混合物在室温搅拌24小时，然后用水处理，并将含水层用乙酸乙酯萃取。将有机层用饱和NaHCO3溶液洗涤一次，用MgSO4干燥，过滤并在减压下浓缩。所得残余物通过硅胶色谱纯化，得到仲醇。(收率：81％，2.6g)。
(b)5-(3,4-二甲氧基苄基)二氢呋喃-2(3H)-酮的制备
将步骤(a)中获得的化合物(1.0g，4.2mmol)溶解于1,4-二噁烷(4ml)和水(1ml)中，在其中添加2,6-二甲基吡啶(0.97ml，8.4mmol)和OsO4。冷却至0℃后，添加高碘酸钠(3.6g，16.8mmol)。将混合物在室温下搅拌17小时，然后用水处理，并将含水层用CH2Cl2萃取。将有机层用盐水洗涤，用MgSO4干燥，过滤并在减压下浓缩，获得内半缩醛化合物。将获得的内半缩醛化合物溶于CH2Cl2(5ml)，冷却至0℃，然后缓慢添加乙酸钠(688mg，8.4mmol)和氯铬酸吡啶鎓(1.8g，8.4mmol)。将混合物在室温下搅拌1小时，然后立即通过硅胶色谱纯化，得到内酯化合物。(收率：73％，724mg)。
(c)5-(3,4-二羟基苯基)-γ-戊内酯的制备
将步骤b)中获得的内酯化合物(500mg，2.1mmol)溶解于CH2Cl2(2ml)中，冷却至-78℃，然后添加三溴化硼(0.81ml，8.4mmol)。将混合物在室温下搅拌10小时，然后用水处理，并将含水层用CH2Cl2萃取。将有机层用盐水洗涤，用MgSO4干燥，过滤并在减压下浓缩。将所得残余物通过硅胶色谱纯化，得到白色固体戊内酯。(收率：66％，288mg)。
DHPV；1H-NMR(CDCl3,800MHz)δ6.69(s,1H),6.68(t,J＝2.8Hz,1H),6.55(dd,J＝8.0,2.9Hz,1H),4.72(td,J＝10.1,6.2Hz,1H),2.87(dd,J＝14.1,6.1Hz,1H),2.78(dd,J＝14.1,6.1Hz,1H),2.47(td,J＝13.4,9.3Hz,1H),2.32(dq,J＝17.7,4.8Hz,1H),2.23(m,1H),1.95(m,1H)；13C-NMR(CDCl3,200MHz)δ181.1,147.1,146.1,129.8,122.7,118.5,117.2,84.1,42.3,30.3,29.7；HR-MS(FAB+)calcd for C11H13O4(M+H+)209.0814；found209.0820。
Claims (7)
1.一种制备以下化学式1的DHPV的方法，所述方法包括以下步骤：
a）使以下化学式2的芳基卤化物与以下化学式3的环氧化物化合物反应，并进行环氧化物开环反应，以合成以下化学式4的己烯醇化合物；
b）使用一级氧化剂使在步骤a）中合成的化学式4的己烯醇化合物氧化裂解成内半缩醛化合物，然后使用二级氧化剂进行氧化反应，得到以下化学式5的γ-内酯化合物；和
c）使用BBr3使步骤b）中获得的化学式5的γ-内酯化合物脱保护，
[化学式1]
[化学式2]
[化学式3]
[化学式4]
[化学式5]
其中，
X是Cl、Br、或I，并且
R是甲基（Me）、甲氧基甲基（MOM）、苄基（Bn）、TBS、THP、烯丙基、或乙酰基（Ac）。
2.根据权利要求1所述的制备方法，其特征在于，所述芳基卤化物为4-溴-1,2-二甲氧基苯。
3.根据权利要求1所述的制备方法，其特征在于，基于1当量的所述环氧化物化合物，所述芳基卤化物的使用量为1至10当量。
4.根据权利要求1所述的制备方法，其特征在于，步骤b中所述的一级氧化剂为OsO4（四氧化锇）、NaIO4（高碘酸钠）、NMO（N-甲基吗啉氧化物）、KHSO5（过氧单硫酸钾盐）或其组合。
5.根据权利要求1所述的制备方法，其特征在于，步骤b中所述的二级氧化剂为氯铬酸吡啶鎓（PCC）、重铬酸吡啶鎓（PDC）、高锰酸钾（KMnO4）、四甲基哌啶基氧基（TEMPO）、四氧化钌（RuO4）、戴斯-马丁高碘烷（DMP）或四丙基高钌酸铵（TPAP）。
6.根据权利要求1所述的制备方法，其特征在于，在步骤b中，基于1当量的己烯醇化合物，所述一级氧化剂的用量为0.01至50当量，并且基于1当量的内半缩醛化合物，所述二级氧化剂的用量为1至50当量。
7.根据权利要求1所述的制备方法，其特征在于，在步骤c中，基于1当量的内酯化合物，三溴化硼的用量为0.1至50当量。
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