PL226308B1 - Process for preparing (2S,4R)-trans-flavan-4-ol - Google Patents
Process for preparing (2S,4R)-trans-flavan-4-olInfo
- Publication number
- PL226308B1 PL226308B1 PL407241A PL40724114A PL226308B1 PL 226308 B1 PL226308 B1 PL 226308B1 PL 407241 A PL407241 A PL 407241A PL 40724114 A PL40724114 A PL 40724114A PL 226308 B1 PL226308 B1 PL 226308B1
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- Poland
- Prior art keywords
- flavan
- trans
- strain
- organic solvent
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Links
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- YTMFRMLVZQOBDR-DZGCQCFKSA-N (2r,4s)-2-phenyl-3,4-dihydro-2h-chromen-4-ol Chemical compound C1([C@H]2C[C@@H](C3=CC=CC=C3O2)O)=CC=CC=C1 YTMFRMLVZQOBDR-DZGCQCFKSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 241000235015 Yarrowia lipolytica Species 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 230000009466 transformation Effects 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 claims 1
- 239000002609 medium Substances 0.000 claims 1
- 230000000813 microbial effect Effects 0.000 claims 1
- 239000013630 prepared media Substances 0.000 claims 1
- 229930003935 flavonoid Natural products 0.000 description 5
- 235000017173 flavonoids Nutrition 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 150000002215 flavonoids Chemical class 0.000 description 4
- -1 triphillyin A Chemical compound 0.000 description 4
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- FSYDWKPCKNCRDI-OLZOCXBDSA-N (2S,4R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-4,5,7-triol Chemical compound O[C@@H]1C[C@H](Oc2cc(O)cc(O)c12)c1ccc(O)c(O)c1 FSYDWKPCKNCRDI-OLZOCXBDSA-N 0.000 description 2
- IYVFNTXFRYQLRP-VVSTWUKXSA-N 2-[3,4-bis(2-hydroxyethoxy)phenyl]-5-hydroxy-7-(2-hydroxyethoxy)-3-{[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-({[(2r,3r,4r,5r,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}methyl)oxan-2-yl]oxy}-4h-chromen-4-one Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C(C3=C(O)C=C(OCCO)C=C3OC=2C=2C=C(OCCO)C(OCCO)=CC=2)=O)O1 IYVFNTXFRYQLRP-VVSTWUKXSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- FSYDWKPCKNCRDI-STQMWFEESA-N Luteoforol Natural products O[C@@H]1c2c(O)cc(O)cc2O[C@H](c2cc(O)c(O)cc2)C1 FSYDWKPCKNCRDI-STQMWFEESA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 102000015694 estrogen receptors Human genes 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- ZEACOKJOQLAYTD-UHFFFAOYSA-N flavan-3,3',4,4',5,5',7-heptol Chemical compound OC1C(O)C2=C(O)C=C(O)C=C2OC1C1=CC(O)=C(O)C(O)=C1 ZEACOKJOQLAYTD-UHFFFAOYSA-N 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ILHUDIBLZBKODZ-UHFFFAOYSA-N (2R,4S)-5,7-O-beta-D-diglucopyranosyloxy-4'-methoxy-6,8-dimethyl-4,2''-oxidoflavane Natural products C1=CC(OC)=CC=C1C1OC(C(C)=C(OC2C(C(O)C(O)C(CO)O2)O)C(C)=C2OC3OC(CO)C(O)C(O)C3O3)=C2C3C1 ILHUDIBLZBKODZ-UHFFFAOYSA-N 0.000 description 1
- ORJDDOBAOGKRJV-CQSZACIVSA-N (2S)-Pinocembrin Natural products C1([C@H]2CC(=O)C3=C(O)C=C(C=C3O2)OC)=CC=CC=C1 ORJDDOBAOGKRJV-CQSZACIVSA-N 0.000 description 1
- QOLIPNRNLBQTAU-HNNXBMFYSA-N (2S)-flavan Chemical compound C1([C@H]2OC3=CC=CC=C3CC2)=CC=CC=C1 QOLIPNRNLBQTAU-HNNXBMFYSA-N 0.000 description 1
- YEDFEBOUHSBQBT-UHFFFAOYSA-N 2,3-dihydroflavon-3-ol Chemical compound O1C2=CC=CC=C2C(=O)C(O)C1C1=CC=CC=C1 YEDFEBOUHSBQBT-UHFFFAOYSA-N 0.000 description 1
- YTMFRMLVZQOBDR-UHFFFAOYSA-N 2-phenyl-3,4-dihydro-2h-chromen-4-ol Chemical compound O1C2=CC=CC=C2C(O)CC1C1=CC=CC=C1 YTMFRMLVZQOBDR-UHFFFAOYSA-N 0.000 description 1
- 241000208838 Asteraceae Species 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 241000143476 Bidens Species 0.000 description 1
- 244000104272 Bidens pilosa Species 0.000 description 1
- 235000010662 Bidens pilosa Nutrition 0.000 description 1
- 108010044229 Dihydroflavanol 4-reductase Proteins 0.000 description 1
- WZHCAAJIMBUYAS-OLTMIKEFSA-N Eruberin B Chemical compound C1=CC(OC)=CC=C1[C@@H]1OC2=C(C)C(O[C@H]3C([C@@H](O)[C@H](O)C(CO)O3)O)=C(C)C(O[C@H]3C([C@@H](O)[C@H](O)C(CO)O3)O)=C2[C@@H](O)C1 WZHCAAJIMBUYAS-OLTMIKEFSA-N 0.000 description 1
- 241000588698 Erwinia Species 0.000 description 1
- 241000718081 Glaphyropteridopsis erubescens Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229910002567 K2S2O8 Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 240000006394 Sorghum bicolor Species 0.000 description 1
- 235000011684 Sorghum saccharatum Nutrition 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- ILHUDIBLZBKODZ-MOXCVTMHSA-N chembl398501 Chemical compound C1=CC(OC)=CC=C1[C@H]1OC(C(C)=C(O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C(C)=C2O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O3)=C2[C@H]3C1 ILHUDIBLZBKODZ-MOXCVTMHSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000005183 environmental health Effects 0.000 description 1
- WZHCAAJIMBUYAS-UHFFFAOYSA-N eruberin B Natural products C1=CC(OC)=CC=C1C1OC2=C(C)C(OC3C(C(O)C(O)C(CO)O3)O)=C(C)C(OC3C(C(O)C(O)C(CO)O3)O)=C2C(O)C1 WZHCAAJIMBUYAS-UHFFFAOYSA-N 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 150000005836 flavan-4-ols Chemical class 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- FSYDWKPCKNCRDI-UHFFFAOYSA-N luteoforol Chemical compound O1C2=CC(O)=CC(O)=C2C(O)CC1C1=CC=C(O)C(O)=C1 FSYDWKPCKNCRDI-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000013048 microbiological method Methods 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- ORJDDOBAOGKRJV-AWEZNQCLSA-N pinostrobin Chemical compound C1([C@@H]2CC(=O)C3=C(O)C=C(C=C3O2)OC)=CC=CC=C1 ORJDDOBAOGKRJV-AWEZNQCLSA-N 0.000 description 1
- 244000000003 plant pathogen Species 0.000 description 1
- 235000019394 potassium persulphate Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Przedmiotem wynalazku jest sposób wytwarzania (2S,4R)-trans-flawan-4-olu.The present invention relates to a process for the preparation of (2S, 4R) -trans-flavan-4-ol.
Związek ten może znaleźć zastosowanie jako prekursor wielu aktywnych związków użytecznych w przemyśle spożywczym farmaceutycznym i kosmetycznym.This compound may find use as a precursor of many active compounds useful in the food, pharmaceutical and cosmetic industries.
Konfigurację absolutną naturalnych flavan-4-oli przy atomie węgla nr 2 określono jako S, natomiast grupa hydroksylowa obecna przy węglu nr 4 jest usytuowana trans w stosunku do podstawnika fenylowego (Halbwirth, H.; Kahl, S.; Jaeger, W.; Reznicek, G.; Forkmann, G.; Stich, K. (2006) Synthesis of (14C)-labeled 5-deoxyflavonoids and their application in the study of dihydroflavonol/leucoanthocyanidin interconversion by dihydroflavonol 4-reductase. Plant Sci. 170, 587-595; Halbwirth H. The Creation and Physiological Relevance of Divergent Hydroxylation Patterns in the Flavonoid Pathway. International Journal of Molecular Sciences. 2010; 11:595-621). Takie wzajemne położenia podstawników przy 2 i 4 atomie węgla jest opisywane w literaturze dla wielu aktywnych biologicznie związków np.: luteoforolu apiforolu (E.C. Bate-Smith; Luteoforol (3',4,4',5,7-pentahydroxyflavan) in Sorghum vulgare L. Phytochemistry, 8, 1969, 1803-1810; F. Spinelli, J.-B. Speakman, W. Rademacher, H. Halbwirth, K. Stich, G. Costa; Luteoforol, a flavan 4-ol, is induced in pome fruits by prohexadione-calciumand shows phytoalexin-like properties against Erwinia amylovoraand other plant pathogens. European Journal of Plant Pathology, 2005, 112, 133-142) oraz glikozydów: abakopteryny I, triphillyny A, eruberyny B (H. Wei, G. Wu, D. Shi, S. Song, X. Zhang, Y. Lei, J. Ruan; Total flavan glycoside from Abacopteris penangiana rhizomes and its acid hydrolysate: Characterisation and anti-benign prostatic hyperplasia potential. Food Chemistry 134 (2012) 1959-1966; J. Jiang, L. Tian, L. Wang, Y. Liu, Y. Chen; Phenolic compounds from the fern Glaphyropteridopsis erubescens (Hook.) Ching. Biochemical Systematics and Ecology 50 (2013) 136-138).The absolute configuration of the natural flavan-4-ols on carbon 2 is S, while the hydroxyl group on carbon 4 is trans to the phenyl substituent (Halbwirth, H .; Kahl, S; Jaeger, W .; Reznicek , G .; Forkmann, G .; Stich, K. (2006) Synthesis of (14C) -labeled 5-deoxyflavonoids and their application in the study of dihydroflavonol / leucoanthocyanidin interconversion by dihydroflavonol 4-reductase. Plant Sci. 170, 587- 595; Halbwirth H. The Creation and Physiological Relevance of Divergent Hydroxylation Patterns in the Flavonoid Pathway. International Journal of Molecular Sciences. 2010; 11: 595-621). Such mutual positions of the substituents at the 2 and 4 carbon atoms are described in the literature for many biologically active compounds, e.g. apiforolu luteophorol (EC Bate-Smith; Luteoforol (3 ', 4,4', 5,7-pentahydroxyflavan) in Sorghum vulgare L Phytochemistry, 8, 1969, 1803-1810; F. Spinelli, J.-B. Speakman, W. Rademacher, H. Halbwirth, K. Stich, G. Costa; Luteoforol, a flavan 4-ol, is induced in pome fruits by prohexadione-calciumand shows phytoalexin-like properties against Erwinia amylovoraand other plant pathogens. European Journal of Plant Pathology, 2005, 112, 133-142) and glycosides: abacopterin I, triphillyin A, eruberin B (H. Wei, G. Wu , D. Shi, S. Song, X. Zhang, Y. Lei, J. Ruan; Total flavan glycoside from Abacopteris penangiana rhizomes and its acid hydrolysate: Characterization and anti-benign prostatic hyperplasia potential. Food Chemistry 134 (2012) 1959- 1966; J. Jiang, L. Tian, L. Wang, Y. Liu, Y. Chen; Phenolic compounds from the fern Glaphyropteridopsis erubescens ( Hook.) Ching. Biochemical Systematics and Ecology 50 (2013) 136-138).
Przykładem terapeutycznego zastosowania flawonoidów jest ich udział w zwalczaniu różnego rodzaju stanów zapalnych występujących w organizmie (Brandao M.G., Krettli A.U., Soares L.S., Nery C.G., Marinuzzi H.C. 1997. Antimalarial activity of extracts and fractions from Bidens pilosa and other Bidens species (Asteraceae) correlated with the presence of acetylene and flavonoid compounds. Journal of Ethnopharmacology, 57, 131-138; Van Cauwenberge H., Franchimont P. 1967. Action of Z 6000 (trihydroxyethylrutoside) on various experimental inflammation tests carried out in rats. (French). Archives internationales de pharmacodynamie et therap, 170, 74-80).An example of the therapeutic use of flavonoids is their participation in combating various types of inflammation in the body (Brandao MG, Krettli AU, Soares LS, Nery CG, Marinuzzi HC 1997. Antimalarial activity of extracts and fractions from Bidens pilosa and other Bidens species (Asteraceae) correlated with the presence of acetylene and flavonoid compounds. Journal of Ethnopharmacology, 57, 131-138; Van Cauwenberge H., Franchimont P. 1967. Action of Z 6000 (trihydroxyethylrutoside) on various experimental inflammation tests carried out in rats. (French). Archives internationales de pharmacodynamie et therap, 170, 74-80).
Niektóre flawonoidy mogą przyczynić się do zahamowania występowania chorób nowotworowych, szczególnie zależnego od estrogenów raka piersi (Adlercreutz H., Mousavi Y, Hockerstedt K. 1992. Diet and breast cancer. Acta Oncologica, 31, 175-181; Lee H.P., Gourley L., Duffy S., EsteveCertain flavonoids may contribute to the suppression of neoplastic diseases, especially estrogen-dependent breast cancer (Adlercreutz H., Mousavi Y, Hockerstedt K. 1992. Diet and breast cancer. Acta Oncologica, 31, 175-181; Lee HP, Gourley L. , Duffy S., Esteve
J., Lee J., Day N.E. 1991. Dietary effects on breast cancer risk in Singapore. Lancet, 337,1197-1200). Wynika to z faktu, że flawonoidy, które są strukturalnie podobne do estrogenów, są w stanie przyłączać się do receptorów estrogenowych i posiadać estrogenowe lub antyestrogenowe właściwości (Makela S., Davis V.L., Tally W.C., Korkman J., Salo L., Vihko R., Santti R., Korach K.S. 1994. Dietary estrogens act through estrogen receptor-mediated processes and show no antiestrogenicity in cultured breast cancer cells. Environmental Health Perspectives, 102, 9572-578).J., Lee J., Day N.E. 1991. Dietary effects on breast cancer risk in Singapore. Lancet, 337, 1197-1200). This is due to the fact that flavonoids, which are structurally similar to estrogens, are able to attach to estrogen receptors and possess estrogenic or anti-estrogenic properties (Makela S., Davis VL, Tally WC, Korkman J., Salo L., Vihko R ., Santti R., Korach KS 1994. Dietary estrogens act through estrogen receptor-mediated processes and show no antiestrogenicity in cultured breast cancer cells. Environmental Health Perspectives, 102, 9572-578).
Znany jest sposób otrzymywania z wydajnością 19% i z ee > 99 (2S,4R-trans-flawan-4-olu na drodze chemicznego utlenienia (S)-flawanu z wykorzystaniem mieszniny soli: CuSO4 (2 mol ekwiwalent) i K2S2O8 (0,2 mol ekwiwalent) (K.J. Hodgetts; (2001) Approaches to 2-substituted chroman-4-ones: synthesis of (-)-pinostrobin. Tetrahedron Letters 42, 3763-3766). Autor jednak nie podaje danych spektralnych opisywanego związku. Dotychczas brak jest doniesień literaturowych na temat otrzymywania (2S,4R)-trans-flawan-4-olu na drodze mikrobiologicznej.There is a known method of obtaining 19% yield and with ee> 99 (2S, 4R-trans-flavan-4-ol by chemical oxidation of (S) -flavan using a mixture of salts: CuSO4 (2 mole equivalent) and K2S2O8 (0.2 mole equiv.) (KJ Hodgetts; (2001) Approaches to 2-substituted chroman-4-ones: synthesis of (-) - pinostrobin. Tetrahedron Letters 42, 3763-3766) However, the author does not provide spectral data for the described compound. literature reports on the preparation of (2S, 4R) -trans-flavan-4-ol by microbiological method.
Istota wynalazku polega na tym, że enancjoselektywne utlenienie jednego z enancjomerów w mieszaninie racemicznej substratu, którym jest (±)-trans-flawan-4-olu, do ketonu pozwalające na uzyskanie nieprzereagowanego (2S,4R)-trans-flawan-4-olu, o wzorze 2, prowadzi się przy użyciu wodnej kultury szczepu Yarrowia lipolytica KCh 71, przy ciągłym mieszaniu reagentów. Produkt ekstrahuje się rozpuszczalnikiem organicznym niemieszającym się z wodą i oczyszcza chromatograficznie. Otrzymuje się (+)-(2S,4R)-trans-flawan-4-ol z wydajnością 41%, natomiast pozostałe frakcje stanowią zanieczyszczenie.The essence of the invention consists in the enantioselective oxidation of one of the enantiomers in the racemic mixture of the substrate, which is (±) -trans-flavan-4-ol, to a ketone that allows to obtain unreacted (2S, 4R) -trans-flavan-4-ol , of formula 2, is carried out with an aqueous culture of the strain Yarrowia lipolytica KCh 71, with constant mixing of the reagents. The product is extracted with a water-immiscible organic solvent and purified by chromatography. The (+) - (2S, 4R) -trans-flavan-4-ol is obtained with a yield of 41%, while the remaining fractions are impurity.
Korzystne jest, gdy proces prowadzi się w temperaturze od 15 do 35°C.It is preferred that the process is carried out at a temperature of 15 to 35 ° C.
Korzystnie także jest, gdy rozpuszczalnikiem organicznym jest chloroform.It is also preferred that the organic solvent is chloroform.
Zasadniczą zaletą wynalazku jest otrzymanie (+)-(2S,4R)-trans-flawan-4-olu z nadmiarem enancjomerycznym wynoszącym 94%, w temperaturze pokojowej i przy pH naturalnym dla szczepu.The main advantage of the invention is the preparation of (+) - (2S, 4R) -trans-flavan-4-ol with an enantiomeric excess of 94%, at room temperature and the natural pH of the strain.
PL 226 308 B1PL 226 308 B1
Wynalazek jest bliżej objaśniony na przykładzie wykonania.The invention is explained in more detail using an exemplary embodiment.
P r z y k ł a d. Do kolby Erlenmajera o pojemności 2000 cm3, w której znajduje się 500 cm3 sterylnej pożywki zawierającej 5 g aminobaku i 15 g glukozy, wprowadza się szczep Yarrowia lipolyticaExample: The Yarrowia lipolytica strain is introduced into an Erlenmajer flask with a capacity of 2000 cm 3 , in which there is 500 cm 3 of sterile medium containing 5 g of aminobac and 15 g of glucose
KCh 71. Po 48 godzinach jego wzrostu dodaje się 100 mg (±)-trans-flawan-4-olu, o wzorze 1, roz3 puszczonego w 1 cm3 acetonu. Transformację prowadzi się w 25 stopniach Celsjusza przy ciągłym wstrząsaniu przez 24 godziny.SDS 71. After 48 hours, the growth was added 100 mg (±) trans-flavan-4-ol of formula 1, Chapter 3 puszczonego in 1 cm 3 of acetone. The transformation is performed at 25 degrees Celsius with continuous shaking for 24 hours.
Następnie mieszaninę poreakcyjną ekstrahuje się trzykrotnie chloroformem, osusza bezwodnym siarczanem magnezu, po czym odparowuje rozpuszczalnik. Otrzymany ekstrakt oczyszcza się chromatograficznie, używając jako eluentu mieszaniny acetonu i heksanu w stosunku 4:1. trans-flawan-4-ol znajduje się we frakcjach o wyższej polarności.The reaction mixture was then extracted three times with chloroform, dried with anhydrous magnesium sulfate, and the solvent was then evaporated. The extract obtained is purified by chromatography using a 4: 1 mixture of acetone and hexane as eluent. trans-flavan-4-ol is found in the higher polarity fractions.
Na tej drodze otrzymuje się 41 mg (+)-(2S,4R)-trans-flawan-4-olu (wydajność 41%).In this way, 41 mg of (+) - (2S, 4R) -trans-flavan-4-ol are obtained (41% yield).
Uzyskany produkt charakteryzuje się następującymi danymi spektralnymi.The obtained product is characterized by the following spectral data.
(2S,4R)-trans-flavan-4-ol (bezbarwny kryształ); = +12.4° (c = 0.7, CHCI3) (94% ee).(2S, 4R) -trans-flavan-4-ol (colorless crystal); = + 12.4 ° (c = 0.7, CHCl3) (94% ee).
1H NMR (600 MHz) (CDCI3) δ (ppm): 2,12 (ddd, 1H, J = 14,4; 12,2; 3,3 Hz, H-3a); 2,28 (ddd, 1H, J = 14,4, 2,5; 1,7 Hz, H-3e); 4,85 (dd, 1H, J = 3,3; 2,5 Hz, H-4e); 5,28 (dd, 1H, J = 12,2; 1,7 Hz, H-2a); 6,98 (t, 1H, J = 7,8 Hz, H-6), 6.99 (d, 1H, J = 8,1 Hz, H-8), 7,27 (t, 1H, J = 7,6 Hz, H-7), 7,37 (t, 1H, J = 7,6 Hz, H-4'), 7,38 (d, 1H, J = 7,6 Hz, H-5), 7,43 (t, 2H, J = 7,3 Hz, H-3' and H-5'), 7,50 (d, 2H, J = 7,7 Hz, H-2' and H-6') 13C NMR (151 MHz, CDCI3) δ = 38,34 (C-3), 63,73 (C-4), 73,11 (C-2), 117,45 (C-8), 120,80 (C-6), 123,67 (C-4a), 126,29 (C-2' and C-6'), 128,04 (C-4'), 128,60 (C-3' and C-5'), 129,93 (C-7), 130,14 (C-5), 141,04 (C-1'), and 154,90 (C-8a). 1 H NMR (600 MHz) (CDCl 3) δ (ppm): 2.12 (ddd, 1H, J = 14.4; 12.2; 3.3 Hz, H-3a); 2.28 (ddd, 1H, J = 14.4, 2.5, 1.7Hz, H-3e); 4.85 (dd, 1H, J = 3.3, 2.5Hz, H-4e); 5.28 (dd, 1H, J = 12.2, 1.7Hz, H -2a); 6.98 (t, 1H, J = 7.8Hz, H-6), 6.99 (d, 1H, J = 8.1Hz, H-8), 7.27 (t, 1H, J = 7, 6 Hz, H-7), 7.37 (t, 1H, J = 7.6 Hz, H-4 '), 7.38 (d, 1H, J = 7.6 Hz, H-5), 7 , 43 (t, 2H, J = 7.3 Hz, H-3 'and H-5'), 7.50 (d, 2H, J = 7.7 Hz, H-2 'and H-6') 13 C NMR (151 MHz, CDCl3) δ = 38.34 (C-3), 63.73 (C-4), 73.11 (C-2), 117.45 (C-8), 120.80 (C-6), 123.67 (C-4a), 126.29 (C-2 'and C-6'), 128.04 (C-4 '), 128.60 (C-3' and C -5 '), 129.93 (C-7), 130.14 (C-5), 141.04 (C-1'), and 154.90 (C-8a).
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