PL235018B1 - Method for producing 17a-oxa-D-homo-androst-4-en-17-one - Google Patents
Method for producing 17a-oxa-D-homo-androst-4-en-17-one Download PDFInfo
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- PL235018B1 PL235018B1 PL420191A PL42019117A PL235018B1 PL 235018 B1 PL235018 B1 PL 235018B1 PL 420191 A PL420191 A PL 420191A PL 42019117 A PL42019117 A PL 42019117A PL 235018 B1 PL235018 B1 PL 235018B1
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- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 238000000034 method Methods 0.000 claims description 12
- 241001507677 Penicillium commune Species 0.000 claims description 7
- 230000009466 transformation Effects 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 241000233866 Fungi Species 0.000 claims description 2
- 150000003431 steroids Chemical class 0.000 description 6
- CNIXJDVUMXTEKX-DZBHQSCQSA-N testololactone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 CNIXJDVUMXTEKX-DZBHQSCQSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 230000036983 biotransformation Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229960005353 testolactone Drugs 0.000 description 3
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229940122815 Aromatase inhibitor Drugs 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 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 2
- 241000228129 Penicillium janthinellum Species 0.000 description 2
- 241000674483 Penicillium lanosocoeruleum Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003886 aromatase inhibitor Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 238000007273 lactonization reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 208000006155 precocious puberty Diseases 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NOEMICWEDLSYHV-SNZQGMLHSA-N (4R,5S,8S,9S,10S,13S,14S,17R)-4,8,10,14-tetramethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,3,4,5,6,7,9,11,12,13,15,16,17-tetradecahydrocyclopenta[a]phenanthrene Chemical compound CC(C)CCC[C@@H](C)[C@H]1CC[C@@]2(C)[C@H]1CC[C@H]1[C@@]3(C)CCC[C@@H](C)[C@@H]3CC[C@]21C NOEMICWEDLSYHV-SNZQGMLHSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 238000006220 Baeyer-Villiger oxidation reaction Methods 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 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
- 241000187469 Mycobacterium neoaurum Species 0.000 description 1
- CNIXJDVUMXTEKX-UHFFFAOYSA-N Testololactone Natural products O=C1CCC2(C)C3CCC(C)(OC(=O)CC4)C4C3CCC2=C1 CNIXJDVUMXTEKX-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 1
- LUJVUUWNAPIQQI-QAGGRKNESA-N androsta-1,4-diene-3,17-dione Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 LUJVUUWNAPIQQI-QAGGRKNESA-N 0.000 description 1
- 229960005471 androstenedione Drugs 0.000 description 1
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000013048 microbiological method Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest sposób wytwarzania 17a-oxa-D-homo-androst-4-en-3,17-dionu.The present invention relates to a process for the preparation of 17a-oxa-D-homo-androst-4-ene-3,17-dione.
Metoda, według wynalazku może znaleźć zastosowanie w przemyśle farmaceutycznym do wytwarzania leku stosowanego w terapii hormonalnej (Carel J-C., Lahlou N., Roger M., Chaussain J.L. (2004) Precocious puberty and statural growth. Hum Reprod Update. 10, 135-147).The method according to the invention may find application in the pharmaceutical industry for the production of a drug used in hormone therapy (Carel JC., Lahlou N., Roger M., Chaussain JL (2004) Precocious puberty and statural growth. Hum Reprod Update. 10, 135-147. ).
Leki steroidowe są po antybiotykach drugą co do wielkości grupą leków, odgrywającą ważną rolę w leczeniu i zapobieganiu różnym chorobom (Zhang W.Q., Shao M.L., Rao Z.M., Xu M.J., Zhang X., Yang T.W., Li H., Xu Z.H. (2013) Bioconversion of 4-androstene-3,17-dione to androst-1,4-diene-3,17-dione by recombinant Bacillus subtilis expressing ksdd gene encoding 3-ketosteroid-A1-dehydrogenase from Mycobacterium neoaurum JC-12. J Steroid Biochem Mol Biol 135:36-42).Steroid drugs are the second largest group of drugs after antibiotics, playing an important role in the treatment and prevention of various diseases (Zhang WQ, Shao ML, Rao ZM, Xu MJ, Zhang X., Yang TW, Li H., Xu ZH (2013) Bioconversion of 4-androstene-3,17-dione to androst-1,4-diene-3,17-dione by recombinant Bacillus subtilis expressing ksdd gene encoding 3-ketosteroid-A1-dehydrogenase from Mycobacterium neoaurum JC-12. J Steroid Biochem Mol Biol 135: 36-42).
17a-oxa-D-homo-androst-4-en-3,17-dion jest prekursorem testolaktonu - związku stosowanego jako inhibitor aromatazy. Dzięki tej właściwości zapobiega wzrostowi nowotworów sutka, które są aktywowane przez estrogen (Clark R.V., Sherins R.J. (1989) Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone results of a double-blinded, randomized, placebo-controlled trial with crossover. J Androl 10, 240-247. Ze względu na jego zdolność do blokowania wytwarzania estrogenów stwierdzono również skuteczność testolaktonu w zapobieganiu przedwczesnemu pokwitaniu (Carel J-C., Lahlou N., Roger M., Chaussain J.L. (2004) Precocious puberty and statural growth. Hum Reprod Update. 10, 135-147).17a-oxa-D-homo-androst-4-ene-3,17-dione is a precursor of testolactone - a compound used as an aromatase inhibitor. Thanks to this property, it prevents the growth of breast tumors that are activated by estrogen (Clark RV, Sherins RJ (1989) Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone results of a double-blinded, randomized, placebo-controlled trial with crossover J Androl 10, 240-247 Due to its ability to block estrogen production, testolactone has also been found to be effective in preventing premature puberty (Carel JC., Lahlou N., Roger M., Chaussain JL (2004) Precocious puberty and statural growth. Hum Reprod Update. 10, 135-147).
Biotransformacje są ekologiczną alternatywą klasycznej syntezy chemicznej w uzyskiwaniu aktywnych związków i są coraz częściej stosowane w przemyśle biofarmaceutycznym, zwłaszcza do produkcji leków steroidowych (M.-M. Chen, F.-Q. Wang, L.-C. Lin, K. Yao, D.-Z. Wei; Characterization and application of fusidane antibiotic biosynethsis enzyme 3-ketosteroid-A1-dehydrogenase in steroid transformation. Appl Microbiol Biotechnol 96, 2012, 133-142).Biotransformations are an ecological alternative to classical chemical synthesis in obtaining active compounds and are increasingly used in the biopharmaceutical industry, especially for the production of steroid drugs (M.-M. Chen, F.-Q. Wang, L.-C. Lin, K. Yao , D.-Z. Wei; Characterization and application of fusidane antibiotic biosynethsis enzyme 3-ketosteroid-A 1 -dehydrogenase in steroid transformation. Appl Microbiol Biotechnol 96, 2012, 133-142).
Znane są mikrobiologiczne metody uzyskiwania 17a-oxa-D-homo-androst-4-en-3,17-dionu z 3β-hydroksyandrost-5-en-17-onu w wyniku zastosowania szczepu: Penicillium simplicissimum WY134-2 z wydajnością 53% (B. Yang, Y. Wang, X. Chen, J. Feng, Q. Wu, D. Zhu, Y. Ma (2014) Biotransformations of steroids to testololactone by a multifunctional strain Penicillium simplicissimum WY134-2. Tetrahedron 70, 41-46); Penicillium lanosocoeruleum z wydajnością 91% (A. Świzdor (2013) Baeyer-Villiger Oxidation of Some C19 Steroids by Penicilliumlanosocoeruleum. Molecules 18, 13812-13822).There are known microbiological methods of obtaining 17a-oxa-D-homo-androst-4-en-3,17-dione from 3β-hydroxyandrost-5-en-17-one by using the strain: Penicillium simplicissimum WY134-2 with 53% efficiency (B. Yang, Y. Wang, X. Chen, J. Feng, Q. Wu, D. Zhu, Y. Ma (2014) Biotransformations of steroids to testololactone by a multifunctional strain Penicillium simplicissimum WY134-2. Tetrahedron 70, 41 -46); Penicillium lanosocoeruleum with a yield of 91% (A. Świzdor (2013) Baeyer-Villiger Oxidation of Some C19 Steroids by Penicilliumlanosocoeruleum. Molecules 18, 13812-13822).
Istota wynalazku polega na tym, że regioselektywną laktonizację pierścienia D, poprzedza utlenienie grupy hydroksylowej przy trzecim atomie węgla i izomeryzacja wiązania podwójnego z 5-en do 4-en w substracie, którym jest 33-hydroksyandrost-5-en-17-on (DHEA), w wyniku tych przekształceń otrzymuje się 17a-oxa-D-homo-androst-4-en-3,17-dion, prowadzi się w wodnej kulturze szczepu Penicillium commune KCh W7.The essence of the invention is that regioselective lactonization of the D ring is preceded by the oxidation of the hydroxyl group at the third carbon atom and the isomerization of the double bond from 5-en to 4-ene in the substrate, which is 33-hydroxyandrost-5-en-17-one (DHEA ), as a result of these transformations 17a-oxa-D-homo-androst-4-ene-3,17-dione are obtained, it is carried out in an aqueous culture of the strain Penicillium commune KCh W7.
Istota wynalazku polega na tym, że do podłoża odpowiedniego dla grzybów strzępkowych wprowadza się szczep Penicillium commune KCh W7. Po upływie co najmniej 48 godzin do hodowli wprowadza się substrat, którym jest 33-hydroksyandrost-5-en-17-on o wzorze 1, rozpuszczony w rozpuszczalniku organicznym mieszającym się z wodą. Transformację prowadzi się w temperaturze od 20 do 30 stopni Celsjusza, przy ciągłym wstrząsaniu, co najmniej 96 godzin. Kolejno produkt ekstrahuje się rozpuszczalnikiem organicznym niemieszającym się z wodą i oczyszcza chromatograficznie.The essence of the invention consists in introducing the Penicillium commune KCh W7 strain into a medium suitable for filamentous fungi. After at least 48 hours, the substrate is introduced into the culture, which is 33-hydroxyandrost-5-en-17-one of the formula I, dissolved in a water-miscible organic solvent. The transformation is carried out at a temperature of 20 to 30 degrees Celsius with continuous shaking for at least 96 hours. Subsequently, the product is extracted with a water-immiscible organic solvent and purified by chromatography.
Korzystnie jest, gdy stosunek masy dodawanego substratu do objętości hodowli wynosi 0,2 g : 1 L.Preferably, the ratio of the weight of the added substrate to the culture volume is 0.2 g: 1 L.
Korzystnie także jest, gdy proces prowadzi się w temperaturze 25 stopni Celsjusza.It is also preferred that the process is carried out at a temperature of 25 degrees Celsius.
Dodatkowo, korzystnie jest, gdy transformację prowadzi się przez 96 godzin.Additionally, it is preferred that the transformation is carried out for 96 hours.
Postępując zgodnie z wynalazkiem, w wyniku działania układu enzymatycznego zawartego w komórkach szczepu Penicillium commune KCh W7, następuje regioselektywna laktonizacja pierścienia D poprzedzona utlenieniem grupy hydroksylowej przy trzecim atomie węgla i izomeryzacją wiązania podwójnego z 5-en do 4-en. Uzyskany w ten sposób produkt wydziela się z wodnej kultury mikroorganizmu, znanym sposobem, przez ekstrakcję rozpuszczalnikiem organicznym niemieszającym się z wodą (chloroform).In accordance with the invention, as a result of the enzyme system contained in the cells of the Penicillium commune KCh W7 strain, regioselective lactonization of the D-ring takes place, preceded by oxidation of the hydroxyl group at the third carbon atom and isomerization of the 5-ene to 4-ene double bond. The product obtained in this way is separated from the aqueous culture of the microorganism by a known method by extraction with a water-immiscible organic solvent (chloroform).
Zasadniczą zaletą wynalazku jest otrzymanie 17a-oxa-D-homo-androst-4-en-3,17-dionu z wydajnością izolowaną na poziomie 75% (według GC > 85%), w temperaturze pokojowej i przy pH naturalnym dla szczepu.The main advantage of the invention is the preparation of 17a-oxa-D-homo-androst-4-ene-3,17-dione with an isolated yield of 75% (according to GC> 85%), at room temperature and pH natural for the strain.
Wynalazek jest bliżej objaśniony na przykładzie wykonania.The invention is explained in more detail using an exemplary embodiment.
PL 235 018 Β1PL 235 018 Β1
Metoda izolowania szczepu Penicillium commune KCh W7Method of isolating the strain Penicillium commune KCh W7
Próbkę gleby pobranej na Wyspa Słodowa - Wrocław, okolice Starego Miasta i Węzła Wodnego przeniesiono do sterylnej gilzy. Następnie w warunkach aseptycznych 1 g gleby rozpuszczono w 10 ml sterylnej wody. Pobrano 1 cm3 supernatantu i wykonano posiewy z kolejnych rozcieńczeń. Kolejnymi rozcieńczeniami badanego materiału zaszczepiono płytki agarowe (sterylne plastikowe płytki z 20 ml pożywki stałej o składzie: glukoza 3%, aminobak 1%, agar 0,8%). Z jednego z rozcieńczeń wyodrębniono czystą kulturę szczepu Penicillium commune KCh W7, który wykorzystano do biotransformacji. Wyodrębniony szczep przechowywany jest na skosach agarowych w temperaturze +4°C w kolekcji Katedry Chemii Uniwersytetu Przyrodniczego we Wrocławiu, ul. C.K. Norwida 25, 50-375 Wrocław.The soil sample collected at Słodowa Island - Wrocław, near the Old Town and the Water Junction was transferred to a sterile thimble. Then, under aseptic conditions, 1 g of the soil was dissolved in 10 ml of sterile water. 1 cm 3 of the supernatant was taken and inoculated from serial dilutions. The agar plates were inoculated with successive dilutions of the material to be tested (sterile plastic plates with 20 ml of solid medium with the following composition: glucose 3%, amino acid 1%, agar 0.8%). From one of the dilutions, a pure culture of Penicillium commune KCh W7 strain was isolated and used for biotransformation. The extracted strain is stored on agar slants at a temperature of + 4 ° C in the collection of the Department of Chemistry, University of Life Sciences in Wrocław, ul. CK Norwida 25, 50-375 Wrocław.
Szczep dostępny jest również w Katedrze Biotechnologii i Mikrobiologii Żywności, Uniwersytet Przyrodniczy we Wrocławiu, ul. J. Chełmońskiego 37, 51-630 Wrocław.The strain is also available at the Department of Food Biotechnology and Microbiology, Wrocław University of Environmental and Life Sciences, ul. J. Chełmońskiego 37, 51-630 Wrocław.
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 Penicillium commune KCh W7 o sekwencji 1. Po 72 godzinach jego wzrostu dodaje się 100 mg 33-hydroksyandrost-5-en-17-onu o wzorze 1, rozpuszczonego w 1 cm3 tetrahydrofuranu. Transformację prowadzi się w 25 stopniach Celsjusza przy ciągłym wstrząsaniu przez 6 dni. Następnie mieszaninę poreakcyjną ekstrahuje się trzykrotnie chloroformem, osusza bezwodnym siarczanem magnezu i odparowuje rozpuszczalnik. Otrzymany ekstrakt oczyszcza się chromatograficznie, używając jako eluentu mieszaniny heksanu i acetonu w stosunku objętościowym 2:1.Example 1. Penicillium commune KCh W7 strain of sequence 1 is introduced into an Erlenmajer flask with a capacity of 2000 cm 3 , containing 500 cm 3 of sterile medium containing 5 g of aminobac and 15 g of glucose. 100 mg of 33-hydroxyandrost-5-en-17-one of formula I, dissolved in 1 cm 3 of tetrahydrofuran, are obtained. The transformation is carried out at 25 degrees Celsius with continuous shaking for 6 days. The reaction mixture was then extracted three times with chloroform, dried with anhydrous magnesium sulfate and the solvent was evaporated. The extract obtained is purified by chromatography using a 2: 1 v / v mixture of hexane and acetone as eluent.
Na tej drodze otrzymuje się 75,0 mg 17a-oxa-D-homo-androst-4-en-3,17-dionu (wydajność 75%, według GC > 85%).In this way, 75.0 mg of 17a-oxa-D-homo-androst-4-ene-3,17-dione are obtained (yield 75%, according to GC> 85%).
Uzyskany produkt charakteryzuje się następującymi danymi spektralnymi:The obtained product is characterized by the following spectral data:
1H NMR (600MHz) (ppm) (CDCb) δ: 1.03-1.15 (m, 2H, 7-Hoc, 9-H); 1.14 (s, 3H, 18-H); 1.26-1.32 (m, 1H, 11-Ηβ); 1.32 (s, 3H, 19-H); 1.36-1.43 (m, 2H, 8-H, 14-H); 1.48-1.57 (m, 1H, 15-Ηβ); 1.64 (td, 1H, J = 13.3, 4.2 Hz, 12-Haa); 1.70 (td, 1H, J = 13.9, 5.0 Hz, 1-Ha); 1.77 (dq, J = 13.6, 3.7 Hz, 1H, 11-Ha); 1.96-2.05 (m, 4H, 1-Ηβ, 7-Ηβ, 12-Ηβ, 15-Ha); 2.27-2.36 (m, 3H, 2-Ha, 6-Ha, 6-Ηβ); 2.40 (ddd, 1H, J= 17.0, 14.4, 5.1 Hz, 2-Ηβ); 2.56 (dt, 1H, J= 18.8, 9.1 Hz, 16-Ha); 2.67 (ddd, 1H, J= 19.0, 8.8, 1 H NMR (600MHz) (ppm) (CDCl) δ: 1.03-1.15 (m, 2H, 7-Hoc, 9 H); 1.14 (s, 3H, 18-H); 1.26-1.32 (m, 1H, 11-Ηβ); 1.32 (s, 3H, 19-H); 1.36-1.43 (m, 2H, 8-H, 14-H); 1.48-1.57 (m, 1H, 15-Ηβ); 1.64 (td, 1H, J = 13.3, 4.2 Hz, 12-Haa); 1.70 (td, 1H, J = 13.9, 5.0 Hz, 1-Ha); 1.77 (dq, J = 13.6, 3.7 Hz, 1H, 11-Ha); 1.96-2.05 (m, 4H, 1-Ηβ, 7-Ηβ, 12-Ηβ, 15-Ha); 2.27-2.36 (m, 3H, 2-Ha, 6-Ha, 6-Ηβ); 2.40 (ddd, 1H, J = 17.0, 14.4, 5.1 Hz, 2-Ηβ); 2.56 (dt, 1H, J = 18.8, 9.1 Hz, 16-Ha); 2.67 (ddd, 1H, J = 19.0, 8.8,
2.2 Hz, 16-Ηβ); 5.72 (brs, 1H.4-H);2.2 Hz, 16-Ηβ); 5.72 (br s, 1H. 4-H);
13C NMR (151MHz) (ppm) (CDCb) δ: 17,40 (C-18), 19,82 (C-15), 20,11 (C-19), 21,82 (C-11), 28,53 (C-16), 30,37 (C-7), 32,35 (C-6), 33,84 (C-2), 35,46 (C-1), 37,92 (C-8), 38,46 (C-10), 38,93 (C-12), 45,62 (C-14), 52,45 (C-9), 82,87 (C-13), 124,07 (C-4), 169,63 (C-5), 171,44 (C-17), 199,40 (C-3). 13 C NMR (151MHz) (ppm) (CDCb) δ: 17.40 (C-18), 19.82 (C-15), 20.11 (C-19), 21.82 (C-11), 28.53 (C-16), 30.37 (C-7), 32.35 (C-6), 33.84 (C-2), 35.46 (C-1), 37.92 (C -8), 38.46 (C-10), 38.93 (C-12), 45.62 (C-14), 52.45 (C-9), 82.87 (C-13), 124 . 07 (C-4), 169.63 (C-5), 171.44 (C-17), 199.40 (C-3).
CTGATCGAGGTCACCTGGATAAAAATTTGGGTTGATCGGCAAGCGCCGGCC GGGCCTACAGAGCGGGTGACAAAGCCCCATACGCTCGAGGACCGGACGCG GTGCCGCCGCTGCCTTTCGGGCCCGTCCCCCGGGATCGGAGGACGGGGC CCAACACACAAGCCGTGCTTGAGGGCAGCAATGACGCTCGGACAGGCATG CCCCCCGGAATACCAGGGGGCGCAATGTGCGTTCAAAGACTCGATGATTCA CTGAATTTGCAATTCACATTACGTATCGCATTTCGCTGCGTTCTTCATCGATG CCGGAACCAAGAGATCCGTTGTTGAAAGTTTTAAATAATTTATATTTTCACTC AGACTACAATCTTCAGACAGAGTTCGAGGGTGTCTTCGGCGGGCGCGGGC CCGGGGGCGTAAGCCCCCCGGCGGCCAGTTAAGGCGGGCCCGCCGAAGC AACAAGGTAAAATAAACACGGGTGGGAGGTTGGACCCAGAGGCTGATCGAGGTCACCTGGATAAAAATTTGGGTTGATCGGCAAGCGCCGGCC GGGCCTACAGAGCGGGTGACAAAGCCCCATACGCTCGAGGACCGGACGCG GTGCCGCCGCTGCCTTTCGGGCCCGTCCCCCGGGATCGGAGGACGGGGC CCAACACACAAGCCGTGCTTGAGGGCAGCAATGACGCTCGGACAGGCATG CCCCCCGGAATACCAGGGGGCGCAATGTGCGTTCAAAGACTCGATGATTCA CTGAATTTGCAATTCACATTACGTATCGCATTTCGCTGCGTTCTTCATCGATG CCGGAACCAAGAGATCCGTTGTTGAAAGTTTTAAATAATTTATATTTTCACTC AGACTACAATCTTCAGACAGAGTTCGAGGGTGTCTTCGGCGGGCGCGGGC CCGGGGGCGTAAGCCCCCCGGCGGCCAGTTAAGGCGGGCCCGCCGAAGC AACAAGGTAAAATAAACACGGGTGGGAGGTTGGACCCAGAGG
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