Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes

Vicinal fluorocyclopentanol are valuable chiral synthetic blocks for the preparation of a number of natural and synthetic biologically active substances Racemic cis-2-fluorocyclopentanols were separated into enantiomers by the kinetically controlled transesterification with vinyl acetate in the pr...

Повний опис

Збережено в:

Бібліографічні деталі
Дата:	2019
Автори:	Kolodiazhna, O.O., Veriovka, O.S., Kolodiazhna, A.O.
Формат:	Стаття
Мова:	English
Опубліковано:	Видавничий дім "Академперіодика" НАН України 2019
Назва видання:	Доповіді НАН України
Теми:	Хімія
Онлайн доступ:	http://dspace.nbuv.gov.ua/handle/123456789/159960
Теги:	Додати тег Немає тегів, Будьте першим, хто поставить тег для цього запису!
Назва журналу:	Digital Library of Periodicals of National Academy of Sciences of Ukraine
Цитувати:	Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes / O.O. Kolodiazhna, O.S. Veriovka, A.O. Kolodiazhna // Доповіді Національної академії наук України. — 2019. — № 7. — С. 66-74. — Бібліогр.: 13 назв. — англ.

Репозитарії

Digital Library of Periodicals of National Academy of Sciences of Ukraine

id	irk-123456789-159960
record_format	dspace
spelling	irk-123456789-1599602019-10-20T01:25:48Z Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes Kolodiazhna, O.O. Veriovka, O.S. Kolodiazhna, A.O. Хімія Vicinal fluorocyclopentanol are valuable chiral synthetic blocks for the preparation of a number of natural and synthetic biologically active substances Racemic cis-2-fluorocyclopentanols were separated into enantiomers by the kinetically controlled transesterification with vinyl acetate in the presence of lipases in organic media, High enantioselectivity (ee > 98 %) and good yields of compounds were obtained for all substrates using Burkholderia cepacia lipase, The fluorocyclopentanols were converted into enantiomerically pure 1,2-aminofluorocyclopentanes using the Mitsunobu reaction, The enantiomeric purity of the compounds was determined by Mosher's acid derivatization method, and the absolute configurations were determined using the Kazlauskas rule. Віцинальні фтороциклопентаноли є цінними хіральними синтетичними блоками для отримання ряду природних і синтетичних біологічно активних речовин. Ці сполуки використовують у синтезі різних біологічно активних сполук, зокрема простагландинів і прекурсорів лейкотрієнів. Для поділу рацемічних 2-фторгідринів були використані кілька високоефективних ліпаз, які в попередніх дослідженнях показали високу ефективність на багатьох реакціях переетерифікації в органічних розчинниках. Вінілацетат або ізопропіліден ацетат використовували як ацетилюючі агенти. Рацемічні цис-2-фторциклоалканоли були розділені на енантіомери в результаті кінетично контрольованої переестерифікації вінілацетату в присутності біокаталізаторів. Високу енантіоселективність (ee > 98 %) і хороший вихід отримано для всіх субстратів з використанням ліпази Burkholderia cepacia. Фторциклоалканоли перетворили в енантіомерно чисті 1,2-амінофторциклоалкани з використанням реакції Mіцунобу. Реакція відбувалася з інверсією абсолютної конфігурації на атомі вуглецю, що містить гідроксильну групу. Енантіомерну чистоту сполук визначено методом дериватизації кислотою Mошера, а абсолютну конфігурацію встановлено за методом Казлаускаса. Згідно з правилом Казлаускаса, біокаталітичне ацетилювання 2-фторциклопентанолів повинно бути (R)-селективним. Таким чином, енантіоселективність на рівні ee > 98 % і вихід на рівні 90 % отримано для всіх субстратів. Вицинальные фтороциклопентанолы являются ценными хиральными синтетическими блоками для получения ряда природных и синтетических биологически активных веществ. Эти соединения используются в синтезе различных биологически активных соединений, в частности простагландинов и прекурсоров лейкотриенов. Для разделения рацемических 2-фторгидринов были использованы несколько высокоэффективных липаз, которые в предыдущих исследованиях показали высокую эффективность на многих реакциях переэтерификации в органических растворителях. Винилацетат или изопропилиден ацетат использовали в качестве ацилирующих агентов. Рацемические цис-2-фторциклоалканолы были разделены на энантиомеры в результате кинетически контролируемой переэтерификации винилацетатом в присутствии биокатализаторов. Высокая энантиоселективность (ee > 98 %) и хороший выход получены для всех субстратов с использованием липазы Burkholderia cepacia. Фторциклоалканолы превратили в энантиомерно чистые 1,2-аминофторциклоалканы с использованием реакции Mицунобу. Реакция протекала с инверсией абсолютной конфигурации на атоме углерода, содержащего гидроксильную группу. Энантиомерная чистота соединений определена методом дериватизации кислотой Mошера, а абсолютная конфигурация установлена по методу Казлаускаса. Согласно правилу Казлаускаса, биокаталитическое ацетилирование 2-фторциклопентанолов 1,4 должно быть (R)-селективным. Таким образом, энантиоселективность на уровне ee > 98 % и выход соединений на уровне 90 % получены для всех субстратов. 2019 Article Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes / O.O. Kolodiazhna, O.S. Veriovka, A.O. Kolodiazhna // Доповіді Національної академії наук України. — 2019. — № 7. — С. 66-74. — Бібліогр.: 13 назв. — англ. 1025-6415 DOI: doi.org/10.15407/dopovidi2019.07.066 http://dspace.nbuv.gov.ua/handle/123456789/159960 547.783 en Доповіді НАН України Видавничий дім "Академперіодика" НАН України
institution	Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection	DSpace DC
language	English
topic	Хімія Хімія
spellingShingle	Хімія Хімія Kolodiazhna, O.O. Veriovka, O.S. Kolodiazhna, A.O. Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes Доповіді НАН України
description	Vicinal fluorocyclopentanol are valuable chiral synthetic blocks for the preparation of a number of natural and synthetic biologically active substances Racemic cis-2-fluorocyclopentanols were separated into enantiomers by the kinetically controlled transesterification with vinyl acetate in the presence of lipases in organic media, High enantioselectivity (ee > 98 %) and good yields of compounds were obtained for all substrates using Burkholderia cepacia lipase, The fluorocyclopentanols were converted into enantiomerically pure 1,2-aminofluorocyclopentanes using the Mitsunobu reaction, The enantiomeric purity of the compounds was determined by Mosher's acid derivatization method, and the absolute configurations were determined using the Kazlauskas rule.
format	Article
author	Kolodiazhna, O.O. Veriovka, O.S. Kolodiazhna, A.O.
author_facet	Kolodiazhna, O.O. Veriovka, O.S. Kolodiazhna, A.O.
author_sort	Kolodiazhna, O.O.
title	Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes
title_short	Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes
title_full	Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes
title_fullStr	Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes
title_full_unstemmed	Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes
title_sort	enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes
publisher	Видавничий дім "Академперіодика" НАН України
publishDate	2019
topic_facet	Хімія
url	http://dspace.nbuv.gov.ua/handle/123456789/159960
citation_txt	Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes / O.O. Kolodiazhna, O.S. Veriovka, A.O. Kolodiazhna // Доповіді Національної академії наук України. — 2019. — № 7. — С. 66-74. — Бібліогр.: 13 назв. — англ.
series	Доповіді НАН України
work_keys_str_mv	AT kolodiazhnaoo enzymaticsynthesisofenantiomericallypure12fluorocyclopentanolsand12aminofluorocyclopentanes AT veriovkaos enzymaticsynthesisofenantiomericallypure12fluorocyclopentanolsand12aminofluorocyclopentanes AT kolodiazhnaao enzymaticsynthesisofenantiomericallypure12fluorocyclopentanolsand12aminofluorocyclopentanes
first_indexed	2025-07-14T12:32:40Z
last_indexed	2025-07-14T12:32:40Z
_version_	1837625623528341504
fulltext	66 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2019. № 7 Vicinal fluorocyclopentanol are valuable chiral synthetic blocks for the preparation of a number of natural and synthetic biologically active substances [1]. These compounds are used to prepare various biologically active compounds, in particular, prostaglandins and precursors of leukot- rienes [1—4]. 2-Fluorocyclopentanols can be converted to prostaglandin F2a precursors, while 2-substituted cyclopentanols are the starting compounds for the preparation of L7 leukotriene B4, a conformationally restricted leukotriene antagonist used in the enantioselective general syn- thesis of (+)-Estron and Desogestrel [5]. Previously, we reported on the biocatalytic method for the synthesis of chiral halogencyclopentanols and halogenocyclopentanols, which were obtained by the chemoenzymatic transesterification of 2-halogencyclopentanols [6] (Scheme 1). Scheme 1 © O.O. Kolodiazhna, O.S. Veriovka, A.O. Kolodiazhna, 2019 https://doi.org/10.15407/dopovidi2019.07.066 UDC 547.783 O.O. Kolodiazhna, O.S. Veriovka, A.O. Kolodiazhna V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv E-mail: oikol123@bpci.kiev.ua Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes Presented by Corresponding Member of the NAS of Ukraine O.I. Kolodiazhnyi Vicinal fluorocyclopentanol are valuable chiral synthetic blocks for the preparation of a number of natural and syn- thetic biologically active substances Racemic cis-2-fluorocyclopentanols were separated into enantiomers by the ki- netically controlled transesterification with vinyl acetate in the presence of lipases in organic media, High enantiose- lectivity (ee > 98 %) and good yields of compounds were obtained for all substrates using Burkholderia cepacia lipase, The fluorocyclopentanols were converted into enantiomerically pure 1,2-aminofluorocyclopentanes using the Mitsunobu reaction, The enantiomeric purity of the compounds was determined by Mosher's acid derivatization method, and the absolute configurations were determined using the Kazlauskas rule. Keywords: stereochemistry, biocatalysis, lipase Burkholderia cepacia, fluorocyclopentanols, aminofluorocyclopen- tanes, Kazlauskas rule. 67ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2019. № 7 Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes In the present work, we continued these studies using fluorocyclopentanols to synthesize new important synthetic blocks of biologically active compounds. First of all, we focused on the synthesis of enantiomerically pure aminofluorocyclopentane 2, which we planned to obtain from the 1,2-fluorocyclopentanole 1 (Scheme 2). Scheme 2 Results and discussion. Synthesis of starting compounds. The stereoisomers of 1,2-fluoro- cyclopentanols were synthesized from cyclopentane epoxides 3 [7]. With this end, the mixture of epoxide and triethylamine hydrofluoride was heated at 80 °C for several hours. As a result, a ra- cemic mixture of trans-2-fluorocyclopentanol 1 without impurities of cis-isomer 4 was obtained in high yield (Scheme 3). In the next step of the synthesis, trans-2-fluorocyclopentanols 1 was converted into racemic cis-2-fluorocyclopentanols 4. For this, the compound trans-1 was oxidized using the Swern meth- odology and treated at –80 °C with a mixture of dimethyl sulfoxide and oxalyl chloride for 1 h. Then it was treated with triethylamine, resulting in the formation of 2-fluorocyclopentanone 3 in high yield, 2-fluorocyclopentanone 3 was then reduced by triisobutylborane in THF to form ra- cemic cis-2-fluorocyclopentanols. The analysis of NMR spectra of reaction mixtures showed that cis-2-fluoro-fluorocyclopentanol 4 contained minor impurities of trans-isomer 1 (Scheme 3). Scheme 3 In addition, racemic trans-2-fluorocyclopentanol 1 was oxidized by the Johns method. As a result, 2-fluorocyclopentanone 4 was obtained in good yields. The ketones 3 were reduced by sodium borohydride in methanol, triisobutylborane in THF and H-Dibal. Recovery of 2-fluo- rocyclopentanon 3 with sodium borohydride in methanol yielded a mixture of cis- and trans-iso- mers in the ratio of 70 : 30. The reduction with triisobutylborane gave the diastereomers in the ratio of 75 : 25, and the reduction with H-Dibal resulted in the diastereomeric ratio of 55 : 45. The diastereomers were separated by column chromatography. Resolution of 2-fluorocyclopentanols. Previously, chiral cis-2-fluorocyclopentanols 4 were not obtained, although the racemic isomers of 2-fluorocyclopentanols, as well as 2-fluorocyclopen- tanols, were described as the mixtures of cis- and trans- isomers [8, 9]. 68 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2019. № 7 O.O. Kolodiazhna, O.S. Veriovka, A.O. Kolodiazhna For the resolution of racemic 2-fluorohydrins 4, we used several highly effective lipases, which were earlier used and showed the high effectivity on a number of transesterification reactions in organic solvents. Vinyl acetate or isopropylidene acetate were used as acylating agents. We have tested Candida Antarctica (CAL-B), Pseudomonas cepacia (PCL), and Bur hol deria cepacia (BCL) lipases as biocatalysts. The best results (the highest ee) were obtained with BCL, and, therefore, we chose this lipase. The enzymatic esterification with vinyl acetate in the presence of BCL re- sulted in the resolution of racemic cis-fluoro-cyclopentanols into enantiomerically pure, optically active stereoisomers. The esterification was performed at room temperature until the conversion attained 50 %. In all cases, the high enantiomeric excesses (ee’s) were obtained. After the column chromatography, optically active alcohols and acetates were obtained with an optical purity of 98—99 % ee. Acetates 5 were hydrolyzed in a phosphate buffer at pH 7.2 in the presence of PCL lipase. As a result of hydrolysis, optically pure acetates 5 were obtained in contrast to the unreacted alcohols of the opposite configuration. Transesterification with vinyl acetate proceeded for 6—12 h until the 50 % conversion into acetates 5, 6. One of the enantiomers in the racemic mixture reacted and turned into acetate, and the second enantiomer did not react with vinyl acetate. The optical purity of the acylated pro- ducts was determined by the derivatization with (R)- or (S)-methoxy-trifluoromethylpheny la- cetic acid (Mosher’s acid) according to the established protocol. For (S)-acetate, the achievement of 50 % conversion by the enzymatic acylation was established by analyzing the 1H NMR spectra of the enzymatic separation esters. As a result of the enzymatic resolution and subsequent chro- matography, optically active (—)-(1R, 2S)-fluorocyclopentanols and (—)-(1R,2R)-acetates with an optical purity of 98-99 % were obtained. The acetates were purified by the distillation in vacuo and then hydrolyzed in a phosphate buffer at pH 7.2 in the presence of BCL. As a result of the hydrolysis, optically pure (+)-(1R,2S) and (—)-(1R,2R)-fluorocyclopentanols were obtained. The additional low-temperature crys tal- lization of fluorocyclopentanols 4 in pentane allowed the preparation of optically pure alco hols (+)-(1R, 2S)-4 and (—)-(1R,2R)-4, which was established by the derivatization of the compounds with Mosher’s acid. Similarly, the acylation of racemic trans-cyclopentanol with vinyl acetate in the presence of BCL under kinetically controlled conditions (50 % conversion of the α-fluoro- cyclopentanol) led to the formation of (—)-(1R,2S)-alcohol and (+)-(1R,2R)-acetate, which were purified by chromatography. The hydrolysis of (+)-(1R,2R) acetate 5 in a phosphate buffer at pH 7.2 gave the second stereoisomer of trans-cyclopentanol (+)-(1R,2R)-1 with high optical purity. Optically pure 2-fluorocyclopentanols are colorless low-melting substances that are stable at room temperature or in the refrigerator. No racemization during the processing and storage was observed. The structure of the compounds was confirmed by spectroscopic studies. The NMR spectra allow us to easily identify the cis- and trans-isomers. For example, in the 1H NMR spectra of cis-isomers, the signal of CHX protons was displaced to the weak field (Scheme 4). We have used fluorocyclopentanols synthesized for the synthesis of aminofluorocyclo pen- tanes of considerable interest as key reagents in the synthesis of a number of important biologi- cally active compounds. Optically pure 1,2-fluorocyclopentanols were converted into 2-fluorine aminocyclopentanes by the Mitsunobu reaction. The reaction proceeded with the inversion of the absolute configu- ration containing a hydroxyl group at the carbon atom. For the production of aminofluoro- 69ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2019. № 7 Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes cyclopentanes, cis-(1R,2R)-fluorocyclopentanol 4 was dissolved in tetrahydrofuran and triphe- nylphosphine and phthalimide were added to the solution. After the cooling to 0 °C, diethyl azodicarboxylate (DEAD) was added, and the reaction mixture was stirred overnight at room temperature. Upon the completion of the reaction, the solvent was evaporated. 2-((1R,2S)-2- fluorocyclopentyl)isoindoline-1,3-diones 7, 9 were purified by column chromatography. As a result, (S,R)-phthalimide was obtained in 70 % yield. Then phthalimides 7, 9 were hydrolyzed with 6N hydrochloric acid to result in hydrochloride (S,R)-cyclopentylfluoramine 8 and hyd- rochloride (R,S)-cyclopentylfluoramine 10. The optical purity was controlled by Mosher’s acid derivatization method [10]. The products 7, 9 were then treated with hydrochloric acid to form aminofluorocyclopen- tane hydrochlorides 8, 10. As a result, trans-1,2-fluorocyclopentanol 1 was converted into the cis-1,2-aminofluorocyclopentanes 8, 10. Pure products with an enantiomeric excess of 95 % were obtained (Scheme 5). Scheme 4 Scheme 5 + 70 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2019. № 7 O.O. Kolodiazhna, O.S. Veriovka, A.O. Kolodiazhna The Kazlauskas rule [11] was used to determine the absolute stereochemistry of enantio- merically pure products. The Kazlauskas rule is an empirical model based on the postulate that the enantioselectivity is proportional to the difference in size between large (L) and middle (M) substituents in the substrate. According to the Kazlauskas rule, these substitutes are located in two different pockets of the active site of an enzyme, according to their size, which determines the absolute configuration of the products in the enzymatic reaction. According to the Kazlauskas rule, the biocatalytic acetylation of 2-fluorocyclopentanoles 1, 4 should be (R)-selective. Con- sequently, the biocatalytic transesterification of cyclopentanols should lead to the formation of (1R, 2S)-acetates 5 and (1S, 2R)-2-fluorocyclopentanoles 4. So in this work, racemic cis-2-fluorocyclopentanols were resolved into enantiomers by the kinetically controlled biocatalytic transesterification with vinyl acetate in the presence of Bur- kholderia cepacia lipase in organic media. The high enantioselectivity (ee > 98 %) and good yields of compounds were obtained for all substrates. Fluorocyclopentanols were converted into enan- tiomerically pure 1,2-aminofluorocyclopentanes using the Mitsunobu reaction. The enantiome- ric purity of the compounds was determined by Mosher’s acid derivatization method, and the absolute configurations were determined using the Kazlauskas rule [12, 13]. Experimental Part. 1H NMR and 13C NMR spectra were recorded in a CDCl3 solvent on a 500 MHz spectrometer at ambient temperature. The chemical shifts (δ) are given in ppm with respect to TMS as the internal standard. Signals: s, singlet; d, doublet; dd, doublet of doublet; td, triplet of doublets; t, triplet; m, multiplet; br s, broad singlet. The constants of connection J are given in Hertz. All reagents and solvents were purchased from commercial firms and used wi- thout special purification, unless otherwise specified. Column chromatography was performed on silica gel 60 (70—230 mesh) using the indicated eluents. Optical rotations were measured on the Perkin-Elmer 241 polarimeter (sodium D line at 20 °C). Melting points are not corrected. All reactions were carried out in a carefully dried glass dish. Lipase isolated from Burkholderia cepacia (Amano PS) was purchased from Amano Pharmaceutical (Japan). Progression of the reactions and separation of the products by column chromatography were monitored by analy- tical thin layer chromatography (silica gel 60 F254-plate-Merck, Darmstadt, Germany), and the products were visualized with anisaldehyde. The purity of all compounds was verified using NMR measurements. Rac-trans-2-fluorocyclopentanol (1). To 6.00 ml (5.78 g, 0.069 moles) of cyclopenten oxide in 70 ml of 1.0 M triethylamine trihydrofluoride, we added 20 ml of poly(hydrogen fluoride) pyri- dinium slowly via a polypropylene syringe, at 0 °C at the magnetic stirring, The mixture was left warmed to room temperature and then stirred for 3 h, The consecutive treatment with water, diethyl ether extraction, washing with aqueous sodium hydrogen carbonate, drying with anhy- drous magnesium sulfate, and concentrating on a rotary evaporator gave an oil, which was puri- fied by the distillation in vacuo Yield 3.65 g (50 %), bp 55—57 °C (20 mmHg). 1Н NMR(300 MHz, CDC13): δH 1.3—2.00 (m, 6 H), 3.25 (br s, 1 H), 4.30 (d,m, J 14, 1 H), 4.90 (ddt, J 52.0, J 8.4 and J 2.8, 1H). 13C NMR (75.4 MHz, CDCl,), δc: 19.7 (d, J 1.7), 29.0 (d, J 21.54), 31.2 (d, J 1.7), 77.0 (d, J 27.2), 98.9 (d, J 177). NMR 19F, δF-185 ppm. Found, %: C 57.35; H 8.78, C5H9FO, Calculated, %: C 57.68; H 8.71. 71ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2019. № 7 Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes Rac-2-fluorocyclopentanone (3). 3.6 ml (50 mmol) of DMSO in 10 ml of methylene chloride at –70 °C was added dropwise to a solution of oxalyl chloride (2.9 g, 23 mmol) in 40 ml of me- thylene chloride. Trans-2-fluorocyclopentanol (20 mmol) was added at the same temperature, and the reaction mixture was stirred for 20 min. The temperature was then raised to –55 °C, and 16 ml of triethylamine was added. The reaction mixture was stirred for 20 min, warmed to 0 °C, and poured into a 1 M aqueous solution of hydrochloric acid, The aqueous phase was separated and extracted with methylene chloride, the combined extractes were washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off at the atmospheric pressure with an effective column. Synthesis of rac-cis-fluorocyclopentanols (4). To fluorocyclopentanone 3 (10 mmol) in 50 ml of methanol, we added sodium borohydride (0.12 mol) at 0 °C, and the reaction mixture was stirred for 2 h at room temperature. Next, NH4Cl (11 mmol) was added and the reaction mix- ture was stirred for 0.5 h, filtered off, evaporated under reduced pressure, and the residue was extracted with methylene chloride. The extract was then dried over Na2SO4. The solvent was removed under reduced pressure and the residue was distilled under vacuum. The yield 70 %, bp 55 °C (15mm Hg). 1H NMR (500 MHz, CDCl3): δ 1.25–1.35 (m, 2H, CH2), 1.5–1.70 (m, 5H, CH2CH2), 2.0–2.1 (m, 1H, CH2), 2.4 (br, 1 H), OH), 3.78 (d, 1H, J = 5, CHOH), 4.69 (dd, JH, F = 40 Hz, J = 3 Hz, 1H, CHF). 13C NMR (125.74 MHz, CDCl3): 20.90 с, 22.00 с, 28.50 с, 30.10 с, 70.0 с, 92.87. Chiral-1,2-fluorocyclopentanols. (1R, 2R)-2-Fluorocyclopentanol-1 (1R, 2R)-1. Racemic alcohol 1 (10 mmol) was dissolved in MTBE, vinyl acetate (30 mmol) was added as an acy- lating agent. Then the Amano PS (0.1 eq) was added, and the reaction mixture was stirred over- night at room temperature. The course of the reaction was monitored by NMR. When the reac- tion was completed, the lipase was filtered off, and the solvent was evaporated. The residue (mix- ture of cyclopentanol and acetate) was separated by column chromatography. Optical purity was controlled by Mosher’s acid derivatization. (1R,2R)-2-Fluorocyclopentyl acetate 5: Yield 45 %. (1S, 2S)-2-Fluorocyclopentanol-1 1, Yield 45 %, [α]D 20 = +12 (CHCl3). (1S,2S)- Fluorocyclopentane-1-ol (1S, 2S) -1. Racemic alcohol obtained in the previous step (1 eq) was dissolved in MTBE and vinyl acetate (3 eq) as an acylating agent and Amano PS lipase (0,1 eq) as a biocatalyst were added. The reaction mixture was stirred at room tempera- ture for 12—14 h. The reaction was monitored by NMR. When the reaction was completed, the lipase was filtered off, and the solvent was evaporated. The residue (mixture of alcohol and acetate) was separated by column chromatography. Optical purity of the product was established by the Mosher acid derivatization. (1S,2S)-Flurocyclopentanol: Yield 45 %, [α]D 20 = +11 (CHCl3). (1R,2R)-2-Fluorocyclopentyl acetate: Yield 45 %. (1R,2R)-2-Fluorocyclopentyl acetate (10 mmol) was dissolved in MTBE, phosphate buffer (0.05 M, pH = 7.2). Novozyme 435 (0.2 eq) was added, and the reaction mixture was stir- red at room temperature for 14 h. The course of the reaction was monitored by NMR. When the reaction was completed, the lipase was filtered off. The organic phase was separated from the water phase. The water phase was extracted 2 times with MTBE. The combined organic extracts 72 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2019. № 7 O.O. Kolodiazhna, O.S. Veriovka, A.O. Kolodiazhna were dried over sodium sulfate and evaporated. Optical purity was determined by the Mosher acid derivatization, The yield of (R, R)-alcohol was 95 %, [α]D 20 = –5.5 (CHCl3). (1S, 2S)-2-Fluorocyclopentanol, [α]D 22 = +10.3 (CHCl3, c = 1.1). Spectral data correspond to the literature data [6]. ((1R, 2S)-2-Fluorocyclopentyl) isoindolyl-1,3-dione. (1R, 2R)-Fluorocyclopentan-1-ol (0.02 mol) was dissolved in absolute THF. Triphenylphosphine (0.024 mol) and phthalimide (0.02 mol) were added to the solution. Then the DEAD was added to the reaction mixture at the cooling with an ice-water bath, and the mixture was stirred overnight at room temperature. When the reaction was completed, the solvent was evaporated, and the the residue was purified by co- lumn chromatography, The yield of (S, R)-phthalimide is 70 %. 1H NMR (500 MHz, CDCl3): δH 1.75 (m, 2H, CH2), 1.90 (m, 2H, CH2CH2), 2.6—2.8 (m, 2H, CH2), 4.5 (d,m, 1H, J = 5, CHOH), 5.2 (d,m, JH, F = 50 Hz, 1H, CHF), 7.83; 7.91 (C6H4). (1R,2S)-1-Amino-2-fluorocyclopentane). ((1R,2S)-2-Fluorocyclopentyl) isoindolyl-1,3-di- one was dissolved in 6N hydrochloric acid and refluxed for 5 h. When the reaction was com- pleted, the precipitate (phthalic acid) was filtered off. The solvent was evaporated. In the residue, pure (1S,2R)-fluorocyclopentylphenamine hydrochloride was found. The optical purity of the product was determined by Mosher’s acid derivatization. Yield of 90 %, ee = 95 %, [α]D 20 = –9.98 (C = 0.1, Ethanol). Optical purity was controlled by Mosher’s acid derivatization method. 1H NMR (DMSO-D6), δ, ppm, ( J, Hz): δH 1.9 m (2H, CH2); 1.95 m (2H, CH2); 2.3 m (2H, CH2); 3.2 m (2H, CH2); 4.5 m (CHNH2, 1H); 5.0 d (JHF 55, CHF); 6.78 c (2H, NH3 +). 13C NMR (125.74 MHz, CDCl3): δC: 19.90 с, 28.00 с, 30.50 с, 31.10 с, 77.0 d J 28, 98.0 d J 180 (C-F). 19F NMR, δF -190 ppm. Found, %: C 43.45; H 8.21. C5H11ClFN. Calculated, %: C, 43.02; H, 7.94. REFERENCES 1. Eliel, E. L., Wilen, S. H.& Mander, L. N. (1994). Stereochemistry of organic compounds. Wiley: New York. 2. Sate, T., Gotoh, Y., Watanabe, M. & Fujisawa, T. (1983). Stereoselective total synthesis of (4s)-trans-β- elemenone from (S)-2-cyclopenten-1-ol. Chem. Lett., No. 10, pp. 1533-1536. https://doi.org/10,1246/ cl,1983,1533 3. Hayes, R. & Wallace, T. W. (1990). A simple route to methyl 5S-(benzoyloxy)-6-oxopentanoate, a key inter- mediate in leukotriene synthesis. Tetrahedron Lett., 31, No. 10, pp. 3355-3356. https://doi.org/10.1016/ S0040-4039(00)89063-2 4. Sabol, J. S. & Cregge, R. J. (1989). Conformationally restricted leukotriene antagonists. Asymmetric synthe- sis of some nor-leukotriene D4 analogs, Tetrahedron Lett., 30, No. 26, 3377. https://doi.org/10,1016/S0040- 4039(00)99249-9 5. Hu, Q.-Y., Rege, P. D. & Corey, E. J. (2004). Simple, catalytic enantioselective syntheses of estrone and des- ogestrel. J. Am. Chem. Soc., 126, No. 19, pp. 5984-5986. https://doi.org/10,1021/ja048808x 6. Kolodiazhna, O. O., Kolodiazhna, A. O. & Kolodiazhnyi, O. I. (2013). Enzymatic preparation of (1S,2R)- and (1R,2S)-stereoisomers of 2-halocyclopentanols. Tetrahedron: Asymmetry, 24, No. 1, pp. 37-42. https://doi. org/10.1016/ j.tetasy.2012.11.011 7. Haufe, G. & Bruns, S. (2002). (Salen)chromium complex mediated asymmetric ring opening of meso- and racemic epoxides with different fluoride sources. Adv. Synth. Catal., 344, No. 2, pp. 165-171. https://doi. org/10.1002/1615-4169(200202)344:2<165:AID-ADSC165>3,0,CO;2-1 8. Wolker, D. & Haufe, G. (2002). Synthesis of optically active vicinal fluorohydrins by lipase-catalyzed dera- cemization. J. Org. Chem., 67, No. 9, pp. 3015-3021. https://doi.org/10.1021/jo016331r 73ISSN 1025-6415. Допов. Нац. акад. наук Укр. 2019. № 7 Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes 9. Honig, H. & Seufer-Wasserthal, P. (1990). General method for the separation of enantiomeric trans-2-substi- tuted cyclopentanols. Synthesis, No. 12, pp. 1137-1140. https://doi.org/10.1055/s-1990-27115 10. Dale, J. A. & Mosher, H. S. (1973). Nuclear magnetic resonance enantiomer regents, Configurational correla- tions via nuclear magnetic resonance chemical shifts of diastereomeric mandelate. O-methylmandelate, and alpha,-methoxy-alpha-trifluoromethylphenylacetate (MTPA) esters. J. Am. Chem. Soc., 95, No. 2, pp. 512- 519. https://doi.org/10.1021/ja00783a034 11. Kazlauskas, R. J., Weissfloch, A., N. E., Rappaport, A. T. & Cuccia, L. A. (1991). A rule to predict which enan- tiomer of a secondary alcohol reacts faster in reactions catalyzed by cholesterol esterase, lipase from Pseudomonas cepacia, and lipase from Candida rugose. J. Org. Chem., 56, No. 10, pp. 2656-2665. https://doi. org/10.1021/jo00008a016 12. Parker, D. (1991). NMR determination of enantiomeric purity. Chem. Rev., 91, 7, pp. 1441-1457. https:// pubs.acs.org/doi/10.1021/cr00007a009 13. Ohtani, I., Kusumi, T., Kashman, Y. & Kakisawa, H. (1991). High-field FT NMR application of Mosher’s method. The absolute configurations of marine terpenoids. J. Am. Chem. Soc., 113, No. 11, pp. 4092-4096. https://doi.org/10,1021/ja00011a006 Received 14.03.2019 O.O. Колодяжна, О.С. Верьовка, А.O. Колодяжна Інститут біоорганічної хімії та нафтохімії НАН України ім. В.П. Кухаря, Київ E-mail: oikol123@bpci.kiev.ua ФЕРМЕНТАТИВНИЙ СИНТЕЗ ЕНАНТІОМЕРНО ЧИСТИХ 1,2-ФТОРЦИКЛОАЛКАНОЛІВ І 1,2-АМІНОФТОРЦИКЛОАЛКАНІВ Віцинальні фтороциклопентаноли є цінними хіральними синтетичними блоками для отримання ряду природних і синтетичних біологічно активних речовин. Ці сполуки використовують у синтезі різних біо- логічно активних сполук, зокрема простагландинів і прекурсорів лейкотрієнів. Для поділу рацемічних 2-фторгідринів були використані кілька високоефективних ліпаз, які в попередніх дослідженнях показали високу ефективність на багатьох реакціях переетерифікації в органічних розчинниках. Вінілацетат або ізопропіліден ацетат використовували як ацетилюючі агенти. Рацемічні цис-2-фторциклоалканоли були розділені на енантіомери в результаті кінетично контрольованої переестерифікації вінілацетату в при- сутності біокаталізаторів. Високу енантіоселективність (ee > 98 %) і хороший вихід отримано для всіх субстратів з використанням ліпази Burkholderia cepacia. Фторциклоалканоли перетворили в енантіомерно чисті 1,2-амінофторциклоалкани з використанням реакції Mіцунобу. Реакція відбувалася з інверсією аб- солютної конфігурації на атомі вуглецю, що містить гідроксильну групу. Енантіомерну чистоту сполук визначено методом дериватизації кислотою Mошера, а абсолютну конфігурацію встановлено за методом Казлаускаса. Згідно з правилом Казлаускаса, біокаталітичне ацетилювання 2-фторциклопентанолів пови- нно бути (R)-селективним. Таким чином, енантіоселективність на рівні ee > 98 % і вихід на рівні 90 % отримано для всіх субстратів. Ключові слова: стереохімія, біокаталіз, ліпаза Burkholderia cepacia, фторциклоалканоли, амінофторцикло- алкани, правило Казлаускаса. O.O. Колодяжна, О.С. Верёвка, А.O. Колодяжна Институт биоорганической химии и нефтехимии НАН Украины им В.П. Кухаря, Киев E-mail: oikol123@bpci.kiev.ua ФЕРМЕНТАТИВНЫЙ СИНТЕЗ ЭНАНТИОМЕРНО ЧИСТЫХ 1,2-ФТОРЦИКЛОАЛКАНОЛОВ И 1,2-АМИНОФТОРЦИКЛОАЛКАНОВ Вицинальные фтороциклопентанолы являются ценными хиральными синтетическими блоками для по- лучения ряда природных и синтетических биологически активных веществ. Эти соединения использу- ются в синтезе различных биологически активных соединений, в частности простагландинов и прекур- 74 ISSN 1025-6415. Dopov. Nac. akad. nauk Ukr. 2019. № 7 O.O. Kolodiazhna, O.S. Veriovka, A.O. Kolodiazhna соров лейкотриенов. Для разделения рацемических 2-фторгидринов были использованы несколько высо- коэффективных липаз, которые в предыдущих исследованиях показали высокую эффективность на многих реакциях переэтерификации в органических растворителях. Винилацетат или изопропилиден ацетат использовали в качестве ацилирующих агентов. Рацемические цис-2-фторциклоалканолы были разделены на энантиомеры в результате кинетически контролируемой переэтерификации винилацета- том в присутствии биокатализаторов. Высокая энантиоселективность (ee > 98 %) и хороший выход полу- чены для всех субстратов с использованием липазы Burkholderia cepacia. Фторциклоалканолы превратили в энантиомерно чистые 1,2-аминофторциклоалканы с использованием реакции Mицунобу. Реакция про- текала с инверсией абсолютной конфигурации на атоме углерода, содержащего гидроксильную группу. Энантиомерная чистота соединений определена методом дериватизации кислотой Mошера, а абсолютная конфигурация установлена по методу Казлаускаса. Согласно правилу Казлаускаса, биокаталитическое ацетилирование 2-фторциклопентанолов 1,4 должно быть (R)-селективным. Таким образом, энантиосе- лективность на уровне ee > 98 % и выход соединений на уровне 90 % получены для всех субстратов. Ключевые слова: стереохимия, биокатализ, липаза Burkholderia cepacia, фторциклоалканолы, амино ф тор- циклоалканы, правило Казлаускаса.

Enzymatic synthesis of enantiomerically pure 1,2-fluorocyclopentanols and 1,2-aminofluorocyclopentanes

Репозитарії

Схожі ресурси