- Process for producing optically active (R)-tetrahydrothiophene-3-ol with high optical purity and high purity: Bioconversion and crystallization
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(R)-Tetrahydrothiophene-3-ol (1) is a key intermediate in the synthesis of penem-based antibiotics. However, it is a viscous liquid at room temperature, which makes it impossible to purify the (R)-isomer especially in the presence of the (S)-isomer. In this study, we successfully developed a process for producing (R)-alcohol 1 with high optical purity by combining bioconversion and crystallization. (R)-Alcohol 1 was prepared by enantioselective bioreduction which used tetrahydrothiophene-3-one (2) as the substrate, and the optical purity was 70-92% ee. The (R)-alcohol 1 liquid was collected from incubation solution and purified to furnish (R)-alcohol 1 with 98.7% ee by cooling crystallization from organic solvents. The scale-up using common crystallization process was difficult, but we developed a crystallization process that employed a jacketed pressure filtration vessel equipped with an agitator which can be operated under low temperature from crystallization to filtration. This led to the establishment of a process for producing (R)-alcohol 1 with high optical purity, and the validity of this process was proved by the scale-up test.
- Konuki, Kaname,Nagai, Hazuki,Ito, Masashi,Sameshima, Tomohiro
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- Methodology Development in Directed Evolution: Exploring Options when Applying Triple-Code Saturation Mutagenesis
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Directed evolution of stereo- or regioselective enzymes as catalysts in asymmetric transformations is of particular interest in organic synthesis. Upon evolving these biocatalysts, screening is the bottleneck. To beat the numbers problem most effectively, methods and strategies for building “small but smart” mutant libraries have been developed. Herein, we compared two different strategies regarding the application of triple-code saturation mutagenesis (TCSM) at multiresidue sites of the Thermoanaerobacter brockii alcohol dehydrogenase by using distinct reduced amino-acid alphabets. By using the synthetically difficult-to-reduce prochiral ketone tetrahydrofuran-3-one as a substrate, highly R- and S-selective variants were obtained (92–99 % ee) with minimal screening. The origin of stereoselectivity was provided by molecular dynamics analyses, which is discussed in terms of the Bürgi–Dunitz trajectory.
- Qu, Ge,Lonsdale, Richard,Yao, Peiyuan,Li, Guangyue,Liu, Beibei,Reetz, Manfred T.,Sun, Zhoutong
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- Highly enantioselective reduction of a small heterocyclic ketone: Biocatalytic reduction of tetrahydrothiophene-3-one to the corresponding (R)-Alcohol
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By leveraging enzyme evolution technologies, the enantioselectivity of a KetoREDuctase (KRED) towards the nearly spatially symmetrical ketone tetrahydrothiophene-3-one was increased from 63% ee to 99.3% ee. The biocatalytic process gives (R)-tetrahy- drothiophene-3-ol in one step from a commodity chemical and supplants the original multistep hazardous processes starting from the chiral pool. The biocatalytic process has been successfully scaled to 100 kg.
- Liang, Jack,Mundorff, Emily,Voladri, Rama,Jennet, Stephan,Gilson, Lynne,Conway, Aaron,Krebber, Anke,Wong, John,Huisman, Gjalt,Truesdell, Susan,Lalonde, James
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- Catalytic Asymmetric Reduction of Difficult-to-Reduce Ketones: Triple-Code Saturation Mutagenesis of an Alcohol Dehydrogenase
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Catalytic asymmetric reduction of prochiral ketones with the formation of enantio-pure secondary alcohols is of fundamental importance in organic chemistry, chiral man-made transition-metal catalysts, or organocatalysts and enzymes of the alcohol dehydrogenase (ADH) type. A distinct limitation is the traditional requirement that the α- and α′-moieties flanking the carbonyl function differ sterically and/or electronically. Difficult-to-reduce ketones such as tetrahydrofuran-3-one and tetrahydrothiofuran-3-one and related substrates are particularly challenging, irrespective of the catalyst type. The ADH from Thermoethanolicus brockii (TbSADH) is an attractive industrial biocatalyst, because of its high thermostability, but it also fails in the reduction of such ketones. We have successfully applied directed evolution using the previously developed concept of triple-code saturation mutagenesis at sites lining the TbSADH binding pocket with tetrahydrofuran-3-one serving as the model compound. Highly (R)- and (S)-selective variants were evolved (95%-99% ee) with minimal screening. These robust catalysts also proved to be effective in the asymmetric reduction of tetrahydrothiofuran-3-one and other challenging prochiral ketones as well. The chiral products, which are generally prepared by multistep routes, serve as synthons in the preparation of several important therapeutic drugs.
- Sun, Zhoutong,Lonsdale, Richard,Ilie, Adriana,Li, Guangyue,Zhou, Jiahai,Reetz, Manfred T.
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- Enantioselective reduction of heterocyclic ketones with low level of asymmetry using carrots
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A whole spectrum of biocatalysts for asymmetric reduction of prochiral ketones is well known including the Daucus carota root. However, this type of reaction is still challenging when pro-chiral ketones present low level of asymmetry, like heterocyclic ketones. In this work, 4,5-dihydro-3(2H)-thiophenone (1), 2-methyltetrahydrofuran-3-one (2), N-Boc-3-pyrrolidinone (3), 1-Z-3-pyrrolidinone (4) and 1-benzyl-3-pyrrolidinone (5) were studied in order to obtain the respective enantioselective heterocyclic secondary alcohols. Except for 5, the corresponding alcohols were obtained in high values of conversion and with high selectivity. In order to circumvent the low isolated yield of the corresponding chiral alcohol from 2, we observed that the use of carrots in the absence of water is feasible. Addition of co-solvents was needed to the water-insoluble ketones 3 and 4. Comparatively, baker’s yeast was used for bio reductions of 1, 3 and 4. And in terms of conversion, selectivity and work-up, the use of carrots were a more efficient biocatalyst, as well as a viable method for obtaining 5-member heterocyclic secondary alcohols.
- Machado, Naira Vieira,Omori, álvaro Takeo
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p. 475 - 480
(2021/09/27)
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- Synthesis method of thiophanate side chain
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The invention relates to a synthesis method of a thiophanate side chain, which comprises the following steps: using a material shown in the description as a raw material, using ketone reductase to reduce to produce a product shown in the description, and using monooxygenase to oxidize to produce a product shown in the description, after protection of para-tosyl, carrying out sulfonyl protection toobtain a target product shown in the description, according to the technical scheme, by using the ketone reductase and the monooxygenase, a first step of biotransformation and a second step of biotransformation are carried out respectively, the oxidation product in the second step is subjected to Ts (para-tosyl) protection, finally, sulfonyl protection is carried out to obtain the target product,because the first step and the second step are both biotransformation, extraction by using ethyl acetate is not needed, the use amount of the ethyl acetate is reduced.
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Paragraph 0030; 0031; 0032; 0033; 0034; 0035; 0047; 0048
(2019/06/27)
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- Process for preparing 3-Hydroxythiolane
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A process for preparing 3-hydroxythiolane which is characterized by reacting a compound of the following formula, ???wherein X is a halogen atom, and R2 is a substituted or unsubstituted alkyl group, substituted or unsubstituted aralkyl group, or substituted or unsubstituted aryl group, with a metal sulfide.
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Page/Page column 3
(2008/06/13)
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- The Development of Cyclic Sulfolanes as Novel and High-Affinity P2 Ligands for HIV-1 Protease Inhibitors
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Design and synthesis of a novel series of protease inhibitors incorporating conformationally constrained cyclic ligands for the S2-substrate binding site of HIV-1 protease is described. We recently reported urethanes of 3-tetrahydrofuranyl as P2 ligands for HIV-1 protease inhibitors. Subsequently, we have found that the urethane of 3(S)-hydroxysulfolane further increased the in vitro potency of these inhibitors. Furthermore, introduction of a small 2-alkyl group cis to the 3-hydroxyl group of either heterocyclic system further enhanced enzyme affinity. The cis-2-isopropyl group thus far offered optimum enhancement of the inhibitory properties. This led to the discovery of inhibitor 43 (IC50 3.5 nM, CIC95 50+/-14 nM) of comparable in vitro antiviral potency to the current clinical candidate 1 (Ro 31-8959) but of reduced molecular weight due to the exclusion of the P3 quinoline ligand. Also, it has been demonstrated that the octahydropyrindene derivative 34 is an effective replacement of the P1' decahydroisoquinoline derivative.
- Ghosh, Arun K.,Lee, Hee Yoon,Thompson, Wayne J.,Culberson, Chris,Holloway, M. Katharine,et al.
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p. 1177 - 1188
(2007/10/02)
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- 2-Thioalkyl Penems: An Efficient Synthesis of Sulopenem, a (5R,6S)-6-(1(R)-Hydroxyethyl)-2--2-penem Antibacterial
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A practical synthesis of potent penem antibacterials, CP-70,429 (1) (sulopenam) and CP-81,054 (2), is described. (L)-Aspartic acid was utilized to generate both the (3S)- and (3R)-thiolanylthio side chains of (5R,6S)-6-(1-(R)-hydroxyethyl)-2--2-penem-3-carboxylic acids 1 and 2.This synthetic pathway provided in high yield enantiopure thioacetate intermediates 15 and 19.To accommodate the fragile side chain sulfoxide moiety of the targeted β-lactams, standard penem synthetic methodology was modified to facilitate the conversion of 15 and 19 to 1 and 2.The reactive chloroazetidinone 4b was utilized to generate key azetidinone trithiocarbonate intermediate 22 which contains the requisite penem side chain.A chemoselective oxalofluoride-based azetidinone N-acylation procedure, which avoids sulfoxide O-acylation, was required for the conversion of 22 to the penem framework.
- Volkmann, Robert A.,Kelbaugh, Paul R.,Nason, Deane M.,Jasys, V. John
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p. 4352 - 4361
(2007/10/02)
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- Diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acids
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Diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(1S-oxo-3R-thiolanylthio)-2-penem-3-carboxylic acid and 5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio )-2-penem-3-carboxylic acid, and pharmaceutically-acceptable salts and in vivo hydrolyzable esters thereof, useful as systemic antibacterial agents; and intermediates and processes which are useful in the said synthesis of said diastereoisomers.
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- Chiral Synthesis via Organoboranes. 6. Hydroboration. 74. Asymmetric Hydroboration of Representative Heterocyclic Olefins with Diisopinocamphenylborane. Synthesis of Heterocyclic Boronates and Heterocyclic Alcohols of Very High Enantiomeric Purity
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The hydroboration of representative heterocycles bearing an endocyclic double bond with diisopinocamphenylborane (Ipc2BH) was investigated systematically to establish the asymmetric induction achieved in the reaction.The hydroboration of 2,3- and 2,5-dihydrofurans, 1,4-epoxy-1,4-dihydronaphthalene, and 2,3-dihydrothiophene with Ipc2BH in THF at -25 deg C proceeded very cleanly to afford the corresponding trialkylboranes.These trialkylboranes readily eliminate α-piene on treatment with acetaldehyde to give the corresponding boronates, R*B(OR)2.Oxidation afforded in high yields the corresponding heterocyclic alcohols of 100percent ee.N-(Carbobenzyloxy)-3-pyrroline could not be hydroborated with Ipc2BH below 0 deg C.The oxidation of the intermediate trialkylborane gave N-(carbobenzyloxy)-3-pyrrolidinol in 89percent ee.Similarly, six-membered heterocyclic olefins, namely, 3,4-dihydropyran and 3,4-dihydrothiapyran, were hydroborated with Ipc2BH at 0 deg C in THF.The resulting trialkylboranes on treatment with acetaldehyde followed by oxidation yielded 3-hydroxytetrahydropyran and 3-hydroxytetrahydrothiapyran of 83percent and 66percent ee, respectively.N-(Carbobenzyloxy)-1,2,3,6-tetrahydropyridine, hydroborated with Ipc2BH at 0 deg C, followed by oxidation, afforded the corresponding 3- and 4-piperidinols in an 85:15 ratio.The asymmetric induction achieved during hydroboration was 70percent.The five-membered heterocyclic boronates of very high optical purity, highly versatile synthetic intermediates, were isolated both as the diethyl and the diethanolamine esters.
- Brown, Herbert C.,Prasad, J. V. N. Vara
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p. 2049 - 2054
(2007/10/02)
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