- Asymmetric azidohydroxylation of styrene derivatives mediated by a biomimetic styrene monooxygenase enzymatic cascade
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Enantioenriched azido alcohols are precursors for valuable chiral aziridines and 1,2-amino alcohols, however their chiral substituted analogues are difficult to access. We established a cascade for the asymmetric azidohydroxylation of styrene derivatives leading to chiral substituted 1,2-azido alcohols via enzymatic asymmetric epoxidation, followed by regioselective azidolysis, affording the azido alcohols with up to two contiguous stereogenic centers. A newly isolated two-component flavoprotein styrene monooxygenase StyA proved to be highly selective for epoxidation with a nicotinamide coenzyme biomimetic as a practical reductant. Coupled with azide as a nucleophile for regioselective ring opening, this chemo-enzymatic cascade produced highly enantioenriched aromatic α-azido alcohols with up to >99% conversion. A bi-enzymatic counterpart with halohydrin dehalogenase-catalyzed azidolysis afforded the alternative β-azido alcohol isomers with up to 94% diastereomeric excess. We anticipate our biocatalytic cascade to be a starting point for more practical production of these chiral compounds with two-component flavoprotein monooxygenases.
- Franssen, Maurice C. R.,Hollmann, Frank,Martínez-Montero, Lía,Paul, Caroline E.,Süss, Philipp,Schallmey, Anett,Tischler, Dirk
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p. 5077 - 5085
(2021/08/16)
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- OXYSTEROLS AND METHODS OF USE THEREOF
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Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R2, R3, R4, R5, and and R6 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.
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Paragraph 00592
(2018/05/16)
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- COMPOUNDS AND USES THEREOF
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The present invention features compounds useful in the treatment of BAF complex related disorders.
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Page/Page column 86;
(2018/12/12)
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- Biocatalytic Formal Anti-Markovnikov Hydroamination and Hydration of Aryl Alkenes
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Biocatalytic anti-Markovnikov alkene hydroamination and hydration were achieved based on two concepts involving enzyme cascades: epoxidation-isomerization-amination for hydroamination and epoxidation-isomerization-reduction for hydration. An Escherichia coli strain coexpressing styrene monooxygenase (SMO), styrene oxide isomerase (SOI), ω-transaminase (CvTA), and alanine dehydrogenase (AlaDH) catalyzed the hydroamination of 12 aryl alkenes to give the corresponding valuable terminal amines in high conversion (many ≥86%) and exclusive anti-Markovnikov selectivity (>99:1). Another E. coli strain coexpressing SMO, SOI, and phenylacetaldehyde reductase (PAR) catalyzed the hydration of 12 aryl alkenes to the corresponding useful terminal alcohols in high conversion (many ≥80%) and very high anti-Markovnikov selectivity (>99:1). Importantly, SOI was discovered for stereoselective isomerization of a chiral epoxide to a chiral aldehyde, providing some insights on enzymatic epoxide rearrangement. Harnessing this stereoselective rearrangement, highly enantioselective anti-Markovnikov hydroamination and hydration were demonstrated to convert α-methylstyrene to the corresponding (S)-amine and (S)-alcohol in 84-81% conversion with 97-92% ee, respectively. The biocatalytic anti-Markovnikov hydroamination and hydration of alkenes, utilizing cheap and nontoxic chemicals (O2, NH3, and glucose) and cells, provide an environmentally friendly, highly selective, and high-yielding synthesis of terminal amines and alcohols.
- Wu, Shuke,Liu, Ji,Li, Zhi
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p. 5225 - 5233
(2017/08/17)
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- PPAR-sparing thiazolidinedione salts for the treatment of metabolic diseases
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The present invention relates to novel salts of thiazolidinediones and other pharmaceutical agents that are useful for treating and/or preventing metabolic diseases (e.g., diabetes, or neurodegenerative diseases (e.g., Alzheimer's Disease).
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Page/Page column 104
(2015/09/28)
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- Rhodium-catalyzed transannulation of N-sulfonyl-1,2,3-triazoles and epoxides: Regioselective synthesis of substituted 3,4-dihydro-2 H-1,4-oxazines
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Rhodium-catalyzed transannulation of 1,2,3-triazoles and ring-opening reactions of epoxides is described. A number of 3,4-dihydro-2H-1,4-oxazines are obtained in moderate yields probably involving generation of α-imino rhodium(II) carbene species.
- Ma, Xueji,Pan, Shanfei,Wang, Hangxiang,Chen, Wanzhi
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supporting information
p. 4554 - 4557
(2015/02/19)
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- PPAR-SPARING THIAZOLIDINEDIONES AND COMBINATIONS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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The present invention relates to PPARy- sparing compounds and pharmaceutical compositions formulated with such compounds that are useful for treating, delaying the onset of, or reducing the symptoms of a neurodegenerative disorder including Huntington's disease, epilepsy, AMS, and MS.
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Paragraph 0369; 0370
(2014/07/07)
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- 2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; A new class of potent, selective and orally active glycogen synthase kinase-3β inhibitors
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A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3β (GSK-3β). We found 21, 29 and 30 to possess potent in vitro GSK-3β inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.
- Fukunaga, Kenji,Uehara, Fumiaki,Aritomo, Keiichi,Shoda, Aya,Hiki, Shinsuke,Okuyama, Masahiro,Usui, Yoshihiro,Watanabe, Kazutoshi,Yamakoshi, Koichi,Kohara, Toshiyuki,Hanano, Tokushi,Tanaka, Hiroshi,Tsuchiya, Susumu,Sunada, Shinji,Saito, Ken-Ichi,Eguchi, Jun-Ichi,Yuki, Satoshi,Asano, Shoichi,Tanaka, Shinji,Mori, Akiko,Yamagami, Keiji,Baba, Hiroshi,Horikawa, Takashi,Fujimura, Masatake
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p. 6933 - 6937
(2014/01/06)
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- Engineered P450pyr monooxygenase for asymmetric epoxidation of alkenes with unique and high enantioselectivity
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A triple mutant of P450pyr monooxygenase (P450pyrTM) catalysed the epoxidation of several para-substituted styrenes as the first enzyme showing high (R)-enantioselectivity and high conversion, demonstrated a broad substrate range, and showed high enantioselectivity for the epoxidation of an unconjugated 1,1-disubstituted alkene, 2-methyl-3-phenyl-1-propene, and a cyclic alkene, N-phenoxycarbonyl-1,2,5,6-tetrahydropyridine, respectively.
- Li, Aitao,Liu, Ji,Pham, Son Q.,Li, Zhi
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supporting information
p. 11572 - 11574
(2013/12/04)
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- Efficient biocatalysis for the production of enantiopure (S)-epoxides using a styrene monooxygenase (SMO) and Leifsonia alcohol dehydrogenase (LSADH) system
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Herein we report the production of enantiopure epoxides through biocatalysis using recombinant Escherichia coli cells expressing Rhodococcus sp. ST-10 styrene monooxygenase (SMO) and Leifsonia sp. S749 alcohol dehydrogenase (LSADH) genes are described. Rhodococcus sp. ST-10 SMO catalyzed the epoxidation of various alkenes, including styrene derivatives, vinyl pyridines, and linear alkenes, to give (S)-epoxides. NADH was regenerated by the reduction of NAD + by LSADH with 2-propanol. The E. coli biocatalyst was used in an aqueous/organic biphasic reaction system and the reaction conditions were optimized. Under the optimized conditions, 170 mM of (S)-styrene oxide was obtained from styrene in the organic phase with excellent enantiomeric excess (99.8%). This biocatalytic process was used to synthesize various (S)-epoxides.
- Toda, Hiroshi,Imae, Ryouta,Itoh, Nobuya
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p. 1542 - 1549
(2013/02/21)
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- Lithiated fluorinated styrene oxides: Configurational stability, synthetic applications, and mechanistic insight
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The configurational stability of some lithiated fluorinated styrene oxides has been investigated. Chemical studies have shown that in ethereal solvents α-lithiated ortho-, meta-, and para-fluorostyrene oxides (2-Li, α-5-Li, and α-6-Li) are all configurationally stable in the reaction time scale, whereas a-lithiated ortho-, meta-, and paratrifluoromethylstyrene oxides (9-Li, 13-Li, and 14-Li) are configurationally unstable. Optically active oxiranyllithiums 2-Li and 9-Li, could be stereospecifically generated and quenched with electrophiles. The corresponding derivatives were then successfully subjected to regiospecific ring-opening reactions with amines to give fluorinated ssamino alcohols with a stereodefined quaternary carbinol center, which are useful synthons in medicinal chemistry. The barriers of inversion have been calculated (Eyring equation) for oxiranyllithiums 9-Li, 13-Li, and 14-Li by determining the enantiomeric ratios after electrophilic quenching on aging the enantioenriched organolithium for different times in THF; in the case of 9-Li, activation parameters have also been determined. Mechanisms that may be responsible of the racemization oxiranyllithiums 9-Li, 13-Li, and 14-Li undergo once generated are also discussed.
- Capriati, Vito,Florio, Saverio,Perna, Filippo Maria,Salomone, Antonio
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scheme or table
p. 9778 - 9788
(2010/11/02)
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- THIAZOLIDINEDIONE ANALOGUES
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The present invention relates to thiazolidinedione analogues that are useful for treating hypertension, diabetes, and inflammatory diseases. In other aspects, the present invention also presents methods of treating hypertension, diabetes, or other inflamm
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Page/Page column 58
(2010/10/03)
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- THIAZOLIDINEDIONE ANALOGUES FOR THE TREATMENT OF HYPERTENSION
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The present invention relates to thiazolidinedione analogues that are useful for treating hypertension, diabetes, and inflammatory diseases. Formula (I), wherein: each of R1 and R4 is independently selected from H, halo, aliphatic, a
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Page/Page column 34
(2009/04/25)
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- Effective asymmetric epoxidation of styrenes by chiral dioxirane
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High enantioselectivity (80-92% enantiomeric excess (ee)) has been obtained for the epoxidation of various styrenes using an easily prepared ketone (4) catalyst.
- Goeddel, David,Shu, Lianhe,Yuan, Yi,Wong, O. Andrea,Wang, Bin,Shi, Yian
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p. 1715 - 1717
(2007/10/03)
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- Stereo- and enantioselective alkene epoxidations: A comparative study of D4- and D2-symmetric homochiral trans-dioxoruthenium(VI) porphyrins
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The mechanism of stoichiometric enantioselective alkene epoxidations by the D4- and D2-symmetric homochiral trans-dioxoruthenium(VI) porphyrins, [RuVI(D4-Por*)O2] (1) and [RuVI(D2-Por*)O2] (2a), in the presence of pyrazole (Hpz) was studied by UV/ Vis spectrophotometry and analysis of the organic products. The enantioselectivity of styrene oxidations is more susceptible to steric effects than to substituent electronic effects. Up to 72% ee was achieved for epoxidation of 3-substituted and cis-disubstituted styrenes by employing 1 as the oxidant, whereas entantioselectivities of only 20-40 % were obtained in the reactions with 2-substituted and trans-disubstituted styrenes. Complex 2a oxidized 2-substituted styrenes to their epoxides in up to 88% ee. Its reactions with transalkenes are more enantioselective (67 % ee) than with the cis-alkenes (40 % ee). Based on a two-dimensional NOESY NMR study, 2a was found to adopt a more open conformation in benzene than in dichloromethane, which explains the observed solvent-dependent enantioselectivity of its reactions with alkenes. The oxidation of aromatic alkenes by the chiral dioxoruthenium(VI) porphyrins proceeds through the ratelimiting formation of a benzylic radical intermediate; the observed enantioselectivity (eeobs) depends on both the facial selectivity of the first C-O bond formation step and the diastereoselectivity of the subsequent epoxide ring closure. To account for the observed facial selection, "side-on" and "top-on" approach transition state models are examined (see: B. D. Brandes, E. N. Jacobsen, Tetrahedron Lett. 1995, 36, 5123).
- Zhang, Rui,Yu, Wing-Yiu,Sun, Hong-Zhe,Liu, Wei-Sheng,Che, Chi-Ming
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p. 2495 - 2507
(2007/10/03)
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- Kinetics of MTO-catalyzed oferin epoxidation in ambient temperature ionic liquids: UV/Vis and 2H NMR study
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The kinetics of oxygen-atom transfer from the peroxo complexes of methyltrioxorhenium (MTO) to alkenes in ionic liquids have been investigated. Noncatalytic conversions of alkenes to epoxide were monitored by UV/Vis at 360 nm, where the monoperoxorhenium
- Owens, Gregory S.,Durazo, Armando,Abu-Omar, Mahdi M.
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p. 3053 - 3059
(2007/10/03)
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- Enantioselective epoxidation of terminal olefins by chiral dioxirane.
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[see reaction]. This paper describes an enantioselective epoxidation of terminal olefins using chiral ketone 3 as catalyst and Oxone as oxidant. Up to 85% ee has been obtained.
- Tian,She,Xu,Shi
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p. 1929 - 1931
(2007/10/03)
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- Tricyclic compounds and drug compositions containing the same
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Compounds having a β-3 adrenaline receptor agonist and are useful as drugs for the treatment and prevention of diabetes, obesity, hyperlipemia, etc., represented by a general formula (I) and salts thereof, and a process for producing these, and their intermediates, wherein R represents hydrogen or methyl; R1 represents hydrogen, halogen, hydroxy, benzyloxy, amino, or hydroxymethyl; R2 represents hydrogen, hydroxymethyl, NHR3, SO2 NR4 R4', or nitro; R6 represents hydrogen or lower alkyl; and X represents nitrogen, R9 represents hydrogen, one of R7 and R8 represent hydrogen, and the other thereof represents hydrogen, amino, acetylamino, or hydroxy.
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- Phenethanolamines, compositions containing the same, and method for effecting weight control
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Optically active N-3-(4-substituted phenyl)propyl-β-phenethanolamines are provided as well as pharmaceutical compositions containing such compounds. A method for effecting weight control in obese animals utilizing optically active phenethanolamines is disclosed. Novel intermediates useful in the preparation of optically active β-phenethanolamines are provided.
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