- Enantioselective Aminohydroxylation of Styrenyl Olefins Catalyzed by an Engineered Hemoprotein
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Chiral 1,2-amino alcohols are widely represented in biologically active compounds from neurotransmitters to antivirals. While many synthetic methods have been developed for accessing amino alcohols, the direct aminohydroxylation of alkenes to unprotected, enantioenriched amino alcohols remains a challenge. Using directed evolution, we have engineered a hemoprotein biocatalyst based on a thermostable cytochrome c that directly transforms alkenes to amino alcohols with high enantioselectivity (up to 2500 TTN and 90 % ee) under anaerobic conditions with O-pivaloylhydroxylamine as an aminating reagent. The reaction is proposed to proceed via a reactive iron-nitrogen species generated in the enzyme active site, enabling tuning of the catalyst's activity and selectivity by protein engineering.
- Cho, Inha,Prier, Christopher K.,Jia, Zhi-Jun,Zhang, Ruijie K.,G?rbe, Tamás,Arnold, Frances H.
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supporting information
p. 3138 - 3142
(2019/02/01)
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- DOPAMINE D3 RECEPTOR ANTAGONISTS HAVING A MORPHOLINE MOIETY
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The disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof: The disclosure also provides processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them, and their use
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Paragraph 0246
(2018/11/21)
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- Novel morpholine scaffolds as selective dopamine (DA) D3 receptor antagonists
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A new series of morpholine derivatives has been identified as selective DA D3 receptor antagonists; their in vitro profile and pharmacokinetic data are provided.
- Micheli, Fabrizio,Cremonesi, Susanna,Semeraro, Teresa,Tarsi, Luca,Tomelleri, Silvia,Cavanni, Paolo,Oliosi, Beatrice,Perdon, Elisabetta,Sava, Anna,Zonzini, Laura,Feriani, Aldo,Braggio, Simone,Heidbreder, Christian
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p. 1329 - 1332
(2016/02/23)
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- One-pot combination of enzyme and Pd nanoparticle catalysis for the synthesis of enantiomerically pure 1,2-amino alcohols
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One-pot combinations of sequential catalytic reactions can offer practical and ecological advantages over classical multi-step synthesis schemes. In this context, the integration of enzymatic and chemo-catalytic transformations holds particular potential for efficient and selective reaction sequences that would not be possible using either method alone. Here, we report the one-pot combination of alcohol dehydrogenase-catalysed asymmetric reduction of 2-azido ketones and Pd nanoparticle-catalysed hydrogenation of the resulting azido alcohols, which gives access to both enantiomers of aromatic 1,2-amino alcohols in high yields and excellent optical purity (ee >99%). Furthermore, we demonstrate the incorporation of an upstream azidolysis and a downstream acylation step into the one-pot system, thus establishing a highly integrated synthesis of the antiviral natural product (S)-tembamide in 73% yield (ee >99%) over 4 steps. Avoiding the purification and isolation of intermediates in this synthetic sequence leads to an unprecedentedly low ecological footprint, as quantified by the E-factor and solvent demand.
- Schrittwieser, Joerg H.,Coccia, Francesca,Kara, Selin,Grischek, Barbara,Kroutil, Wolfgang,D'Alessandro, Nicola,Hollmann, Frank
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p. 3318 - 3331
(2013/12/04)
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- Efficient preparation of biologically important 1,2-amino alcohols
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An efficient three-step methodology developed for the preparation of 1,2-amino alcohols. In the first step a rapid coupling between bromoketones and potassium phthalimide in ionic liquid produced-phthalimido ketones in quantitative yields, which is followed by a facile reduction using NaCNBH 3 in acetic acid to give corresponding phthalimido alcohols and finally effecting hydrazinolysis in water at 60C to yield biologically important 1,2-amino alcohols.
- Gupta, Pankaj,Rouf, Abdul,Shah, Bhahwal A.,Mukherjee, Debaraj,Taneja, Subhash C.
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p. 505 - 519
(2013/01/15)
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- Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors
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Protein arginine methyltransferases (PRMTs) play an important role in diverse biological processes. Among the nine known human PRMTs, PRMT3 has been implicated in ribosomal biosynthesis via asymmetric dimethylation of the 40S ribosomal protein S2 and in c
- Liu, Feng,Li, Fengling,Ma, Anqi,Dobrovetsky, Elena,Dong, Aiping,Gao, Cen,Korboukh, Ilia,Liu, Jing,Smil, David,Brown, Peter J.,Frye, Stephen V.,Arrowsmith, Cheryl H.,Schapira, Matthieu,Vedadi, Masoud,Jin, Jian
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p. 2110 - 2124
(2013/05/08)
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- Regio-selective synthesis of 1,2-aminoalcohols from epoxides and chlorohydrins
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A simple and efficient procedure for the regio-selective synthesis of 1,2-aminoalcohols from terminal epoxides and chlorohydrins by using NaHMDS as the source of amine is reported. The wider scope and utility of this method is demonstrated.
- Murugan, Andiappan,Kadambar, Vasantha Krishna,Bachu, Sreekanth,Rajashekher Reddy,Torlikonda, Venkatarao,Manjunatha, Sulur G.,Ramasubramanian, Sridharan,Nambiar, Sudhir,Howell, Gareth P.,Withnall, Jane
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supporting information
p. 5739 - 5741
(2012/11/06)
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- Novel amide- and sulfonamide-based aromatic ethanolamines: Effects of various substituents on the inhibition of acid and neutral ceramidases
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In the present study we describe the design and synthesis of a series of amide- and sulfonamide-based compounds as inhibitor of recombinant acid and neutral ceramidases. Inhibition of ceramidases has been shown to induce apoptosis and to increase the efficacy of conventional chemotherapy in several cancer models. B-13, lead in vitro inhibitor of acid ceramidase has been recently shown to be virtually inactive towards lysosomal acid ceramidase in living cells at lower concentrations and for a shorter time of treatment, suggesting the development of more potent inhibitors. In this study, a detailed SAR investigation has been performed to understand the effect of different substituents on the phenyl ring of amide- and sulfonamide-based compounds that partially resemble the structure of well-known inhibitors such as B-13, D-e-MAPP as well as NOE. Our results suggest that the electronic effects of the substituents on phenyl ring in B-13 and D-e-MAPP analogues have negligible effects either in enhancing the inhibition potencies or for selectivity towards aCDase over nCDase. However, the hydrophobicity and the steric effects of longer alkyl chains (n-Pr, n-Bu or t-Bu groups) at the phenyl ring were found to be important for an enhanced selectivity towards aCDase over nCDase.
- Bhabak, Krishna P.,Arenz, Christoph
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p. 6162 - 6170
(2012/11/06)
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- ARYL-HYDROXYETHYLAMINO-PYRIMIDINES AND TRIAZINES AS MODULATORS OF FATTY ACID AMIDE HYDROLASE
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Certain aryl-hydroxyethylamino-pyrimidine and triazine compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, energy metabolism disorders, and movement disorders (e.g., multiple sclerosis). Methods of synthesizing such compounds are also disclosed.
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Page/Page column 121
(2009/10/18)
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- Indole, indazole and indoline derivatives as CETP inhibitors
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The present invention relates to compounds of formula (I): wherein —X—Y—, R1 to R11 and n are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are mediated by CETP inhibitors.
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Page/Page column 29
(2010/02/15)
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- Synthesis of enantiopure 2-amino-1-phenyl and 2-amino-2-phenyl ethanols using enantioselective enzymatic epoxidation and regio- and diastereoselective chemical aminolysis
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Several enantiopure 1,2-amino alcohols have been prepared by combining a stereoselective enzymatic epoxidation of styrenes with regio- and stereoselective chemical reactions. An interesting reactivity has been noted concerning the reaction of epoxides and NH3 under microwave activation.
- Sello, Guido,Orsini, Fulvia,Bernasconi, Silvana,Gennaro, Patrizia Di
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p. 372 - 376
(2007/10/03)
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- SUBSTITUTED MORPHOLINE AND THIOMORPHOLINE DERIVATIVES
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The present invention relates to morpholine and thiomorpholine derivatives of the general formula I or pharmaceutically acceptable salts thereof and their use.
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Page/Page column 43-44
(2008/06/13)
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- Process for producing optically active amino alcohols and intermediates therefore
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A process for producing an optically active amino alcohol is provided that includes a step in which a nitro ketone or a cyano ketone is reacted with a hydrogen-donating organic or inorganic compound in the presence of a transition metal compound catalyst having an optically active nitrogen-containing compound as an asymmetric ligand to give an optically active nitro alcohol or an optically active cyano alcohol, and a step in which the above optically active alcohol is further reduced to efficiently produce an optically active amino alcohol.
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- Application of optically active 1,2-diol monotosylates for synthesis of β-azido and β-amino alcohols with very high enantiomeric purity. Synthesis of enantiopure (R)-octopamine, (R)-tembamide and (R)-aegeline
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A very convenient and highly efficient synthesis of near enantiopure β-azido and β-amino alcohols including biologically active substances such as (R)-octopamine, (R)-tembamide and (R)-aegeline from optically active 1,2-diol monotosylates is reported.
- Tae Cho, Byung,Kyu Kang, Sang,Hye Shin, Sung
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p. 1209 - 1217
(2007/10/03)
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- Practical synthesis of optically active amino alcohols via asymmetric transfer hydrogenation of functionalized aromatic ketones
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2-Substituted acetophenones such as 2-cyano-, 2-azido-, or 2-nitroacetophenones were effectively reduced with a mixture of HCOOH/N(C2H5)3 containing a chiral Ru(II) catalyst, RuCl[(S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine](p-cymene), giving the corresponding optically active alcohols, which can be converted to optically active amino alcohols with excellent ee's. Similarly, the reaction of 2-benzoylacetophenone with the same Ru catalyst gave a quantitative yield of the corresponding optically active 1,3-diol with 99% ee.
- Watanabe, Masahito,Murata, Kunihiko,Ikariya, Takao
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p. 1712 - 1715
(2007/10/03)
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- 1,4-benzodioxin derivatives
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PCT No. PCT/JP96/01252 Sec. 371 Date Nov. 12, 1997 Sec. 102(e) Date Nov. 12, 1997 PCT Filed May 13, 1996 PCT Pub. No. WO96/35685 PCT Pub. Date Nov. 14, 1996A 1,4-benzodioxin derivative represented by formula (I) wherein A is an aryl group or a (C3-C8)cycloalkyl group, R1 and R2 individually are a hydrogen atom, a halogen atom, an alkyl group, a trifluoromethyl group, an alkoxy group, an aryl group, an aryloxy group, or R1 and R2 together form a methylenedioxy group, R3 is a hydrogen atom or an alkyl group, R4 is a hydrogen atom or CO2R5, R5 is a hydrogen atom or an alkyl group, X is a radical of formula (II) or (III) wherein n is 1 or 2. The compounds are useful for a prophylactic or therapeutic agent for diabetes, hyperglycemia and obesity.
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