- A Simple Biosystem for the High-Yielding Cascade Conversion of Racemic Alcohols to Enantiopure Amines
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The amination of racemic alcohols to produce enantiopure amines is an important green chemistry reaction for pharmaceutical manufacturing, requiring simple and efficient solutions. Herein, we report the development of a cascade biotransformation to aminate racemic alcohols. This cascade utilizes an ambidextrous alcohol dehydrogenase (ADH) to oxidize a racemic alcohol, an enantioselective transaminase (TA) to convert the ketone intermediate to chiral amine, and isopropylamine to recycle PMP and NAD+ cofactors via the reversed cascade reactions. The concept was proven by using an ambidextrous CpSADH-W286A engineered from (S)-enantioselective CpSADH as the first example of evolving ambidextrous ADHs, an enantioselective BmTA, and isopropylamine. A biosystem containing isopropylamine and E. coli (CpSADH-W286A/BmTA) expressing the two enzymes was developed for the amination of racemic alcohols to produce eight useful and high-value (S)-amines in 72–99 % yield and 98–99 % ee, providing with a simple and practical solution to this type of reaction.
- Li, Zhi,Tian, Kaiyuan
-
supporting information
p. 21745 - 21751
(2020/09/21)
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- Generation of amine dehydrogenases with increased catalytic performance and substrate scope from ε-deaminating L-Lysine dehydrogenase
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Amine dehydrogenases (AmDHs) catalyse the conversion of ketones into enantiomerically pure amines at the sole expense of ammonia and hydride source. Guided by structural information from computational models, we create AmDHs that can convert pharmaceutically relevant aromatic ketones with conversions up to quantitative and perfect chemical and optical purities. These AmDHs are created from an unconventional enzyme scaffold that apparently does not operate any asymmetric transformation in its natural reaction. Additionally, the best variant (LE-AmDH-v1) displays a unique substrate-dependent switch of enantioselectivity, affording S- or R-configured amine products with up to >99.9% enantiomeric excess. These findings are explained by in silico studies. LE-AmDH-v1 is highly thermostable (Tm of 69 °C), retains almost entirely its catalytic activity upon incubation up to 50 °C for several days, and operates preferentially at 50 °C and pH 9.0. This study also demonstrates that product inhibition can be a critical factor in AmDH-catalysed reductive amination.
- Tseliou, Vasilis,Knaus, Tanja,Masman, Marcelo F.,Corrado, Maria L.,Mutti, Francesco G.
-
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- Rapid and Quantitative Profiling of Substrate Specificity of ω-Transaminases for Ketones
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ω-Transaminases (ω-TAs) have gained growing attention owing to their capability for asymmetric synthesis of chiral amines from ketones. Reliable high-throughput activity assay of ω-TAs is essential in carrying out extensive substrate profiling and establishing a robust screening platform. Here we report spectrophotometric and colorimetric methods enabling rapid quantitation of ω-TA activities toward ketones in a 96-well microplate format. The assay methods employ benzylamine, a reactive amino donor for ω-TAs, as a cosubstrate and exploit aldehyde dehydrogenase (ALDH) as a reporter enzyme, leading to formation of benzaldehyde detectable by ALDH owing to concomitant NADH generation. Spectrophotometric substrate profiling of two wild-type ω-TAs of opposite stereoselectivity was carried out at 340 nm with 22 ketones, revealing subtle differences in substrate specificities that were consistent with docking simulation results obtained with cognate amines. Colorimetric readout for naked eye detection of the ω-TA activity was also demonstrated by supplementing the assay mixture with color-developing reagents whose color reaction could be quantified at 580 nm. The colorimetric assay was applied to substrate profiling of an engineered ω-TA for 24 ketones, leading to rapid identification of reactive ketones. The ALDH-based assay is expected to be promising for high-throughput screening of enzyme collections and mutant libraries to fish out the best ω-TA candidate as well as to tailor enzyme properties for efficient amination of a target ketone.
- Han, Sang-Woo,Shin, Jong-Shik
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p. 3287 - 3295
(2019/06/21)
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- Enantioselective synthesis of amines via reductive amination with a dehydrogenase mutant from Exigobacterium sibiricum: Substrate scope, co-solvent tolerance and biocatalyst immobilization
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In recent years, the reductive amination of ketones in the presence of amine dehydrogenases emerged as an attractive synthetic strategy for the enantioselective preparation of amines starting from ketones, an ammonia source, a reducing reagent and a cofactor, which is recycled in situ by means of a second enzyme. Current challenges in this field consists of providing a broad synthetic platform as well as process development including enzyme immobilization. In this contribution these issues are addressed. Utilizing the amine dehydrogenase EsLeuDH-DM as a mutant of the leucine dehydrogenase from Exigobacterium sibiricum, a range of aryl-substituted ketones were tested as substrates revealing a broad substrate tolerance. Kinetics as well as inhibition effects were also studied and the suitability of this method for synthetic purpose was demonstrated with acetophenone as a model substrate. Even at an elevated substrate concentration of 50 mM, excellent conversion was achieved. In addition, the impact of water-miscible co-solvents was examined, and good activities were found when using DMSO of up to 30% (v/v). Furthermore, a successful immobilization of the EsLeuDH-DM was demonstrated utilizing a hydrophobic support and a support for covalent binding, respectively, as a carrier.
- L?we, Jana,Ingram, Aaron A.,Gr?ger, Harald
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p. 1387 - 1392
(2018/03/21)
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- Identification of (S)-selective transaminases for the asymmetric synthesis of bulky chiral amines
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The use of transaminases to access pharmaceutically relevant chiral amines is an attractive alternative to transition-metal-catalysed asymmetric chemical synthesis. However, one major challenge is their limited substrate scope. Here we report the creation of highly active and stereoselective transaminases starting from fold class I. The transaminases were developed by extensive protein engineering followed by optimization of the identified motif. The resulting enzymes exhibited up to 8,900-fold higher activity than the starting scaffold and are highly stereoselective (up to >99.9% enantiomeric excess) in the asymmetric synthesis of a set of chiral amines bearing bulky substituents. These enzymes should therefore be suitable for use in the synthesis of a wide array of potential intermediates for pharmaceuticals. We also show that the motif can be engineered into other protein scaffolds with sequence identities as low as 70%, and as such should have a broad impact in the field of biocatalytic synthesis and enzyme engineering.
- Pavlidis, Ioannis V.,Wei?, Martin S.,Genz, Maika,Spurr, Paul,Hanlon, Steven P.,Wirz, Beat,Iding, Hans,Bornscheuer, Uwe T.
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p. 1076 - 1082
(2016/11/02)
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- Expanding Substrate Specificity of ω-Transaminase by Rational Remodeling of a Large Substrate-Binding Pocket
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Production of structurally diverse chiral amines via biocatalytic transamination is challenged by severe steric interference in a small active site pocket of ω-transaminase (ω-TA). Herein, we demonstrated that structure-guided remodeling of a large pocket by a single point mutation, instead of excavating the small pocket, afforded desirable alleviation of the steric constraint without deteriorating parental activities toward native substrates. Molecular modeling suggested that the L57 residue of the ω-TA from Ochrobactrum anthropi acted as a latch that forced bulky substrates to undergo steric interference with the small pocket. Removal of the latch by a L57A substitution allowed relocation of the small pocket and dramatically improved activities toward various arylalkylamines and alkylamines (e.g., 1100-fold increase in kcat/KM for α-propylbenzylamine). This approach may provide a facile strategy to broaden the substrate specificity of ω-TAs.
- Han, Sang-Woo,Park, Eul-Soo,Dong, Joo-Young,Shin, Jong-Shik
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p. 2712 - 2720
(2015/09/01)
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- Liquid chromatographic resolution of fendiline and its analogues on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid
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Fendiline, an effective anti-anginal drug for the treatment of coronary heart diseases, and its sixteen analogues were resolved on a CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Fendiline was resolved quite well with the separation factor (α) of 1.25 and resolution (RS ) of 1.55 when a mobile phase consisting of methanol-acetonitrile-trifluoroacetic acid-triethylamine at a ratio of 80/20/0.1/0.5 (v/v/v/v) was used. The comparison of the chromatographic behaviors for the resolution of fendiline and its analogues indicated that the 3,3-diphenylpropyl group bonded to the secondary amino group of fendiline is important in the chiral recognition and the difference in the steric bulkiness between the phenyl group and the methyl group at the chiral center of fendiline is also important in the chiral recognition.
- Lee, Ga Ram,Hyun, Myung Ho
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p. 21386 - 21397
(2015/02/19)
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- Microwave-Enhanced Asymmetric Transfer Hydrogenation of N-(tert-Butylsulfinyl)imines
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Microwave irradiation has considerably enhanced the efficiency of the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)imines in isopropyl alcohol catalyzed by a ruthenium complex bearing the achiral ligand 2-amino-2-methylpropan-1-ol. In addition to shortening reaction times for the transfer hydrogenation processes to only 30 min, the amounts of ruthenium catalyst and isopropyl alcohol can be considerably reduced in comparison with our previous procedure assisted by conventional heating, which diminishes the environmental impact of this new protocol. This methodology can be applied to aromatic, heteroaromatic and aliphatic N-(tert-butylsulfinyl)ketimines, leading, after desulfinylation, to the expected primary amines in excellent yields and with enantiomeric excesses of up to 96 %. Microwave irradiation promotes the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)imines in 2-propanol catalysed by a ruthenium complex bearing an achiral β-amino alcohol as ligand. After desulfinylation, α-branched primary amines containing aromatic, heteroaromatic and aliphatic substituents are obtained in excellent yields and with enantiomeric excesses of up to 96 %.
- Pablo, Oscar,Guijarro, David,Yus, Miguel
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p. 7034 - 7038
(2016/02/19)
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- Synthesis and optimization of novel (3S,5R)-5-(2,2-dimethyl-5-oxo-4- phenylpiperazin-1-yl)piperidine-3-carboxamides as orally active renin inhibitors
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We report synthesis and optimization of a series of (3S,5R)-5-(2,2- dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P1, P2 and P 3 portions led to a promising 3
- Mori, Yutaka,Ogawa, Yasuyuki,Mochizuki, Akiyoshi,Nakamura, Yuji,Fujimoto, Teppei,Sugita, Chie,Miyazaki, Shojiro,Tamaki, Kazuhiko,Nagayama, Takahiro,Nagai, Yoko,Inoue, Shin-Ichi,Chiba, Katsuyoshi,Nishi, Takahide
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p. 5907 - 5922
(2013/09/12)
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- Asymmetric synthesis of chiral primary amines by transfer hydrogenation of N -(tert -Butanesulfinyl)ketimines
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(Figure presented) The diastereoselective reduction of (R)-N-(tert- butanesulfinyl)ketimines by a ruthenium-catalyzed asymmetric transfer hydrogenation process in isopropyl alcohol, followed by desulfinylation of the nitrogen atom, is an excellent method to prepare highly enantiomerically enriched α-branched primary amines (up to >99% ee) in short reaction times (1-4 h). (1S,2R)-1-Amino-2-indanol has been shown to be a very efficient ligand to perform this transformation. Ketimines bearing either an aryl or a heteroaryl group and an alkyl group as substituents of the iminic carbon atom are very good substrates for this process. The reduction of a dialkyl ketimine could also be achieved, affording the expected amine with moderate optical purity (69% ee). Some amines which are precursors of very interesting biologically and pharmacologically active compounds have been prepared in excellent yields and enantiomeric excesses.
- Guijarro, David,Pablo, Oscar,Yus, Miguel
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supporting information; experimental part
p. 5265 - 5270
(2010/10/21)
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- Efficient kinetic resolution of racemic amines using a transaminase in combination with an amino acid oxidase
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A range of enantiomerically pure (R)- and (S)-configured chiral amines has been prepared in excellent e.e. (99%) by combining a transaminase enzyme with an amino acid oxidase and catalytic quantities of pyruvate.
- Truppo, Matthew D.,Turner, Nicholas J.,Rozzell, J. David
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supporting information; experimental part
p. 2127 - 2129
(2009/09/06)
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- New C5-alkylated indolobenzazepinones acting as inhibitors of tubulin polymerization: Cytotoxic and antitumor activities
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A series of 5-alkylindolobenzazepin-7-ones was synthesized by Suzuki coupling between 3-iodoindole-2-carboxylates and the appropriate α-alkylbenzylamino α-boronic acids followed by cyclization to the lactam. Derivatives having a linear alkyl chain at C5 were found to be highly cytotoxic to KB cells with IC50 values in the 30-80 nM range. These compounds also inhibited the polymerization of tubulin with IC50's of 1-2 μM. Compound 4f ((S)-5-ethyl) showed comparable antiproliferative activities (IC50's of 30-70 nM) in a variety of cancer cell lines, cell growth being arrested at the G2/M phase. Compound 4f induced apoptosis in a dose-dependent manner in three different cancer cell lines and was shown to affect cell morphology in a manner consistent with its inhibitory action on tubulin polymerization. Using the experimental model of glioma grafted on the chick chorio-allantoic membrane, local treatment with compound 4f markedly reduced tumor progression.
- Keller, Laurent,Beaumont, Stéphane,Liu, Jian-Miao,Thoret, Sylviane,Bignon, Jér?me S.,Wdzieczak-Bakala, Joanna,Dauban, Philippe,Dodd, Robert H.
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supporting information; experimental part
p. 3414 - 3421
(2009/05/26)
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- Rational design, synthesis, and structure-Activity relationships of aryltriazoles as novel corticotropin-releasing factor-1 receptor antagonists
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Following the discovery of the very high binding affinity of 4-anilinopyrimidines against corticotropin-releasing factor receptor-1 (CRF 1) (e.g., 1, Ki = 2 nM), a new series of triazoles bearing different groups has been synthesized
- Lowe, Richard F.,Nelson, Jodene,Dang, Trunghau N.,Crowe, Paul D.,Pahuja, Anil,McCarthy, James R.,Grigoriadis, Dimitri E.,Conlon, Paul,Saunders, John,Chen, Chen,Szabo, Thomas,Chen, Ta Kung,Bozigian, Haig
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p. 1540 - 1549
(2007/10/03)
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- Synthesis of enantiopure 1-aryl-1-butylamines and 1-aryl-3-butenylamines by diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide
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The synthesis of enantiopure 1-aryl-1-butylamines via a highly diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide is reported. These are synthesised by a three-step procedure, which involves: (a) formation of the chiral imines; (b) asymmetric addition of the allylzinc reagent; (c) removal of the chiral auxiliary by means of a reductive or non-reductive method. The reductive method provides 1-aryl-1-butylamines whereas the non-reductive method preserves the double bond to afford 1-aryl-3-butenylamines. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Dalmolen, Jan,Van Der Sluis, Marcel,Nieuwenhuijzen, Jose W.,Meetsma, Auke,De Lange, Ben,Kaptein, Bernard,Kellogg, Richard M.,Broxterman, Quirinus B.
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p. 1544 - 1557
(2007/10/03)
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- Asymmetric synthesis of allyl- and α-allenylamines from chiral imines and alkynes via (η2-imine)Ti(O-i-Pr)2 complexes
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(Matrix presented) The reaction of a divalent titanium reagent Ti(O-i-Pr)4/2i-PrMgX with optically active arylaldimines derived from arylaldehydes and O-methylphenylglycinol provided, in a highly diastereoselective manner, chiral (η2-imine)Ti(O-i-Pr) 2 complexes, which in turn reacted with 1-alkynes or propargyl compounds to give optically active allyl- and α-allenylamines, respectively.
- Fukuhara, Kohki,Okamoto, Sentaro,Sato, Fumie
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p. 2145 - 2148
(2007/10/03)
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- Hetero Diels-Alder reactions of nitroso alkenes with alkoxyallene derivatives bearing carbohydrate auxiliaries: Asymmetric synthesis of 6H-1,2-oxazines and subsequent reductive transformations
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Alkoxyallene derivatives 1a-f bearing carbohydrate auxiliaries at the oxygen were examined in asymmetric hetero Diels-Alder reactions with nitroso alkenes. Diacetoneglucose derived compound aa turned out to be the best precursor furnishing the primary cyc
- Zimmer, Reinhold,Orschel, Beate,Scherer, Stefan,Reissig, Hans-Ulrich
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p. 1553 - 1563
(2007/10/03)
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- Kinetic Resolution of (±)-1-Phenylbutan-1-ol by Means of CALB-Catalyzed Aminolyses: A Study on the Role of the Amine in the Alcohol Resolution
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The kinetic resolution of (±)-1-phenylbutan-1-ol [(±)-1] by means of CALB-catalyzed aminolysis of its acetyl derivative [(±)-2] using (±)-1-phenylethanamine [(±)-3] as nucleophile is a slower but more enantioselective process (E = 50) than the corresponding CALB-catalyzed transesterification of (±)-1 with vinyl acetate (E = 19). The use of triethylamine and acetanilide as additives in the transesterification of (±)-1 enhanced the enantiomeric ratio (E = 43 and 38, respectively), thus showing that both the basic character of the amine as well as its structural nature could be responsible for the enantioselectivity differences observed between the transesterification and aminolysis reactions. We have also carried out the aminolysis of (±)-2 using different chiral and non-chiral amines. Enantiomeric ratio values varied significantly with the amine employed, but the enzyme always remained more selective towards the R-enantiomer of the substrate. Among all the amines tested, (±)-1-phenylpropan-1-amine [(±)-5] was the nucleophile of choice. Analysis of the conversion values for each enantiomer of (±)-2 showed that the selectivity differences exhibited by the lipase in the aminolysis reactions were due to the different stabilization of the fast-reacting enantiomer of the substrate [(R)-2] during the catalytic process. The CALB behavior in these reactions could be explained on the basis of substrate imprinting effects, which were corroborated by means of enzyme recycling experiments. Finally, a solvent screening allowed the kinetic resolution of this alcohol for synthetic purposes.
- Garci?a-Urdiales, Eduardo,Rebolledo, Francisca,Gotor, Vicente
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p. 646 - 654
(2007/10/03)
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- Diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide
-
equation presented The highly diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide is reported. Homoallylamines with high enantiomeric purity are obtained from the adducts in three steps on removal of the chiral
- Van Der Sluis, Marcel,Dalmolen, Jan,De Lange, Ben,Kaptein, Bernard,Kellogg, Richard M.,Broxterman, Quirinus B.
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p. 3943 - 3946
(2007/10/03)
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- Synthesis of optically-active benzylic amines; asymmetric reduction of ketoxime ethers with chiral oxazaborolidines
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The preparation of novel optically active benzylic amines by the enantioselective reduction of phenone oximes using chiral oxazaborolidine is described. The choice of the chiral 1,2-amino alcohol (S)-diphenylvalinol as chiral inducer and that of the benzy
- Fontaine, Evelyne,Namane, Claudie,Meneyrol, Jerome,Geslin, Michel,Serva, Laurence,Roussey, Eliane,Tissandie, Stephanie,Maftouh, Mohamed,Roger, Pierre
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p. 2185 - 2189
(2007/10/03)
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- Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 2. Identification of (S)-N-(1-phenylpropyl)-3- hydroxy-2-phenylquinoline-4-carboxamide (SB 223412)
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Optimization of the previously reported 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonist 14, with regard to potential metabolic instability of the ester moiety and affinity and selectivity for the human neurokinin-3 (hNK-3) receptor, is described. The ester functionality could be successfully replaced by the ketone (31) or by lower alkyl groups (Et, 21, or n-Pr, 24). Investigation of the substitution pattern of the quinoline ring resulted in the identification of position 3 as a key position to enhance hNK-3 binding affinity and selectivity for the hNK-3 versus the hNK-2 receptor. All of the chemical groups introduced at this position, with the exception of halogens, increased the hNK-3 binding affinity, and compounds 53 (3-OH, SB 223412, hNK- 3-CHO binding K(i) = 1.4 nM) and 55 (3-NH2, hNK-3-CHO binding K(i) = 1.2 nM) were the most potent compounds of this series. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 53 is about 100-fold selective for the hNK-3 versus hNK-2 receptor, with no affinity for the hNK-1 at concentrations up to 100 μM. In vitro studies demonstrated that 53 is a potent functional antagonist of the hNK-3 receptor (reversal of senktide-induced contractions in rabbit isolated iris sphincter muscles and reversal of NKB-induced Ca2+ mobilization in CHO cells stably expressing the hNK-3 receptor), while in vive this compound showed oral and intravenous activity in NK-3 receptor-driven models (senktide-induced behavioral responses in mice and senktide-induced miosis in rabbits). Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy- 2-phenylquinoline-4-carboxamide (53, SB 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK-3 receptor antagonists.
- Giardina, Giuseppe A. M.,Raveglia, Luca F.,Grugni, Mario,Sarau, Henry M.,Farina, Carlo,Medhurst, Andrew D.,Graziani, Davide,Schmidt, Dulcie B.,Rigolio, Roberto,Luttmann, Mark,Cavagnera, Stefano,Foley, James J.,Vecchietti, Vittorio,Hay, Douglas W. P.
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p. 1053 - 1065
(2007/10/03)
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- Enantioselective syntheses of α-phenylalkanamines via intermediate addition of Grignard reagents to chiral hydrazones derived from (R)-(-)-2- aminobutan-1-ol
-
The hydrazine (R)-(-)-28 was obtained in four steps from 2-aminobutan- 1-ol (R)-(-)-11, and reacted with benzaldehyde to give the hydrazone (R)-(- )-29. Nucleophilic addition of various alkyl Grignard reagents to the latter yielded the corresponding trisubstituted hydrazines (R,R)-30a-g in 70-89% yields and having d.e.s=100% (1H and 13C NMR). Catalytic hydrogenolysis of these hydrazines afforded the corresponding (R)(+)-α-phenylalkanamines (R)- (+)-31a-g having e.e.s=90-92% (chiral GPC).
- Bataille, Patricia,Paterne, Michel,Brown, Eric
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p. 2181 - 2192
(2007/10/03)
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- Chiral Oximes in Asymmetric Synthesis. Addition of Organometallic Reagents to O-(1-Phenylethyl) Aldoximes
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Addition of Grignard and organolithium reagents to O-(1-phenylethyl) aldoximes in the presence of boron trifluoride etherate gives secondary hydroxylamines in 21-84percent yield with up to 95percent diastereomeric excess.
- Brown, David S.,Gallagher, Peter T.,Lightfoot, Andrew P.,Moody, Christopher J.,Slawin, Alexandra M. Z.,Swann, Elizabeth
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p. 11473 - 11488
(2007/10/02)
-
- Synthesis of α,α-Disubstituted α-Amino Acid Amides by Phase-Transfer Catalyzed Alkylation
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α,α-Disubstituted α-amino acid amides were prepared in 17-88 percent chemical yield by the phase-transfer catalyzed alkylation of N-benzylidene α-H amino acid amides, followed by weak acidic hydrolysis of the Schiff bases.
- Kaptein, Bernard,Boesten, Wilhelmus H. J.,Broxterman, Quirinus B.,Schoemaker, Hans E.,Kamphuis, Johan
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p. 6007 - 6010
(2007/10/02)
-
- Preparation of Secondary Carbinamines via N-Boryl Imines Generated in situ from Nitriles and Borane-Tetrahydrofuran
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N-Boryl imines obtained from partial reduction of nitriles with borane-tetrahydrofuran have been alkylated with organolithium or Grignard reagents to afford secondary carbinamines in moderate to excellent yields.
- Itsuno, Shinichi,Hachisuka, Chiharu,Ito, Koichi
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p. 1767 - 1769
(2007/10/02)
-
- A Mild Reduction of Azomethines with Zinc Borohydride. Synthetic Application to Tandem Alkylation-Reduction of Nitriles
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The reduction of Schiff bases; N-benzylidene- and N-(1-phenylethylidene)arylamines with zinc borohydride in diethyl ether gave the corresponding amines in excellent yield.N-benzylidene-benzyl- and cyclohexylamine, N-(1-phenylethylidene)- and N-(cyclohexylidene)cyclohexylamines, however, require additional treatment with 6 N HCl to liberate the amine-borane complex to give the corresponding amines in quantitative yield.The procedure was also applied in the tandem alkylation-reduction of nitriles to yield 1-phenylalkylamines in good yield.
- Kotsuki, Hiyoshizo,Yoshimura, Naka,Kadota, Isao,Ushio, Yasuyuki,Ochi, Masamitsu
-
p. 401 - 402
(2007/10/02)
-
- Asymmetric Reduction of Ketoxime O-Alkyl Ethers with Chirally Modified NaBH4-ZrCl4
-
Reducing agents prepared from sodium borohydride (NaBH4), zirconium tetrachloride (ZrCl4), and chiral amino alcohols have been successfully applied to the enantioselective reduction of oxime ethers.Optically active primary amines were obtained in high enantiomeric excess ( : : : .
- Itsuno, Shinichi,Sakurai, Yoshiki,Shimizu, Koji,Ito, Koichi
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p. 1859 - 1863
(2007/10/02)
-
- Asymmetric Reduction of Ketoxime O-Alkyl Ethers with Sodium Borohydride-Lewis Acid
-
Novel hydride agents formed by combining Lewis acids with sodium borohydride (NaBH4) reduce quantitatively ketoxime O-alkyl ethers to the corresponding optically active primary amines with high enantioselectivities (up to 95percent e.e.) in the presence of chiral amino alcohols.
- Itsuno, Shinichi,Sakurai, Yoshiki,Shimizu, Koji,Ito, Koichi
-
p. 1548 - 1549
(2007/10/02)
-
- Synthesis and Anticonvulsant Activity of Analogues of 4-Amino-N-(1-phenylethyl)benzamide
-
A group of amides and amines related to 4-amino-N-(1-phenylethyl)benzamide, 1, were prepared in a study on the relationship of structure to anticonvulsant activity in this compound. Acylation and alkylation of the amino group of 1 resulted in almost total loss of anticonvulsant activity. Insertion of a methylene between the 4-amino group and the aromatic ring of 1 produced a slight increase in anticonvulsant potency and a significant increase in toxicity. Hydride reduction of the amide carbonyl in 1 also yielded compounds having a slightly lower ED50 against convulsions induced by electroshock and a much lower TD50 in the rotorod assay. Modification of the 1-phenylethyl group of 1 also decreased anticonvulsant potency.
- Clark, C. Randall,Davenport, Timothy W.
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p. 1214 - 1218
(2007/10/02)
-
- BASIC STUDY OF THE AMINO ACID RESIDUE IN PROTEIN. THE ROLE OF HYDROCARBON GROUPS IN ENANTIOMER-DIFFERENTIATING ACYLATION.
-
The enantiomer-differentiation acylation (kinetic resolution) of 1-phenylalkylamines and their derivatives was carried out with (S)-2-phenylbutyric anhydride and its derivatives in aqueous and nonaqueous media. On the basis of the distributions of the two diastereomeric products, the molecular interactions between hydrocarbon residues responsible for the structural recognition of the reacting molecules were studied. In nonpolar media, the (R,S)-isomer was predominantly formed over the (S,S)-isomer. Moreover, the differentiation was mainly controlled by the size of the alkyl substituents of the substrates.
- Hiraki,Tai
-
p. 1570 - 1575
(2007/10/02)
-
- Probes of the Active Site of Norepinephrine N-Methyltransferase: Effect of Hydrophobic and Hydrophilic Interactions on Side-Chain Binding of Amphetamine and α-Methylbenzylamine
-
A series of ω-substituted analogues of amphetamine and α-methylbenzylamine were prepared and evaluated as inhibitors of norepinephrine N-methyltransferase (NMT).These included several alkyl side chain extended analogues (1-5), as well as the terminally hydroxylated derivatives phenylalanol (6a) and Phenylglycinol (7a).None of the alkyl-substituted derivatives displayed appreciable activity as inhibitors; however, the hydroxylated analogues were up to twofold more potent than the parent compounds.The positive contribution of the side-chain hydroxy suggests that theterminal methyl group of the lead compounds is situated close to a hydrophilic area or hydrogen bonding functional group within the active site.
- Grunewald, Gary L.,Monn, James A.,Rafferty, Michael F,,Borchardt, Ronald T.,Krass, Polina
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p. 1248 - 1250
(2007/10/02)
-
