- Stereo-complementary bioreduction of saturated N-heterocyclic ketones
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The asymmetric bioreduction of several saturated N-heterocyclic ketones is demonstrated in a stereo-complementary fashion using the ketoreductases READH and ChKRED20 for the production of (S)- and (R)-alcohols, respectively. The reaction accepts substrates with a five-, six- or seven-membered ring, and exhibits excellent stereoselectivity when using 2-propanol as both the ultimate reducing agent and cosolvent, achieve >99% ee in the majority of cases for both enantiomers.
- Li, Chao,Liu, Yan,Pei, Xiao-Qiong,Wu, Zhong-Liu
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- Exploring Derivatives of Quinazoline Alkaloid l-Vasicine as Cap Groups in the Design and Biological Mechanistic Evaluation of Novel Antitumor Histone Deacetylase Inhibitors
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l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.
- Ahmad, Mudassier,Aga, Mushtaq A.,Bhat, Javeed Ahmad,Kumar, Brijesh,Rouf, Abdul,Capalash, Neena,Mintoo, Mubashir Javeed,Kumar, Ashok,Mahajan, Priya,Mondhe, Dilip Manikrao,Nargotra, Amit,Sharma, Parduman Raj,Zargar, Mohmmad Afzal,Vishwakarma, Ram A.,Shah, Bhahwal Ali,Taneja, Subhash Chandra,Hamid, Abid
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p. 3484 - 3497
(2017/05/05)
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- Preparation of enantiomerically pure N-heterocyclic amino alcohols by enzymatic kinetic resolution
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Abstract The synthesis of both enantiomers of N-benzyl-3-hydroxypyrrolidine and N-benzyl-3-hydroxypiperidine via enzymatic kinetic resolution of the corresponding racemic esters is described. Various commercially available hydrolases were studied as biocatalysts in native and immobilized form. The best results were obtained with lipases PS, AK, CAL-B and with protease Alcalase, which were active and selective for the kinetic resolutions of racemic esters (E > 100). Under optimized reaction conditions, highly enantiomerically enriched (up to 99.5% ee) resolution products were obtained. Lipase and protease showed opposite enantiopreference on the esters, allowing the preparation of both enantiomers of the target compounds. Semi-continuous reactions in column reactors with immobilized biocatalysts were also performed with high enantioselectivities. Inversion of the configuration at C(3) of N-benzyl-3-hydroxypyrrolidine was quantitatively effected in a short number of steps.
- Tofani, Giorgio,Petri, Antonella,Piccolo, Oreste
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p. 638 - 643
(2015/08/03)
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- 3-Hydroxypyrrolidine and (3,4)-dihydroxypyrrolidine derivatives: Inhibition of rat intestinal α-glucosidase
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Thirteen pyrrolidine-based iminosugar derivatives have been synthesized and evaluated for inhibition of α-glucosidase from rat intestine. The compounds studied were the non-hydroxy, mono-hydroxy and dihydroxypyrrolidines. All the compounds were N-benzylated apart from one. Four of the compounds had a carbonyl group in the 2,5-position of the pyrrolidine ring. The most promising iminosugar was the trans-3,4-dihydroxypyrrolidine 5 giving an IC50 of 2.97 ± 0.046 and a KI of 1.18 mM. Kinetic studies showed that the inhibition was of the mixed type, but predominantly competitive for all the compounds tested. Toxicological assay results showed that the compounds have low toxicity. Docking studies showed that all the compounds occupy the same region as the DNJ inhibitor on the enzyme binding site with the most active compounds establishing similar interactions with key residues. Our studies suggest that a rotation of ~90° of some compounds inside the binding pocket is responsible for the complete loss of inhibitory activity. Despite the fact that activity was found only in the mM range, these compounds have served as simple molecular tools for probing the structural features of the enzyme, so that inhibition can be improved in further studies.
- Carreiro, Elisabete P.,Louro, Patrícia,Adriano, Gizé,Guedes, Romina A.,Vannuchi, Nicholas,Costa, Ana R.,Antunes, Célia M.M.,Guedes, Rita C.,Burke
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- Natural (-)-vasicine as a novel source of optically pure 1-benzylpyrrolidin-3-ol
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A facile and scalable methodology for the preparation of optically active (3S)-1-benzylpyrrolidin-3-ol (3), an important drug precursor, is reported. Starting from the naturally occurring alkaloid (-)-vasicine (1), a major alkaloid of the plant Adhatoda vasica, 3 was obtained in 84% overall yield (Scheme 3). Copyright
- Aga, Mushtaq A.,Kumar, Brijesh,Rouf, Abdul,Shah, Bhahwal A.,Andotra, Samar S.,Taneja, Subhash C.
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p. 969 - 977
(2013/06/27)
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- Evolving P450pyr hydroxylase for highly enantioselective hydroxylation at non-activated carbon atom
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Directed evolution of a monooxygenase to achieve very high enantioselectivity for hydroxylation at non-activated carbon atoms is demonstrated for the first time, where a triple mutant of P450pyr hydroxylase is obtained via determination of enzyme structure, iterative saturation mutagenesis, and high-throughput screening with a MS-based ee assay to increase the product ee from 53% to 98% for the hydroxylation of N-benzyl pyrrolidine to (S)-N-benzyl 3-hydroxypyrrolidine. The Royal Society of Chemistry 2012.
- Pham, Son Quang,Pompidor, Guillaume,Liu, Ji,Li, Xiao-Dan,Li, Zhi
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supporting information; experimental part
p. 4618 - 4620
(2012/06/05)
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- PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE N-BENZYL-3 HYDROXYPYRROLIDINES
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The present invention relates to a facile, highly efficient and economical process for the preparation of optically active N-benzyl-3-hydroxypyrrolidine in high yield from a naturally occurring alkaloid vasicine. The natural alkaloid vasicine is used as a precursor of (S)—N-benzyl-3-hydroxypyrrolidine and (R)—N-benzyl-3-hydroxypyrrolidines which can easily be sourced from the medicinal plant Adatoda vasica by the method known in the art and transformed to optical isomers (R) and (S)—N-benzyl-3-hydroxypyrrolidine by the method described in the present invention.
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- A study on the racemization step in the synthesis of pyrrolidinols via cyclic α-hydroxyimides
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Analytical HPLC methods for the determination of the enantiomeric excess of N-protected malimides 1 as well as the corresponding pyrrolidinol 5 and tartarimides 2 and 3 have been established. On this basis, a study to reveal the racemization step in the synthesis of pyrrolidinols from α-hydroxyacids, via chiral cyclic α-hydroxyimides, has been undertaken. It was confirmed that the known, one-step method for the synthesis of the N-protected chiral cyclic imides from α-hydroxydiacids proceeded with little racemization, and partial racemization has been proven to occur during the reduction of the resultant imide 1a with LAH to yield the corresponding pyrrolidinol 5. Conditions have been defined in order to avoid racemization in the LAH reduction step.
- Zheng, Jin-Li,Liu, Hui,Zhang, Yu-Feng,Zhao, Wei,Tong, Jin-Shuan,Ruan, Yuan-Ping,Huang, Pei-Qiang
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p. 257 - 263
(2011/05/12)
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- Inverting the enantioselectivity of P450pyr monooxygenase by directed evolution
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We report the first example of directed evolution of a P450 monooxygenase with inverted enantioselectivity for asymmetric biohydroxylation. The biohydroxylation product of the best mutant 1AF4A has an ee of 83% (R) compared to the wild type's ee of 43% (S). The Royal Society of Chemistry 2010.
- Tang, Weng Lin,Li, Zhi,Zhao, Huimin
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supporting information; experimental part
p. 5461 - 5463
(2010/09/10)
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- High-throughput method for determining the enantioselectivity of enzyme-catalyzed hydroxylations based on mass spectrometry
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(Chemical equation presented) Up to speed: An accurate, sensitive, high-throughput, and simple method for measuring the product ee value of enzyme-catalyzed hydroxylations (see scheme) is based on the use of enantiopure or enantioenriched deuterated substrates and mass spectrometric detection.
- Chen, Yongzheng,Tang, Weng Lin,Mou, Jie,Li, Zhi
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supporting information; experimental part
p. 5278 - 5283
(2010/10/19)
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- A PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE N-BENZYL-3 HYDROXYPYRROLIDINES
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The present invention relates to a facile, highly efficient and economical process for the preparation of optically active N-benzyl-3-hydroxypyrrolidine in high yield from a naturally occurring alkaloid vasicine. The natural alkaloid vasicine is used as a precursor of (S)-N-benzyl-3-hydroxypyrrolidine and (R)-N-benzyl-3-hydroxypyrrolidines which can easily be sourced from the medicinal plant Adatoda vasica by the method known in the art and transformed to optical isomers (R) and (S)-N-benzyl-3-hydroxypyrrolidine by the method described in the present invention.
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Page/Page column 15
(2010/07/10)
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- Highly regioselective oxirane ring-opening of a versatile epoxypyrrolidine precursor of new imino-sugar-based sphingolipid mimics
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An in-depth study of the oxirane ring-opening reaction of a pivotal epoxypyrrolidine is reported. The introduction of various carbon- and heteroatom-centered nucleophiles at C4 has been achieved with high regiocontrol. The structures of the major products were assigned on the basis on an X-ray crystallographic study of six examples. A mechanistic study carried out at the B3LYP/6-31G** level of theory suggested that the steric control of the vinyl substituent was responsible for the regioselectivity. Finally, this approach was used to design and prepare imino-sugar-based sphingolipid mimics. A highly cytotoxic C-octylpyrrolidine is described. This compound was shown to interfere with the metabolism of sphing-olipids in murine melanoma cells, notably in inhibiting the production of glucosylceramide. Wiley-VCH Verlag GmbH & Co. KGaA.
- Rives, Arnaud,Genisson, Yves,Faugeroux, Vanessa,Zedde, Chantal,Lepetit, Christine,Chauvin, Remi,Saffon, Nathalie,Andrieu-Abadie, Nathalie,Colie, Sandra,Levade, Thierry,Baltas, Michel
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experimental part
p. 2474 - 2489
(2009/09/29)
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- PROCESS FOR THE EFFICIENT PREPARATION OF 3-HYDROXY PYRROLIDINE AND DERIVATIVES THEREOF
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The present invention relates to an effective process for the preparation of 3-hydroxypyrrolidine or derivatives thereof. The process comprises (a) protecting a hydroxyl group of 4-halo-3-hydroxybutyric acid, (b) reducing an ester group of the compound obtained from the step (a) to obtain a corresponding alcohol compound, (c) reacting the compound obtained from the step (b) with sulfonyl halide to produce a corresponding sulfonate compound, (d) reacting the compound obtained from the step (c) with an amine to obtain 3-hydroxy-protected pyrrolidine compound, and (e) deprotecting the compound obtained from the step (d) to produce the targeted 3-hydroxypyrrolidine or derivatives thereof. The process provides 3-hydroxypyrrolidine or derivatives thereof with high optical purity, because optical purity of the starting material is substantially retained. In the process, each of the steps is carried out in a mild condition and does not require any special purification. This means that the process is useful and adequate for industrial mass production of 3-hydroxypyrrolidine and derivatives thereof having high optical purity.
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Page/Page column 17
(2009/03/07)
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- PROCESS FOR THE PREPARATION OF CHIRAL 3-HYDROXY PYRROLIDINE COMPOUND AND DERIVATIVES THEREOF HAVING HIGH OPTICAL PURITY
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The present invention relates to an effective process for the preparation of optically pure chiral 3-hydroxypyrrolidine or derivatives thereof. More particularly, the present invention relates to an efficient process for the preparation of chiral 3-hydroxypyrrolidine or derivatives thereof, comprised of introducing a suitable protecting group to the starting material 4-chloro-3-hydroxybutyronitrile. Introduction of the hydroxy-protecting group provides advantages: efficient prevention of formation of side products, enhanced performance of the reduction of the nitrile group of the starting material, and enhanced performance of in-situ in? tramolecular cyclization. The chiral 3-hydroxypyrrolidine compound is produced in high yield and with high purity.
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Page/Page column 18-19
(2010/11/26)
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- PYRROLIDINE DERIVATIVES AS MUSCARINIC RECEPTOR ANTAGONISTS
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This invention relates to pyrrolidine derivatives, which are useful, among other uses, for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors. Processes for the preparation of described compounds, pharmaceutical compositions containing the described compounds and the methods for treating the diseases mediated through muscarinic receptors are also provided.
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Page/Page column 25
(2010/10/20)
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- 1-SUBSTITUTED-3-PYRROLIDINE DERIVATIVES AS MUSCARINIC RECEPTOR ANTAGONISTS
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This invention generally relates to the derivatives of 1 -substituted-3 -pyrroli dines having the structure of Formula (I): The compounds of this invention can function as..muscarinic receptor antagonists, and can be used for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors. The invention also relates to a process for the preparation of the compounds of the present invention. pharmaceutical compositions containing the compounds of the present invention and the methods for treating the diseases mediated through muscarinic receptors.
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- Preparation of (R)- and (S)-N-protected 3-hydroxypyrrolidines by hydroxylation with Sphingomonas sp. HXN-200, a highly active, regio- and stereoselective, and easy to handle biocatalyst
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Hydroxylation of N-benzylpyrrolidine 8 with resting cells of Sphingomonas sp. HXN-200 gave N-benzyl-3-hydroxypyrrolidine 15 in 53% ee (S) with an activity of 5.8 U/g CDW. By changing the "docking/protecting group" in pyrrolidines, hydroxylation activity and enantioselectivity were further improved and the enantiocomplementary formation of 3-hydroxypyrrolidines was achieved: hydroxylation of N-benzoyl-, N-benzyloxycarbonyl-, N-phenoxycarbonyl-, and N-tert-butoxycarbonyl-pyrrolidines 9-12 gave the corresponding 3-hydroxypyrrolidines 16-19 in ee of 52% (R), 75% (R), 39% (S), and 23% (R), respectively, with an activity of 2.2, 16, 14, and 24 U/g CDW, respectively. Simple crystallizations increased the ee of 16-18 to 95% (R), 98% (R), and 96% (S), respectively. Hydroxylation of pyrrolidines 8-12 with soluble cell-free extracts of Sphingomonas sp. HXN-200 and equimolar NADH gave 3-hydroxypyrrolidines 15-19 in nearly the same ee as the products generated by whole cell transformation, suggesting that this strain possesses a novel soluble alkane monooxygenase. Cells of Sphingomonas sp, HXN-200 were produced in large amounts and could be stored at -80 °C for 2 years without significant loss of activity. The frozen cells can be thawed and resuspended for biohydroxylation, providing a highly active and easy to handle biocatalyst for the regio- and stereoselective hydroxylation of nonactivated carbon atoms. These cells were used to prepare 1.0-3.2 g (66.4-93.5% yield) of 3-hydroxypyrrolidines 16-19 by hydroxylation of pyrrolidines 9-12 on 0.9-2 L scale. Preparative hydroxylation was also achieved with growing cells as biocatalysts; hydroxylation of pyrrolidine 11 on 1 L scale gave 1.970 g (79.7% yield) of 3-hydroxypyrrolidine 18.
- Li,Feiten,Chang,Duetz,Van Beilen,Witholt
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p. 8424 - 8430
(2007/10/03)
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- Synthesis, 18F-labeling, and biological evaluation of piperidyl and pyrrolidyl benzilates as in vivo ligands for muscarinic acetylcholine receptors
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A series of 31 compounds based on the piperidyl or pyrrolidyl benzilate scaffold were prepared from methyl benzilate and 4-piperidinol, (R)-(+)-3-piperidinol, or (R)-(+)-3-pyrrolidinol. Amine substituents included alkyl and aralkyl groups. In vitro Ki values ranged from 0.05 nM to >100 nM. (R)-N-(2-Fluoroethyl)-3-piperidyl benzilate (3-FEPB, 22, Ki = 12.1 nM) and N-(2-fluoroethyl)-4-piperidyl benzilate (4-FEPB, 8, Ki = 1.83 nM) were selected for radiolabeling with fluorine-18. Using alkylation with 2-[18F]fluoroethyl triflate, 3-[18F]FEPB (42) and 4-[18F]-FEPB (43) were produced in 7-9% radiochemical yield and >97% radiochemical purity. For in vivo studies, retention was moderate in mouse brain for 42; however, blocking with scopolamine showed that uptake was not muscarinic cholinergic receptor-mediated. Conversely, 43 exhibited high, receptor-mediated retention in mouse brain, with significant clearance after 1 h. These results suggest that 43 could have applications as an in vivo probe for measuring endogenous acetylcholine levels.
- Skaddan,Kilbourn,Snyder,Sherman,Desmond,Frey
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p. 4552 - 4562
(2007/10/03)
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- Preparation of optically active N-benzyl-3-hydroxypyrrolidine by enzymatic hydroxylation
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Hydroxylation of N-benzylpyrrolidine 2 with Pseudomonas oleovorans GPo1 afforded 62% of (R)-N-benzyl-3-hydroxypyrrolidine 3 in 52% e.e. This reaction was catalyzed by the alkane hydroxylase system in this strain, which was demonstrated by hydroxylation of 2 with Escherichia coli GEc137 (pGEc47), a recombinant strain that carries the genes for the alkane hydroxylase system of P. oleovorans GPo1. In a set of 70 alkane-degrading microorganisms, 12 were found to catalyze the biotransformation of 2 into 3 by screening with a microtiter plate technique. Hydroxylation of 2 with isolates HXN-1100 and HXN-200 gave 67% of (R)-3 in 70% e.e. and 62% of (S)-3 in 53% e.e., respectively.
- Li, Zhi,Feiten, Hans-Juergen,Van Beilen, Jan B.,Duetz, Wouter,Witholt, Bernard
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p. 1323 - 1333
(2007/10/03)
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- Lipase-catalyzed practical synthesis of (R)-1-benzyl-3-hydroxy-2,5-pyrrolidinedione and its related compounds
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A practical method for preparing (R)-1-benzyl-3-hydroxy-2,5-pyrrolidinedione (1) was investigated by the use of the enzymatic hydrolysis of its acetate (2a). Among several hydrolases examined here, lipase PS from Pseudomonas cepacia gave the best result: In a mixed solvent (1:1 v/v) of dioxane and a phosphate buffer (pH 7), the hydrolysis took place smoothly with a high enantioselectivity (E > 3000). Several 3-alkanoyl derivatives of 1 were subjected to the lipase PS-catalyzed hydrolysis. The chain length of the alkanoyl does not noticeably influence the reaction rate or the enantioselectivity. In contrast, the hydrolysis of the 1-benzoyl derivative proceeded slowly with a low enantioselectivity (E = 19). The syntheses of optically active 3-hydroxypyrrolidines and 3-hydroxypiperidines were also achieved under the reaction conditions similar to the lipase PS-catalyzed hydrolysis of 2a.
- Tomori, Hiroshi,Shibutani, Kuniko,Ogura, Katsuyuki
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p. 207 - 215
(2007/10/03)
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- 2-Dibenzylaminobutane-1,4-diol: A Versatile Intermediate for a Chirospecific β-amino Acid Synthesis
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Starting from the chiral building block 1, which is readily available from natural aspartic acid, a concise and versatile synthesis of optically active β-amino acids including β-proline derivatives is reported.Regioselective transformations of the 1,4-bis-electrophile 2 are facilitated by an anchimeric participation.
- Gmeiner, Peter,Orecher, Florian,Thomas, Christoph,Weber, Klaus
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p. 381 - 382
(2007/10/02)
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- 4-[(Alkylamino)methyl]furo[3,2-c]pyridines: A new series of selective κ- receptor agonists
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The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2- c]pyridines (16-23, 26, 27) and their activities as κ-opioid receptor agonists are described. κ-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (κ- specific tissue), the 3-pyrrolidinol analogue 17 (IC50 = 2.7 nM) was found to be approximately 5-fold more potent than the corresponding pyrrolidine analogue 16 (IC50 = 15 nM). In the rat and hamster vasa deferentia (μ- specific and δ-specific tissues, respectively), 17 showed only weak antagonist activity (pK(B) > 5.5), underlining its selectivity for the κ- opioid receptor. The major activity for 17 is resident in the 4S,3'S-isomer 26 (rabbit vas deferens IC50 = 1.1 nM). Compound 26 displays excellent antinociceptive activity, as determined in the mouse acetylcholine-induced abdominal constriction test (ED50 = 0.001 mg/kg, sc).
- Naylor,Judd,Scopes,Hayes,Birch
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p. 2138 - 2144
(2007/10/02)
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- Fluoronaphthyridines and -quinolines as Antibacterial Agents. 5. Synthesis and Antimicrobial Activity of Chiral 1-tert-Butyl-6-fluoro-7-substituted-naphthyridones
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A series of novel 7-substituted-1-tert-butyl-6-fluoronaphthyridone-3-carboxylic acids has been prepared.These derivatives are characterized by chiral aminopyrrolidine substituents at the 7 position.In this paper we report the full details of the asymmetric synthesis of this series of compounds.Structure-activity relationship studies indicate that the absolute stereochemistry at the asymmetric centers of the pyrrolidine ring is critical for maintaining good activity.Compounds 60 and 61 (3-amino-4-methylpyrrolidine enantiomers) were selected for preclinical evaluation.
- Cesare, P. Di,Bouzard, D.,Essiz, M.,Jacquet, J. P.,Ledoussal, B.,et al.
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p. 4205 - 4213
(2007/10/02)
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- Stereoselectivity of a Potent Calcium Antagonist, 1-Benzyl-3-pyrrolidinyl Methyl 2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
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Four enantiomers (3a-d) of the title compound, YM-09730 (3), were synthesized by the reaction of (-)- or (+)-5-(methoxycarbonyl)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1a or 1b) with (S)- or (R)-1-benzyl-3-pyrrolidinol (2a or 2b). Nitrendipine binding affinity and coronary vasodilating activity of these compounds were evaluated.The absolute configuration of the most potent enantiomer (3a) with the longest duration was unequivocally determined to be (S)-1,4-dihydropyridine-C4 and (S)-pyrrolidine-C3 (S,S) by X-ray crystallographic study on 3a*HBr as well as 3a*HCl.The configuration of 1a corresponds to R, and the other enantiomers of 3 were respectively determined by chemical correlation.The potency order of the four enantiomers was (S,S)-3a > (S,R)-3b > (R,R)-3d > (R,S)-3c.Latent chiral characters of nifedipine derivatives with the identical ester groups were assigned by comparison of their puckering modes of 1,4-dihydropyridine (DHP) rings with those found in 3a*HCl or 3a*HBr.On the basis of the assignment, it has been revealed that the (S)-DHP nifedipine derivatives possess the synperiplanar carbonyl group at C5.The conformational restriction may be a factor causing stereoselectivity of antagonism.
- Tamazawa, Kazuharu,Arima, Hideki,Koijma, Tadao,Isomura, Yasuo,Okada, Minoru,et al.
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p. 2504 - 2511
(2007/10/02)
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- SYNTHETIC ROUTES TO CHIRAL 3-PYRROLIDINOLS
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Short convenient syntheses of chiral 3-pyrrolidinols and related compounds are described.
- Bhat, Krishna L.,Flanagan, Denise M.,Joullie, Madeleine M.
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p. 587 - 598
(2007/10/02)
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