- Rapid Synthesis of α-Chiral Piperidines via a Highly Diastereoselective Continuous Flow Protocol
-
A practical continuous flow protocol has been developed using readily accessible N-(tert-butylsulfinyl)-bromoimine and Grignard reagents, providing various functionalized piperidines (34 examples) in superior results (typically >80% yield and with >90:10 dr) within minutes. The high-performance scale-up is smoothly carried out, and efficient synthesis of the drug precursor further showcases its utility. This flow process offers rapid and scalable access to enantioenriched α-substituted piperidines.
- Shan, Chao,Xu, Jinping,Cao, Liming,Liang, Chaoming,Cheng, Ruihua,Yao, Xiantong,Sun, Maolin,Ye, Jinxing
-
p. 3205 - 3210
(2022/05/07)
-
- Borenium-Catalyzed Reduction of Pyridines through the Combined Action of Hydrogen and Hydrosilane
-
Mesoionic carbene-stabilized borenium ions efficiently reduce substituted pyridines to piperidines in the presence of a hydrosilane and a hydrogen atmosphere. Control experiments and deuterium labeling studies demonstrate reversible hydrosilylation of the pyridine, enabling full reduction of the N-heterocycle under milder conditions. The silane is a critical reaction component to prevent adduct formation between the piperidine product and the borenium catalyst.
- Clarke, Joshua J.,Maekawa, Yuuki,Nambo, Masakazu,Crudden, Cathleen M.
-
supporting information
p. 6617 - 6621
(2021/09/02)
-
- Zinc-Catalyzed Asymmetric Hydrosilylation of Cyclic Imines: Synthesis of Chiral 2-Aryl-Substituted Pyrrolidines as Pharmaceutical Building Blocks
-
The first successful enantioselective hydrosilylation of cyclic imines promoted by a chiral zinc complex is reported. In situ generated zinc-ProPhenol complex with silane afforded pharmaceutically relevant enantioenriched 2-aryl-substituted pyrrolidines in high yields and with excellent enantioselectivities (up to 99% ee). The synthetic utility of presented methodology is demonstrated in an efficient synthesis of the corresponding chiral cyclic amines, being pharmaceutical drug precursors to the Aticaprant and Larotrectinib. (Figure presented.).
- W?glarz, Izabela,Michalak, Karol,Mlynarski, Jacek
-
supporting information
p. 1317 - 1321
(2020/12/09)
-
- Borane-Catalyzed Reduction of Pyridines via a Hydroboration/Hydrogenation Cascade
-
We have developed a method for a B(C6F5)3-catalyzed hydroboration/hydrogenation cascade reduction of pyridines. The method was particularly effective for 2,3-disubstituted pyridines, which generated piperidines in high yields with high cis selectivity. Mechanistic studies indicated that the pyridine substrates and the piperidine products sequentially acted as bases in cooperation with B(C6F5)3to split H2. The broad functional group tolerance of the method allowed its use for the synthesis of some biologically active molecules.
- Yang, Zhao-Ying,Luo, Heng,Zhang, Ming,Wang, Xiao-Chen
-
p. 10824 - 10829
(2021/09/08)
-
- Enantioselective Synthesis of 2-Substituted Pyrrolidines via Intramolecular Reductive Amination
-
Catalyzed by the complex generated in situ from iridium and the chiral ferrocene ligand, tert -butyl (4-oxo-4-arylbutyl)carbamate substrates were deprotected and then reductively cyclised to form 2-substituted arylpyrrolidines in a one-pot manner, in which the intramolecular reductive amination was the key step. A range of chiral 2-substituted arylpyrrolidines were synthesised in up to 98percent yield and 92percent ee.
- Chang, Mingxin,Guo, Haodong,Huang, Haizhou,Zhang, Tao,Zhao, Wenlei,Zhou, Huan
-
p. 2713 - 2719
(2019/06/19)
-
- α-Functionalization of Cyclic Secondary Amines: Lewis Acid Promoted Addition of Organometallics to Transient Imines
-
Cyclic imines, generated in situ from their corresponding N-lithiated amines and a ketone hydride acceptor, undergo reactions with a range of organometallic nucleophiles to generate α-functionalized amines in a single operation. Activation of the transient imines by Lewis acids that are compatible with the presence of lithium alkoxides was found to be crucial to accommodate a broad range of nucleophiles including lithium acetylides, Grignard reagents, and aryllithiums with attenuated reactivities.
- Paul, Anirudra,Seidel, Daniel
-
supporting information
p. 8778 - 8782
(2019/06/07)
-
- H2 Activation by Non-Transition-Metal Systems: Hydrogenation of Aldimines and Ketimines with LiN(SiMe3)2
-
In recent years, H2 activation at non-transition-metal centers has met with increasing attention. Here, a system in which H2 is activated and transferred to aldimines and ketimines using substoichiometric amounts of lithium bis(trimethylsilyl)amide is reported. Notably, the reaction tolerates the presence of acidic protons in the α-position. Mechanistic investigations indicated that the reaction proceeds via a lithium hydride intermediate as the actual reductant.
- Elliott, Daniel C.,Marti, Alex,Mauleón, Pablo,Pfaltz, Andreas
-
p. 1918 - 1922
(2019/01/16)
-
- Hydrogenation of N-Heteroarenes Using Rhodium Precatalysts: Reductive Elimination Leads to Formation of Multimetallic Clusters
-
A rhodium-catalyzed method for the hydrogenation of N-heteroarenes is described. A diverse array of unsubstituted N-heteroarenes including pyridine, pyrrole, and pyrazine, traditionally challenging substrates for hydrogenation, were successfully hydrogenated using the organometallic precatalysts, [(η5-C5Me5)Rh(N-C)H] (N-C = 2-phenylpyridinyl (ppy) or benzo[h]quinolinyl (bq)). In addition, the hydrogenation of polyaromatic N-heteroarenes exhibited uncommon chemoselectivity. Studies into catalyst activation revealed that photochemical or thermal activation of [(η5-C5Me5)Rh(bq)H] induced C(sp2)-H reductive elimination and generated the bimetallic complex, [(η5-C5Me5)Rh(μ2,η2-bq)Rh(η5-C5Me5)H]. In the presence of H2, both of the [(η5-C5Me5)Rh(N-C)H] precursors and [(η5-C5Me5)Rh(μ2,η2-bq)Rh(η5-C5Me5)H] converted to a pentametallic rhodium hydride cluster, [(η5-C5Me5)4Rh5H7], the structure of which was established by NMR spectroscopy, X-ray diffraction, and neutron diffraction. Kinetic studies on pyridine hydrogenation were conducted with each of the isolated rhodium complexes to identify catalytically relevant species. The data are most consistent with hydrogenation catalysis prompted by an unobserved multimetallic cluster with formation of [(η5-C5Me5)4Rh5H7] serving as a deactivation pathway.
- Kim, Sangmin,Loose, Florian,Bezdek, Máté J.,Wang, Xiaoping,Chirik, Paul J.
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p. 17900 - 17908
(2019/11/19)
-
- Chemoenzymatic Synthesis of Substituted Azepanes by Sequential Biocatalytic Reduction and Organolithium-Mediated Rearrangement
-
Enantioenriched 2-aryl azepanes and 2-arylbenzazepines were generated biocatalytically by asymmetric reductive amination using imine reductases or by deracemization using monoamine oxidases. The amines were converted to the corresponding N′-aryl ureas, which rearranged on treatment with base with stereospecific transfer of the aryl substituent to the 2-position of the heterocycle via a configurationally stable benzyllithium intermediate. The products are previously inaccessible enantioenriched 2,2-disubstituted azepanes and benzazepines.
- Zawodny, Wojciech,Montgomery, Sarah L.,Marshall, James R.,Finnigan, James D.,Turner, Nicholas J.,Clayden, Jonathan
-
supporting information
p. 17872 - 17877
(2019/01/04)
-
- One-Pot Reductive Allylation of Amides by Using a Combination of Titanium Hydride and an Allylzinc Reagent: Application to a Total Synthesis of (-)-Castoramine
-
A one-pot direct reductive allylation protocol has been developed for the synthesis of secondary amines by using titanium hydride and an allylzinc reagent. This protocol is applicable to a broad range of substrates, including acyclic amides, benzamides, α,β-unsaturated amides, and lactams. The stereochemical outcome obtained from the reaction with crotylzinc reagent suggested that the allylation reaction proceeds through a six-membered cyclic transition state. A total synthesis of (-)-castoramine was accomplished by following this protocol for the highly stereoselective construction of contiguous stereocenters.
- Itabashi, Suguru,Shimomura, Masashi,Sato, Manabu,Azuma, Hiroki,Okano, Kentaro,Sakata, Juri,Tokuyama, Hidetoshi
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p. 1786 - 1790
(2018/07/03)
-
- Hydrogenation of Pyridines Using a Nitrogen-Modified Titania-Supported Cobalt Catalyst
-
Novel heterogeneous catalysts were prepared by impregnation of titania with a solution of cobalt acetate/melamine and subsequent pyrolysis. The resulting materials show an unusual nitrogen-modified titanium structure through partial implementation of nitrogen into the support. The optimal catalyst displayed good activity and selectivity for challenging pyridine hydrogenation under acid free conditions in water as solvent.
- Chen, Feng,Li, Wu,Sahoo, Basudev,Kreyenschulte, Carsten,Agostini, Giovanni,Lund, Henrik,Junge, Kathrin,Beller, Matthias
-
supporting information
p. 14488 - 14492
(2018/10/26)
-
- Direct α-C-H bond functionalization of unprotected cyclic amines
-
Cyclic amines are ubiquitous core structures of bioactive natural products and pharmaceutical drugs. Although the site-selective abstraction of C-H bonds is an attractive strategy for preparing valuable functionalized amines from their readily available parent heterocycles, this approach has largely been limited to substrates that require protection of the amine nitrogen atom. In addition, most methods rely on transition metals and are incompatible with the presence of amine N-H bonds. Here we introduce a protecting-group-free approach for the α-functionalization of cyclic secondary amines. An operationally simple one-pot procedure generates products via a process that involves intermolecular hydride transfer to generate an imine intermediate that is subsequently captured by a nucleophile, such as an alkyl or aryl lithium compound. Reactions are regioselective and stereospecific and enable the rapid preparation of bioactive amines, as exemplified by the facile synthesis of anabasine and (-)-solenopsin A.
- Chen, Weijie,Ma, Longle,Paul, Anirudra,Seidel, Daniel
-
p. 165 - 169
(2018/02/06)
-
- Catalytic Hydrogenation of Arenes in Water Over In Situ Generated Ruthenium Nanoparticles Immobilized on Carbon
-
We describe a tandem process to generate active Ru nanoparticles (≈7 nm) immobilised in situ on carbon from an organometallic precursor and formic acid to afford the hydrogenation of a wide range of arenes and heteroarenes in yields up to 72 % with high conversions and selectivities for the desired products. The hydrogenation of several substrates analogous to lignin-derived fragments to the corresponding alicyclic products was also achieved. Our experimental investigations evidenced that the observed enhanced activity for arene hydrogenation was driven by the unique structural advantages of the organometallic precursor to activate formic acid, in which the presence of a nitrogen ligand is crucial to achieve a high catalytic activity. TEM analysis revealed the formation of Ru0 nanoparticles, and Hg0 poisoning experiments support the heterogeneous nature of the active catalyst.
- Dwivedi, Ambikesh Dhar,Rai, Rohit Kumar,Gupta, Kavita,Singh, Sanjay Kumar
-
p. 1930 - 1938
(2017/06/13)
-
- Synthesis of chiral cyclic amines via Ir-catalyzed enantioselective hydrogenation of cyclic imines
-
A highly enantioselective hydrogenation of cyclic imines for synthesis of chiral cyclic amines has been realized. With the complex of iridium and (R,R)-f-spiroPhos as the catalyst, a range of cyclic 2-aryl imines were smoothly hydrogenated under mild conditions without any additive to provide the corresponding chiral cyclic amines with excellent enantioselectivities of up to 98% ee. Moreover, this method could be successfully applied to the synthesis of (+)-(6S,10bR)-McN-4612-Z.
- Zhang, Ying,Kong, Duanyang,Wang, Rui,Hou, Guohua
-
p. 3006 - 3012
(2017/04/11)
-
- NHC-stabilised Rh nanoparticles: Surface study and application in the catalytic hydrogenation of aromatic substrates
-
New Rh-NPs stabilised by N-Heterocyclic Carbenes (NHC) were synthesized by decomposition of [Rh(η3-C3H5)3] under H2 atmosphere and fully characterized. Surface studies by FT-IR and NMR spectroscopy employing isotopically labelled ligands were also performed. The Rh0.2 NPs are active catalysts in the reduction of various aromatic substrates. In the reduction of phenol, high selectivities to cyclohexanone or cyclohexanol were obtained depending on the reaction conditions. However, this catalytic system exhibited much lower activity in the hydrogenation of substituted phenols. Pyridine was easily hydrogenated under mild conditions and interestingly, the hydrogenation of 4-methyl and 4-trifluoromethylpyridine resulted slower than that of 2-methylpyridine. The hydrogenation of 1-(pyridin-2-yl)propan-2-one provided the β-enaminone 13a in high yield as a consequence of the partial reduction of the pyridine ring followed by isomerization. Quinoline could be either partially hydrogenated to 1,2,3,4-tetrahydroquinoline or fully reduced to decahydroquinoline by adjusting the reaction conditions.
- Martinez-Espinar, Francisco,Blondeau, Pascal,Nolis, Pau,Chaudret, Bruno,Claver, Carmen,Castillón, Sergio,Godard, Cyril
-
p. 113 - 127
(2017/09/08)
-
- Iterative direct C(sp3)-H functionalization of amines: diastereoselective divergent syntheses of ??,α′-disubstituted alicyclic amines
-
A novel iterative C(sp3)-H oxygenation/C-C bond formation strategy, which avoids repetitive N-protection/-deprotection steps, was developed for direct α,α′-difunctionalization of alicyclic amines. The method is highly efficient and stereoselective in producing syn-α,α′-disubstituted aliphatic N-heterocycles. Synthetic potential and practicability of the method was demonstrated by an easy and straightforward synthesis of neuroactive alkaloid nor-lobelane and its derivatives.
- Mahato, Sujit,Jana, Chandan K.
-
supporting information
p. 1655 - 1660
(2017/02/23)
-
- Exploration of flexible phenylpropylurea scaffold as novel cardiac myosin activators for the treatment of systolic heart failure
-
A series of flexible urea derivatives have been synthesized and demonstrated as selective cardiac myosin ATPase activator. Among them 1-phenethyl-3-(3-phenylpropyl)urea (1, cardiac myosin ATPase activation at 10?μM?=?51.1%; FS?=?18.90; EF?=?12.15) and 1-benzyl-3-(3-phenylpropyl)urea (9, cardiac myosin ATPase activation?=?53.3%; FS?=?30.04; EF?=?18.27) showed significant activity in?vitro and in?vivo. The change of phenyl ring with tetrahydropyran-4-yl moiety viz., 1-(3-phenylpropyl)-3-((tetrahydro-2H-pyran-4-yl)methyl)urea (14, cardiac myosin ATPase activation?=?81.4%; FS?=?20.50; EF?=?13.10), and morpholine moiety viz., 1-(2-morpholinoethyl)-3-(3-phenylpropyl)urea (21, cardiac myosin ATPase activation?=?44.0%; FS?=?24.79; EF?=?15.65), proved to be efficient to activate the cardiac myosin. The potent compounds 1, 9, 14 and 21 were found to be selective for cardiac myosin over skeletal and smooth myosins. Thus, these urea derivatives are potent scaffold to develop as a newer cardiac myosin activator for the treatment of systolic heart failure.
- Manickam, Manoj,Jalani, Hitesh B.,Pillaiyar, Thanigaimalai,Sharma, Niti,Boggu, Pulla Reddy,Venkateswararao, Eeda,Lee, You-Jung,Jeon, Eun-Seok,Jung, Sang-Hun
-
p. 379 - 391
(2017/04/24)
-
- B(C6F5)3-Catalyzed Cascade Reduction of Pyridines
-
B(C6F5)3 has been found to be an effective catalyst for reduction of pyridines and other electron-deficient N-heteroarenes with hydrosilanes (or hydroboranes) and amines as the reducing reagents. The success of this development hinges upon the realization of a cascade process of dearomative hydrosilylation (or hydroboration) and transfer hydrogenation. The broad functional-group tolerance (e.g. ketone, ester, unactivated olefins, nitro, nitrile, heterocycles, etc.) implies high practical utility.
- Liu, Zhi-Yun,Wen, Zhi-Hui,Wang, Xiao-Chen
-
supporting information
p. 5817 - 5820
(2017/05/12)
-
- A General and Highly Selective Cobalt-Catalyzed Hydrogenation of N-Heteroarenes under Mild Reaction Conditions
-
Herein, a general and efficient method for the homogeneous cobalt-catalyzed hydrogenation of N-heterocycles, under mild reaction conditions, is reported. Key to success is the use of the tetradentate ligand tris(2-(diphenylphosphino)phenyl)phosphine). This non-noble metal catalyst system allows the selective hydrogenation of heteroarenes in the presence of a broad range of other sensitive reducible groups.
- Adam, Rosa,Cabrero-Antonino, Jose R.,Spannenberg, Anke,Junge, Kathrin,Jackstell, Ralf,Beller, Matthias
-
supporting information
p. 3216 - 3220
(2017/03/17)
-
- Simultaneous engineering of an enzyme's entrance tunnel and active site: The case of monoamine oxidase MAO-N
-
A new directed evolution approach is presented to enhance the activity of an enzyme and to manipulate stereoselectivity by focusing iterative saturation mutagenesis (ISM) simultaneously on residues lining the entrance tunnel and the binding pocket. This combined mutagenesis strategy was applied successfully to the monoamine oxidase from Aspergillus Niger (MAO-N) in the reaction of sterically demanding substrates which are of interest in the synthesis of chiral pharmaceuticals based on the benzo-piperidine scaffold. Reversal of enantioselectivity of Turner-type deracemization was achieved in the synthesis of (S)-1,2,3,4-tetrahydro-1-methyl-isoquinoline, (S)-1,2,3,4-tetrahydro-1-ethylisoquinoline and (S)-1,2,3,4-tetrahydro-1-isopropylisoquinoline. Extensive molecular dynamics simulations indicate that the altered catalytic profile is due to increased hydrophobicity of the entrance tunnel acting in concert with the altered shape of the binding pocket.
- Li, Guangyue,Yao, Peiyuan,Gong, Rui,Li, Jinlong,Liu, Pi,Lonsdale, Richard,Wu, Qiaqing,Lin, Jianping,Zhu, Dunming,Reetz, Manfred T.
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p. 4093 - 4099
(2017/07/10)
-
- Enantioselective Direct Synthesis of Free Cyclic Amines via Intramolecular Reductive Amination
-
Chiral cyclic amines can be prepared via intramolecular reductive amination of N-Boc-protected amino ketones in a one-pot process. With the complex of iridium and f-spiroPhos as the catalyst, a range of N-Boc-protected amino ketones are smoothly transformed into chiral cyclic free amines in high yields and excellent enantioselectivities (up to 97% ee). Moreover, this method can also be successfully applied to the synthesis of a κ-opioid receptor selective antagonist, (S)-1.
- Zhang, Ying,Yan, Qiaozhi,Zi, Guofu,Hou, Guohua
-
supporting information
p. 4215 - 4218
(2017/08/23)
-
- Determination of the Absolute Configuration of Cyclic Amines with Bode's Chiral Hydroxamic Esters Using the Competing Enantioselective Conversion Method
-
The competing enantioselective conversion (CEC) strategy has been extended to cyclic amines. The basis for the CEC approach is the use of two complementary, enantioselective reactions to determine the configuration of the enantiopure substrate. Bode's chiral acylated hydroxamic acids are very effective enantioselective acylating agents for a variety of amines. Pseudoenantiomers of these acyl-transfer reagents were prepared and demonstrated to react with enantiopure cyclic amines with modest to high selectivity. The products were analyzed by ESI-MS to determine selectivity, and the results were used to assign the configuration of the amine substrate. The method was applicable to a variety of cyclic amines as well as primary amines and acyclic secondary amines. The method is limited to amines that are unhindered enough to react with the reagents, and not all amine substitution patters lead to high selectivity.
- Burtea, Alexander,Rychnovsky, Scott D.
-
p. 4195 - 4198
(2017/08/23)
-
- Enzyme Cascades in Whole Cells for the Synthesis of Chiral Cyclic Amines
-
The increasing diversity of reactions mediated by biocatalysts has led to development of multistep in vitro enzyme cascades, taking advantage of generally compatible reaction conditions. The construction of pathways within single whole cell systems is much less explored, yet has many advantages. Herein we report the generation of a successful whole cell de novo enzyme cascade for the diastereoselective and/or enantioselective conversion of simple, linear keto acids into valuable cyclic amine products. The pathway starts with carboxylic acid reduction that triggers a transamination, imine formation, and subsequent imine reduction. Construction and optimization of the system was achieved by standard genetic manipulation and the cascade required only starting material, amine donor, and whole cell catalyst with cofactors provided internally by glucose metabolism. A panel of synthetic keto acids provided access to piperidines in high conversions (up to 93%) and enantiomeric excess (up to 93%).
- Hepworth, Lorna J.,France, Scott P.,Hussain, Shahed,Both, Peter,Turner, Nicholas J.,Flitsch, Sabine L.
-
p. 2920 - 2925
(2017/05/31)
-
- Stereoselectivity and Structural Characterization of an Imine Reductase (IRED) from Amycolatopsis orientalis
-
The imine reductase AoIRED from Amycolatopsis orientalis (Uniprot R4SNK4) catalyzes the NADPH-dependent reduction of a wide range of prochiral imines and iminium ions, predominantly with (S)-selectivity and with ee's of up to >99%. AoIRED displays up to 100-fold greater catalytic efficiency for 2-methyl-1-pyrroline (2MPN) compared to other IREDs, such as the enzyme from Streptomyces sp. GF3546, which also exhibits (S)-selectivity, and thus, AoIRED is an interesting candidate for preparative synthesis. AoIRED exhibits unusual catalytic properties, with inversion of stereoselectivity observed between structurally similar substrates, and also, in the case of 1-methyl-3,4-dihydroisoquinoline, for the same substrate, dependent on the age of the enzyme after purification. The structure of AoIRED has been determined in an "open" apo-form, revealing a canonical dimeric IRED fold in which the active site is formed between the N- and C-terminal domains of participating monomers. Co-crystallization with NADPH gave a "closed" form in complex with the cofactor, in which a relative closure of domains, and associated loop movements, has resulted in a much smaller active site. A ternary complex was also obtained by cocrystallization with NADPH and 1-methyl-1,2,3,4-tetrahydroisoquinoline [(MTQ], and it reveals a binding site for the (R)-amine product, which places the chiral carbon within 4 ? of the putative location of the C4 atom of NADPH that delivers hydride to the C? -N bond of the substrate. The ternary complex has permitted structure-informed mutation of the active site, resulting in mutants including Y179A, Y179F, and N241A, of altered activity and stereoselectivity.
- Aleku, Godwin A.,Man, Henry,France, Scott P.,Leipold, Friedemann,Hussain, Shahed,Toca-Gonzalez, Laura,Marchington, Rebecca,Hart, Sam,Turkenburg, Johan P.,Grogan, Gideon,Turner, Nicholas J.
-
p. 3880 - 3889
(2016/07/06)
-
- Novel Approach toward 3,3-Difluoropiperidines from Easily Available Starting Materials and Synthesis of a New Phosphodiesterase Inhibitor
-
A novel methodology for the synthesis of 3,3-difluoropiperidines has been developed. The target compounds are prepared in three steps using a robust protocol and simple starting materials. The incorporation of the fluorine is achieved by using the cheap and easily available ethyl 2-bromo-2,2-difluoroacetate as building block. Using this methodology, a new potent in vitro phosphodiesterase 2A (PDE2A) inhibitor containing the functionalized fluorinated piperidine scaffold has been prepared.
- Giacoboni, Jessica,Clausen, Rasmus P.,Marigo, Mauro
-
p. 2803 - 2806
(2016/12/16)
-
- Compounds with cardiac myosin activating function and pharmaceutical composition containing the same for treating or preventing heart failure
-
The present invention relates to a compound having a cardiotonic activating function and a pharmaceutical composition containing the same. The composition comprising the compound according to the present invention is effective in preventing or treating heart failure. In addition, the compound is represented by chemical formula 2 or is pharmaceutically acceptable salt thereof.COPYRIGHT KIPO 2016
- -
-
Paragraph 0646-0648
(2017/02/02)
-
- One-Pot Cascade Synthesis of Mono- and Disubstituted Piperidines and Pyrrolidines using Carboxylic Acid Reductase (CAR), ω-Transaminase (ω-TA), and Imine Reductase (IRED) Biocatalysts
-
Access to enantiomerically pure chiral mono- and disubstituted piperidines and pyrrolidines has been achieved using a biocatalytic cascade involving carboxylic acid reductase (CAR), ω-transaminase (ω-TA), and imine reductase (IRED) enzymes. Starting from keto acids or keto aldehydes, substituted piperidine or pyrrolidine frameworks can be generated in high conversion, ee, and de in one pot, with each biocatalyst exhibiting chemo-, regio-, and/or stereoselectivity during catalysis. The study also includes a systematic investigation of the effect of the position of a methyl group ring substituent on the IRED-catalyzed reduction of a chiral imine. Analysis of the selectivity observed in these reactions revealed an interesting balance between substrate versus enzyme control; the configurations of the products obtained were rationalized on the basis of minimizing 1,3- or 1,2-steric interactions with incoming NADPH.
- France, Scott P.,Hussain, Shahed,Hill, Andrew M.,Hepworth, Lorna J.,Howard, Roger M.,Mulholland, Keith R.,Flitsch, Sabine L.,Turner, Nicholas J.
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p. 3753 - 3759
(2016/07/06)
-
- Combined Imine Reductase and Amine Oxidase Catalyzed Deracemization of Nitrogen Heterocycles
-
A novel amine oxidase (AO)/imine reductase (IRED) system was developed for the deracemization of racemic amines. By combining (R)-6-hydroxy-d-nicotine oxidase (6-HDNO) with an (R)-IRED, a panel of racemic 2-substituted piperidines and pyrrolidines were deracemized to yield the (S)-amines in high yields and enantiomeric excess values. Other N-heterocycles were deracemized with monoamine oxidase (MAO-N) or 6-HDNO in combination with ammonia borane, which allowed comparison of the two enzyme deracemization approaches with that involving a chemical reducing agent.
- Heath, Rachel S.,Pontini, Marta,Hussain, Shahed,Turner, Nicholas J.
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p. 117 - 120
(2016/01/26)
-
- An (R)-imine reductase biocatalyst for the asymmetric reduction of cyclic imines
-
Although the range of biocatalysts available for the synthesis of enantiomerically pure chiral amines continues to expand, few existing methods provide access to secondary amines. To address this shortcoming, we have over-expressed the gene for an (R)-imine reductase [(R)-IRED] from Streptomyces sp. GF3587 in Escherichia coli to create a recombinant whole-cell biocatalyst for the asymmetric reduction of prochiral imines. The (R)-IRED was screened against a panel of cyclic imines and two iminium ions and was shown to possess high catalytic activity and enantioselectivity. Preparative-scale synthesis of the alkaloid (R)-coniine (90 % yield; 99 % ee) from the imine precursor was performed on a gram-scale. A homology model of the enzyme active site, based on the structure of a closely related (R)-IRED from Streptomyces kanamyceticus, was constructed and used to identify potential amino acids as targets for
- Hussain, Shahed,Leipold, Friedemann,Man, Henry,Wells, Elizabeth,France, Scott P.,Mulholland, Keith R.,Grogan, Gideon,Turner, Nicholas J.
-
p. 579 - 583
(2015/03/05)
-
- Structure, activity and stereoselectivity of NADPH-dependent oxidoreductases catalysing the S-selective reduction of the imine substrate 2-methylpyrroline
-
Oxidoreductases from Streptomyces sp. GF3546 [3546-IRED], Bacillus cereus BAG3X2 (BcIRED) and Nocardiopsis halophila (NhIRED) each reduce prochiral 2-methylpyrroline (2MPN) to (S)-2-methylpyrrolidine with >95 % ee and also a number of other imine substrates with good selectivity. Structures of BcIRED and NhIRED have helped to identify conserved active site residues within this subgroup of imine reductases that have S selectivity towards 2MPN, including a tyrosine residue that has a possible role in catalysis and superimposes with an aspartate in related enzymes that display R selectivity towards the same substrate. Mutation of this tyrosine residue - Tyr169 - in 3546-IRED to Phe resulted in a mutant of negligible activity. The data together provide structural evidence for the location and significance of the Tyr residue in this group of imine reductases, and permit a comparison of the active sites of enzymes that reduce 2MPN with either R or S selectivity.
- Man, Henry,Wells, Elizabeth,Hussain, Shahed,Leipold, Friedemann,Hart, Sam,Turkenburg, Johan P.,Turner, Nicholas J.,Grogan, Gideon
-
p. 1052 - 1059
(2015/05/05)
-
- Compounds with cardiac myosin activating function and pharmaceutical composition containing the same for treating or preventing heart failure
-
Disclosed are a compound having cardiotonic activity and a pharmaceutical composition containing the same, and the composition containing the compound, according to the present invention, is useful for preventing and treating heart failure.COPYRIGHT KIPO 2016
- -
-
Paragraph 0646-0650
(2016/10/07)
-
- Synthesis and kinetic resolution of N-Boc-2-arylpiperidines
-
The chiral base n-BuLi/(-)-sparteine or n-BuLi/(+)-sparteine surrogate promotes kinetic resolution of N-Boc-2-arylpiperidines by asymmetric deprotonation. The enantioenriched starting material was recovered with yields 39-48% and ers up to 97:3. On lithiation then electrophilic quench, 2,2-disubstituted piperidines were obtained with excellent yields and enantioselectivities.
- Cochrane, Edward J.,Leonori, Daniele,Hassall, Lorraine A.,Coldham, Iain
-
p. 9910 - 9913
(2014/08/18)
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- Removal of the pyridine directing group from α-substituted N-(pyridin-2-yl)piperidines obtained via directed Ru-catalyzed sp3 C-H functionalization
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Two strategies, "hydrogenation-hydride reduction" and "quaternization-hydride reduction", are reported that make use of mild reaction conditions (room temperature) to efficiently remove the N-pyridin-2-yl directing group from a diverse set of C-2-substituted piperidines that were synthesized through directed Ru-catalyzed sp3 C-H functionalization. The deprotected products are obtained in moderate to good overall yields irrespective of the strategy followed, indicating that both methods are generally equally effective. Only in the case of 2,6-disubstituted piperidines, could the "quaternization-hydride reduction" strategy not be used. The "hydrogenation-hydride reduction" protocol was successfully applied to trans- and cis-2-methyl-N-(pyridin-2-yl)-6-undecylpiperidine in a short synthetic route toward (±)-solenopsin A (trans diastereoisomer) and (±)-isosolenopsin A (cis diastereoisomer). The absolute configuration of the enantiomers of these fire ant alkaloids could be determined via VCD spectroscopy.
- Smout, Veerle,Peschiulli, Aldo,Verbeeck, Stefan,Mitchell, Emily A.,Herrebout, Wouter,Bultinck, Patrick,Vande Velde, Christophe M. L.,Berthelot, Didier,Meerpoel, Lieven,Maes, Bert U. W.
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p. 9803 - 9814
(2013/10/22)
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- First selective direct mono-arylation of piperidines using ruthenium-catalyzed C-H activation
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A Ru-catalyzed mono-arylation in α-position of saturated cyclic amines is reported employing a C-H activation protocol. Substitution of the pyridine directing group with a bulky group, e.g., trifluoromethyl in the 3-position, proved to be crucial to avoid bis-arylation. This highly selective transformation can be performed with different amines and arylboronate esters. Additionally, the directing group can be cleaved, taking advantage of an unprecedented detrifluoromethylation reaction.
- Schwarz, Maria C.,Dastbaravardeh, Navid,Kirchner, Karl,Schnuerch, Michael,Mihovilovic, Marko D.
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p. 539 - 552
(2013/07/26)
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- An experimental and in situ IR spectroscopic study of the lithiation-substitution of N-Boc-2-phenylpyrrolidine and -piperidine: Controlling the formation of quaternary stereocenters
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A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation-substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified: n-BuLi in THF at -50 °C for 5-30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation-substitution of N-Boc-2-phenylpyrrolidine at -78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using density functional theory calculations and variable-temperature 1H NMR spectroscopy. For the pyrrolidine, the half-life (t1/2) for rotation of the Boc group was found to be ~10 h at -78 °C and ~3.5 min at -50 °C. In contrast, for the piperidine, t1/2 was determined to be ~4 s at -78 °C.
- Sheikh, Nadeem S.,Leonori, Daniele,Barker, Graeme,Firth, James D.,Campos, Kevin R.,Meijer, Anthony J. H. M.,O'Brien, Peter,Coldham, Iain
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supporting information; experimental part
p. 5300 - 5308
(2012/05/05)
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- The development of a Selectfluor-mediated oxidative Mannich reaction
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Selectfluor is an easy to handle, air-stable and powerful electrophilic fluorination agent that can be used in a novel oxidative Mannich-type carbon-carbon bond forming process to allylate electron deficient tertiary amines in moderate to good yields. This process is rapid, operationally simple, insensitive to atmospheric conditions and of potentially broad use, especially in the construction of homoallylamines.
- Daniels, Matthew H.,Hubbs, Jed
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scheme or table
p. 3543 - 3546
(2011/07/31)
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- Applications of N′-alkylated derivatives of TsDPEN in the asymmetric transfer hydrogenation of C=O and C=N bonds
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Arene/Ru(II) complexes of (R,R)-N-alkyl-TsDPEN ligands are effective in the asymmetric transfer hydrogenation of ketones and imines in formic acid/triethylamine solution. The complex derived from the N′-Bn derivative of TsDPEN reduces monocyclic imines in up to 60% ee, whilst the N′-Me derivative of TsDPEN forms a more active catalyst than the non-alkylated analogue and reduces ketones in up to 97% ee.
- Martins, Jose E.D.,Contreras Redondo, Miguel A.,Wills, Martin
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experimental part
p. 2258 - 2264
(2010/11/03)
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- C-2 arylation of piperidines through directed transition-metal-catalyzed sp3 C-H activation
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All you need is an open vial! The direct α arylation of cyclic alkylamines (see scheme) requires an open vial, as the hydrogen atom involved in the C(sp3)-H-activation process is ultimately released as hydrogen gas. Reports on the formation of hydrogen gas in direct transition-metal- catalyzed functionalizations are still rare. Open-vial reactions proved crucial to this direct arylation procedure as, upon sealing, catalyst deactivation occurs.
- Prokopcova, Hana,Bergman, Sheba D.,Aelvoet, Karel,Smout, Veerle,Herrebout, Wouter,Van Der Veken, Benjamin,Meerpoel, Lieven,Maes, Bert U. W.
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supporting information; experimental part
p. 13063 - 13067
(2011/02/21)
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- Chiral Lewis base promoted trichlorosilane reduction of ketimines. An enantioselective organocatalytic synthesis of chiral amines
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The reduction of the carbon-nitrogen double bond is an important transformation. Here we report our studies on a family of chiral organic catalysts able to promote the stereoselective reduction of ketimines with trichlorosilane. The very cheap, metal-free catalysts were easily prepared in one step from commercially available products, namely a chiral aminoalcohol and picolinic acid derivatives. The catalyst structure was extensively modified in a study that allowed to identify an extremely active species, able to promote the reduction on a large variety of substrates with high efficiency (up to 95% ee). A three component methodology has been also developed, where the enantiomerically enriched amine was isolated after performing the reaction by mixing a ketone and an amine in the presence of trichlorosilane and the catalyst. Its synthetic potentiality was demonstrated by employing the present metal-free catalytic procedure in the preparation of (S)-metolachlor, a potent and widely used herbicide.
- Guizzetti, Stefania,Benaglia, Maurizio,Cozzi, Franco,Annunziata, Rita
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experimental part
p. 6354 - 6363
(2010/01/06)
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- Synthesis and structure-activity relationship studies of 2-(N-substituted)-aminobenzimidazoles as potent negative gating modulators of small conductance Ca2+-activated K+ channels
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Small conductance Ca2+-activated K+ channels (SK channels) participate in the control of neuronal excitability, in the shaping of action potential firing patterns, and in the regulation of synaptic transmission. SK channel inhibitors have the potential of becoming new drugs for treatment of various psychiatric and neurological diseases such as depression, cognition impairment, and Parkinson's disease. In the present study we describe the structure-activity relationship (SAR) of a class of 2-(N-substituted)-2- aminobenzimidazoles that constitute a novel class of selective SK channel inhibitors that, in contrast to classical SK inhibitors, do not block the pore of the channel. The pore blocker apamin is not displaced by these compounds in binding studies, and they still inhibit SK channels in which the apamin binding site has been abolished by point mutations. These novel SK inhibitors shift the concentration-response curve for Ca2+ toward higher values and represent the first example of negative gating modulation as a mode-of-action for inhibition of SK channels. The first described compound in this class is NS8593 (14), and the most potent analogue identified in this study is the racemic compound 39 (NS11757), which reversibly inhibits SK3-mediated currents with a Kd value of 9 nM.
- S?rensen, Ulrik S.,Str?b?k, Dorte,Christophersen, Palle,Hougaard, Charlotte,Jensen, Marianne L.,Nielsen, Elsebet ?.,Peters, Dan,Teuber, Lene
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scheme or table
p. 7625 - 7634
(2009/12/07)
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- Selective synthesis of secondary and tertiary amines by Cp*iridium-catalyzed multialkylation of ammonium salts with alcohols
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(Chemical Equation Presented) The efficient selective synthesis of secondary and tertiary amines has been achieved by means of Cp*Ir- catalyzed multialkylation of ammonium salts with alcohols without solvent: the reactions of ammonium acetate with alcohols gave tertiary amines exclusively, while those of ammonium tetrafluoroborate afforded secondary amines selectively. Using this method, secondary 5- and 6-membered cyclic amines were synthesized from ammonium tetrafluoroborate and diols in one pot.
- Yamaguchi, Ryohei,Kawagoe, Shoko,Asai, Chiho,Fujita, Ken-Ichi
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p. 181 - 184
(2008/09/18)
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- Ruthenium catalyzed decarbonylative arylation at sp3 carbon centers in pyrrolidine and piperidine heterocycles
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This paper describes the development of a new catalytic transformation, the ruthenium-catalyzed decarbonylative arylation of cyclic 2-amino esters, which replaces the ester group with an aryl ring at the sp3 carbon center. For example, proline ester amidine 1 is converted to 2-arylpyrrolidine 3 in the presence of arylboronic acids or esters as arene donors and Ru 3(CO)12 as the catalyst. This process provides a rapid access to a variety of 2-arylpyrrolidines and piperidines from commercially available proline, hydroxyproline, and pipecolinate esters. The examination of the substrate scope also showed that many arene boronic acids and boronate esters serve as coupling partners. The high chemoselectivity of this process was demonstrated and ascribed to the significant rate difference between the decarbonylative arylation and the C-H arylation. The decarbonylative arylation complements the C-H arylation, since the latter process lacks control over the extent of functionalization, affording a mixture of mono- and bis-arylpyrrolidines. When applied in tandem, these two processes provide 2,5-diarylpyrrolidines in two steps from the corresponding proline esters. It was also demonstrated that the required amidine or iminocarbamate directing group fulfills two major functions: first, it is essential for the ester activation step, which occurs via the coordination-assisted metal insertion into the acyl C-O bond; second, it facilitates the decarbonylation, via the stabilization of a metallacycle intermediate, assuring the formation of the 2-arylated products instead of the corresponding ketones observed before by others.
- Gribkov, Denis V.,Pastine, Stefan J.,Schnuerch, Michael,Sames, Dalibor
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p. 11750 - 11755
(2008/03/15)
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- Alkylation of aryl N-(2-pyridylsulfonyl)aldimines with organozinc halides: Conciliation of reactivity and chemoselectivity
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(Chemical Equation Presented) The best of both worlds: With a coordinating 2-pyridylsulfonyl group as the N-activating group, aromatic aldimines show unprecedented high reactivity towards the direct addition of alkyl zinc bromide reagents in the presence of catalytic amounts of Cu(OTf)2. The reaction combines high reactivity with wide functional-group compatibility to provide ready access to functionalized benzylamines and derivatives (see example). Tf=trifluoromethanesulfonyl.
- Esquivias, Jorge,Arrayas, Ramon Gomez,Carretero, Juan Carlos
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p. 9257 - 9260
(2008/12/22)
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- An efficient synthesis of nitrogen heterocycles by Cp*Ir-catalyzed N-cycloalkylation of primary amines with diols
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A new efficient method for the N-cycloalkylation of primary amines with diols catalyzed by a Cp*Ir complex have been developed. A variety of five-, six-, and seven-membered cyclic amines are synthesized in good to excellent yields in environmentally benign and atom economical manner with the formation of only water as a coproduct. A large scale synthesis of N-benzylpiperidine and a two-step asymmetric synthesis of (S)-2-phenylpiperidine using (R)-1-phenylethylamine as a starting primary amine have been also achieved.
- Fujita, Ken-ichi,Fujii, Takeshi,Komatsubara, Atsuo,Enoki, Youichiro,Yamaguchi, Ryohei
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p. 673 - 682
(2008/09/18)
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- Dynamic kinetic resolution and desymmetrization processes: A straightforward methodology for the enantioselective synthesis of piperidines
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A straightforward procedure for the synthesis of enantiopure polysubstituted piperidines is reported. It involves the direct generation of chiral non-racemic oxazolo[3,2-a]piperidone lactams that already incorporate carbon substituents on the heterocyclic ring and the subsequent removal of the chiral auxiliary. The key step is a cyclocondensation reaction of (R)-phenylglycinol or other amino alcohols with racemic or prochiral δ-oxo (di)acid derivatives in highly stereoselective processes involving dynamic kinetic resolution and/or desymmetrization of diastereotopic or enantiotopic ester groups.
- Amat, Mercedes,Bassas, Oriol,Llor, Nuria,Canto, Margalida,Perez, Maria,Molins, Elies,Bosch, Joan
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p. 7872 - 7881
(2007/10/03)
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- Double reduction of cyclic aromatic sulfonamides: A novel method for the synthesis of 2- and 3-aryl-substituted cyclic amines
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(Chemical Equation Presented) The facile double reduction of bicyclic aromatic sulfonamides was used to synthesize a variety of 2- and 3-aryl-substituted pyrrolidines and 2-phenylpiperidine. The method features a combined nitrogen protection and a traceless tether for the transposition of the aromatic moiety from nitrogen to carbon.
- Evans, Paul,McCabe, Thomas,Morgan, Ben S.,Reau, Sophie
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- ASYMMETRIC IMINE HYDROGENATION PROCESSES
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A process for the catalytic hydrogenation or asymmetric hydrogenation of imines of Formula (I) to the corresponding amines of Formula (II) is provided in which R1 is aryl ; R2 is aryl, cyclic, alkyl, alkenyl or alkynyl; and R3 is alky l. The catalytic system includes a ruthenium complex containing (1) a diamine and (2) a diphosphine or two monodentate phosphines ligands. Such process also relates to the asymmetric hydrogenation of prochiral imines to the chiral amines using chiral ruthenium complexes bearing chiral diphosphines or chiral monodentate phosphines and chiral diamines.
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Page/Page column 30
(2008/06/13)
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- ASYMMETRIC SYNTHESIS CATALYZED BY TRANSITION METAL COMPLEXES WITH CYCLIC CHIRAL PHOSPHINE LIGANDS
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The present invention relates to rigid chiral ligands usefull in making catalysts for asymmetric synthesis. More particularly, the present invention relates to new monodentate and bidentate cyclic chiral phosphine ligands which are formed into catalysts to provide high selectivity of the enantiomeric structure of the end-product.
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- Asymmetric synthesis and applications of β-amino Weinreb amides: Asymmetric synthesis of (S)-coniine
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Conjugate addition of lithium (S)-N-benzyl-N-a-methylbenzylamide to a range of α,β-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The β-amino Weinreb amide products may be transformed into β-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes β-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral δ-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.
- Burke, Anthony J.,Davies, Stephen G.,Garner, A. Christopher,McCarthy, Tom D.,Roberts, Paul M.,Smith, Andrew D.,Rodriguez-Solla, Humberto,Vickers, Richard J.
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p. 1387 - 1394
(2007/10/03)
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