The Experts below are selected from a list of 114 Experts worldwide ranked by ideXlab platform
Michal Szostak - One of the best experts on this subject based on the ideXlab platform.
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nickel catalyzed Diaryl Ketone synthesis by n c cleavage direct negishi cross coupling of primary amides by site selective n n di boc activation
Organic Letters, 2016Co-Authors: Shicheng Shi, Michal SzostakAbstract:A general Negishi acylation of primary amides enabled by a combination of site-selective N,N-di-Boc activation and nickel catalysis is reported for the first time. The reaction is promoted by a bench-stable, inexpensive Ni catalyst. The reaction shows excellent functional group compatibility, affording functionalized Diaryl Ketones by selective N–C cleavage. Most notably, this protocol represents the first amide cross-coupling by direct metal insertion of simple and readily available primary amides. The overall strategy by N,N-di-Boc activation/metal insertion is suitable for a broad range of coupling protocols via acylmetals. Mechanistic experiments suggest high reactivity of N,N-di-Boc activated 1° amides in direct amide C–N cross-couplings.
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efficient synthesis of Diaryl Ketones by nickel catalyzed negishi cross coupling of amides by carbon nitrogen bond cleavage at room temperature accelerated by a solvent effect
Chemistry: A European Journal, 2016Co-Authors: Shicheng Shi, Michal SzostakAbstract:The first Negishi cross-coupling of amides for the synthesis of versatile Diaryl Ketones by selective C−N bond activation under exceedingly mild conditions is reported. The cross-coupling was accomplished with bench-stable, inexpensive precatalyst [Ni(PPh3)2Cl2] that shows high functional-group tolerance and enables the synthesis of highly functionalized Diaryl Ketone motifs. The coupling occurred with excellent chemoselectivity favoring the Ketone (cf. biaryl) products. Notably, this process represents the mildest conditions for amide N−C bond activation accomplished to date (room temperature, <10 min). Considering the versatile role of polyfunctional biaryl Ketone linchpins in modern organic synthesis, availability, and excellent functional-group tolerance of organozinc reagents, this strategy provides a new platform for amide N−C bond/organozinc cross-coupling under mild conditions.
Jiahai Zhou - One of the best experts on this subject based on the ideXlab platform.
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structural insight into enantioselective inversion of an alcohol dehydrogenase reveals a polar gate in stereorecognition of Diaryl Ketones
Journal of the American Chemical Society, 2018Co-Authors: Jieyu Zhou, Yue Wang, Ruizhi Han, Ulrich Schwaneberg, Yijian Rao, Yilei Zhao, Jiahai ZhouAbstract:Diaryl Ketones are important building blocks for synthesizing pharmaceuticals and are generally regarded as “difficult-to-reduce” Ketones due to the large steric hindrance of their two bulky aromatic side chains. Alcohol dehydrogenase from Kluyveromyces polyspora (KpADH) has been identified as a robust biocatalyst due to its high conversion of Diaryl Ketone substrate (4-chlorophenyl)(pyridine-2-yl)Ketone (CPMK) with a moderate R-selectivity of 82% ee. To modulate the stereoselectivity of KpADH, a “polarity scanning” strategy was proposed, in which six key residues inside and at the entrance of the substrate binding pocket were identified. After iterative combinatorial mutagenesis, variants Mu-R2 and Mu-S5 with enhanced (99.2% ee, R) and inverted (97.8% ee, S) stereoselectivity were obtained. The crystal structures of KpADH and two mutants in complex with NADPH were resolved to elucidate the evolution of enantioselective inversion. Based on MD simulation, Mu-R2–CPMKProR and Mu-S5–CPMKProS were more favorab...
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Structural Insight into Enantioselective Inversion of an Alcohol Dehydrogenase Reveals a “Polar Gate” in Stereorecognition of Diaryl Ketones
2018Co-Authors: Jieyu Zhou, Yue Wang, Ruizhi Han, Ulrich Schwaneberg, Yijian Rao, Yilei Zhao, Jiahai ZhouAbstract:Diaryl Ketones are important building blocks for synthesizing pharmaceuticals and are generally regarded as “difficult-to-reduce” Ketones due to the large steric hindrance of their two bulky aromatic side chains. Alcohol dehydrogenase from Kluyveromyces polyspora (KpADH) has been identified as a robust biocatalyst due to its high conversion of Diaryl Ketone substrate (4-chlorophenyl)(pyridine-2-yl)Ketone (CPMK) with a moderate R-selectivity of 82% ee. To modulate the stereoselectivity of KpADH, a “polarity scanning” strategy was proposed, in which six key residues inside and at the entrance of the substrate binding pocket were identified. After iterative combinatorial mutagenesis, variants Mu-R2 and Mu-S5 with enhanced (99.2% ee, R) and inverted (97.8% ee, S) stereoselectivity were obtained. The crystal structures of KpADH and two mutants in complex with NADPH were resolved to elucidate the evolution of enantioselective inversion. Based on MD simulation, Mu-R2–CPMKProR and Mu-S5–CPMKProS were more favorable in the formation of prereaction states. Interestingly, a quadrilateral plane formed by α-carbons of four residues (N136, V161, C237, and G214) was identified at the entrance of the substrate binding pocket of Mu-S5; this plane acts as a “polar gate” for substrates. Due to the discrepancy in charge characteristics between chlorophenyl and pyridine substituents, the pro-S orientation of CPMK is defined when it passes through the “polar gate” in Mu-S5, whereas the similar plane in wild-type is blocked by several aromatic residues. Our result paves the way for engineering stereocomplementary ADH toward bulky Diaryl Ketones and provides structural insight into the mechanism of stereoselective inversion
Shicheng Shi - One of the best experts on this subject based on the ideXlab platform.
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nickel catalyzed Diaryl Ketone synthesis by n c cleavage direct negishi cross coupling of primary amides by site selective n n di boc activation
Organic Letters, 2016Co-Authors: Shicheng Shi, Michal SzostakAbstract:A general Negishi acylation of primary amides enabled by a combination of site-selective N,N-di-Boc activation and nickel catalysis is reported for the first time. The reaction is promoted by a bench-stable, inexpensive Ni catalyst. The reaction shows excellent functional group compatibility, affording functionalized Diaryl Ketones by selective N–C cleavage. Most notably, this protocol represents the first amide cross-coupling by direct metal insertion of simple and readily available primary amides. The overall strategy by N,N-di-Boc activation/metal insertion is suitable for a broad range of coupling protocols via acylmetals. Mechanistic experiments suggest high reactivity of N,N-di-Boc activated 1° amides in direct amide C–N cross-couplings.
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efficient synthesis of Diaryl Ketones by nickel catalyzed negishi cross coupling of amides by carbon nitrogen bond cleavage at room temperature accelerated by a solvent effect
Chemistry: A European Journal, 2016Co-Authors: Shicheng Shi, Michal SzostakAbstract:The first Negishi cross-coupling of amides for the synthesis of versatile Diaryl Ketones by selective C−N bond activation under exceedingly mild conditions is reported. The cross-coupling was accomplished with bench-stable, inexpensive precatalyst [Ni(PPh3)2Cl2] that shows high functional-group tolerance and enables the synthesis of highly functionalized Diaryl Ketone motifs. The coupling occurred with excellent chemoselectivity favoring the Ketone (cf. biaryl) products. Notably, this process represents the mildest conditions for amide N−C bond activation accomplished to date (room temperature, <10 min). Considering the versatile role of polyfunctional biaryl Ketone linchpins in modern organic synthesis, availability, and excellent functional-group tolerance of organozinc reagents, this strategy provides a new platform for amide N−C bond/organozinc cross-coupling under mild conditions.
Jieyu Zhou - One of the best experts on this subject based on the ideXlab platform.
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structural insight into enantioselective inversion of an alcohol dehydrogenase reveals a polar gate in stereorecognition of Diaryl Ketones
Journal of the American Chemical Society, 2018Co-Authors: Jieyu Zhou, Yue Wang, Ruizhi Han, Ulrich Schwaneberg, Yijian Rao, Yilei Zhao, Jiahai ZhouAbstract:Diaryl Ketones are important building blocks for synthesizing pharmaceuticals and are generally regarded as “difficult-to-reduce” Ketones due to the large steric hindrance of their two bulky aromatic side chains. Alcohol dehydrogenase from Kluyveromyces polyspora (KpADH) has been identified as a robust biocatalyst due to its high conversion of Diaryl Ketone substrate (4-chlorophenyl)(pyridine-2-yl)Ketone (CPMK) with a moderate R-selectivity of 82% ee. To modulate the stereoselectivity of KpADH, a “polarity scanning” strategy was proposed, in which six key residues inside and at the entrance of the substrate binding pocket were identified. After iterative combinatorial mutagenesis, variants Mu-R2 and Mu-S5 with enhanced (99.2% ee, R) and inverted (97.8% ee, S) stereoselectivity were obtained. The crystal structures of KpADH and two mutants in complex with NADPH were resolved to elucidate the evolution of enantioselective inversion. Based on MD simulation, Mu-R2–CPMKProR and Mu-S5–CPMKProS were more favorab...
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Structural Insight into Enantioselective Inversion of an Alcohol Dehydrogenase Reveals a “Polar Gate” in Stereorecognition of Diaryl Ketones
2018Co-Authors: Jieyu Zhou, Yue Wang, Ruizhi Han, Ulrich Schwaneberg, Yijian Rao, Yilei Zhao, Jiahai ZhouAbstract:Diaryl Ketones are important building blocks for synthesizing pharmaceuticals and are generally regarded as “difficult-to-reduce” Ketones due to the large steric hindrance of their two bulky aromatic side chains. Alcohol dehydrogenase from Kluyveromyces polyspora (KpADH) has been identified as a robust biocatalyst due to its high conversion of Diaryl Ketone substrate (4-chlorophenyl)(pyridine-2-yl)Ketone (CPMK) with a moderate R-selectivity of 82% ee. To modulate the stereoselectivity of KpADH, a “polarity scanning” strategy was proposed, in which six key residues inside and at the entrance of the substrate binding pocket were identified. After iterative combinatorial mutagenesis, variants Mu-R2 and Mu-S5 with enhanced (99.2% ee, R) and inverted (97.8% ee, S) stereoselectivity were obtained. The crystal structures of KpADH and two mutants in complex with NADPH were resolved to elucidate the evolution of enantioselective inversion. Based on MD simulation, Mu-R2–CPMKProR and Mu-S5–CPMKProS were more favorable in the formation of prereaction states. Interestingly, a quadrilateral plane formed by α-carbons of four residues (N136, V161, C237, and G214) was identified at the entrance of the substrate binding pocket of Mu-S5; this plane acts as a “polar gate” for substrates. Due to the discrepancy in charge characteristics between chlorophenyl and pyridine substituents, the pro-S orientation of CPMK is defined when it passes through the “polar gate” in Mu-S5, whereas the similar plane in wild-type is blocked by several aromatic residues. Our result paves the way for engineering stereocomplementary ADH toward bulky Diaryl Ketones and provides structural insight into the mechanism of stereoselective inversion
Gérard Jaouen - One of the best experts on this subject based on the ideXlab platform.
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Atypical McMurry Cross-Coupling Reactions Leading to a New Series of Potent Antiproliferative Compounds Bearing the Key [Ferrocenyl-Ene-Phenol] Motif
Molecules, 2014Co-Authors: Pascal Pigeon, Meral Goermen, Konrad Kowalski, Helge Mueller-bunz, Michael J. Mcglinchey, Siden Top, Gérard JaouenAbstract:In the course of the preparation of a series of ferrocenyl derivatives of diethylstilbestrol (DES), in which one of the 4-hydroxyphenyl moieties was replaced by a ferrocenyl group, the McMurry reaction of chloropropionylferrocene with a number of mono-aryl Ketones unexpectedly yielded the hydroxylated ferrocenyl DES derivatives, 5a-c, in poor yields (10%-16%). These compounds showed high activity on the hormone-independent breast cancer cell line MDA-MB-231 with IC50 values ranging from 0.14 to 0.36 mu M. Surprisingly, non-hydroxylated ferrocenyl DES, 4, showed only an IC50 value of 1.14 mu M, illustrating the importance of the hydroxyethyl function in this promising new series. For comparison, McMurry reactions of the shorter chain analogue chloroacetylferrocene were carried out to see the difference in behaviour with mono-aryl Ketones versus a Diaryl Ketone. The effect of changing the length of the alkyl chain adjacent to the phenolic substituent of the hydroxylated ferrocenyl DES was studied, a mechanistic rationale to account for the unexpected products is proposed, and the antiproliferative activities of all of these compounds on MDA-MB-231 cells lines were measured and compared. X-ray crystal structures of cross-coupled products and of pinacol-pinacolone rearrangements are reported.