gem‐Disubstituent Effect: Theoretical Basis and Synthetic Applications

Jung, Michael E.; Piizzi, Grazia

doi:10.1002/chin.200536231

Cited by 57 publications

(97 citation statements)

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“…Such interactions specifically accelerate autoproteolysis with Thr when the γ-methyl forms unfavorable steric interactions in nonproductive rotamers. This reactive rotamer effect (RRE) is disrupted by the Thr → Ser mutation, which shifts the ground state rotamer distribution away from a reactive state, accounting for the entropically derived rate deceleration (29). The RRE may contribute to the previously unexplainable observation that Thr nucleophiles are rare outside of cis-autoproteolytically activated systems, but common among the Ntn and D/O hydrolases (14,30,31).…”

Section: Resultsmentioning

confidence: 99%

Insights into cis-autoproteolysis reveal a reactive state formed through conformational rearrangement

Buller

Freeman

Wright

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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ThnT is a pantetheine hydrolase from the DmpA/OAT superfamily involved in the biosynthesis of the β-lactam antibiotic thienamycin. We performed a structural and mechanistic investigation into the cis-autoproteolytic activation of ThnT, a process that has not previously been subject to analysis within this superfamily of enzymes. Removal of the γ-methyl of the threonine nucleophile resulted in a rate deceleration that we attribute to a reduction in the population of the reactive rotamer. This phenomenon is broadly applicable and constitutes a rationale for the evolutionary selection of threonine nucleophiles in autoproteolytic systems. Conservative substitution of the nucleophile (T282C) allowed determination of a 1.6-Å proenzyme ThnT crystal structure, which revealed a level of structural flexibility not previously observed within an autoprocessing active site. We assigned the major conformer as a nonreactive state that is unable to populate a reactive rotamer. Our analysis shows the system is activated by a structural rearrangement that places the scissile amide into an oxyanion hole and forces the nucleophilic residue into a forbidden region of Ramachandran space. We propose that conformational strain may drive autoprocessing through the destabilization of nonproductive states. Comparison of our data with previous reports uncovered evidence that many inactivated structures display nonreactive conformations. For penicillin and cephalosporin acylases, this discrepancy between structure and function may be resolved by invoking the presence of a hidden conformational state, similar to that reported here for ThnT.crystallography | mechanism | reactive rotamer effect | self-cleavage

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Section: Resultsmentioning

confidence: 99%

Insights into cis-autoproteolysis reveal a reactive state formed through conformational rearrangement

Buller

Freeman

Wright

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…[ 113 ] In contrast to the previous reports [ 114‐118 ] that the dicarbofunctionalization of alkenes was restricted to the formation of five‐membered rings, this method could afford piperidine derivatives by 6‐exo‐trig cyclization. Thorpe‐Ingold effect [ 119 ] played a crucial role on the efficiency of the radical cyclization, as the unsubstituted carbochain favored direct coupling with another electronphile, such as arylbromide, prior to cyclization.…”

Section: Intramolecular Dicarbofunctionalization Of Alkenes Via Cyclimentioning

confidence: 99%

Nickel‐CatalyzedDicarbofunctionalization of Alkenes^†

2020

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As a straightforward strategy for rapidly increasing molecular complexity, dicarbofunctionalization of alkenes has attracted substantial interests of organic synthesis, medicine chemistry, and materials science. Nickel-catalyzed cascade dicarbofunctionalizations have been flourished in this area recently, and nickel-mediated radical pathways particularly offer new opportunities in conjunctive cross-couplings with alkyl coupling partners. Herein, we give a comprehensive review of nickel-catalyzed dicarbofunctionalization of alkenes through a historical perspective, including intermolecular three-component reactions and intramolecular cascade reactions. Among the pathways discussed in this review, the carbometallation/cross-coupling process and the radical addition/cross-coupling process are the two major pathways for the nickel-catalyzed dicarbofunctionalization of alkenes. The oxidative cyclization and 1,2-metallate shift processes are also selectively discussed. These methods overcome the limitations associated with the reactions using noble metals in the field, providing an efficient and straightforward access to structurally diversified molecules. Yun-Cheng Luo (right) received his BSc degree in 2016 and master degree in 2019 from University of Science and Technology of China. Then he joined Professor Xingang Zhang's group at Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences to pursue his doctorate in organic chemistry. His research interests are focused on the activation of inert C-H or C-X bonds of bulky chemicals and their applications in the synthesis of fluorine-containing compounds. Chang Xu (middle) obtained his BSc degree in basic pharmacy from China Pharmaceutical University (China) in 2015. With an interest in organic chemistry and medicinal chemistry, he then began his graduate studies at Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences under the supervision of Professor Xingang Zhang. His research interests are focused on the activation and transformations of fluoroalkylanes and their applications in medicinal chemistry. Xingang Zhang (left) obtained his BSc degree in 1998 from Sichuan University (China) and received the Ph.D. in 2003 at Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences. After his postdoctoral work at University of Illinois at Urbana Champaign (USA), he joined the faculty team of SIOC as a research associate professor in 2008, and became research professor in 2012. His current research interests are focused on organofluorine chemistry and chemical biology.

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“…Replacement of the phenyl substituents with methyl groups ( 1l ) or hydrogens ( 1m ) led to a dramatic decrease in the yield of cyclization product 2l or even a complete deactivation for the formation of 2m (Scheme a). These results demonstrated that the phenyl substituents had an obvious Thorpe‐Ingold effect on the intramolecular hydroalkoxylation . Reaction of 2‐allylphenol ( 1n ) under the standard conditions did not give the corresponding cyclized hydroalkoxylation product, but produced hydrochlorination product 4 (Scheme b).…”

Section: Resultsmentioning

confidence: 94%

Asymmetric Intramolecular Hydroalkoxylation of Unactivated Alkenes Catalyzed by Chiral N‐Triflyl Phosphoramide and TiCl₄^†

et al. 2020

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gem‐Disubstituent Effect: Theoretical Basis and Synthetic Applications

Abstract: Organic chemistry Z 0200 gem-Disubstituent Effect: Theoretical Basis and Synthetic Applications -[about 120 refs.]. -(JUNG, M. E.; PIIZZI, G.; Chem. Rev. (Washington, D. C.) 105 (2005) 5, 1735-1766; Dep. Chem. Biochem., Univ. Calif., Los Angeles, CA 90095, USA; Eng.) -Lindner 36-231

Cited by 57 publications

References 1 publication

Insights into cis-autoproteolysis reveal a reactive state formed through conformational rearrangement

Insights into cis-autoproteolysis reveal a reactive state formed through conformational rearrangement

Nickel‐CatalyzedDicarbofunctionalization of Alkenes^†

Asymmetric Intramolecular Hydroalkoxylation of Unactivated Alkenes Catalyzed by Chiral N‐Triflyl Phosphoramide and TiCl₄^†

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gem‐Disubstituent Effect: Theoretical Basis and Synthetic Applications

Abstract: Organic chemistry Z 0200 gem-Disubstituent Effect: Theoretical Basis and Synthetic Applications -[about 120 refs.]. -(JUNG, M. E.; PIIZZI, G.; Chem. Rev. (Washington, D. C.) 105 (2005) 5, 1735-1766; Dep. Chem. Biochem., Univ. Calif., Los Angeles, CA 90095, USA; Eng.) -Lindner 36-231

Cited by 57 publications

References 1 publication

Insights into cis-autoproteolysis reveal a reactive state formed through conformational rearrangement

Insights into cis-autoproteolysis reveal a reactive state formed through conformational rearrangement

Nickel‐CatalyzedDicarbofunctionalization of Alkenes†

Asymmetric Intramolecular Hydroalkoxylation of Unactivated Alkenes Catalyzed by Chiral N‐Triflyl Phosphoramide and TiCl4†

Contact Info

Product

Resources

About

Nickel‐CatalyzedDicarbofunctionalization of Alkenes^†

Asymmetric Intramolecular Hydroalkoxylation of Unactivated Alkenes Catalyzed by Chiral N‐Triflyl Phosphoramide and TiCl₄^†