Chemoselective, Isomerization‐Free Synthesis of <i>N</i>‐Acylketimines from N–H Imines

Kwon, Yearang; Rhee, Young Ho; Park, Jaiwook

doi:10.1002/adsc.201601406

Cited by 9 publications

(6 citation statements)

References 41 publications

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“…In addition, there is no efficient synthetic method to access stereochemically pure N -acyl ketimine. One study reported an isomerization-free method to access N -acyl imines from hazardous secondary azides under light irradiation, but the compatibility of this method for the synthesis of α-alkylated ketimines with large steric hindrance was not demonstrated.…”

Section: Resultsmentioning

confidence: 99%

Palladium-Catalyzed Dual Ligand-Enabled Alkylation of Silyl Enol Ether and Enamide under Irradiation: Scope, Mechanism, and Theoretical Elucidation of Hybrid Alkyl Pd(I)-Radical Species

et al. 2019

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We report herein that a palladium catalyst in combination with a dual phosphine ligand system catalyzes alkylation of silyl enol ether and enamide with a broad scope of tertiary, secondary, and primary alkyl bromides under mild irradiation conditions by blue light-emitting diodes. The reactions effectively deliver α-alkylated ketones and α-alkylated N-acyl ketimines, and it is difficult to prepare the latter by other methods in a stereoselective manner. The α-alkylated N-acyl ketimine products can be further subjected to chiral phosphoric acid-catalyzed asymmetric reduction with Hantzsch ester to deliver chiral N-acyl-protected α-arylated aliphatic amines in high enantioselectivity up to 99% ee, thus providing a method for facile synthesis of chiral α-arylated aliphatic amines, which are of importance in medicinal chemistry research. The N-acetyl ketimine product also reacted smoothly with various types of Grignard reagents to afford sterically bulky N-acetyl α-tertiary amines in high yields. Theoretical studies in combination with experimental investigation provide understanding of the reaction mechanism with respect to the dual ligand effect and the irradiation effect in the catalytic cycle. The reaction is suggested to proceed via a hybrid alkyl Pd(I)-radical species generated by inner-sphere electron transfer of phosphine-coordinated Pd(0) species with alkyl bromide. This intriguing hybrid alkyl Pd(I)-radical species is elucidated by theoretical calculation to be a triplet species coordinated by three phosphine atoms with a distorted tetrahedral geometry, and spin prohibition rather than metal-to-ligand charge transfer contributes to the kinetic stability of the hybrid alkyl Pd(I)-radical species to impede alkyl recombination to generate Pd(II) alkyl intermediate.

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Section: Resultsmentioning

confidence: 99%

Palladium-Catalyzed Dual Ligand-Enabled Alkylation of Silyl Enol Ether and Enamide under Irradiation: Scope, Mechanism, and Theoretical Elucidation of Hybrid Alkyl Pd(I)-Radical Species

et al. 2019

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“…Unfortunately, we were unable to find a set of conditions that provided detectable amounts of desired macrocycle 44 . We also attempted to close the macrocycle with an intramolecular Mannich reaction using photochemistry to generate the requisite imine . Azide 45 was transformed to imine smoothly by a ruthenium catalyst, followed by in situ acylation-delivered N -acylimine 46 in one pot.…”

Section: Approaches Toward Lankacidin C and 4-methyl Lankacidin Cmentioning

confidence: 99%

Modular Approaches to Lankacidin Antibiotics

et al. 2020

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Lankacidins are a class of polyketide natural products isolated from Streptomyces spp. that show promising antimicrobial activity. Owing to their complex molecular architectures and chemical instability, structural assignment and derivatization of lankacidins are challenging tasks. Herein we describe three fully synthetic approaches to lankacidins that enable access to new structural variability within the class. We use these routes to systematically generate stereochemical derivatives of both cyclic and acyclic lankacidins. Additionally, we access a new series of lankacidins bearing a methyl group at the C4 position, a modification intended to increase chemical stability. In the course of this work, we discovered that the reported structures for two natural products of the lankacidin class were incorrect, and we determine the correct structures of 2,18-seco-lankacidinol B and iso-lankacidinol. We also evaluate the ability of several iso- and seco-lankacidins to inhibit the growth of bacteria and to inhibit translation in vitro. This work grants insight into the rich chemical complexity of this class of antibiotics and provides an avenue for further structural derivatization.

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“…We were able to successfully affect ring closure on a derivative with an extra methyl group at C4 (resulting in a quaternary center), supporting the hypothesis that the β-keto-δ-lactone motif decomposes via β-elimination . We next screened a Mannich approach for macrocycle formation by means of photochemical imine formation (Scheme B) . Azide 129 , generated with a Mitsunobu reaction, was transformed into the imine in the presence of a ruthenium catalyst and light, followed by in situ acylation delivered N -acylimine 130 in one pot.…”

Section: Modular Approaches To Lankacidin Antibioticsmentioning

confidence: 62%

Modular Chemical Synthesis of Streptogramin and Lankacidin Antibiotics

Cai

Seiple

2021

Acc. Chem. Res.

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Conspectus Continued, rapid development of antimicrobial resistance has become worldwide health crisis and a burden on the global economy. Decisive and comprehensive action is required to slow down the spread of antibiotic resistance, including increased investment in antibiotic discovery, sustainable policies that provide returns on investment for newly launched antibiotics, and public education to reduce the overusage of antibiotics, especially in livestock and agriculture. Without significant changes in the current antibiotic pipeline, we are in danger of entering a post-antibiotic era. In this Account, we summarize our recent efforts to develop next-generation streptogramin and lankacidin antibiotics that overcome bacterial resistance by means of modular chemical synthesis. First, we describe our highly modular, scalable route to four natural group A streptogramins antibiotics in 6–8 steps from seven simple chemical building blocks. We next describe the application of this route to the synthesis of a novel library of streptogramin antibiotics informed by in vitro and in vivo biological evaluation and high-resolution cryo-electron microscopy. One lead compound showed excellent inhibitory activity in vitro and in vivo against a longstanding streptogramin-resistance mechanism, virginiamycin acetyltransferase. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms. Second, we recount our modular approaches toward lankacidin antibiotics. Lankacidins are a group of polyketide natural products with activity against several strains of Gram-positive bacteria but have not been deployed as therapeutics due to their chemical instability. We describe a route to several diastereomers of 2,18-seco-lankacidinol B in a linear sequence of ≤8 steps from simple building blocks, resulting in a revision of the C4 stereochemistry. We next detail our modular synthesis of several diastereoisomers of iso-lankacidinol that resulted in the structural reassignment of this natural product. These structural revisions raise interesting questions about the biosynthetic origin of lankacidins, all of which possessed uniform stereochemistry prior to these findings. Finally, we summarize the ability of several iso- and seco-lankacidins to inhibit the growth of bacteria and to inhibit translation in vitro, providing important insights into structure–function relationships for the class.

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Chemoselective, Isomerization‐Free Synthesis of N‐Acylketimines from N–H Imines

Cited by 9 publications

References 41 publications

Palladium-Catalyzed Dual Ligand-Enabled Alkylation of Silyl Enol Ether and Enamide under Irradiation: Scope, Mechanism, and Theoretical Elucidation of Hybrid Alkyl Pd(I)-Radical Species

Palladium-Catalyzed Dual Ligand-Enabled Alkylation of Silyl Enol Ether and Enamide under Irradiation: Scope, Mechanism, and Theoretical Elucidation of Hybrid Alkyl Pd(I)-Radical Species

Modular Approaches to Lankacidin Antibiotics

Modular Chemical Synthesis of Streptogramin and Lankacidin Antibiotics

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