Stereoselective nucleophilic addition reactions to cyclic <i>N</i>-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations

Mitsudo, Koichi; Yamamoto, Junya; Akagi, T.; Yamashita, Atsuhiro; Haisa, M.; Yoshioka, Kazuki; Mandai, Hiroki; Ueoka, Koji; Hempel, Christian; Yoshida, Jun; Suga, Seiji

doi:10.3762/bjoc.14.100

Cited by 16 publications

(8 citation statements)

References 14 publications

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“…Furthermore, this methodology could be expanded beyond methylation to other alkylation and arylation reactions to facilitate synthetic and medicinal studies. Notably, dialkylzinc reagents have rarely been used for the alkylation of N -protected iminium ions …”

Section: Resultsmentioning

confidence: 99%

Exploring Electrochemical C(sp³)–H Oxidation for the Late-Stage Methylation of Complex Molecules

Novaes

Mao

et al. 2022

J. Am. Chem. Soc.

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The "magic methyl" effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp 3 )−H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C−C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the "magic methyl" effect. This synthesis strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.

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Section: Resultsmentioning

confidence: 99%

Exploring Electrochemical C(sp³)–H Oxidation for the Late-Stage Methylation of Complex Molecules

Novaes

Mao

et al. 2022

J. Am. Chem. Soc.

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“…[21] This reaction is thought to proceed via am echanism involving two successive hydrogen-borrowing alkylations, the final step of which would be the reduction of a cyclic iminium species 42.T he diastereoselectivity of this process was systematicallyi nvestigatedb yi ntroducing as econd substituent at each possible positiona roundt he heterocyclic core leading to piperidines 41 a-d in high yields.F or 41 a-c the relative stereochemistry is consistent with axial addition of iridium hydride to ah alf-chair bearing an equatorial (or pseudoequatorial) substituent. [22] For 41 d,i tw as proposed that A 1,3 strain forces the methyl group into apseudoaxial conformation leadingtot he cis-diastereoisomer.…”

Section: Enantiopure Alcoholsmentioning

confidence: 99%

Control of Absolute Stereochemistry in Transition‐Metal‐Catalysed Hydrogen‐Borrowing Reactions

Kwok

Hoff

Armstrong

et al. 2020

Chemistry A European J

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Hydrogen-borrowing catalysis represents ap owerful method for the alkylation of amineo re nolate nucleophiles with non-activated alcohols. This approach relies upon ac atalystt hat can mediateastrategic series of redox events, enabling the formation of CÀCa nd CÀNb onds and producing water as the sole by-product. In the majority of cases these reactions have been employed to target achiral or racemic products.I nc ontrast, the focus of this Minireview is upon hydrogen-borrowing-catalysed reactions in which the absolute stereochemical outcome of the process can be controlled. Asymmetric hydrogen-borrowing catalysis is rapidly emerging as ap owerful approach for the synthesis of enantioenricheda mine and carbonyl containing products and examples involving both CÀNa nd CÀCb ond formation are presented. Av ariety of different approaches are discussed including use of chiral auxiliaries, asymmetric catalysis and enantiospecific processes. Scheme1.Contrasting classical alkylation of amines and enolates with hydrogen-borrowing catalysis.

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“…We have been interested in electrochemical transformations for a long time [27][28][29][30][31] and are paying the most attention to the utility of PEM reactors for organic syntheses, especially chemo- selective transformations. In our research, we examined the hydrogenation of enones using a PEM reactor.…”

Section: Introductionmentioning

confidence: 99%

Electrochemical hydrogenation of enones using a proton-exchange membrane reactor: selectivity and utility

Mitsudo¹,

Inoue²,

Niki³

et al. 2022

Beilstein J. Org. Chem.

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Stereoselective nucleophilic addition reactions to cyclic N-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations

Cited by 16 publications

References 14 publications

Exploring Electrochemical C(sp³)–H Oxidation for the Late-Stage Methylation of Complex Molecules

Exploring Electrochemical C(sp³)–H Oxidation for the Late-Stage Methylation of Complex Molecules

Control of Absolute Stereochemistry in Transition‐Metal‐Catalysed Hydrogen‐Borrowing Reactions

Electrochemical hydrogenation of enones using a proton-exchange membrane reactor: selectivity and utility

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Stereoselective nucleophilic addition reactions to cyclic N-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations

Cited by 16 publications

References 14 publications

Exploring Electrochemical C(sp3)–H Oxidation for the Late-Stage Methylation of Complex Molecules

Exploring Electrochemical C(sp3)–H Oxidation for the Late-Stage Methylation of Complex Molecules

Control of Absolute Stereochemistry in Transition‐Metal‐Catalysed Hydrogen‐Borrowing Reactions

Electrochemical hydrogenation of enones using a proton-exchange membrane reactor: selectivity and utility

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Product

Resources

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Exploring Electrochemical C(sp³)–H Oxidation for the Late-Stage Methylation of Complex Molecules

Exploring Electrochemical C(sp³)–H Oxidation for the Late-Stage Methylation of Complex Molecules