C–H Methylation of Heteroarenes Inspired by Radical SAM Methyl Transferase

Gui, Jinghan; Zhou, Qianghui; Pan, Chung‐Mao; Yabe, Yuki; Burns, Aaron C.; Collins, Michael R.; Ornelas, Martha A.; Ishihara, Yoshihiro; Baran, Phil S.

doi:10.1021/ja5007838

Cited by 183 publications

(112 citation statements)

References 43 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…64 The method is very efficient, tolerant of sensitive functional groups and can be run on gram scale. Using a newly developed zinc bis(phenylsulfonyl methane sulfonate reagent), a two-step protocol involving radical generation of phenylsulfonyl methylated intermediate followed by desulfonylation under three different and orthogonal conditions gave the methylated heteroarenes in good yields (Scheme 32).…”

Section: C-h Functionalization Of Heterocyclesmentioning

confidence: 99%

Modern advances in heterocyclic chemistry in drug discovery

et al. 2016

View full text Add to dashboard Cite

New advances in synthetic methodologies that allow rapid access to a wide variety of functionalized heterocyclic compounds are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Furthermore, the development of robust synthetic routes that can readily generate bulk quantities of a desired compound help to accelerate the drug development process. While established synthetic methodologies are commonly utilized during the course of a drug discovery program, the development of innovative heterocyclic syntheses that allow for different bond forming strategies are having a significant impact in the pharmaceutical industry. This review will focus on recent applications of new methodologies in C-H activation, photoredox chemistry, borrowing hydrogen catalysis, multicomponent reactions, regio- and stereoselective syntheses, as well as other new, innovative general syntheses for the formation and functionalization of heterocycles that have helped drive project delivery. Additionally, the importance and value of collaborations between industry and academia in shaping the development of innovative synthetic approaches to functionalized heterocycles that are of greatest interest to the pharmaceutical industry will be highlighted.

show abstract

Section: C-h Functionalization Of Heterocyclesmentioning

confidence: 99%

Modern advances in heterocyclic chemistry in drug discovery

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In this instance,t he conversion of 5 to 5a improved to 85 %( 4h)a nd 77 %( 4j)r elative to 49 %w hen SAM was generated in situ ( Figure 5). Exploration of the wider scope of methylating (5a-13 a)a nd ethylating (5b-13 b)asuite of 3-substituted coumarins (5)(6)(7)(8)(9)(10)(11)(12)(13)e xemplified the superiority of using nucleobase-modified SAM/SAE analogues ( Figure 6). [34] The2 -modified alkyne cofactor 4i displayed comparable conversion (5a,5 0%)t oS AM, whereas the formation of the 2-amino-6-chloro analogue (4g)i nsitu did not form 5a.…”

Section: Zuschriftenmentioning

confidence: 99%

“…[1,2] From an industrial perspective,m ethylation of small molecules is ap owerful strategy to fine-tune their physicochemical properties and enhance overall drug potency. [5][6][7] Tr aditional synthetic approaches have typically involved using Friedel-Crafts, [8] radical-based methods, [9,10] and more recently,t ransition-metal catalyzed activation of C(sp 2 )ÀH bonds. [5][6][7] Tr aditional synthetic approaches have typically involved using Friedel-Crafts, [8] radical-based methods, [9,10] and more recently,t ransition-metal catalyzed activation of C(sp 2 )ÀH bonds.…”

mentioning

confidence: 99%

S‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C‐Alkylation

et al. 2019

View full text Add to dashboard Cite

Atandem enzymatic strategy to enhance the scope of C-alkylation of small molecules via the in situ formation of Sadenosyl methionine (SAM) cofactor analogues is described. As olvent-exposed channel present in the SAM-forming enzyme SalL tolerates 5'-chloro-5'-deoxyadenosine (ClDA) analogues modified at the 2-position of the adenine nucleobase.C oupling SalL-catalyzed cofactor production with C-(m)ethyl transfer to coumarin substrates catalyzedb yt he methyltransferase (MTase) NovOf orms C-(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications.E stablishing the molecular determinants that influence C-alkylation provides the basis to develop al ate-stage enzymatic platform for the preparation of high value small molecules.

show abstract

“…In 2014, inspired by S ‐adenosylmethionine ( SAM ), a common biological methylation reagent, Baran et al. developed zinc bis( p henyl s ulfonyl m ethane s ulfinate) ( PSMS ) as a novel phenylsulfonylmethylation reagent (Table ) . The reaction is compatible with several sensitive functional groups and substitutions, such as esters, phenols, alcohols, anilines.…”

Section: C‐methylationmentioning

confidence: 99%

Advances in the Synthesis of Methylated Products through Indirect Approaches

Chen

2019

Adv Synth Catal

View full text Add to dashboard Cite

Methylation is a well‐known structural modification in organic and medicinal chemistry. In addition to using conventional methylation reagents for direct methylation, indirect methylation approaches have been also successfully applied, particularly to tackle the isolation difficulty among the methylated product, the unreacted starting material, and the dimethylated by‐product due to the structural similarities between them. This review summarizes recent advances in the synthesis of methylated products through indirect approaches – transforming functionalized intermediates into the methylated products. The indirect methodologies surveyed in this review are useful for chemists to select appropriate methylation strategies, particularly for the challenging synthesis of methylated products at a large scale in drug discovery. Abbreviations: AIBN: azobisisobutyronitrile; Cbz: carbobenzyloxy; DBU: 1,8‐diazabicyclo[5.4.0]undec‐7‐ene; DIBAL: diisobutylaluminium hydride; FA: formic acid; Fmoc: fluorenylmethyloxycarbonyl; KOTMS: potassium trimethylsilanolate; LAH: lithium aluminium hydride; LiHBEt3: lithium triethylborohydride; PC: photocatalyst; PMHS: polymethylhydrosiloxane; PSMS: zinc bis(phenylsulfonylmethanesulfinate); SAM: S‐adenosylmethionine; SET: single electron transfer; TBAF: tetra‐n‐butylammonium fluoride; TBS: tert‐butyldimethylsilyl; TEA: trimethylamine; TFA: trifluoroacetic acid; TMS: trimethylsilyl; Ts: 4‐toluenesulfonyl.

show abstract

C–H Methylation of Heteroarenes Inspired by Radical SAM Methyl Transferase

Cited by 183 publications

References 43 publications

Modern advances in heterocyclic chemistry in drug discovery

Modern advances in heterocyclic chemistry in drug discovery

S‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C‐Alkylation

Advances in the Synthesis of Methylated Products through Indirect Approaches

Contact Info

Product

Resources

About