Imine as a linchpin approach for meta-C–H functionalization

Bag, Sukdev; Jana, Sadhan; Pradhan, Sukumar; Bhowmick, Suman; Goswami, Nupur; Sinha, Sucharita; Maiti, Debabrata

doi:10.1038/s41467-021-21633-2

Cited by 65 publications

(37 citation statements)

References 51 publications

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“…Method 2: Following the general procedure, the title compound was prepared from 3-bromo-5- In accordance with previously reported data. [275] 4-Nitro-2-(quinolin-3-yl)aniline (69g)…”

Section: General Proceduresmentioning

confidence: 99%

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Håheim¹

2022

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Malaria is a devastating tropical disease, claiming approximately 627 000 lives in 2020. Due to the appearance of resistance towards artemisinin-based therapies, the discovery of novel treatments are of paramount importance. The indoloquinoline natural products cryptolepine, neocryptolepine and isocryptolepine, first discovered in the extracts of the African bush plant Cryptolepis sanguinolenta, have been found to exhibit potent antimalarial properties. More- over, several functionalized derivatives of these compounds have shown great promise as an- tiplasmodial agents. The indoloquinoline alkaloids have also been found to possess significant antiproliferative and antimicrobial properties, making them ideal targets for the development into novel drug candidates. The first project in this work details the application of a synthetic approach first devel- oped by Helgeland and Sydnes to assemble various tetracyclic ring systems. The key synthetic strategies being a Suzuki-Miyaura cross-coupling reaction followed by a palladium-catalyzed intramolecular cyclization. Though the approach was unsuitable to construct all the intended target molecules, it furnished the unexpected pyridophenanthridine scaffold. By further inves- tigating alternative protocols for the construction of indoloquinolines, a regiodivergent inter- mediate was discovered, which allowed for the synthesis of both novel pyridophenanthridine and pyridocarbazole scaffolds by utilizing two different reaction protocols. By subjecting this common intermediate to a diazotization-azidation-nitrene insertion approach, the novel pyrido- carbazoles could be furnished in excellent yields. The unexpected formation of a biquinoline bridged by an aniline during a Suzuki-Miyaura cross-coupling reaction, was deemed interesting for development into a transition metal com- plex for catalysis. Through a collaborative effort with Dr. Eugene Khaskin’s group at Oki- nawa Institute of Science and Technology, five quinoline/pyridine N,N,N ligands were designed and synthesized. The key synthetic tools utilized in their construction was either a sequential Suzuki-Miyaura cross-coupling reaction and Buchwald-Hartwig amination or reductive amina- tion. A novel two-step approach for the synthesis of the natural product neocryptolepine from commercially available bromoquinolines was developed. The key transformations being re- gioselective N-alkylations followed by a cascade Suzuki-Miyaura cross-coupling reaction and intramolecular nucleophilic C-N bond formation. The scope and limitations for the novel pro- tocol was evaluated through the preparation of 24 neocryptolepine derivatives, bearing a diverse range of functional groups, where electron-withdrawing group substitutions were generally su- perior. It became apparent that it would also be possible to prepare a library of indolo[3,2-c]quino- lines from the same starting material as the newly devised strategy to produce neocryptolepines. By utilizing a reaction sequence consisting of a Suzuki-Miyaura cross-coupling reaction, in- stallation of an azido moiety and finally photochemical cyclization, this goal was realized, producing a total of 19 indoloquinolines. This protocol was less robost towards substrate func- tionalizations than the neocryptolepine approach, with no apparent trend concerning electron- withdrawing and electron-donating groups being apparent. The photochemical cyclization was hypothesized to proceed via the formation of a reactive singlet nitrene intermediate. Finally, a selection of the prepared tetracyclic compounds assembled during this work was evaluated for their antiplasmodial, antiproliferative and antimicrobial activities by the help of various external collaborators. The most successful compound was revealed to be the novel pyridophenanthridines, displaying more potent antiproliferative activities than doxoru- bicin against human prostate cancer (IC50 = 24 nM). The novel pyridocarbazoles moreover showed excellent inhibition of biofilm formation, with the potential to be developed into a dual anticancer-antimicrobial agent. Of all the tested compounds, only N-methylated pyridocar- bazole was found to contain any significant activity against the evaluated Plasmodium falci- parum strain. The antimicrobial assays revealed the importance of the inclusion of a methyl group for activity, but not strictly in the form of an N-methyl unit, which is the general con- census in the literature thus far. Further, chlorinated indoloquinolines were revealed to contain excellent antimicrobial activity against both Gram-positive and Gram-negative bacterial cell lines.

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“…Method 2: Following the general procedure, the title compound was prepared from 3-bromo-5- In accordance with previously reported data. [275] 4-Nitro-2-(quinolin-3-yl)aniline (69g)…”

Section: General Proceduresmentioning

confidence: 99%

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Håheim¹

2022

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“…(1) and ( 2)]. [69] Atroposelective processes have also been developed based on the use of homochiral aminoacids as transient directing mediators. Indeed, the Shi group reported in 2017, the atroposelective C(sp 2 )À H olefination of various biaryl aldehydes with different acrylates and styrenes via (dynamic) kinetic resolution (DKR).…”

Section: Alkenylation Reactionsmentioning

confidence: 99%

Transient Directing Groups in Metal−Organic Cooperative Catalysis

Jacob

Maes

Evano

2021

Chemistry A European J

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The direct functionalization of CÀ H bonds is among the most fundamental chemical transformations in organic synthesis. However, when the innate reactivity of the substrate cannot be utilized for the functionalization of a given single CÀ H bond, this selective CÀ H bond functionalization mostly relies on the use of directing groups that allow bringing the catalyst in close proximity to the CÀ H bond to be activated and these directing groups need to be installed before and cleaved after the transformation, which involves two additional undesired synthetic operations. These additional steps dramatically reduce the overall impact and the attractiveness of CÀ H bond functionalization techniques since classical approaches based on substrate pre-functionalization are sometimes still more straightforward and appealing. During the past decade, a different approach involving both the in situ installation and removal of the directing group, which can then often be used in a catalytic manner, has emerged: the transient directing group strategy. In addition to its innovative character, this strategy has brought CÀ H bond functionalization to an unprecedented level of usefulness and has enabled the development of remarkably efficient processes for the direct and selective introduction of functional groups onto both aromatic and aliphatic substrates. The processes unlocked by the development of these transient directing groups will be comprehensively overviewed in this review article.

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“…This strategy has been subsequently extended to other directing templates and metal catalysts by the groups of Tan, Maiti, Yu and Li. 4 In these systems, the linear nitrile-based template preferentially activates the meta -C–H bond, and the weak coordinating nature of the directing template also assists the formation of a macrocyclic organometallic intermediate. Another elegant solution to this selectivity is to use a transient directing group strategy ( Scheme 1c ), which involves the initial ortho -C–H activation, and subsequently second C–H activation occurs at the meta -C–H bond.…”

Section: Introductionmentioning

confidence: 99%

Rhodium^III-catalyzed remote difunctionalization of arenes assisted by a relay directing group

et al. 2022

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Imine as a linchpin approach for meta-C–H functionalization

Cited by 65 publications

References 51 publications

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Transient Directing Groups in Metal−Organic Cooperative Catalysis

Rhodium^III-catalyzed remote difunctionalization of arenes assisted by a relay directing group

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Imine as a linchpin approach for meta-C–H functionalization

Cited by 65 publications

References 51 publications

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Transient Directing Groups in Metal−Organic Cooperative Catalysis

RhodiumIII-catalyzed remote difunctionalization of arenes assisted by a relay directing group

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Rhodium^III-catalyzed remote difunctionalization of arenes assisted by a relay directing group