Single-atom logic for heterocycle editing

Jurczyk, Justin; Woo, Jisoo; Kim, Sojung F.; Dherange, Balu D.; Sarpong, Richmond; Levin, Mark D.

doi:10.1038/s44160-022-00052-1

Cited by 238 publications

(173 citation statements)

References 79 publications

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“…1A). In contrast, complementary approaches that can directly modify the underlying core skeleton of a molecule are less common, despite their potential to expand the accessible chemical space (4)(5)(6)(7)(8)(9)(10)(11). Formal single atom insertion reactions to modify aromatic moieties have proven to be especially challenging given the inherent inertness of aromatic carbon-based skeleton towards cleavage of a carbon-carbon bond (12).…”

Section: Main Textmentioning

confidence: 99%

“…Indoles are among the most widespread nitrogen-containing heterocycles in medicinal chemistry and natural products (30) and thus represent an ideal substrate class for the development of latestage skeletal editing reactions (6). Such an approach is particularly attractive if less naturally abundant, yet pharmaceutically interesting scaffolds, could be rapidly accessed (Fig.…”

Section: Main Textmentioning

confidence: 99%

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Late-stage diversification of indole skeletons through nitrogen atom insertion

Reisenbauer

Green

Franchino

et al. 2022

Preprint

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Advances in the field of late-stage functionalization have expedited lead-structure discovery and established new opportunities to access valuable molecules. Although many peripheral late-stage transformations, mainly focusing on C–H functionalizations, have been reported, reliable strategies to directly edit the core skeleton of lead compounds have remained scarce. Late-stage remodeling strategies of widely encountered and pharmaceutically relevant scaffolds, such as indoles, would offer enormous potential to expand accessible chemical space. Herein, we report the skeletal editing of indoles through nitrogen atom insertion, accessing their corresponding quinazoline or quinoxaline bioisosteres via trapping of an electrophilic nitrene species generated from ammonium carbamate and hypervalent iodine. This unique reactivity is unlocked through the strategic use of a silyl group which acts as a reactivity-controlling element to suppress the inherent nucleophilicity of the nitrogen in indoles. Importantly, the utility of this highly functional group-tolerant methodology in the context of late-stage skeletal editing of several commercial drugs is demonstrated.

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Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Late-stage diversification of indole skeletons through nitrogen atom insertion

Reisenbauer

Green

Franchino

et al. 2022

Preprint

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“…[1] Single-atom transfer reactions that perform atomically precise additions of molecular architectures are one of the ideal approaches (Figure 1a). [2] Indeed, precise delivery of a chalcogen atom to a low valent main group center has opened avenues to unique species. [3] For example, oxidation of silylenes, [4] germinylenes, [5] an aluminyl anion [6] or a base-stabilized [P + ] cation [7] with N2O has proven to give access to the respective silanones, germanones, a monoalumoxane anion or a base-stabilized [PO + ] cation.…”

Section: Introductionmentioning

confidence: 99%

“…This indicates very weak or almost negligible N-to-Al π donation. [37] Indeed, for 4 and 5, the secondorder perturbation theory of the natural bond orbital (NBO) method reveals that the donor-acceptor interaction from a N lone pair into a vacant p orbital at Al has stabilization energies E (2) of 2.0 and 1.8 kcal mol -1 , respectively (Figures S27 and S28), while no N-to-Al π donation was observed for 2. These values are much smaller than those calculated for t Bu2AlNMes2 [38] (Mes = mesityl) (4.4 kcal mol -1 ) and (Mes*AlNPh)2 [39] (Mes* = 2,4,6-( t Bu)3C6H2) (21.3 kcal mol -1 ) at the same level of theory.…”

Section: Introductionmentioning

confidence: 99%

Precise Transfer of an Aluminium Atom: An Avenue to Aluminium Heterocycles

Zhang

Wang

Lan

et al. 2022

Preprint

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Synthetic chemistry targets building up molecular complexity using simple substrates through simple processes. We disclose an unprecedented Al-atom transfer strategy for the synthesis of aluminium heterocycles with high atom economy. This strategy involves an effective cycloaddition of a free carbazolyl-aluminylene with unsaturated hydrocarbons, followed by facile cleavage of the N-Al bond. The aluminylene formally behaves as an [Al+] cation transfer reagent in a two-step manner, and the only byproduct is a carbazolide salt that can be utilized to regenerate the aluminylene. The carbazolyl Al-heterocycles show unique luminescent properties, one of which exhibits dual emission. Our approach not only has a significant impact on the future design of single-atom addition reactions, but also paves the way for emissive materials based on Al-heterocycles.

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“…Ideally, such transformations would enable control at the level of single-atom precision (Fig. 1C), with more sophisticated changes possible through iterative elementary skeletal modifications (10). Notable recent contributions from several groups have been reported in the context of saturated aliphatic heterocycles (11)(12)(13).…”

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confidence: 99%

Scaffold hopping by net photochemical carbon deletion of azaarenes

Woo

Christian

Burgess

et al. 2022

Science

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128

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Discovery chemists routinely identify purpose-tailored molecules through an iterative structural optimization approach, but the preparation of each successive candidate in a compound series can rarely be conducted in a manner matching their thought process. This is because many of the necessary chemical transformations required to modify compound cores in a straightforward fashion are not applicable in complex contexts. We report a method that addresses one facet of this problem by allowing chemists to hop directly between chemically distinct heteroaromatic scaffolds. Specifically, we show that selective photolysis of quinoline N -oxides with 390-nanometer light followed by acid-promoted rearrangement affords N -acylindoles while showing broad compatibility with medicinally relevant functionality. Applications to late-stage skeletal modification of compounds of pharmaceutical interest and more complex transformations involving serial single-atom changes are demonstrated.

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Single-atom logic for heterocycle editing

Cited by 238 publications

References 79 publications

Late-stage diversification of indole skeletons through nitrogen atom insertion

Late-stage diversification of indole skeletons through nitrogen atom insertion

Precise Transfer of an Aluminium Atom: An Avenue to Aluminium Heterocycles

Scaffold hopping by net photochemical carbon deletion of azaarenes

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