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. 2024 Jun 14;26(23):4873-4876.
doi: 10.1021/acs.orglett.4c01269. Epub 2024 May 31.

Synthesis of Complex Tetracyclic Fused Scaffolds Enabled by (3 + 2) Cycloaddition

Vincent Porte  1 , Branca C van Veen  1 , Haoqi Zhang  1 , Paolo Piacentini  1 , Sergio Armentia Matheu  1 , Sophie Woolford  1 , Kevin R Sokol  2 , Saad Shaaban  1 , Harald Weinstabl  2 , Nuno Maulide  1
Affiliations

Synthesis of Complex Tetracyclic Fused Scaffolds Enabled by (3 + 2) Cycloaddition

Vincent Porte et al. Org Lett. .

Abstract

We describe the single-step formation of complex tetracyclic fused scaffolds enabled by (3 + 2) cycloaddition of azomethine ylides. Various indoles, N-protecting groups, and amino acids are well tolerated. The products are obtained in a catalyst-free manner with moderate to excellent yield and high diastereoselectivity. Representing a new scaffold that is not yet found in nature, the construction of pyrrolidine-fused cyclohepta-, azepino-, or oxepinoindoles could be found valuable in the synthesis of new pseudo-natural products.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Design of a Complex Tetracyclic Scaffold on the Basis of Fragments Derived from Azepino/Cycloheptaindoles and Pyrrolidine-Containing Natural Products
Scheme 2
Scheme 2. Scope of the (3 + 2) Cycloaddition of Indole-2-carbaldehydes
Reactions were carried out on 0.03–0.3 mmol scale, and combined isolated yields were reported unless otherwise stated. Scale-up: 1 mmol. Minor diastereomer was not isolated. Reaction was performed at 60 °C. Unseparable mixture of diastereomers.
Scheme 3
Scheme 3. (3 + 2) Cycloaddition of Nitrone-Containing Substrates
Scheme 4
Scheme 4. (3 + 2) Cycloaddition of In Situ Generated Nitrile Oxide-Containing Substrates
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References

    1. Neumann A.; Marrison L.; Klein R. Relevance of the Trillion-Sized Chemical Space “eXplore” as a Source for Drug Discovery. ACS Med. Chem. Lett. 2023, 14 (4), 466–472. 10.1021/acsmedchemlett.3c00021. - DOI - PMC - PubMed
    1. Reymond J.-L.; van Deursen R.; Blum L. C.; Ruddigkeit L. Chemical Space as a Source for New Drugs. Med. Chem. Commun. 2010, 1 (1), 30–38. 10.1039/c0md00020e. - DOI
    1. Reymond J.-L. The Chemical Space Project. Acc. Chem. Res. 2015, 48 (3), 722–730. 10.1021/ar500432k. - DOI - PubMed
    1. Erlanson D. A.; Fesik S. W.; Hubbard R. E.; Jahnke W.; Jhoti H. Twenty Years on: The Impact of Fragments on Drug Discovery. Nat. Rev. Drug Discovery 2016, 15 (9), 605–619. 10.1038/nrd.2016.109. - DOI - PubMed
    1. Over B.; Wetzel S.; Grütter C.; Nakai Y.; Renner S.; Rauh D.; Waldmann H. Natural-Product-Derived Fragments for Fragment-Based Ligand Discovery. Nat. Chem. 2013, 5 (1), 21–28. 10.1038/nchem.1506. - DOI - PubMed