Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Nov 2;20(21):6840-6844.
doi: 10.1021/acs.orglett.8b02968. Epub 2018 Oct 15.

Radical/Polar Annulation Reactions (RPARs) Enable the Modular Construction of Cyclopropanes

John A Milligan  1 , James P Phelan  1 , Viktor C Polites  1 , Christopher B Kelly  2   3 , Gary A Molander  1
Affiliations

Radical/Polar Annulation Reactions (RPARs) Enable the Modular Construction of Cyclopropanes

John A Milligan et al. Org Lett. .

Abstract

An annulation process for the construction of 1,1-disubstituted cyclopropanes via a radical/polar crossover process is described. The cyclopropanation proceeds by the addition of a photocatalytically generated radical to a homoallylic tosylate. Reduction of the intermediate radical alkylation adduct (via single electron transfer) furnishes an anion that undergoes an intramolecular substitution. The process displays excellent functional group tolerance, characteristic of proceeding through odd-electron intermediates, and occurs under mild conditions with visible light irradiation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Examples of therapeutic agents containing a 1,1-disubstituted cyclopropane unit.
Figure 2.
Figure 2.
Proposed mechanistic pathway for the described annulation process.
Scheme 1.
Scheme 1.
Comparison of cyclopropanation strategies and implications of the envisioned approach.
Scheme 2.
Scheme 2.. Scope of the Annulative Process via Radical/Polar Crossover.a
aUnless otherwise noted, the reactions were carried out on a 0.3 mmol scale at 35 ±C; isolated yields after purification. bReaction carried out in DMSO for 2 h. cReaction conducted on 1 mmol scale. dReaction carried out in DMSO for 16 h. eReaction carried out in DMA for 4 h.
Scheme 3.
Scheme 3.
Synthesis of pyrrolidine 21 from various radical precursors.
See this image and copyright information in PMC

References

    1. Ma S Handbook of Cyclization Reactions, 1st ed.; Wiley-VCH: Weinheim, 2009.
    2. Molander GA Diverse Methods for Medium Ring Synthesis. Acc. Chem. Res 1998, 31, 603.
    1. Talele TT The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules. J. Med. Chem 2016, 59, 8712. - PubMed
    2. Taylor RD; MacCoss M; Lawson ADG Rings in Drugs. J. Med. Chem 2014, 57, 5845. - PubMed
    3. Chen DY-K; Pouwer RH; Richard J-A Recent advances in the total synthesis of cyclopropane-containing natural products. Chem. Soc. Rev 2012, 41, 4631. - PubMed
    4. Hansen TV; Stenstrøm Y Naturally Occurring Cyclobutanes In Organic Synthesis: Theory and Applications; Hudlicky T, Ed.; Elsevier: Oxford, U.K., 2001; 5, 1–38.
    1. Funel JA; Abele S Industrial Applications of the Diels–Alder Reaction. Angew. Chem. Int. Ed 2013, 52, 3822. - PubMed
    2. Nicolaou KC; Snyder SA; Montagnon T; Vassilikogiannakis G The Diels–Alder Reaction in Total Synthesis. Angew. Chem., Int. Ed 2002, 41, 1668. - PubMed
    3. Remy R; Bochet CG Arene–Alkene Cycloaddition. Chem. Rev, 2016, 116, 9816. - PubMed
    4. Jones AC; May JA; Sarpong R; Stoltz BM Toward a Symphony of Reactivity: Cascades Involving Catalysis and Sigmatropic Rearrangements. Angew. Chem. Int. Ed 2014, 53, 2556. - PMC - PubMed
    1. Mal D Anionic Annulations in Organic Synthesis: A Versatile and Prolific Class of Ring-Forming Reactions 1st ed.; Elsevier Science: USA, 2018.
    1. Jasperse CP; Curran DP; Fevig TL Radical reactions in natural product synthesis Chem. Rev 1991, 91, 1237.
    2. Giese B; Kopping B; Göbel T; Dickhaut J; Thoma G; Kulicke KJ; Trach F Radical Cyclization Reactions Org. React 1996, 48, 301.
    3. Romero KJ; Galliher MS; Pratt DA; Stephenson CRJ Radicals in natural product synthesis Chem. Soc. Rev, 2018. Advance article, DOI: 10.1039/C8CS00379C. - DOI - PMC - PubMed

Publication types