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. 2023 May 26;25(20):3818-3822.
doi: 10.1021/acs.orglett.3c01398. Epub 2023 May 16.

Aqueous Flavin Photoredox Catalysis Drives Exclusive C3-Alkylation of Indolyl Radical Cations in Route to Unnatural Tryptophan Mimetics

Jacob R Immel  1 , Bayan M Alghafli  1 , Allen Alonso Rodríguez Ugalde  1 , Steven Bloom  1
Affiliations

Aqueous Flavin Photoredox Catalysis Drives Exclusive C3-Alkylation of Indolyl Radical Cations in Route to Unnatural Tryptophan Mimetics

Jacob R Immel et al. Org Lett. .

Abstract

One way to build chemical diversity into indoles is to oxidize them to indolyl radical cations (Ind•+). These intermediates can accept new functional groups across C2-C3 bonds or independently at C2. Less encountered is selective diversification at C3, a position plagued by competing dearomative side reactions. We disclose an aqueous photoredox-catalyzed method for transforming Ind•+ into C3-substituted tryptophan mimetics that uses water as a transient protecting group to guide site-selective C3 alkylation.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Reactivity of indolyl radical cations can be directed toward C3 addition under aqueous flavin photoredox conditions.
Figure 2.
Figure 2.
(A) Scope of indoles. (B) Peptide reaction. All reactions were performed on a 0.35 mmol scale with 3 equiv of an indole derivative in a 20/80 TFE/H2O solvent (10 mM) with phosphate buffer (pH 7, 10 mM) added and 1 mol % lumiflavin. Reaction mixtures were then sparged with N2 and irradiated for 16 h with two 40 W, 440 nm Kessil lights. Compounds 1–14 are depicted with isolated yields.
Figure 3.
Figure 3.
(A) Stern–Volmer quenching studies. (B) Isodesmic calculations and TEMPO trapping experiment.
See this image and copyright information in PMC

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