Issue 41, 2023

Mild and scalable synthesis of phosphonorhodamines

Abstract

Since their discovery in 1887, rhodamines have become indispensable fluorophores for biological imaging. Recent studies have extensively explored heteroatom substitution at the 10′ position and a variety of substitution patterns on the 3′,6′ nitrogens. Although 3-carboxy- and 3-sulfono-rhodamines were first reported in the 19th century, the 3-phosphono analogues have never been reported. Here, we report a mild, scalable synthetic route to 3-phosphonorhodamines. We explore the substrate scope and investigate mechanistic details of an exogenous acid-free condensation. Tetramethyl-3-phosphonorhodamine (phosTMR) derivatives can be accessed on the 1.5 mmol scale in up to 98% yield (2 steps). phosTMR shows a 12- to 500-fold increase in water solubility relative to 3-carboxy and 3-sulfonorhodamine derivatives and has excellent chemical stability. Additionally, phosphonates allow for chemical derivatization; esterification of phosTMR facilitates intracellular delivery with localization profiles that differ from 3-carboxyrhodamines. The free phosphonate can be incorporated into a molecular wire scaffold to create a phosphonated rhodamine voltage reporter, phosphonoRhoVR. PhosRhoVR 1 can be synthesized in just 6 steps, with an overall yield of 37% to provide >400 mg of material, compared to a 6-step, ∼2% yield for the previously reported RhoVR 1. PhosRhoVR 1 possesses excellent voltage sensitivity (37% ΔF/F) and a 2-fold increase in cellular brightness compared to RhoVR 1.

Graphical abstract: Mild and scalable synthesis of phosphonorhodamines

Supplementary files

Article information

Article type
Edge Article
Submitted
22 may 2023
Accepted
28 avq 2023
First published
05 okt 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 11365-11373

Mild and scalable synthesis of phosphonorhodamines

J. L. Turnbull, R. P. Golden, B. R. Benlian, K. M. Henn, S. M. Lipman and E. W. Miller, Chem. Sci., 2023, 14, 11365 DOI: 10.1039/D3SC02590J

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