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Biocompatible Photochemistry: From Photochemical Synthesis to Biological Modulation

1. Photochemical Synthesis

Photochemical reactions utilize light energy to drive high-barrier transformations (> 40 kcal/mol) under mild conditions, holding great promise for synthetic applications. However, their widespread adoption is challenged by the transient nature of excited states and complex, often poorly understood, reaction pathways. Compounds featuring organoboron, iodine, and oxygen functionalities are of significant interest due to their unique reactivity, yet their photochemical exploration remains in its infancy. Structural limitations and a lack of mechanistic understanding have resulted in a scarcity of reported studies, leaving substantial potential for discovery in this area.

1.1 Cyclic Iodine(III) Benziodoxole (BI) Photocatalysis:

Unlike conventional hypervalent iodine reagents, cyclic iodine(III) compounds such as benziodoxole (BI) were historically considered chemically inert.¹ In 2013, we overturned this view by demonstrating for the first time that BI reagents exhibit unique reactivity under visible-light photocatalysis.³ We showed that BI–OH and BI–OAc serve as mild oxidative quenchers, while BI–alkyne acts as a radical acceptor, enabling previously unreported redox-neutral transformations under visible light (Fig. 1). Subsequent studies revealed that BI reagents mimic transition-metal-like behavior by activating substrates—including vinyl carboxylic acids, keto acids, and alcohols—through covalent B–O bond formation.^4,5 More recently, we discovered their ability to activate N–H bonds via non-covalent interactions, as demonstrated by a novel 6-endo-trig radical addition of cycloalkylamides for pyridine synthesis.⁶ These diverse activation modes and key intermediates, unequivocally characterized by NMR spectroscopy and X-ray crystallography, have established a broad reactivity profile for BI reagents. This utility is evidenced by their subsequent adoption by over 80 research groups worldwide for diverse synthetic and biological applications.²

Fig. 1 Cyclic iodine(III) benziodoxole BI reagents enable new photocatalytic reactions.

Selected Publications:

1. Jia, K.; Chen, Y.* Photochemistry of hypervalent iodine compounds, In Patai Chemistry of Functional Groups, Chemistry of Hypervalent Halogen Compounds, Olofsson, B.; Marek, I., Rappoport, Z. Eds.; John Wiley & Sons, 2019, 855−896.

2. Dong, J.; Qin, H.; Chen, Y.* Hypervalent iodine reagents in photochemistry, In Science of Synthesis: Hypervalent Halogens in Organic Synthesis, Waser, J. Ed.; Thieme: Stuttgart, 2025, in press.

3. Huang, H.; Zhang, G.; Gong, L.; Zhang, S.; Chen, Y.* Visible-Light-Induced Chemoselective Deboronative Alkynylation under Biomolecule-Compatible Conditions. J. Am. Chem. Soc. 2014, 136, 2280−2283.

4. Huang, H.¹; Zhang, G.¹; Chen, Y.* Dual Hypervalent Iodine(III) Reagents and Photoredox Catalysis Enable Decarboxylative Ynonylation under Mild Conditions. Angew. Chem., Int. Ed. 2015, 54, 7872−7876.

5. Jia, K.; Zhang, F.; Huang, H.; Chen, Y.* Visible-Light-Induced Alkoxyl Radical Generation Enables Selective C(sp³)-C(sp³) Bond Cleavage and Functionalizations. J. Am. Chem. Soc. 2016, 138, 1514−1517.

6. Dong, X.¹; Shao, Y.¹; Liu, Z.; Huang, X.; Xue, X.*; Chen, Y.* Radical 6-Endo Addition Enables Pyridine Synthesis under Metal-Free Conditions. Angew. Chem., Int. Ed. 2024, 63, e202410297.

 

1.2  Oxygen Radicals and Organoboron Rearrangements:

Traditional methods for generating alkoxyl radicals rely on harsh conditions such as high heat, strong oxidants, or UV light, and early visible-light photocatalytic approaches proved ineffective.¹ Our group has since established a suite of mild, visible-light-driven alternatives: beginning in 2015 with reductive generation from N-alkoxyphthalimides,² followed in 2016 by an oxidative route using BI reagents to generate radicals directly from alcohols, and later a photocatalyst-free electron donor–acceptor (EDA) complex system³ (Fig. 2).Unlike conventional methods, alkoxyl radicals generated under visible light display versatile reactivity, facilitating novel C–C bond-forming reactions through pathways such as δ-C–H functionalization and β-scission of C–C bonds. We further systematically investigated the underexplored α-site reactivity of these radicals, demonstrating pathways including 1,2-hydrogen atom transfer (HAT) to form ketyl radicals and α-site HX elimination, leading to the first reported generation of formyl radicals.⁵ More recently, we developed a visible-light-driven method that enables the addition of alkyl boronic acids to ketoacids,⁴ as well as a 1,3-boronate rearrangement onto ketones and imines.⁶ The latter transformation proceeds via an in situ-formed boron–enolate complex, which upon visible-light excitation undergoes selective 1,3-boryl migration, offering a versatile route to valuable tertiary alcohols.

Fig. 2 Oxygen Radicals and Organoboron Rearrangements.

Selected Publications:

1. Zhang, J.; Liu, D.; Chen, Y.* Oxygen-centered radicals, In Science of Synthesis: Free Radicals: Fundamentals and Applications in Organic Synthesis, Fensterbank, L.; Ollivier, D., Eds.; Thieme: Stuttgart, 2021, Vol. 1, 323−380.

2. Zhang, J.; Li, Y.; Zhang, F.; Hu, C.; Chen, Y.* Generation of Alkoxyl Radicals by Photoredox Catalysis Enables Selective C(sp³)-H Functionalization under Mild Reaction Conditions. Angew. Chem., Int. Ed. 2016, 55, 1872−1875.

3. Zhang, J.; Li, Y.; Xu, R.; Chen, Y.* Donor-Acceptor Complex Enables Alkoxyl Radical Generation for Metal-Free C(sp³)-C(sp³) Cleavage and Allylation/Alkenylation. Angew. Chem., Int. Ed. 2017, 56, 12619−12623.

4. Xie, S.; Li, D.; Huang, H.; Zhang, F.; Chen, Y.* Intermolecular Radical Addition to Ketoacids Enabled by Boron Activation. J. Am. Chem. Soc. 2019, 141, 16237−16242.

5. Liu, D.¹; Yang, K.¹; Fang, D.¹; Li, S.; Lan, Y.*; Chen, Y.* Formyl Radical Generation from α-Chloro N-Methoxyphthalimides Enables Selective Aldehyde Synthesis. Angew. Chem., Int. Ed. 2023, 62, e202213686.

6. Hao, K.¹; Li, D.¹; Fu, D.; Zou, P.; Xie, S.; Lan, Y.*; Chen, Y.* Metal-Free 1,3-Boronate Rearrangement to Ketones Driven by Visible Light. Angew. Chem., Int. Ed. 2024, 63, e202316481.

 

2. Photochemical Biology

Optogenetics employs light-sensitive proteins to modulate biological activity, yet its reliance on protein-scale actuators limits molecular-level precision. In contrast, visible-light photocatalysis operates directly at the molecular scale, enabling highly specific control over bioactive compounds for both investigative and therapeutic purposes.

2.1 Photocontrolled Drug Release​:

Recognizing the potential of visible light to drive biocompatible bond-forming and bond-cleavage reactions,¹ we introduced in 2018 a class of metal-free, visible-light-induced deboronative hydroxylation reactions that operate under physiological conditions and enable spatiotemporally precise release of bioactive molecules.² These transformations employ boronic acids as versatile substrates and organic dyes as catalysts, functioning efficiently in aqueous media at room temperature to achieve controlled delivery of neuroactive and antimuscarinic drugs directly in living cells and neurons. We subsequently developed a second-generation system based on SNAP-tag-directed heterozymes as targeted photocatalysts,³ enabling circuit-specific release of neuroactive compounds for real-time receptor modulation.⁴ More recently, we established a third-generation strategy using the genetically encodable miniSOG photoenzyme for organelle-selective drug delivery without the need for exogenous catalysts.⁵ All three generations of this photocatalytic platform operate without heavy metals and together constitute a versatile toolbox supporting both fundamental research and therapeutic development.

Fig. 3 Photocontrolled Drug Release​.

Selected Publications:

1. Hu, C.; Chen, Y.* Biomolecule-Compatible Chemical Bond-Formation and Bond-Cleavage Reactions Induced by Visible Light. Tetrahedron Lett. 2015, 56, 884−888.

2. Wang, H; Li, W.; Zeng, K.; Wu, Y.; Zhang, Y.; Xu, T.*; Chen, Y.* Photocatalysis Enables Visible Light Uncaging of Bioactive Molecules in Live Cells. Angew. Chem., Int. Ed. 2019, 58, 561−565.  

3. Zhang, Y.¹; Han, L.¹; Tian, X.; Peng, C.; Chen, Y.* Ligand-Directed Caging Enables the Control of Endogenous DNA Alkyltransferase Activity with Light inside Live Cells. Angew. Chem., Int. Ed. 2022, 61, e202115472.

4. Zeng, K.¹; Jiao, Z.¹; Jiang, Q.; He, R.; Zhang, Y.; Li, W.*; Xu, T.*; Chen, Y.* Genetically Encoded Photocatalysis Enables Spatially Restricted Optochemical Modulation of Neurons in Live Mice. ACS Cent. Sci. 2024, 10, 1, 163–175.

5. Che, Q.¹; He, R.¹; Zhang, Y.¹; Zhang, H.; Zeng, K.; Chen, Y.* Miniature Photoenzyme Enables Organelle-Specific Cellular Control via Deboronative Hydroxylation. Angew. Chem., Int. Ed.  2025, doi: 10.1002/anie.202515137.

 

2.2 Photolabeling of Proteins, Lipids, and Nucleic Acids:

Recognizing the potential of photoreductive coupling for biomolecular labeling as early as 2014,¹ we developed a labeling toolkit—including aldehyde allylation^2,5 and pinacol coupling^2,6—enabling effective modification of nucleic acids⁵ and proteins⁶ in live cells. Building on this foundation, we pioneered a visible-light-activated labeling technique in 2021 that employs common organic dyes and aryl azides to achieve rapid, genetic-modification-free protein labeling within specific organelles of live cells.³ This approach led to the discovery of novel mitochondrial stress-response proteins and was further adapted to monitor subcellular lipid dynamics in real time,⁴ establishing a powerful method for studying organelle function with high spatiotemporal resolution.

Fig. 4 Photolabeling of Proteins, Lipids, and Nucleic Acids.

Selected Publications:

1. Yang, J.; Zhang, J.; Qi, L.; Hu, C.; Chen, Y.* Visible-Light-Induced Chemoselective Reductive Decarboxylative Alkynylation under Biomolecule-Compatible Conditions. Chem. Commun. 2015, 51, 5275−5278.

2. Qi, L.; Chen, Y.* Polarity-Reversed Allylations of Aldehydes, Ketones, and Imines Enabled by Hantzsch Ester in Photoredox Catalysis.  Angew. Chem., Int. Ed. 2016, 55, 13312−13315.

3. Wang, H.¹; Zhang, Y.¹; Zeng, K.¹; Qiang, J.¹; Cao, Y.; Li, Y.; Fang, Y.; Zhang, Y.*; Chen, Y.* Selective Mitochondrial Protein Labeling Enabled by Biocompatible Photocatalytic Reactions inside Live Cells. JACS Au 2021, 1, 1066−1075.  

4. Chen, X.¹; He, R.¹; Xiong, H.; Wang. R.; Yin, Y.; Chen, Y.*; Zhu, Z.* Quantitative Profiling of Lipid Transport between Organelles Enabled by Subcellular Photocatalytic Labeling. Nat. Chem. 2025, 17, 1534–1545.

5. Zhang, Y.¹; Huang, Y.¹; Che, Q.¹; Chen, Y.* Photocatalytic Aldehyde Allylation for Site-Specific DNA Functionalization. Chin. J. Chem. 2025, 43, 97−103.

6. Tan, J.¹; Hao, K.¹; Yuan, Y.¹; Xie, S.¹; Qi, L.¹; Che, Q.¹; Li, Y.; Wang, R.*; Zhang, Y.*; Chen, Y.* Bioorthogonal Photocatalytic Protein Labeling and Cross-Linking Enabled by Stabilized Ketyl Radicals. J. Am. Chem. Soc. 2025, doi: 10.1021/jacs.5c18652.