Jeh-Jeng Wang

Selective γ-C(sp³)–H functionalization within radical cascade sequences for constructing spiroheterocycles remains a significant challenge in organic synthesis, particularly when targeting sterically encumbered, conformationally rigid scaffolds with high stereocontrol. Herein, we report a visible-light-driven, metal-, photocatalyst-, and additive-free radical cascade enabling highly diastereoselective (dr > 20 : 1) synthesis of densely functionalized spirocyclic-azaspiro[4.5]decane derivatives from 1,1-disubstituted cyclohexanes. Employing diverse bifunctional reagents—including sulfonyl iodides, selenosulfonates, and thiosulfonates—this cascade proceeds via regio- and chemoselective radical addition, intramolecular 5-exo–dig spirocycliza-tion, and stereodefined 1,5-hydrogen atom transfer (1,5-HAT) from an in situ-generated C(sp²) radical center, culminating in remote C–X (X = I, SePh, SPh) bond formation. This method achieves site-, regio-, chemo-, and stereocontrol under mild, sustainable conditions. Based on the obtained X-ray crystallographic data, DFT calculations on representative isomers show excellent agreement, supporting the stereochemical assignments and providing insight into the observed diastereoselectivity. The approach is green, atom-economical (100%), and operationally simple, and, based on green chemistry metrics, it is efficient and environmentally benign, featuring a low E-factor and high EcoScale score (71 on a scale of 0–100), thereby providing a practical and sustainable method for spiroheterocycle synthesis.

A metal-free three-component radical cascade cyclization of unactivated 1,6-enynes has been developed using 1-phenylethan-1-one oxime as a novel in situ nitrogen dioxide (NO₂) radical source under I₂/aqueous TBHP conditions. This transformation proceeds through a chemo- and regioselective sequence involving NO₂· addition to the terminal alkene, 5-exo-dig cyclization onto the alkyne, and iodine trapping of the resulting carbon-centered radical, yielding 4-(iodo(phenyl)methylene)-3-(nitromethyl)-1-tosylpyrrolidines. This strategy avoids transition metals, photocatalysts, or prefunctionalized nitrogen reagents and highlights the previously unexplored potential of oximes as bench-stable NO₂-radical donors for cascade transformations.

A green, metal-free dearomative cycloaddition of non-activated arenes in 2-MeTHF at room temperature, enabling rapid access to complex N -heterocycles with a recyclable organophotocatalyst (5 cycles, >86% yield).

We have demonstrated a highly efficient synthetic strategy for assembling amide-functionalized fluorenes via cascade reactions between nitriles and 1,5-enynes in a one-pot assembly. This approach provides a simple, atom-economic, practical, and robust path to synthesize highly versatile rare carbocyclic scaffolds under transition-metal- and additive-free conditions with good reaction yields. Its most noteworthy features include high compatibility with various functionalities, mild conditions, easily accessible precursors, and gram-scale synthesis.

Dual-labeled, profluorescent chemical probes have been developed to quantify and visualize a specific enzyme’s activity in complex biological media. The intact chemical probes often exhibit minimal fluorescence due to fluorescence quenching, but their intrinsic fluorescence can be released by a favorable enzyme-catalyzed reaction. Contact quenching represents one of several fluorescence quenching mechanisms. However, it is seldom intentionally implemented in the synthesis of dual-labeled, profluorescent chemical probes, because the structure of a contact quenching construct requires the formation of a ground-state fluorophore-quencher/-fluorophore complex. The ability of such dual-labeled molecular probes to act as intramolecular dimers cannot be predicted. We previously revealed that a mono exo-bicyclo­[6.1.0]­nonyne (exo-BCN)-derivatized cystamine framework was critical to synthesizing sensitive, dual-labeled, profluorescent chemical probes capable of contact quenching. Here, we exploited the nonsymmetrical mono-exo-BCN-cystamine backbone by sequentially coupling it with two different carboxyfluorescein (FAM) derivatives and subsequently synthesizing four nonsymmetrical bis-FAM chemical probes. The fluorescence turn-on properties of the bis-FAM chemical probe with the lowest background FAM fluorescence were characterized by kinetic studies. Moreover, the release of two FAM equivalents from the fluorescence turn-on chemical probe during reactions was utilized to develop sensitive assays for measuring the activity and inhibition of two serum biomarkers, butyrylcholinesterase (BChE) and paraoxonase 1 (PON1) lactonase. We also developed an efficient, high-throughput assay for detecting BChE activity based on the chemical probe. Finally, the fluorescence assays successfully quantified the activities of BChE and PON1 lactonase in human serum.

Herein, we developed an intramolecular Ag(I)/K₂S₂O₈-mediated selective oxidation of alkyne in the ynamide-yne framework. Through structural reshuffling and consecutive N-desulfonylation, this process produces multisubstituted indoles (1,2-dicarbonyl). The developed intramolecular methodology exhibits remarkable advantages, including regioselective and chemoselective alkyne oxidation, the use of K₂S₂O₈ as an oxidant and oxygen source, multiple bond cleavages (N-C(sp), O-SO₃^-, N-SO₂R), and the formation of multiple new bonds (two C═O, two C(sp²)-C(sp²), and one N-C(sp²)) in a one-pot reaction. Moreover, this protocol is applicable to gram-scale synthesis and enables further synthetic transformations of the products.

This work introduces a workup-free p -TsOH-initiated yne-ynamide skeletal rearrangement process for the synthesis of stereospecific E -alkenyl sulfonate-tethered and ketone-tethered indoles via heterolytic N –Csp bond cleavage.

We report a metal additive–free iodine‐promoted one‐step structural reorganization of ynamide‐ynes and simultaneous stereoselective 1,2‐diiodination of the migrated alkyne to form stereospecific tetrasubstituted alkenyl diiodo‐tethered indoles (E‐isomer). Molecular iodine is cost effective, user friendly, less toxic, commercially available, and easy to handle. The key features of the reaction include metal–and additive–free environment, selectivity, structural reorganization, mild reaction conditions, simple workup, and gram‐scale synthesis. This transformation generates multiple bonds [nitrogen (N)‐carbon (C)sp2, Csp2−Csp2, 2 Csp2‐iodine (I)] via N−Csp bond cleavage in ynamide‐ynes.

Herein, we describe a base‐promoted regioselective and chemoselective cascade cyclization, ynamide N−Csp bond cleavage, selective intramolecular 1,3‐migration, and simultaneous N‐desulfonylation strategy for the synthesis of 2‐phenyl‐3‐(phenylethynyl)‐1H‐indole derivatives. We observed multiple bond breaking (−N−Ts, and Csp²−Ts, Csp²−I/Csp²−SePh) from (E)‐3‐(1‐iodo‐2‐phenyl‐2‐tosylvinyl)‐2‐phenyl‐1‐tosyl‐indole/(E)‐2‐phenyl‐3‐(2‐phenyl‐1‐(phenylselanyl)‐2‐tosylvinyl)‐1‐tosyl‐indole derivatives to prepare 2‐phenyl‐3‐(phenylethynyl)‐1H‐indole in 15–60 min using our standard reaction conditions. A gram‐scale experiment as well as postsynthetic transformations of the synthesized 2‐phenyl‐3‐(phenylethynyl)‐1H‐indole were performed to exhibit the advantages of this synthetic methodology.

A dual nickel- and iridium-photocatalyzed radical cascade bicyclization reaction for the synthesis of highly complex molecular structures in an atom- and step-economic manner has been described. A series of radical precursors are utilized for the divergent synthesis of diversely substituted fluorenes and indenoazepinones bearing quaternary carbons by using cascade cyclization reactions of 1,5-enynes. This reaction is characterized by its mild conditions, broad substrate scope, excellent selectivity, and satisfactory yield including facile scale-up synthesis.