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Baran Lab
1.5K posts
Baran Lab
@BaranLabReads
Electrifying chemistry...
La Jolla, CA Katılım Ocak 2014
123 Takip Edilen26.2K Takipçiler
Baran Lab retweetledi
Great collaboration with @BaranLabReads on a simple 2 step method to complex C-glycosides without protecting groups. @BristolChem
Baran Lab@BaranLabReads
Making C-glycosides SWEET and simple! Today in @ChemRxiv we disclose (chemrxiv.org/doi/full/10.26…), in collaboration with @GroupAggarwal, an incredibly easy way to achieve radical functionalization of sugars. In this video (youtu.be/Fqdbgmx7zEI), a two-step synthesis of the billion dollar drug Dapagliflozin is achieved using household vinegar and dextrose powder from the local supplement store. High Level Summary: The work addresses a longstanding challenge in carbohydrate chemistry: the efficient, scalable, and stereocontrolled synthesis of C-aryl glycosides directly from unprotected native sugars. C-Aryl glycosides form the core pharmacophore of the SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, and related agents), which are frontline therapies for type 2 diabetes and represent one of the highest-grossing classes of small-molecule drugs. Conventional synthetic routes to these molecules generally require extensive protecting-group manipulations, multi-step activation of glycosyl donors, or organometallic additions under demanding conditions. Recent advances in radical and transition-metal-catalyzed cross-couplings have improved access, yet most approaches still depend on protected precursors, specialized reagents, or protocols that are difficult to scale. We report a practical alternative based on glycosyl sulfonyl hydrazides—stable, crystalline radical precursors that are prepared in a single step from unprotected sugars by treatment with tosylhydrazine in acetic acid, followed by simple crystallization. These hydrazides undergo redox-neutral nickel-catalyzed radical cross-coupling with aryl iodides or bromides under mild conditions (70 °C, DMSO, tetramethylguanidine as base). The reaction requires no external oxidant or reductant, no photocatalyst, and no organotin species. In glucose-derived systems the coupling typically delivers high β-selectivity (>19:1 in many cases), an outcome that appears to depend on hydrogen-bonding interactions between tetramethylguanidine and the free hydroxyl groups. The main findings are as follows: All five FDA-approved SGLT2 inhibitors, as well as several clinical candidates, can be prepared in a single coupling step from the corresponding glycohydrazide. Decagram-scale synthesis of dapagliflozin was demonstrated starting from commercial dextrose; the product was isolated by aqueous workup and recrystallization (no column chromatography required at this scale). Di- and trisaccharides (lactose, cellobiose, maltose, maltotriose) couple directly to give aryl-linked oligosaccharides. Several natural products and medicinally relevant structures (salmochelin-SX, neopetrosin C, the tryptophan-mannose conjugate, and a ribose-derived IMPDH inhibitor) that previously required 9–20 steps or costly reagents are now accessible in 1–4 steps with good stereocontrol. The platform extends to non-anomeric C–C bond formation at positions C2–C6 on glucose and ribose scaffolds, providing the first systematic exploration of radical diversification across these positions. Stereoretentive radical cross-coupling, using configurationally pure hydrazides, enables programmable delivery of either α- or β-anomers, overriding inherent substrate biases and providing access to stereoisomers not previously obtainable by radical methods. The chemistry builds on our earlier development of sulfonyl hydrazide-based redox-neutral cross-coupling and stereoretentive radical arylation, here adapted and optimized for carbohydrate substrates. The method is operationally straightforward, uses inexpensive reagents and starting materials, and eliminates protecting-group strategies.
English
Making C-glycosides SWEET and simple! Today in @ChemRxiv we disclose (chemrxiv.org/doi/full/10.26…), in collaboration with @GroupAggarwal, an incredibly easy way to achieve radical functionalization of sugars. In this video (youtu.be/Fqdbgmx7zEI), a two-step synthesis of the billion dollar drug Dapagliflozin is achieved using household vinegar and dextrose powder from the local supplement store.
High Level Summary:
The work addresses a longstanding challenge in carbohydrate chemistry: the efficient, scalable, and stereocontrolled synthesis of C-aryl glycosides directly from unprotected native sugars. C-Aryl glycosides form the core pharmacophore of the SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, and related agents), which are frontline therapies for type 2 diabetes and represent one of the highest-grossing classes of small-molecule drugs.
Conventional synthetic routes to these molecules generally require extensive protecting-group manipulations, multi-step activation of glycosyl donors, or organometallic additions under demanding conditions. Recent advances in radical and transition-metal-catalyzed cross-couplings have improved access, yet most approaches still depend on protected precursors, specialized reagents, or protocols that are difficult to scale.
We report a practical alternative based on glycosyl sulfonyl hydrazides—stable, crystalline radical precursors that are prepared in a single step from unprotected sugars by treatment with tosylhydrazine in acetic acid, followed by simple crystallization. These hydrazides undergo redox-neutral nickel-catalyzed radical cross-coupling with aryl iodides or bromides under mild conditions (70 °C, DMSO, tetramethylguanidine as base). The reaction requires no external oxidant or reductant, no photocatalyst, and no organotin species. In glucose-derived systems the coupling typically delivers high β-selectivity (>19:1 in many cases), an outcome that appears to depend on hydrogen-bonding interactions between tetramethylguanidine and the free hydroxyl groups.
The main findings are as follows:
All five FDA-approved SGLT2 inhibitors, as well as several clinical candidates, can be prepared in a single coupling step from the corresponding glycohydrazide.
Decagram-scale synthesis of dapagliflozin was demonstrated starting from commercial dextrose; the product was isolated by aqueous workup and recrystallization (no column chromatography required at this scale).
Di- and trisaccharides (lactose, cellobiose, maltose, maltotriose) couple directly to give aryl-linked oligosaccharides.
Several natural products and medicinally relevant structures (salmochelin-SX, neopetrosin C, the tryptophan-mannose conjugate, and a ribose-derived IMPDH inhibitor) that previously required 9–20 steps or costly reagents are now accessible in 1–4 steps with good stereocontrol.
The platform extends to non-anomeric C–C bond formation at positions C2–C6 on glucose and ribose scaffolds, providing the first systematic exploration of radical diversification across these positions.
Stereoretentive radical cross-coupling, using configurationally pure hydrazides, enables programmable delivery of either α- or β-anomers, overriding inherent substrate biases and providing access to stereoisomers not previously obtainable by radical methods.
The chemistry builds on our earlier development of sulfonyl hydrazide-based redox-neutral cross-coupling and stereoretentive radical arylation, here adapted and optimized for carbohydrate substrates. The method is operationally straightforward, uses inexpensive reagents and starting materials, and eliminates protecting-group strategies.
YouTube
English
👋DRUG HUNTERS👋 N₂ extrusion from alkyl hydrazines delivers complex, medicinally relevant alkyl S(VI)-chemical space with exceptional chemoselectivity and operational simplicity.
Appearing today in @ChemRxiv: chemrxiv.org/doi/full/10.26…
Alkyl hydrazines (or their sulfonyl derivatives) serve as practical radical precursors readily prepared from ketones, alcohols, amines, and complex molecules. Simple thermal activation triggers clean N₂ extrusion to generate alkyl radicals that are captured by inexpensive SO₂ sources, delivering versatile sulfinates convertible in situ to sulfonyl fluorides or sulfinamides.
70+ examples, protecting-group-free late-stage functionalization of natural products and drugs (ticagrelor, erythromycin, spiramycin), 100-g scale with trivial work-up, and stereoretentive variants round out a unified platform that directly addresses the growing need for complex alkyl S(VI) motifs in medicinal chemistry. Detailed mechanistic studies, including temperature scanning calorimetry, radical clocks, and DFT calculations help to demystify the process.
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Baran Lab retweetledi
We are excited by the recent work of Phil S. Baran and co-authors disclosing a general redox-neutral platform for radical cross-coupling that significantly streamlines C–C bond construction (lnkd.in/dhHr53Tk). Using sulfonyl hydrazides as both radical precursors and internal electron donors, the method eliminates the need for external chemical, photochemical, or electrochemical redox inputs.
The platform delivers versatile C–C bond formation with olefins, alkyl and aryl halides, redox-active esters, and trifluoromethylating reagents under simple, homogeneous, water-tolerant conditions. Bench-stable sulfonyl hydrazides enable reactivity comparable in practicality to Suzuki couplings — while eliminating the need for external redox systems.
This work has inspired Enamine to expand our portfolio of building blocks for redox-neutral radical couplings. Leveraging the platform’s simplicity, scalability, and robustness, we support accelerated route design and efficient late-stage functionalization in modern medicinal and synthetic chemistry.
🛒 Commercial quantities of sulfonyl hydrazides and complementary cross-coupling building blocks are available directly from the EnamineStore - lnkd.in/dWNcRX_9.
#OrganicSynthesis #RadicalChemistry #CrossCoupling #BuildingBlocks #Enamine
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Tonight, we held our annual Paper of the Year meeting, during which we celebrated the great chemistry published in 2025. This year’s winner was the Stereoretentive Radical Cross-Coupling from @BaranLabReads nature.com/articles/s4158…
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Baran Lab retweetledi
3D degraders, enabled by redox-neutral radical cross-coupling, appearing today in @ChemRxiv : chemrxiv.org/doi/full/10.26…. A fabulous collaboration with BMS and the Parker lab.
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Baran Lab retweetledi
Super pleasant to see this radical-radical cross-coupling coming out. It's great to use high throughput experiments (HTE) screening to help with the optimization of the pyrrolidine coupling.
Baran Lab@BaranLabReads
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Baran Lab retweetledi
Thrilled to share another breakthrough: stereoretentive radical–radical cross-coupling (RRCC). Unprotected piperidines are well tolerated, and secondary iodides perform exceptionally well.
Baran Lab@BaranLabReads
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Baran Lab retweetledi
Another breakthrough!! A “Nose Ring” for a wild radical has been installed using a sulfonyl hydrazide. The Ni–diazene intermediate guides the radical to find the right partner (alkyl iodide), enabling precise control of stereochemistry. Please check out our latest RRCC reaction!!
Baran Lab@BaranLabReads
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Baran Lab retweetledi
@BaranLabReads Rapid radical rebound ➡️⬅️ energetically driven by N2 extrusion 💥 enables alkyl radical + alkyl radical coupling without the loss of stereochemistry -- no chiral catalyst needed! Supported by experiment and DFT 🧪💻
GIF
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Baran Lab retweetledi
Well, my favorite part is the team’s mindset: How do you convince yourself you can control a thing that loses its stereochemistry instantly and trap it fast enough with ANOTHER transient radical. Thinking this could work (and actually making it work) is kind of crazy.
Baran Lab@BaranLabReads
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Baran Lab retweetledi
Chemists have been trying to synthesise natural products in the lab for around two centuries. Nina Notman looks at what the future holds – and what the field is up against in terms of a variety of obstacles.
chemistryworld.com/features/the-f…
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