Benedikt Buchberger

Graduate student @Scrippsresearch @Baranlabreads

[Baran Lab @BaranLabReads]

Radical cross-coupling, simplified. No specialized equipment. No exogenous redox. No stoichiometric organometallics. The best part is no part. 

A perspective on the field, appearing today in @ChemRxiv : https://t.co/g65WPyAVSx

[Benedikt Buchberger @Bene_Buchberger]

Very excited to share that our recent work was accepted. Awesome teamwork!! We developed a radical cross-coupling platform using readily accessible glycohydrazides to enable C–C bond formation across carbohydrate scaffolds.

[Baran Lab @BaranLabReads]

Appearing today as an Accelerated Article Preview publication in @Nature :https://t.co/uWKIj77IR7

[Baran Lab @BaranLabReads]

Making C-glycosides SWEET and simple! Today in @ChemRxiv we disclose (https://t.co/VDfit7itxh), in collaboration with @GroupAggarwal, an incredibly easy way to achieve radical functionalization of sugars. In this video (https://t.co/GRf6w9ZA7z), 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.

[Olalla Vázquez @OlallaLab]

@Chemie_UMR day!🤩We've missed this so much.Our contribution: @miomiomarco @Bene_Buchberger talks,Kaijun & Johannes, Nina (from @hantschel_lab )posters & 🥪😋. Well-done everybody!💪🙂♥️Day's golden clasp was Dehnicke PhD prize for our @GretaLinden 👏🍾🎇♥️ #ProudDoktorMutti