Many widely used pharmaceuticals depend on a carbohydrate class known as C-glycosides, which are metabolically stable and acid-resistant. Although they can be made from common sugars like dextrose, C-glycosides have proven difficult to synthesize due to the preponderance of hydroxyl groups that act as hurdles to forging new carbon-carbon bonds.
A research team at Scripps Research (La Jolla, Calif.; www.scripps.edu) has demonstrated a simplified C-glycoside synthesis pathway that eliminates hazardous reagents and overcomes the need to “shield” and “unshield” hydroxyls during the formation of key chemical bonds. The cornerstone of the platform is the precise conversion and deployment of specialized reactive radicals known as glycosyl sulfonyl hydrazides, which serve as the precursor for generating glycosyl radicals, using a simple nickel catalyst. Critically, the method works directly on unprotected native sugars, skipping the extensive protecting-group chemistry that traditional C-glycoside synthesis requires, while producing only nitrogen gas as a stoichiometric byproduct.
“Many current industrial radical processes rely on photoredox catalysis (which needs specialized light sources and often expensive or proprietary photocatalysts), electrochemistry (requiring electrodes and conductivity management) or stoichiometric metals like magnesium or zinc that generate waste or byproducts, or are difficult to scale up,” explains Phil Baran, Scripps professor of chemistry.
Source: Scripps Research
During the nickel-catalyzed cycle, the short-lived radicals are precisely “caged” so that they can encounter each other in a controlled manner to ensure proper bond formation. As Baran explains: “In the nickel-catalyzed cycle, the glycosyl radical is generated from the hydrazide via a diazene intermediate and is rapidly captured (the diazene is the cage) by a low-valent nickel species to form a transient organonickel intermediate before it can freely diffuse and engage in unproductive side reactions, such as dimerization or hydrogen abstraction. This fast capture is key to selectivity and efficiency.”
The team has demonstrated the technology at the decagram scale, preparing glycosyl hydrazide using commodity dextrose powder via stirring and crystallization and subsequently carrying out the main cross-coupling step. “The nickel-catalyzed coupling to produce one of the gliflozin cores proceeded smoothly to give the product in 61% isolated yield with excellent diastereoselectivity. This is well beyond typical academic milligram-scale work and shows that the chemistry behaves well when you increase mass,” adds Baran.
The team has confidence that the technology can translate to larger, industrially relevant scales due to its inherent simplicity — it operates with a homogeneous solution at moderate temperatures, requires no specialized equipment and the nickel catalyst and its bipyridine ligands are widely available. “The novelty of the process stems from the use of glycosyl sulfonyl hydrazide precursors and the specific conditions (base, solvent and temperature) that allow this common nickel system to perform exceptionally well with highly polar, unprotected carbohydrate substrates that have historically been problematic,” notes Baran.
By unlocking a simpler synthesis route using glycosyl radicals, production of certain existing drugs could be made significantly more economical, and it could also uncover new drug candidates that were previously too synthetically costly to pursue.