Liebeskind–Srogl coupling

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The Liebeskind–Srogl coupling is a chemical method that links a thioester and a boronic compound to form a new carbon–carbon bond, using copper and palladium catalysts. It is a cross-coupling reaction named after Jiri Srogl and Lanny Liebeskind.

Generations
- First generation: Uses catalytic palladium(0) with a special ligand (tris(2-furyl)phosphine) and stoichiometric copper(I) thiophene-2-carboxylate as a co-catalyst. It must be done without air. This version works with thioesters and boronic acids, and can also use other partners like stannanes. Mechanistically, the thioester binds copper, palladium inserts into the carbon–sulfur bond, the two parts transfer (transmetallation), and reductive elimination forms the ketone while regenerating catalysts.
- Second generation: Reactions are catalytic in copper and do not need palladium. An extra equivalent of boronic acid is used under air to keep copper turning over. This version is mainly limited to thioesters and sulfides, and the cost/availability of boron reagents can be a factor.
- Third generation: Copper-catalyzed with only one equivalent of boronic acid and no palladium. It often uses a thio-auxiliary that helps copper turnover and can be done under microwave conditions. This version follows a mechanism similar to the second generation but taps the auxiliary to release copper back into the cycle.

Scope
The reaction is most common with sulfide or thioester electrophiles and boronic acids or stannanes as nucleophiles, but many other partners can work. Beyond alkyl and aryl thioesters, (hetero)aryl thio compounds, thioamides, sulfanyl alkynes, and thiocyanates can be used. In general, nearly any metal–carbon bond that can transfer its carbon to copper or palladium can participate (though some nucleophiles, like certain indium reagents, can work without copper or base).

Applications
The Liebeskind–Srogl coupling is a useful tool in complex molecule synthesis. It has helped chemists construct challenging carbon frameworks in natural products, such as:
- Goniodomin A (used to build the northern half of the molecule)
- Viridin (made on a multi-gram scale)
- Amphidinolide F (used to assemble part of the macrocycle and side chains)

Other work shows selective functionalization strategies when multiple sulfide bonds are present, and different setups can influence whether the reaction targets one position or another.