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Aryl-aryl bond formation one century after the discovery of the Ullmann reaction.

In 2010, Richard Heck, Ei-ichi Negishi, and Akira Suzuki joined the prestigious circle of Nobel Laureate chemists for their roles in discovering and developing highly practical methodologies for C-C bond construction. From their original contributions in the early 1970s the landscape of the strategies and methods of organic synthesis irreversibly changed for the modern chemist, both in academia and in industry. In this Review, we attempt to trace the historical origin of these powerful reactions, and outline the developments from the seminal discoveries leading to their eminent position as appreciated and applied today.

Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize

Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals.

Palladium-catalyzed coupling reactions have become a central tool for the synthesis of biologically active compounds both in academia and industry. Most of these transformations make use of easily available substrates and allow for a shorter and more selective preparation of substituted arenes and heteroarenes compared to non-catalytic pathways. Notably, molecular-defined palladium catalysts offer high chemoselectivity and broad functional group tolerance. Considering these advantages, it is not surprising that several palladium-catalyzed coupling reactions have been implemented in the last decade into the industrial manufacture of pharmaceuticals and fine chemicals. In this review different examples from 2001-2008 are highlighted, which have been performed at least on a kilogram scale in the chemical and pharmaceutical industries.

Recent Applications of Palladium-Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries

Suzuki–Miyaura (SM) cross-coupling is arguably the most widely-applied transition metal catalysed carbon–carbon bond forming reaction to date. Its success originates from a combination of exceptionally mild and functional group tolerant reaction conditions, with a relatively stable, readily prepared and generally environmentally benign organoboron reagent. A variety of such reagents have been developed for the process, with properties that have been tailored for application under specific SM coupling conditions. This review analyses the seven main classes of boron reagent that have been developed. The general physical and chemical properties of each class of reagent are evaluated with special emphasis on the currently understood mechanisms of transmetalation. The methods to prepare each reagent are outlined, followed by example applications in SM coupling.

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Selection of boron reagents for Suzuki-Miyaura coupling

Efficient Synthesis of Losartan, A Nonpeptide Angiotensin II Receptor Antagonist

Palladium-catalyzed cyanation of aryl bromides promoted by low-level organotin compounds.

Synthesis of an anti-methicillin-resistant Staphylococcus aureus (MRSA) carbapenem via stannatrane-mediated Stille coupling.

A practical, efficient synthesis of 1, a hepatitis C virus RNA replication inhibitor, is described. Starting with the inexpensive diacetone glucose, the 12-step synthesis features a novel stereoselective rearrangement to prepare the key crystalline furanose diol intermediate. This is followed by a highly selective glycosidation to couple the C-2 branched furanose epoxide with deazapurine.

Practical synthesis of a potent hepatitis C virus RNA replication inhibitor.

A practical preparation of an αvβ3 antagonist is reported. The antagonist consists of three key components, a tetrahydronaphthyridine moiety, a β-alanine moiety, and a central imidazolidone moiety. The tetrahydronaphthyridine component was prepared using two different methods, both of which relied on variations of the Friedlander reaction to establish the desired regiochemistry. The β-alanine component was prepared using Davies' asymmetric 1,4-addition methodology as the key stereo-defining step. The central imidazolidone portion was created from these two components using an effective three-step cyclization protocol. Thus, a highly convergent process for the drug candidate was defined.

Chunhua Yang

Papers

Efficient Synthesis of Losartan, A Nonpeptide Angiotensin II Receptor Antagonist

Palladium-catalyzed cyanation of aryl bromides promoted by low-level organotin compounds.

Synthesis of an anti-methicillin-resistant Staphylococcus aureus (MRSA) carbapenem via stannatrane-mediated Stille coupling.

Practical synthesis of a potent hepatitis C virus RNA replication inhibitor.

An Efficient Synthesis of an αvβ3 Antagonist