Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

The combinatorial synthesis of bicyclic privileged structures or privileged substructures

In studying the evolution of organic chemistry and grasping its essence, one comes quickly to the conclusion that no other type of reaction plays as large a role in shaping this domain of science than carbon-carbon bond-forming reactions. The Grignard, Diels-Alder, and Wittig reactions are but three prominent examples of such processes, and are among those which have undeniably exercised decisive roles in the last century in the emergence of chemical synthesis as we know it today. In the last quarter of the 20th century, a new family of carbon-carbon bond-forming reactions based on transition-metal catalysts evolved as powerful tools in synthesis. Among them, the palladium-catalyzed cross-coupling reactions are the most prominent. In this Review, highlights of a number of selected syntheses are discussed. The examples chosen demonstrate the enormous power of these processes in the art of total synthesis and underscore their future potential in chemical synthesis.

Palladium-catalyzed cross-coupling reactions in total synthesis.

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

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Advances in transition metal (Pd, Ni, Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners.

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

Stereo- and regiodefined alkenylmetals containing Al, Zr, and Zn react with aryl and alkenyl iodides and bromides in the presence of catalytic amounts of Pd or Ni complexes containing phosphine ligands, such as PPh/sub 3/, to give the corresponding cross-coupled products. Palladium catalysts permit nearly 100% stereospecificity in both alkenyl-aryl and alkenyl-alkenyl coupling reactions, whereas nickel catalysts lead to partial stereochemical scrambling in the alkenyl-alkenyl coupling. Although many other metals including Li, Mg, Cd, Hg, B, Si, Sn, Ti, and Ce were also used, the results were inferior to those obtained with Al, Zr, and Zn under the conditions used in the present study. The turnover numbers for the palladium-catalyzed reactions of PhI with (E)-1-octenylmetals containing Al, Zr, and Zn were 2, 3, and > 2000 mmol of (E)-1-octenylbenzene (8) per mmol of Pd(PPh/sub 3/)/sub 4/ per hour at room temperature, respectively. The stoichiometric reaction of PhPd(PPh/sub 3/)/sub 2/I (6) with 1.2 equiv of (E)-1-octenylzinc chloride (7) in a 2:1 mixture of CD/sub 2/Cl/sub 2/ and THF was examined in detail. The reaction follows second-order kinetics (k/sub 2/ = 2.9 L/(mol.min) at 0/sup 0/C) to give 8 without the buildup of any intermediate.

Palladium- or nickel-catalyzed reactions of alkenylmetals with unsaturated organic halides as a selective route to arylated alkenes and conjugated dienes: scope, limitations, and mechanism

Acetylene, z.B. (I) oder (VI), reagieren mit organometallischen Reagenzien, die durch Mischen von Organo-alanen (II) mit Zirconocen-dichlorid (III) erhalten werden, unter Bildung intermediarer metallierter Alkene; nach hydrolytischer Aufarbeitung werden Alkene wie (IV) bzw. (VII) erhalten.

Selective carbon-carbon bond formation via transition metal catalysts. 8. Controlled carbometalation. Reaction of acetylenes with organoalane-zirconocene dichloride complexes as a route to stereo- and regio-defined trisubstituted olefins

A general synthesis of terminal and internal arylalkynes by the palladium-catalyzed reaction of alkynylzinc reagents with aryl halides

Chemistry of organoborates

A highly stereo- , regio- , and chemoselective synthesis of conjugated dienes by the palladium-catalyzed reaction of ()-1-alkenylzirconium derivatives with alkenyl halides

E. Negishi

Papers

Palladium- or nickel-catalyzed reactions of alkenylmetals with unsaturated organic halides as a selective route to arylated alkenes and conjugated dienes: scope, limitations, and mechanism

Selective carbon-carbon bond formation via transition metal catalysts. 8. Controlled carbometalation. Reaction of acetylenes with organoalane-zirconocene dichloride complexes as a route to stereo- and regio-defined trisubstituted olefins

A general synthesis of terminal and internal arylalkynes by the palladium-catalyzed reaction of alkynylzinc reagents with aryl halides

Chemistry of organoborates

A highly stereo- , regio- , and chemoselective synthesis of conjugated dienes by the palladium-catalyzed reaction of ()-1-alkenylzirconium derivatives with alkenyl halides