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.

Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously. This kind of addition and reaction has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects. All these advantages, together with the high level of stereoselectivity attained in some of these reactions, will force chemists in industry as in academia to adopt this new strategy of synthesis, or at least to consider it as a viable option. The positive aspects as well as the drawbacks of this strategy are discussed in this Review.

Asymmetric multicomponent reactions (amcrs): the new frontier

The 3,3′-disubstituted oxindole structural motif is a prominent feature in many alkaloid natural products, which include all kinds of tetrasubstituted carbon stereocenters, spirocyclic or not, all-carbon or heteroatom-containing. The catalytic asymmetric synthesis of the tetrasubstituted carbon stereocenter at the C-3 position of the oxindole framework integrates new synthetic methods and chiral catalysts, reflects the latest achievements in asymmetric catalysis, and facilitates the synthesis of sufficient quantities of related compounds as potential medicinal agents and biological probes. This review summarizes the recent progress in this area, and applications in the total synthesis of related bioactive compounds.

Catalytic Asymmetric Synthesis of Oxindoles Bearing a Tetrasubstituted Stereocenter at the C‐3 Position

Only a few catalytic asymmetric C—C bond-forming reactions have been shown to be useful for constructing all-carbon quaternary stereocenters. This Perspective examines the current state of such methods.

https://www.pnas.org/content/pnas/101/15/5363.full.pdf

Catalytic asymmetric synthesis of all-carbon quaternary stereocenters

The direct catalytic asymmetric addition of unmodified carbonyl compounds to preformed or in situ-generated imines has emerged as a promising new route to optically enriched alpha- and beta-amino acid derivatives, beta-lactams, and 1,2- and gamma-amino alcohols. The direct catalytic asymmetric Mannich reactions are mediated by small organometallic and organic amine catalysts that can achieve levels of selectivity similar to those possible with natural enzymes. The different small-molecule catalysts described here are complementary in their applications. They also complement each other in syn or anti selectivity of the direct asymmetric Mannich reaction. In this Account, we highlight the recent developments in and contributions to this research.

The direct catalytic asymmetric mannich reaction.

The stereoselective formation of C-C bonds is of great importance for the synthesis of enantiomerically pure natural products and pharmaceuticals. A broad repertoire of chiral auxiliaries, reagents, and catalysts can be utilized for the reliable generation of tertiary stereocenters. In contrast, the synthesis of organic compounds with quaternary stereocenters is a much more demanding and challenging task. Every enantioselective synthetic method can demonstrate its value through the generation of a fully substituted carbon center. In this Minireview examples of newer stoichiometric and catalytic methods are summarized which have proved their suitability for the enantioselective construction of quaternary stereocenters.

Enantioselective Construction of Quaternary Stereocenters

Die stereoselektive Knupfung von C-C-Bindungen ist von zentraler Bedeutung fur die Synthese enantiomerenreiner Natur- und Wirkstoffe. Dank eines grosen Arsenals chiraler Auxiliare, Reagentien und Katalysatoren ist der Aufbau tertiarer Stereozentren in der Regel mit hoher Zuverlassigkeit moglich. Dagegen ist die Synthese komplexer Molekule mit quartaren Stereozentren eine wesentlich anspruchsvollere Aufgabe. Jede enantioselektive Synthesemethode demonstriert ihren Wert, wenn es um den Aufbau dieser vollstandig substituierten Kohlenstoffzentren geht. Der vorliegende Kurzaufsatz stellt exemplarisch einige neuere stochiometrische und katalytische Methoden zusammen, die ihre besondere Eignung mit dem enantioselektiven Aufbau von quartaren Stereozentren bewiesen haben.

Alexander Mann

Papers

Enantioselective Construction of Quaternary Stereocenters

Enantioselektiver Aufbau quartärer Stereozentren

Enantioselective Construction of Quaternary Stereocenters