Indoles in multicomponent processes (MCPs).

Stereocontrolled Domino Reactions

Asymmetric catalysis with transition-metal complexes is the basis for a vast array of stereoselective transformations and has changed the face of modern synthetic chemistry. Key to this success has been the design of chiral ligands to control the regio-, diastereo-, and enantioselectivity. Phosphoramidites have emerged as a highly versatile and readily accessible class of chiral ligands. Their modular structure enables the formation of ligand libraries and easy fine-tuning for a specific catalytic reaction. Phosphoramidites frequently show exceptional levels of stereocontrol, and their monodentate nature is essential in combinatorial catalysis, where a ligand-mixture approach is used. In this Review, recent developments in asymmetric catalysis with phosphoramidites used as ligands are discussed, with a focus on the formation of carbon-carbon and carbon-heteroatom bonds.

Phosphoramidites: Privileged Ligands in Asymmetric Catalysis

In this review, we summarize the origin and advancements of iridium-catalyzed asymmetric allylic substitution reactions during the past two decades. Since the first report in 1997, Ir-catalyzed asymmetric allylic substitution reactions have attracted intense attention due to their exceptionally high regio- and enantioselectivities. Ir-catalyzed asymmetric allylic substitution reactions have been significantly developed in recent years in many respects, including ligand development, mechanistic understanding, substrate scope, and application in the synthesis of complex functional molecules. In this review, an explicit outline of ligands, mechanism, scope of nucleophiles, and applications is presented.

Iridium-Catalyzed Asymmetric Allylic Substitution Reactions

ConspectusMetal catalyzed allylic substitution is a cornerstone of organometallic and synthetic chemistry. Enantioselective versions have been developed with catalysts derived from transition metals, most notably molybdenum, nickel, ruthenium, rhodium, iridium, palladium, and copper. The palladium- and the iridium-catalyzed versions have turned out to be particularly versatile in organic synthesis because of the very broad scope of the nucleophile and great functional group compatibility. Assets of the iridium-catalyzed reaction are the formation of branched, chiral products from simple monosubstituted allylic substrates, high degrees of regio- and enantioselectivity, and use of modular, readily available chiral ligands. The possibility to use carbon, nitrogen, oxygen, and sulfur compounds as well as fluoride as nucleophiles allows a wide range of chiral building blocks to be prepared.Our Account begins with the presentation of fundamental reaction schemes and chiral ligands. We will focus our discussion ...

Applications of Iridium-Catalyzed Asymmetric Allylic Substitution Reactions in Target-Oriented Synthesis

Enantioselective total synthesis of (-)-alpha-kainic acid.

Combination of enantioselective allylation reactions with a tandem hydroformylation–Fischer indole synthesis sequence as a highly diversity-oriented strategy for the synthesis of tryptamines and homologues was explored. This modular approach allows the substituents at C3 of the indole core, the type of the amine moiety, and the distance of the amine moiety to the indole core in the final synthetic step to be defined. The starting materials required for the hydroformylation step were synthesized viairidium catalyzed enantioselective allylic substitution reactions in high yields and excellent enantioselectivities. The Rh catalyzed hydroformylation step in the presence of phenyl hydrazine, allows the in situ formed aldehyde to be trapped as the hydrazone. Subsequent acid catalyzed indolization furnishes the desired indole structures in moderate to good yields.

Application of iridium catalyzed allylic substitution reactions in the synthesis of branched tryptamines and homologues via tandem hydroformylation-Fischer indole synthesis.

Enantioselective syntheses of bicyclic cyclopentenones are described. Key steps are an iridium-catalyzed allylic substitution and an intramolecular diastereoselective Pauson–Khand reaction. The diastereoselectivity of the Pauson–Khand reaction was found to be crucially dependent on the unit connecting the propargylic and the olefinic parts of the precursor. Very high degrees of diastereoselection were obtained with an NBoc unit as connector. This methodology has been illustrated by application within an enantioselective formal total synthesis of (−)--kainic acid.

Bicyclic cyclopentenones via the combination of an iridium- catalyzed allylic substitution with a diastereoselective intramolecular Pauson–Khand reaction

Under appropriate reaction conditions, a domino hydroformylation/Wittig olefination can be accomplished with derivatives of allylamines and stabilized Wittig ylides. A further highly diastereoselective aza-Michael reaction yields β-proline derivatives. These are, for example, useful as building blocks for alkaloid syntheses.

Stereoselective Synthesis of β-Proline Derivatives from Allylamines via Domino Hydroformylation/Wittig Olefination and Aza-Michael Addition

Chiral 1,6-enynes were prepared via Ir-catalyzed allylic substitutions. Their platinum(II) chloride-catalyzed domino enyne isomerization/Diels−Alder reaction provided stereoselective access to complex heterocycles. Very high diastereoselectivity was induced by a chirality center of the enyne.

Andreas Farwick

Papers

Enantioselective total synthesis of (-)-alpha-kainic acid.

Application of iridium catalyzed allylic substitution reactions in the synthesis of branched tryptamines and homologues via tandem hydroformylation-Fischer indole synthesis.

Bicyclic cyclopentenones via the combination of an iridium- catalyzed allylic substitution with a diastereoselective intramolecular Pauson–Khand reaction

Stereoselective Synthesis of β-Proline Derivatives from Allylamines via Domino Hydroformylation/Wittig Olefination and Aza-Michael Addition

Platinum(II) chloride-catalyzed stereoselective domino enyne isomerization/Diels-Alder reaction.