Metal-catalyzed enantioselective allylation, which involves the substitution of allylic metal intermediates with a diverse range of different nucleophiles or S(N)2'-type allylic substitution, leads to the formation of C-H, -C, -O, -N, -S, and other bonds with very high levels of asymmetric induction. The reaction may tolerate a broad range of functional groups and has been applied successfully to the synthesis of many natural products and new chiral compounds.

Metal-catalyzed enantioselective allylation in asymmetric synthesis.

Some Typical Advances in the Synthetic Applications of Allenes

Catalytic Asymmetric Synthesis of α-Amino Acids

Enantioselective palladium-catalyzed transformations

Durch metallkatalysierte enantioselektive Allylierungen, die unter Substitution von Allylmetall-Zwischenstufen mit zahlreichen Nucleophilen oder als allylische SN2′-Substitution verlaufen, werden in Gegenwart ausgewahlter Kombinationen aus Metallen und chiralen Liganden C-H-, C-C-, C-O-, C-N-, C-S- und andere Bindungen mit sehr hoher asymmetrischer Induktion geknupft. Die Reaktionen sind mit einer Vielzahl funktioneller Gruppen vereinbar und wurden erfolgreich in der Synthese vieler Naturstoffe und neuer chiraler Verbindungen verwendet.

Metallkatalysierte enantioselektive Allylierungen in der asymmetrischen Synthese

Simple additions are the most atom economic way to effect alkylations. The ability to effect the hydrocarbonation of allenes asymmetrically then becomes a highly efficient alkylation protocol. The first example of such a protocol involves the ability of a palladium(0) catalyst derived from palladium trifluoroacetate dimer and the bis-2-diphenylphosphinobenzamide of trans-1,2-diamininocyclohexane to catalyze additions to benzyloxyalkene. Various substituted Meldrum's acids including hydroxy Meldrum's acid react well in the presence of 1 mol % trifluoroacetic acid to give one regioisomer with ee's ranging from 82 to 99%. Switching to azlactones to access unusual quarternary amino acids requires somewhat more basic conditions. Thus, use of 2 mol % potassium alpha-butoxide and 20 mol % hippuric acid leads to a smooth reaction to produce a simple regiosomer. This nucleophile raises the question of facial selectivity with respect to both the nucleophile and the electrophile. Excellent diastereoselectivity (dr 13-20:1) and enantioselectivity (85-94% ee) are obtained. Thus, a new approach for asymmetric allylic alkylations of carbon pronucleophiles by simple additions provides a very efficient, more atom economic strategy for asymmetric C-C bond formation.

Palladium-catalyzed asymmetric addition of pronucleophiles to allenes.

Enhancing atom economy of the metal-catalyzed asymmetric allylic alkylation (AAA) shifts from the usual nucleophilic displacement of a leaving group to an addition of a pronucleophile to a double bond. Using 1-alkoxyallenes as proelectrophiles, the palladium-catalyzed AAA proceeds with 1,3-dicarbonyl compounds as pronucleophiles with excellent regioselectivity and enantiomeric excess under optimized conditions. The pH of the medium proved crucial for reactivity/ selectivity. By using the more acidic Meldrum's acids, the reactions required a co-catalytic amount of Bronsted acid. such as trifluoroacetic acid. Single regioisomeric products of 82-99% ee were obtained. On the other hand, the less acidic 1,3-diketones failed to react under such conditions. The fact that a less acidic acid like benzoic acid sufficed, suggested the need for general base catalysis as well. Thus, a mixture of triethylamine and benzoic acid proved optimal (ee's 93-99). Employment of the (/?,/?)-phenyl Trost ligand gave a product with S configuration. A model to rationalize the results has been developed.

Christoph Jäkel

Papers

Palladium-catalyzed asymmetric addition of pronucleophiles to allenes.

Enantioselective palladium-catalyzed addition of 1,3-dicarbonyl compounds to an allene derivative.