Publications

The present article summarizes the development of two novel and complementary catalytic methods to access α-chiral aldehydes. A C ₁-symmetric chiral (P,N) ligand with a structure derived from the ubiquitous binepine scaffold has been specifically designed for the Pd-catalyzed α-arylation of aldehydes to access indane derivatives with a well-defined quaternary stereocenter in high yields and excellent enantioselectivities. In addition, a dinuclear palladium hydride catalyst has been synthesized for the isomerization of terminal and trisubstituted epoxides into aldehydes and ketones respectively. Combined experimental and theoretical investigations pointed to an unprecedented 'epoxide-opening/hydride-transfer' sequence. The mechanism also features two distinct enantio-determining steps in the kinetic resolution of racemic epoxides.

The selective α-arylation and α-arylative esterification of linear and branched aldehydes is reported for a variety of bromoarenes. The acylation of aryl bromides can be achieved with linear aldehydes (see scheme). All these transformations were performed with a single [(N-heterocyclic carbene)Pd] catalyst through adjustment of the stoichiometry of the reagents and the appropriate base.

The palladium-catalyzed intermolecular γ-arylation of γ-branched α,β-unsaturated aldehydes has been developed. The reaction allows congested quaternary centers to be forged on a remote position of the carbonyl group affording a variety of products in high yield and with consistently high stereoselectivity using very low catalyst loadings. The synthetic utility of the products has been highlighted by a series of derivatizations and the potential of the method to extend to remote ε-functionalization has been demonstrated.

An unusual palladium hydride complex has been shown to be a competent catalyst in the isomerization of a variety of terminal epoxides. The reaction displayed broad scope and synthetic utility. Experimental and theoretical evidences are provided for an unprecedented hydride mechanism characterized by two distinct enantio-determining steps. These results hold promise for the development of an enantioselective variant of the reaction.

The direct enantioselective α-arylations of linear and α-branched aldehydes are faced by different but equally difficult challenges. This account covers the most recent contributions in this exciting field of research.

The evaluation of a series of cationic iridium complexes in the isomerization of primary allylic alcohols has revealed the unique ability of Crabtree catalysts [(Cy₃P)(C₆H₅N)Ir(cod)]·X 1a (X = PF₆) and 1b (X = BAr_F; cod = 1,5-cyclooctadiene) to catalyze efficiently this transformation. Emphasis has been placed on understanding the electronic factors that govern the catalytic process by using a range of para-substituted pyridine N-donor ligands. Excellent correlations between analytical data (¹³C NMR chemical shift; ν_CO) and established thermodynamic and kinetic parameters (pK_a, Mayr nucleophilicity parameter N) have been elaborated. Overall, the results obtained point to the possibility of qualitatively predicting the activity of Crabtree catalyst analogues in the isomerization of primary allylic alcohols.

A short synthetic route readily gives access to a new class of chiral (P,N) ligands characterized by three distinct elements of chirality. These ligands are highly enantioselective in the challenging Pd-catalyzed intramolecular asymmetric α-arylation of α-branched aldehydes.

The present article describes the recent catalytic asymmetric methods developed in our group to access enantioenriched chiral aldehydes. We are generally aiming at developing complementary strategies based on either homogeneous organometallic catalysts or amino-catalysts and sometimes on a combination of both. Recent successes comprise a perfectly redox-economical iridium-catalyzed asymmetric isomerization of primary allylic alcohols under very mild conditions and the development of a transition metal-catalyzed anti-Markovnikov asymmetric hydroboration of 1,1-disubstituted olefins. The developments of these two processes along with preliminary mechanistic investigations are presented herein.

Past and recent advances in the metal-catalyzed asymmetric isomerization of allylic alcohols into carbonyl compounds are discussed in the present Highlight. Emphasis is placed on rhodium, ruthenium, and iridium; the only three metals that have proven successful to date for this most challenging transformation.

Independent workers with team spirit: A catalytic sequence that exploits the compatibility of (chiral) cationic iridium catalysts for the isomerization of primary allylic alcohols to aldehydes with organocatalysts has been developed for the highly enantioselective α functionalization of aldehydes (see scheme: up to 66 % yield, d.r. 49:1, 99 % ee). The reaction displayed useful generality with respect to both the nucleophile and the electrophile.

The catalytic asymmetric hydroboration of a variety of 1,1-disubstituted olefins has been achieved with excellent yields, perfect regioselectivity and high levels of enantioselectivity.

An improved generation of chiral cationic iridium catalysts for the asymmetric isomerization of primary allylic alcohols is disclosed. The design of these air stable complexes relied on preliminary mechanistic information available and on Charton analyses using two preceding generations of iridium catalysts developed for this highly challenging transformation.

The catalytic asymmetric isomerization of allylic amines to enamines stands out as one of the most accomplished and well-studied reactions in asymmetric catalysis as illustrated by its industrial application. In contrast, the related asymmetric isomerization of primary allylic alcohols to the corresponding aldehydes still constitutes a significant challenge in organic synthesis. Herein, we show that under appropriate reaction conditions, iridium-hydride catalysts promote the isomerization of primary allylic alcohols under very mild reaction conditions. The best catalysts deliver the desired chiral aldehydes with unprecedented levels of enantioselectivity and good yields. Mechanistic hypotheses have been drawn based on preliminary investigations.

Transition metal- catalyzed asymmetric β-boration of α,β- unsaturated carbonyl derivatives has recently received much attention. Although a variety of metals can be used to promote this reaction, copper has recently emerged as the candidate of choice. Given the appropriate chiral ligand and reaction conditions, the challenging β-boration of β,β-disubstituted cyclic enones is achieved with excellent yields and enantioselectivities.

A second generation of chiral (P,N)-iridium catalysts—readily accessible from inexpensive L-serine—displays expanded scope for the asymmetric isomerization of primary allylic alcohols.

Nothing to sm(Ir)k at: Under appropriate reaction conditions, iridium hydride catalysts promote the isomerization of primary allylic alcohols. The best catalysts, like (R)-1 (P green, O red, N blue, Ir yellow), deliver the desired chiral aldehydes with excellent enantioselectivity and good yields. Mechanistic hypotheses have been developed on the basis of preliminary investigations.

The isomerization of primary allylic alcohols into the corresponding aldehydes has been accomplished using an analogue of Crabtree’s iridium hydrogenation catalyst and by adequately tuning the experimental conditions. A wide range of substrates is converted quantitatively into the desired aldehyde at room temperature in expedient reaction times by using catalyst loading as low as 0.25 mol %.

A readily accessible iridium hydrogenation catalyst displays high reactivity for the isomerization of primary allylic alcohols under mild reaction conditions. Key to the efficiency of the catalytic system is to deviate from the conventional hydrogenation route in favor of the desired isomerization pathway by adequately tuning the reaction conditions as indicated by preliminary mechanistic investigations.