Per Ryberg

Rhodium-Catalyzed Enantioselective Silylation of Arene C–H Bonds: Desymmetrization of Diarylmethanols

We report a Rh-catalyzed, enantioselective silylation of arene C-H bonds directed by a (hydrido)silyl group. (Hydrido)silyl ethers that are formed in situ by hydrosilylation of benzophenone or its derivatives undergo asymmetric C-H silylation in high yield with excellent enantioselectivity in the presence of [Rh(cod)Cl]2 and a chiral bisphosphine ligand. The stereoselectivity of this process also allows enantioenriched diarylmethanols to react with site selectivity at one aryl group over the other. Enantioenriched benzoxasiloles from the silylation process undergo a range of transformations to form C-C, C-O, C-I, or C-Br bonds.

Mechanistic investigations into the asymmetric transfer hydrogenation of ketones catalyzed by pseudo-dipeptide ruthenium complexes.

The combination of N-Boc-protected alpha-amino acid hydroxyamides (pseudo-dipeptides) and [{Ru(p-cymene)Cl(2)}(2)] resulted in the formation of superior catalysts for the asymmetric transfer hydrogenation (ATH) of non-activated aryl alkyl ketones in propan-2-ol. The overall kinetics of the ATH of acetophenone to form 1-phenylethanol in the presence of ruthenium pseudo-dipeptide catalysts were studied, and the individual rate constants for the processes were determined. Addition of lithium chloride to the reaction mixtures had a strong influence on the rates and selectivities of the processes. Kinetic isotope effects (KIEs) for the reduction were determined and the results clearly show that the hydride transfer is rate-determining, whereas no KIEs were detected for the proton transfer. From these observations a novel bimetallic outer-sphere-type mechanism for these ATH process is proposed, in which the bifunctional catalysts mediate the transfer of a hydride and an alkali metal ion between the hydrogen donor and the substrate. Furthermore, the use of a mixture of propan-2-ol and THF (1:1) proved to enhance the rates of the ATH reactions. A series of aryl alkyl ketones were reduced under these conditions in the presence of 0.5 mol % of catalyst, and the corresponding secondary alcohols were formed in high yields and with excellent enantioselectivities (>99% ee) in short reaction times.

Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Amino Acid Derived Rhodium Complexes: On the Origin of Enantioselectivity and Enantioswitchability

Amino acid based thioamides, hydroxamic acids, and hydrazides have been evaluated as ligands in the rhodium-catalyzed asymmetric transfer hydrogenation of ketones in 2-propanol. Catalysts containing thioamide ligands derived from L-valine were found to selectively generate the product with an R configuration (95 % ee), whereas the corresponding L-valine-based hydroxamic acids or hydrazides facilitated the formation of the (S)-alcohols (97 and 91 % ee, respectively). The catalytic reduction was examined by performing a structure-activity correlation investigation with differently functionalized or substituted ligands and the results obtained indicate that the major difference between the thioamide and hydroxamic acid based catalysts is the coordination mode of the ligands. Kinetic experiments were performed and the rate constants for the reduction reactions were determined by using rhodium-arene catalysts derived from amino acid thioamide and hydroxamic acid ligands. The data obtained show that the thioamide-based catalyst systems demonstrate a pseudo-first-order dependence on the substrate, whereas pseudo-zero-order dependence was observed for the hydroxamic acid containing catalysts. Furthermore, the kinetic experiments revealed that the rate-limiting steps of the two catalytic systems differ. From the data obtained in the structure-activity correlation investigation and along with the kinetic investigation it was concluded that the enantioswitchable nature of the catalysts studied originates from different ligand coordination, which affects the rate-limiting step of the catalytic reduction reaction.

tBu or not tBu

The regioselectivity in the palladium-catalyzed Heck coupling reaction between an aryl halide and ethyl vinyl ether with four different phosphine ligands: PPh(n)tBu(m) (n=0-3, m=3-n) has been investigated both experimentally and computationally. A zigzag selectivity pattern was experimentally observed upon consecutive replacement of Ph by tBu in the phosphine ligand. Use of a standard DFT method (B3LYP) was shown to give a correct prediction of product preference. However, the trend in relative selectivity among the different ligands could not be correctly described. The use of a more recent DFT functional (M06) parameterized to reproduce dispersion interactions resulted in an improved description. For the sterically most demanding ligands, PtBu(3) and PPhtBu(2), unexpectedly large deviations between experimental and M06 calculated selectivities raised the question of an alternative mechanism for these ligands. In the case of PtBu(3) it was found, in agreement with literature data, that the phosphine ligand could be replaced by a second halide ligand, resulting in an anionic mechanism, with a calculated selectivity in excellent agreement with experimental data. For the PPhtBu(2) ligand, two mechanisms are suggested to operate in parallel, as demonstrated both by computational studies and experimental observation of halide-dependent selectivity. A Halpern effect is observed for all phosphine ligands investigated, that is, the least stable pre-complex results in the most abundant product.

High Throughput Screening of a Catalyst Library for the Asymmetric Transfer Hydrogenation of Heteroaromatic Ketones : Formal Syntheses of (R)-Fluoxetine and (S)-Duloxetine

A total of 21 amino acid based ligands including hydroxy amide, thioamide, and hydroxamic acid functionalities, respectively, were combined with [Ru(p‐cymene)Cl2]2 and [RhCp*Cl2]2, and used as catalysts for the asymmetric transfer hydrogenation of four different heteroaromatic ketones in 2‐propanol. The reactions were performed on a Chemspeed automated high‐throughput screening robotic platform. Optimal catalysts were identified for the individual heterocyclic substrate classes. Based on these results, the formal syntheses of the antidepressant drugs (R)‐fluoxetine and (S)‐duloxetine were conducted by using the found catalysts in the key reaction step, which results in high isolated yields (94 %) and excellent product enantioselectivities (>99 % ee) of the formed 1,3‐amino alcohols.

Asymmetric Reduction of Lactam-Based β-Aminoacrylates. Synthesis of Heterocyclic β2-Amino Acids

The ability to affect asymmetric reduction of heterocyclic β-aminoacrylates 1 (n = 1-3) has been assessed with pyrrolidine and piperidone variants generating the corresponding N-heterocyclic β(2)-amino acids 3b and 5b with high enantioselectivity (≥97% ee) using a Rh/WALPHOS catalyst combination. The use of the carboxylic acid substrate was essential; the corresponding esters do undergo reduction but led to racemic products. The seven-ring azepanone variant (as the carboxylic acid 9b) underwent reduction, but only a minimal level of asymmetric induction was observed.

Development of a Mild and Robust Method for Palladium Catalyzed Cyanation on Large Scale

The Pd-catalyzed cyanation of aryl halides is a very attractive method to prepare aryl nitriles, yet relatively few large scale applications of the reaction have been reported. The primary reason behind this has been a lack of robust and general conditions for the reaction, and for a long time it had a reputation of being difficult to scale up. Following a general introductory review of the reaction, this case study describes in detail the development of a new improved method for the Pd-catalyzed cyanation under mild conditions, and its successful application on a large scale to prepare multikilogram quantities of a drug candidate. The results and findings are discussed in the context of the current mechanistic understanding of the reaction and from an industrial perspective.