Asymmetric homogeneous hydrogenations at scale.

Asymmetric hydrogenations are increasingly being used to introduce stereogenic centres into products used in the life sciences industries. There are a number of potential pitfalls when moving from a laboratory reaction to a manufacturing process, not least of which is safety. Time-to-market pressure leads to short development times, which in the past could be a large barrier for the implementation of catalytic steps; now there are new ways to minimise this problem. The potential problems associated with impurities and other methods that can shut down the hydrogenation reactions are highlighted in this critical review (353 references).

Cycloruthenated primary and secondary amines as efficient catalyst precursors for asymmetric transfer hydrogenation.

[reaction: see text] Ruthenacycles obtained by cyclometalation of enantiopure aromatic primary or secondary amines with [(eta6-benzene)RuCl2]2 or with [(eta6-p-cymene)RuCl2]2 are efficient catalysts for asymmetric transfer hydrogenation (TOF up to 190 h(-1) at room temperature). Enantioselectivities in the transfer hydrogenation of acetophenone ranged from 38% to 89%. It is possible to prepare the catalysts in situ, which allows the use of high throughput experimentation.

Instant ligand libraries. Parallel synthesis of monodentate phosphoramidites and in situ screening in asymmetric hydrogenation.

Chiral phosphoramidites have been identified as excellent ligands for various metal-catalyzed enantioselective transformations. Taking advantage of their easy preparation and modular nature, we designed a fully automated protocol for the parallel preparation of a library of 32 phosphoramidites and its screening in asymmetric hydrogenation of amino acid precursors. This initial study led to the discovery of a new ligand for the preparation of an enantiopure beta(3)-homoalanine precursor. [structure--see text]

Mono- versus bidentate ligands in rhodium-catalyzed asymmetric hydrogenation. A comparative rate study.

[reaction: see text] Bidentate chiral phosphines are no longer essential for achieving a fast and highly enantioselective hydrogenation of alpha- or beta-dehydroamino acid derivatives. In particular, a readily accessible and stable monodentate phosphoramidite can be highly effective in these asymmetric hydrogenations.

Homeopathic ligand-free palladium as a catalyst in the heck reaction. A comparison with a palladacycle.

[reaction: see text] Ligand-free Pd(OAc)(2) can be used as a catalyst in the Heck reaction of aryl bromides as long as the amount of catalyst is kept between 0.01 and 0.1 mol %. At higher concentrations palladium black forms and the reaction stops. The actual catalyst is monomeric. Palladacycles merely serve as a source of ligand-free palladium in Heck reactions of aryl bromides.

Exploiting noninnocent (E,E)-dibenzylideneacetone (dba) effects in palladium(0)-mediated cross-coupling reactions: modulation of the electronic properties of dba affects catalyst activity and stability in ligand and ligand-free reaction systems.

The reactivity of palladium(0) complexes, [Pd(0) (2)(dba-n,n'-Z)(3)] (n,n'-Z=4,4'-F; 4,4'-CF(3); 4,4'-H; 4,4'-MeO) and [Pd(0)(dba-n,n'-Z)(2)] (n,n'-Z=4,4'-CF(3); 4,4'-H; 3,3',5,5'-OMe), used as precursor catalysts with suitable donor ligands (e.g. phosphines, N-heterocyclic carbenes), has been correlated in several palladium(0)-mediated cross-coupling processes. Increasing the electron density on the aryl moiety of the dba-n,n'-Z ligand increases the overall catalytic activity in the majority of these processes. This effect primarily derives from destabilization of the L(n)Pd(0)-eta(2)-dba interaction (in dpi-pi* synergic bonding, n=1 or 2), which ultimately increases the global concentration of catalytically active L(n)Pd(0) available for reaction with aryl halide in the first committed step in the general catalytic cycle(s) (oxidative addition). Decreasing electron density on the aryl moiety of the dba-n,n'-Z ligand stabilizes the Pd(0)-eta(2)-dba interaction, reducing catalytic activity. The specific type of dba-n,n'-Z ligand appears to also play a stabilizing role in the catalytic cycle, preventing Pd agglomeration, and increasing catalyst longevity. A subtle balance therefore exists between the L(n)Pd(0) concentration (and the associated catalytic activity) and catalyst longevity. Changing the type of dba-n,n'-Z ligand controls the concentration of L(n)Pd(0) and the rate of the oxidative addition step, and not other intimate steps within the catalytic cycle(s), for example, transmetallation (or carbopalladation) and reductive elimination. The role of dba-n,n'-Z ligands in Heck arylation is more convoluted and dependent on the alkene substrate employed, although trends have emerged. Changes in the structure of dba-n,n'-Z had a minimal affect on Buchwald-Hartwig aryl amination processes. A secondary Michael reaction of dba-n,n'-Z with amine and/or base effectively lessens its interference in the catalytic cycle.

Rh-catalyzed asymmetric hydrogenation of prochiral olefins with a dynamic library of chiral TROPOS phosphorus ligands.

A library of 19 chiral tropos phosphorus ligands, based on a flexible (tropos) biphenol unit and a chiral P-bound alcohol (11 phosphites) or secondary amine (8 phosphoramidites), was synthesized. These ligands were screened, individually and as a combination of two, in the rhodium-catalyzed asymmetric hydrogenation of dehydro-alpha-amino acids, dehydro-beta-amino acids, enamides and dimethyl itaconate. ee values up to 98% were obtained for the dehydro-alpha-amino acids, by using the best combination of ligands, a phosphite [4-P(O)2O] and a phosphoramidite [13-P(O)2N]. Kinetic studies of the reactions with the single ligands and with the combination of phosphite [4-P(O)2O] and phosphoramidite [13-P(O)2N] have shown that the phosphite, despite being less enantioselective, promotes the hydrogenation of methyl 2-acetamidoacrylate and methyl 2-acetamidocinnamate faster than the mixture of the same phosphite with the phosphoramidite, while the phosphoramidite alone is much less active. In this way, the reaction was optimized by lowering the phosphite/phosphoramidite ratio (the best ratio is 0.25 equiv phosphite/1.75 equiv phosphoramidite) with a resulting improvement of the product enantiomeric excess. A simple mathematical model for a better understanding of the variation of the enantiomeric excess with the phosphite/phosphoramidite ratio is also presented.

Synthesis and application in asymmetric C-C bond formation of solution phase ligand libraries of monodentate phosphoramidites.

A library of 96 unique monodentate phosphoramidite ligands has been synthesized in solution and used in the asymmetric conjugate addition of potassium vinyltrifluoroborate to enones resulting in up to 88% ee.

Highly enantioselective conjugate additions of potassium organotrifluoroborates to enones by use of monodentate phosphoramidite ligands.

The use of phosphoramidite ligands in the rhodium-catalyzed asymmetric conjugate addition of potassium organotrifluoroborates to various enones in the absence of water is described. A systematic search for effective catalysts has been performed by use of high-throughput screening methods. Initially, we have screened reaction conditions, catalyst precursors, and focused ligand libraries. In the next stage we have used the monodentate ligand combination approach, and finally we have made a library of 96 different phosphoramidites by parallel synthesis in the robot (instant ligand libraries) and have tested these in the vinylation of cyclohexenone (up to 88% enantiomeric excess, ee) and 4-phenyl-3-buten-2-one (up to 42% ee). Arylation of cyclohexenone by use of potassium phenyltrifluoroborate gave 3-phenylcyclohexanone with 99% ee.

Selective Pd-catalyzed oxidative coupling of anilides with olefins through C-H bond activation at room temperature.

Using a high-throughput experimentation approach we found a selective and mild Pd-catalyzed oxidative coupling reaction between anilide derivatives and acrylates that occurs through ortho C-H bond activation. The reaction is carried out in an acidic environment and occurs even at room temperature with use of a cheap oxidant (benzoquinone) in yields up to 91%. The benzoquinone possibly also functions as a ligand, stabilizing the catalyst. From the electronic dependence of the reaction and the observed kinetic isotope effect (kH/kD = 3) the key step of the catalytic cycle is believed to be electrophilic attack by a [PdOAc]+ complex on the pi-system of the arene.