Racemization Catalyst Research Articles

Magnetically Recoverable Palladium Nanocatalyst for Chemoselective Olefin Hydrogenation

Metal nanoparticles proved to be significantly more efficient than their bulk counterparts due to their large surface area. Recently, we reported the use of palladium nanoparticles entrapped in AlO(OH) matrix as the efficient racemization catalyst in the dynamic kinetic resolu-tion of primary amines.

Heterogeneous Catalysts for Racemization and Dynamic Kinetic Resolution of Amines and Secondary Alcohols

This paper gives an overview of the available heterogeneous catalysts for racemization of chirally stable secondary alcohols and amines, and of the combination of these catalysts with immobilized enzymes in dynamic kinetic resolution (DKR) for production of enantiopure esters or amides. For the one-pot DKR process, compatibility of enzyme and heterogeneous catalyst is a major issue, and in some cases the combination fails because of (mutual) deactivation. Heterogeneous catalysts of various types, such as zeolites or oxides effect alcohol racemization; they function either via acid catalysis and carbenium chemistry, or via a redox pathway via the ketone. Dynamic kinetic resolution of aliphatic alcohols using a heterogeneous catalyst in mild conditions is however an open challenge. Heterogeneous amine racemization catalysts invariably operate using a redox mechanism via the imine. In this case, the scope encompasses benzylic and aliphatic amines. The practicality of the approach is illustrated with the production of enantiopure N-acylated homoserine lactones, which are signalling compounds in microbial communities.

Highly Enantioselective Resolution of β‐Amino Esters by Candida antarctica Lipase A Immobilized in Mesocellular Foam: Application to Dynamic Kinetic Resolution.

AbstractCandida antarctica lipase A (CALA) immobilized in functionalized mesocellular foam in the presence of sucrose, followed by lyophilization, led to a dramatic increase in the enantioselectivity as well as an improved thermostability of the enzyme. The immobilized lipase was used for kinetic resolution (KR) and dynamic kinetic resolution (DKR) of the β‐amino ester, ethyl 3‐amino‐3‐phenylpropanoate. The temperature of optimum activity of CALA shifted from 20–30 °C to 80–90 °C on immobilization in the MCF. An “enantiomeric ratio” E (E=νA/νB; νA and νB are the rate constants for entantiomers A and B) of 69 and a conversion of 43 % in 1 h were obtained at 80 °C, whereas non‐immobilized CALA lost its activity at T≥50 °C. The obtained immobilized CALA showed an E value of greater than 500 at 22 °C. Combination of the immobilized CALA with a ruthenium complex, acting as a racemization catalyst, allowed for a successful DKR of ethyl 3‐amino‐3‐phenylpropanoate resulting in 85 % conversion and 89 % ee.

Chemoenzymatic Dynamic Kinetic Resolution of Axially Chiral Allenes

At the palladium: Dimeric palladium bromide complexes bearing monodentate N-heterocyclic carbene ligands have been identified as efficient catalysts for the chemoselective racemization of axially chiral allenyl alcohols. In combination with porcine pancreatic lipase as biocatalyst, a dynamic kinetic resolution has been developed, giving access to optically active allenes in good yield and high enantiomeric purity (see scheme).

Deracemisation methods

New methods continue to be developed for the dynamic kinetic resolution (DKR) and deracemisation of racemic chiral compounds, in particular alcohols, amines and amino acids. Many of the DKR processes involve the combination of an enantioselective enzyme, often a lipase or protease, with a metal racemisation catalyst. A greater range of ruthenium-based racemisation catalysts is now available with some showing good activity for the racemisation of amines that are more difficult to epimerise than the corresponding alcohols. In terms of deracemisation processes, further improvements have been achieved with the deracemisation of alcohols, using combinations of stereocomplementary ketoreductases, and additionally transaminases have been applied to the deracemisation of racemic amines.

Highly efficient dynamic kinetic resolution of secondary aromatic alcohols with low-cost and easily available acid resins as racemization catalysts

A new and efficient dynamic kinetic resolution (DKR) process of secondary aromatic alcohols was developed with acid resins as racemization catalysts. Acid resin CD8604 was shown to have excellent racemization activity and good biocompatibility. When employing CD8604 and complex acyl donors as racemization catalyst and acyl donor, respectively, enantiomerically pure aromatic acetate was obtained with excellent yield and ee values through the DKR process. It is noteworthy that the system could be reused more than 10 times with little loss of yield and ee value.

Mechanism of the chemo–bio catalyzed cascade synthesis of R-1-phenylethyl acetate over Pd/Al2O3, lipase, and Ru-catalysts

One-pot synthesis of R-1-phenylethyl acetate was investigated starting from acetophenone hydrogenation performed over Pd/Al2O3 and PdZn/Al2O3 catalysts followed by acylation of the intermediate secondary alcohol, R-1-phenylethanol, over an immobilized lipase. Furthermore, the performance of a third type of catalyst, Ru supported on hydroxyapatite (HAP) was evaluated for racemization of S-1-phenylethanol in one pot together with the two other catalysts. The main objectives of this work were to separate the effects of different catalysts and to reveal the reaction mechanism. For this purpose not only acetophenone, but also (R,S)-1-phenylethanol, S-1-phenylethanol, R-1-phenylethyl acetate, and styrene were used as reactants in combination with Pd/Al2O3, lipase and Ru/HAP as catalysts. The results revealed that the main side product, ethylbenzene, was formed in two different ways, via dehydration of (R,S)-1-phenylethanol to styrene, followed by its rapid hydrogenation to ethylbenzene, and via debenzylation of the desired product, R-1-phenylethyl acetate to ethylbenzene. The true one-pot synthesis, however, was demonstrated over Shvo’s catalyst, but Ru/HAP was not sufficiently active in the racemization step. Ru/Al2O3 was a promising catalyst for racemization of S-1-phenylethanol and for dynamic kinetic resolution of (R,S)-1-phenylethanol, when using only small amounts of the acyl donor ethyl acetate. The challenge in racemization is that the activity of heterogeneous Ru catalysts was inhibited by esters.

Chemoenzymatic Dynamic Kinetic Resolution of Alcohols and Amines (Eur. J. Org. Chem. 6/2010)

AbstractThe cover picture shows the synthesis of optically active esters and amides by chemoenzymatic dynamic kinetic resolution (DKR) from racemic alcohols and amines, respectively. Racemic substrates are transformed into single enantiomeric products by the combination of metal‐catalyzed racemization and enzymatic acylation. The background is “The Hands of Win‐Win” of Homigot, 22 km east of Pohang along the East Sea of Korea. Many people visit Homigot to see the hands and the sun rise. The hands are chiral and racemic. The Microreview by M.‐J. Kim, J. Park et al. on p. 999 ff describes the DKR of racemic alcohols and amines by emphasizing the characteristics of the racemization catalysts developed so far.

Graphical Abstract: Eur. J. Org. Chem. 6/2010

AbstractThe cover picture shows the synthesis of optically active esters and amides by chemoenzymatic dynamic kinetic resolution (DKR) from racemic alcohols and amines, respectively. Racemic substrates are transformed into single enantiomeric products by the combination of metal‐catalyzed racemization and enzymatic acylation. The background is “The Hands of Win‐Win” of Homigot, 22 km east of Pohang along the East Sea of Korea. Many people visit Homigot to see the hands and the sun rise. The hands are chiral and racemic. The Microreview by M.‐J. Kim, J. Park et al. on p. 999 ff describes the DKR of racemic alcohols and amines by emphasizing the characteristics of the racemization catalysts developed so far.

Chemoenzymatic Dynamic Kinetic Resolution of Alcohols and Amines

AbstractDynamic kinetic resolution (DKR) is an attractive process for the transformation of racemic mixtures into optically active compounds. For successful DKR, efficient racemization is required while the kinetic resolution is proceeding. This Microreview mainly summarizes the recent developments in the DKR of alcohols and amines, based on metal‐catalyzed racemization and enzymatic acylation in a single reaction vessel. Related reactions involving precursors of alcohols and amines such as ketones, enol acetates, and ketoximes are also described. Reaction conditions are arranged according to racemization catalysts, and substrates employed in the DKR are tabulated. Suggested mechanisms for metal‐catalyzed racemizations are also summarized.

Fast Racemisation of Chiral Amines and Alcohols by Using Cationic Half‐Sandwich Ruthena‐ and Iridacycle Catalysts

The lipase-catalysed resolution of alcohols and amines yields only 50 % of the desired enantiopure product. However, addition of a racemisation catalyst leads to 100 % yield in what is called a dynamic kinetic resolution (DKR). There is a need for new racemisation catalysts that are fast and compatible with the conditions of the enzymatic reaction. We show that cationic half-sandwich ruthena- and iridacycle complexes are highly active and efficient in the racemisation of chiral alcohols and amines. Upon activation with base, these complexes are able to selectively racemise alcohols, whereas the non-activated complexes are selective catalysts for the racemisation of amines. We have applied the iridacycles in the DKR of racemic beta-chloroalcohols to produce chiral epoxides in a biphasic system in good yields and high ee (ee=enantiomeric excess).

Efficient Chemoenzymatic Dynamic Kinetic Resolution of 1-Heteroaryl Ethanols

The scope and limitation of the combined ruthenium-lipase induced dynamic kinetic resolution (DKR) through O-acetylation of racemic heteroaromatic secondary alcohols, i.e., 1-heteroaryl substituted ethanols, was investigated. After initial screening of reaction conditions, Candida antarctica lipase B (Novozyme 435, N435) together with 4-chloro-phenylacetate as acetyl-donor for kinetic resolution (KR), in conjunction with the ruthenium-based Shvo catalyst for substrate racemization in toluene at 80 degrees C, enabled DKR with high yields and stereoselectivity of various 1-heteroaryl ethanols, such as oxadiazoles, isoxazoles, 1H-pyrazole, or 1H-imidazole. In addition, DFT calculations based on a simplified catalyst complex model for the catalytic (de)hydrogenation step are in agreement with the previously reported outer sphere mechanism. These results support the further understanding of the mechanistic aspects behind the difference in reactivity of 1-heteroaryl substituted ethanols in comparison to reference substrates, as often referred to in the literature.

Synthesis of Norsertraline

Norsertraline is in clinical trials for the treatment of central nervous system disorders. The synthesis depicted uses Candida antarctica lipase B together with the racemization catalyst B in a one-pot dynamic kinetic resolution of primary amines. The lipase selectively acylates (S)-A whilst the remaining (R)-A is racemized by a catalyst derived in situ from B.

Support influences in the Pd-catalyzed racemization and dynamic kinetic resolution of chiral benzylic amines

The acid–base properties of the supports for Pd catalysts strongly affect their performance in racemization and dynamic kinetic resolution (DKR) of chiral benzylic amines. The need for a basic support was proven by comparing the racemization results obtained for Pd on silica, on LDH (layered double hydroxide) and on carbon. Pd on amine-functionalized silica proved to be more selective for the racemization of ( S)-1-phenylethylamine than Pd on alkaline earth supports or Pd on LDH. The difference in selectivity between various Pd catalysts is determined by the rates of formation of the side products. The rate constants of side product formation processes were even higher in the case of Pd/SiO 2 and Pd/C catalysts. The activity of the various catalysts for the rate determining amine dehydrogenation is similar when calculated per surface Pd atom. Combination of a Pd catalyst with Candida antarctica lipase B (Novozyme 435) for a one-pot DKR of 1-phenylethylamine gave the best results when Pd on 3-aminopropyl functionalized silica or Pd on 3-(1-piperazino)propyl functionalized silica were used as racemization catalysts, namely 93% yield of the corresponding ( R)-amide, with 99% e.e.

A Low-Waste Process To Sertraline By Diastereomeric Crystal Resolution and Waste Isomer Racemisation

A semi-continuous method for recovering waste sertraline isomers from a diastereomeric crystallisation process is described in which the mother liquors from a highly selective mandelic acid resolution for the (1S,4S) isomer are treated sequentially with SCRAM, an iridium-based chiral amine racemisation catalyst, and then catalytic potassium tertiary butoxide to epimerise the methine chiral centre. The green, low-waste process also deals with recovery and recycle of the precious-metal catalyst, providing both good economics and high-quality product.

CO Assistance in Ligand Exchange of a Ruthenium Racemization Catalyst: Identification of an Acyl Intermediate

An acyl intermediate in the activation of eta(5)-(Ph(5)Cp)Ru(CO)(2)Cl by t-BuOK was identified by means of in situ FT-IR measurements and NMR spectroscopy. This strongly supports the conclusion that the ligand exchange takes place via CO assistance, i.e., that the activation occurs via nucleophilic attack by tert-butoxide on one of the CO ligands. The tert-butoxycarbonyl intermediate shows stretching vibrations at 1933 and 1596 cm(-1), corresponding to the CO and COOt-Bu groups, respectively. In the (13)C NMR spectrum, the CO group appears at 209.5 ppm and the COOt-Bu group at 208.7 ppm. The NMR assignments were confirmed by density functional theory calculations. The subsequent alcohol-alkoxide exchange is also thought to take place via CO assistance. However, no intermediate in that step could be detected.

First dynamic kinetic resolution of selenium-containing chiral amines catalyzed by palladium (Pd/BaSO 4) and Candida antartica lipase (CAL-B)

An efficient method for chemoenzymatic dynamic kinetic resolution of selenium-containing chiral amines (organoselenium-1-phenylethanamines) has been developed, leading to the corresponding amides in excellent enantioselectivities and high isolated yields. This one-pot procedure employs two different types of catalysts: Pd on barium sulphate (Pd/BaSO 4) as racemization catalyst and lipase (CAL-B) as the resolution catalyst.

A Chemoenzymatic Approach to Enantiomerically Pure Amines Using Dynamic Kinetic Resolution: Application to the Synthesis of Norsertraline

Racemization catalyst 5 c and the enzyme Candida antarctica lipase B were combined in a one-pot dynamic kinetic resolution (DKR) of primary amines in which a wide range of amines were transformed to their corresponding amides in up to 95 % isolated yield and >99 % ee. The DKR protocol was applicable with either isopropyl acetate or dibenzyl carbonate as the acyl donor. In the latter case, release of the free amine from the carbamate products was carried out under very mild conditions. The racemization of (S)-1-phenylethylamine with several different Ru catalysts was also evaluated. Catalyst 5 c, of the Shvo type, was able to selectively racemize amines and was also compatible with the reaction conditions used for DKR. A racemization study of three different amines with varying electronic properties was also performed. Competitive racemization of a 1:1 mixture of the deuterated and non-deuterated amine was carried out with 5 c and a primary kinetic isotope effect was observed for all three amines, providing support that the rate-determining step is beta-hydride elimination. The chemoenzymatic DKR protocol was applied to the synthesis of norsertraline (16) by using a novel route starting from readily available 1,2,3,4-tetrahydro-1-naphthylamine (1 o).

Dicarbonylchloro(pentabenzylcyclopentadienyl)ruthenium as Racemization Catalyst in the Dynamic Kinetic Resolution of Secondary Alcohols

AbstractDicarbonylchloro(pentabenzylcyclopentadienyl)ruthenium has been prepared and its structure confirmed by X‐ray analysis. This complex shows excellent catalytic activity and modest stability against air in racemization reactions of secondary alcohols. In Candida antarctica lipase B (CAL‐B) catalyzed dynamic kinetic resolution (DKR) of 1‐phenyl‐ and 1‐(furan‐2‐yl)ethanol compounds, the new complex shows improved performance as an alcohol racemization catalyst in comparison with its well‐known pentaphenylcyclopentadienyl analogue, hitherto considered as the leading catalyst candidate. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Cyclopenta[l]phenanthrenyl and Cyclopenta[a]acenaphthylenyl Half-Sandwich Complexes of Ruthenium as Racemization Catalysts for Secondary Alcohols

Several half-sandwich complexes of ruthenium with cyclopenta[l]phenanthrenyl and cyclopenta[a]acenaphthylenyl ligands containing fused aromatic ring substituents on the cyclopentadienyl ring were p...