Dynamic kinetic resolution of secondary alcohols with a readily available ruthenium-based racemization catalyst

An easy to handle and stable racemization catalyst for secondary alcohols is obtained by an in situ mixture of readily available [Ru(cymene)Cl₂]₂ with chelating aliphatic diamines. Optimization of the reaction revealed that N,N,N′,N′-tetramethyl-1,3-propanediamine as ligand racemizes aromatic alcohols completely within 5 h. This easy to handle and stable catalytic system is combined with a lipase-catalyzed resolution to provide an efficient dynamic kinetic resolution of secondary alcohols.     

Ruthenium and enzyme-catalyzed dynamic kinetic resolution of alcohols

Ruthenium acts as a good catalyst for the racemization reaction of secondary alcohols and amines. Ruthenium-catalyzed racemization is coupled with enzymatic kinetic resolution to prepare chiral compounds in 100% theoretical yield. Ten ruthenium complexes (1–10) act as a good catalyst the for racemization reaction and are also compatible with DKR process. Two other ruthenium complexes [RuCl₂(PPh₃)₃] and [Cp^*RuCl(COD)] are active for racemization reaction but their successful compatibility with DKR has not yet been reported. Ru/γ-Al₂O₃ and Ru–HAP are the heterogeneous catalysts used for the racemization reaction. They have also not been employed for DKR process. Polymer supported ruthenium is employed as a reusable racemization catalyst for aerobic DKR of alcohols.     

Acid Zeolites as Alcohol Racemization Catalysts: Screening and Application in Biphasic Dynamic Kinetic Resolution

Acid zeolites were screened as heterogeneous catalysts for racemization of benzylic alcohols. The most promising zeolites appeared to be H‐Beta zeolites, for which the optimal reaction conditions were studied in further detail. The zeolite performance was compared to that of homogeneous acids and acid resins under similar reaction conditions. In a second part of the research, H‐Beta zeolites were applied in dynamic kinetic resolution (DKR) of 1‐phenylethanol, which was conducted by means of a two‐phase approach and which resulted in yields smoothly crossing the 50 % border up to 90 %, with an enantiomeric excess of >99 %. To explore the applicability of this biphasic methodology, several other substrates were examined in the standard racemization reaction and in the biphasic dynamic kinetic resolution.     

Palladium catalysts on alkaline-earth supports for racemization and dynamic kinetic resolution of benzylic amines

Palladium catalysts on alkaline-earth supports were studied as new heterogeneous catalysts for racemization of chiral benzylic amines such as 1-phenylethylamine. Particularly 5 % Pd/BaSO(4) and 5 % Pd/CaCO(3) were able to selectively racemize amines, with minimal formation of secondary amines or hydrogenolysis to ethylbenzene. In contrast, these side reactions were pronounced on Pd/C. A reaction mechanism is proposed that is consistent with the reaction kinetics. The catalyst activity was found to depend on the number of available surface Pd atoms, determined by titration with CO. The selectivity crucially depends on the rate of condensation of the amine and the primary imine, which is highest on Pd/C. The racemization catalysts were combined in one pot with an immobilized lipase to perform dynamic kinetic resolution of chiral amines. High yields (up to 88 %) of essentially enantiopure amides were obtained in a single step. The chemo-enzymatic catalyst system proved to be stable and could be reused without losing the initial activity.     

New air-stable iron catalyst for efficient dynamic kinetic resolution of secondary benzylic and aliphatic alcohols

We herein report a catalyst system for the dynamic kinetic resolution of secondary alcohols by combining the enzymatic resolution with an iron-catalyzed racemization. A new air-stable tricarbonyl (cyclopentadienone)iron complex is identified as the active racemization catalyst for this transformation without any additive. Various substrates including benzylic, heteroaromatic, aliphatic alcohols can be used and afford the corresponding esters in good yields and with excellent enantioselectivities.     

Recent developments in non-enzymatic catalytic oxidative kinetic resolution of secondary alcohols

The goal of this review is to collect the recent developments in non-enzymatic catalytic oxidative kinetic resolutions of secondary alcohols reported since the beginning of 2011. It is divided into four sections, dealing successively with manganese-catalysed oxidative kinetic resolutions of secondary alcohols, palladium-catalysed oxidative kinetic resolutions of secondary alcohols, oxidative kinetic resolutions of secondary alcohols catalysed by other metals and organocatalysed oxidative kinetic resolutions of secondary alcohols.     

Highly efficient dynamic kinetic resolution of secondary aromatic alcohols at low temperature using a low-cost sulfonated sepiolite as racemization catalyst

A highly efficient dynamic kinetic resolution system for secondary aromatic alcohol using low-cost sulfonated sepiolite as a racemization catalyst has been developed. The system operates at 25 °C, achieves good ee_p (>99%) and substrate conversion ratio (>99%), is applicable to a variety of substrates and can be reused more than 10 times.     

Tuning of the electronic properties of a cyclopentadienylruthenium catalyst to match racemization of electron-rich and electron-deficient alcohols

The synthesis of a new series of cyclopentadienylruthenium catalysts with varying electronic properties and their application in racemization of secondary alcohols are described. These racemizations involve two key steps: 1) β-hydride elimination (dehydrogenation) and 2) re-addition of the hydride to the intermediate ketone. The results obtained confirm our previous theory that the electronic properties of the substrate determine which of these two steps is rate determining. For an electron-deficient alcohol the rate-determining step is the β-hydride elimination (dehydrogenation), whereas for an electron-rich alcohol the re-addition of the hydride becomes the rate-determining step. By matching the electronic properties of the catalyst with the electronic properties of the alcohol, we have now shown that a dramatic increase in racemization rate can be obtained. For example, electron-deficient alcohol 15 racemized 30 times faster with electron-deficient catalyst 6 than with the unmodified standard catalyst 4. The application of these protocols will extend the scope of cyclopentadienylruthenium catalysts in racemization and dynamic kinetic resolution.     

Air-stable racemization catalysts for the dynamic kinetic resolution of secondary alcohols

The substitution of a carbonyl ligand with PPh(3) in cyclopentadienylruthenium dicarbonyl complexes produces a new class of recyclable alcohol racemization catalysts. The catalysts are active at room temperature under aerobic conditions in the presence of silver oxide. Furthermore, the catalysts are compatible with the use of a lipase and isopropenyl acetate for the dynamic kinetic resolution (DKR) of secondary alcohols under ambient conditions.     

Highly efficient synthesis of enantiopure diacetylated C(2)-symmetric diols by ruthenium- and enzyme-catalyzed dynamic kinetic asymmetric transformation (DYKAT)

Highly efficient synthesis of enantiopure diacetates of 2,4-pentanediol and 2,5-hexanediol starting from commercially available mixtures of the diols (dl/meso approximately 1:1) has been realized by combining a fast ruthenium-catalyzed epimerization with an enzymatic transesterification. The in situ coupling of these two processes produces the diacetates in high yield in >99 % enantiomeric excess.     

Iterative tandem catalysis of secondary diols and diesters to chiral polyesters

The well-known dynamic kinetic resolution of secondary alcohols and esters was extended to secondary diols and diesters to afford chiral polyesters. This process is an example of iterative tandem catalysis (ITC), a polymerization method where the concurrent action of two fundamentally different catalysts is required to achieve chain growth. In order to procure chiral polyesters of high enantiomeric excess value (ee) and good molecular weight, the catalysts employed need to be complementary and compatible during the polymerization reaction. We here show that Shvo's catalyst and Novozym 435 fulfil these requirements. The optimal polymerization conditions of 1,1'-(1,3-phenylene) diethanol (1,3-diol) and diisopropyl adipate required 2 mol% Shvo's catalyst and 12 mg Novozym 435 per mmol alcohol group in the presence of 0.5 M 2,4-dimethyl-3-pentanol as the hydrogen donor. With these conditions, chiral polyesters were obtained with peak molecular weights up to 15 kDa, an ee value up to 99% and with 1-3 % ketone end groups. Also with the structural isomer, 1,4-diol, a chiral polyester was obtained, albeit with lower molecular weight (8.3 kDa) and slightly lower ee (94%). Aliphatic secondary diols also resulted in enantio-enriched polymers but at most an ee of 46 % was obtained with molecular weights in the range of 3.3-3.7 kDa. This low ee originates from the intrinsic low enantioselectivity of Novozym 435 for this type of secondary aliphatic diols. The results presented here show that ITC can be applied to procure chiral polyesters with good molecular weight and high ee from optically inactive AA-BB type monomers.