The synthesis of (R)-duloxetine is described. Dynamic kinetic resolution of β-hydroxynitrile rac-1 using Candida antarctica lipase B (CALB, N435) and ruthenium catalyst 6 afforded β-cyano acetate (R)-2 in high yield and in excellent enantioselectivity (98% ee). The subsequent synthetic steps were straightforward and (R)-duloxetine was isolated in 37% overall yield over 6 steps. The synthetic route also constitute a formal total synthesis of (S)-duloxetine.

Abstract.A catalyst consisting of palladium nanoparticles supported on amino-functionalized siliceous mesocellular foam (Pd-AmP-MCF) was used in chemoenzymatic dynamic kinetic resolution (DKR) to convert primary amines to amides in high yields and excellent ee's. The efficiency of the nanocatalyst at temperatures below 70 °C enables reaction conditions that are more suitable for enzymes. In the present study this is exemplified by subjecting 1-phenylethylamine (1a) and analogous benzylic amines to DKR reactions using two commercially available lipases, Novozyme-435 (Candida antartica Lipase B) and Amano Lipase PS-C1 (lipase from Burkholderia cepacia) as biocatalysts. The latter enzyme has not previously been used in the DKR of amines, due to its low stability at temperatures over 60 °C. The viability of the heterogeneous Pd-AmP-MCF was further demonstrated in a recycling study, which shows that the catalyst can be reused up to five times.

A mobile region is proposed to be a flap that covers the active site of Candida antarctica lipase A. Removal of the mobile region retains the functional properties of the enzyme. Interestingly interfacial activation, required for the wild-type enzyme, was not observed for the truncated variant, although stability, activity, and stereoselectivity were very similar for the wild-type and variant enzymes. The variant followed classical Michaelis-Menten kinetics, unlike the wild type. Both gave the same relative specificity in the transacylation of a primary and a secondary alcohol in organic solvent. Furthermore, both showed the same enantioselectivity in transacylation of alcohols and the hydrolysis of alcohol esters, as well as in the hydrolysis of esters chiral at the acid part.

Pd-catalyzed C-C bond-forming reactions under oxidative conditions constitute a class of important and widely used synthetic protocols. This Article describes a mechanistic investigation of the arylating carbocyclization of allenynes using boronic acids and focuses on the correlation between reaction conditions and product selectivity. Isotope effects confirm that either allenic or propargylic C-H activation occurs directly after substrate binding. With an excess of HO, a triene product is selectively formed via allenic C-H activation. The latter C-H activation was found to be turnover-limiting and the reaction zeroth order in reactants as well as the oxidant. A dominant feature is continuous catalyst activation, which was shown to occur even in the absence of substrate. Smaller amounts of HO lead to mixtures of triene and vinylallene products, where the latter is formed via propargylic C-H activation. The formation of triene occurs only in the presence of ArB(OH). Vinylallene, on the other hand, was shown to be formed by consumption of (ArBO) as a first-order reactant. Conditions with sub-stoichiometric BF·OEt gave selectively the vinylallene product, and the reaction is first order in PhB(OH). Both C-H activation and transmetalation influence the reaction rate. However, with electron-deficient ArB(OH), C-H activation is turnover-limiting. It was difficult to establish the order of transmetalation vs C-H activation with certainty, but the results suggest that BF·OEt promotes an early transmetalation. The catalytically active species were found to be dependent on the reaction conditions, and HO is a crucial parameter in the control of selectivity.

Tertiary alcohols are important structural motifs in natural productsa nd building blocks in organic synthesis buto nly few methods are known for their enantioselective preparation. Chiral resolution is one of these approaches that leaves one enantiomer (50 %o ft he material) unaffected. An attractive method to increase the efficiency of those resolutions is to racemizet he unaffected enantiomer.I nt he present work, we have developed a practical racemization protocol for tertiary alcohols. Five different acidic resin materials were tested. The Dowex 50WX8 was the resin of choice since it was capable of racemizing tertiary alcohols withouta ny byproductf ormation. Suitable solvents and ab iphasic system were investigated, andt he optimized system was capable of racemizing differently substituted tertiarya lcohols.The stereoselective synthesis of organic moleculesi so fahigh demandi nt he pharmaceutical anda grochemical industry. Three strategies are presently used for the preparation of enantiomerically pure compounds,o ne of them being the chiral pool synthesis, where chiral natural products are used as buildingb locks for the synthesis of complex molecules. [1] The other two strategies include resolution of racemates [2] and asymmetrics ynthesis, where in the latter case chiral reagents or catalysts are used. [3] Although asymmetrics ynthesis based on catalysis (asymmetric catalysis) is av ery powerful method for obtaining enantiomerically pure compounds, the most commonm ethod used in chemical industry for obtaining such compounds is still by resolution. In ar esolution, which could be crystallization, chiral chromatography,o rk inetic resolution, two enantiomers are separated and the desired enantiomer is collected. The drawback of the resolution strategy is that only 50 %o ft he material is used, and the unwanted enantiomer is discarded. As olutiono ft his problem is to racemize the unwanted enantiomer and to recirculate the racemic mixture, which increases efficiency.T herefore, there is ah igh demand of efficient racemizationm ethods in industrial applications.Racemizationc an be achieved by av ariety of techniques: thermalr acemization, enzyme-catalyzed racemization, racemization via meso-intermediates, racemization by nucleophilic substitution, racemizationb yr adicala nd redox reactions, photochemical racemization, and acid-or base-catalyzed racemization. [4] The most common racemization catalysts for secondary alcohols are transition-metal-based hydrogen-transfer catalysts, which racemize the alcoholi nadehydrogenation-hydrogenation (oxidation-reduction) pathway. [5] When such ar acemization catalyst is combinedw ith ak inetic resolution catalyst (e.g. an enzyme)aso called "dynamic kinetic resolution" (DKR) can be achieved. [6] Te rtiary alcohols and their esters are important compounds, which are found in anumber of natural products. [7] These compounds are also important buildingb locks in synthetic chemistry. [8] The synthesis of optically pure tertiary alcohols is still a challengin...