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A very short stereoselective synthesis of enantiomerically pure (3S, 4aS, 10aR)-quinagolide has been developed. The key steps involved are a copper-catalyzed regioselective arylation of (S)-epichlorohydrin with 1,6-dimethoxynaphthalene and a diastereoselective trans-reduction of a cyclic enamine intermediate. The possibility to use both enantiomers of epichlorohydrin and the diastereodivergency found in the reduction process paves the way for a general preparation also in the nonracemic form of chiral trans-fused 3-substituted octahydrobenzo[g]quinolines that are privileged structures in medicinal chemistry.

A large-scale asymmetric synthesis has been developed for the kilo-lab manufacture of AZD8186. The process initially employs a regioselective Heck coupling in water to provide the starting aromatic ketone. This ketone is reduced asymmetrically under ruthenium-catalyzed transfer hydrogenation conditions to provide a chiral alcohol in high enantiomeric purity. The key synthetic step then requires the reaction of this chiral alcohol with the activated derivative of 3,5-difluoroaniline under the Mitsunobu reaction conditions. The common issues associated with the use of the Mitsunobu reaction, such as removal of triphenylphosphine oxide and reduced diisopropyl azodicarboxylate (DIAD) by-products, have been eliminated through crystallization of the relevant intermediates.

The regioselectivity in the palladium‐catalyzed Heck coupling reaction between an aryl halide and ethyl vinyl ether with four different phosphine ligands: PPhntBum(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, PtBu3and PPhtBu2, unexpectedly large deviations between experimental and M06 calculated selectivities raised the question of an alternative mechanism for these ligands. In the case of PtBu3it 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 PPhtBu2ligand, 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.

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 Rconfiguration (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.

Lithium‐powered: A kinetic investigation into the asymmetric transfer hydrogenation of non‐activated aryl alkyl ketones, catalyzed by N‐Boc‐protected α‐amino acid hydroxyamide ruthenium–arene complexes, has revealed that the reactions proceed through an unprecedented bimetallic outer‐sphere mechanism. Under optimized conditions, these catalysts provide access to secondary alcohols in high yields and with excellent enantioselectivities (>99 % ee).

The rates of oxidative addition of phenyl bromide to [Pd(BINAP)2] have been measured in the presence and absence of added amine to assess a previous hypothesis that addition to [Pd(BINAP)(amine)] is faster than addition to [Pd(BINAP)]. These data show that addition to the amine complex is not faster than addition to [Pd(BINAP)]. Instead, they are consistent with oxidative addition, even in the presence of amine, to [Pd(BINAP)] as the major pathway. These data underscore the value of studying the stoichiometric reactions of isolated complexes when assessing the mechanism of a catalytic process.

The secondary α-deuterium, the secondary β-deuterium, the chlorine leaving-group, the nucleophile secondary nitrogen, the nucleophile ¹²C/¹³C carbon, and the ¹¹C/¹⁴C α-carbon kinetic isotope effects (KIEs) and activation parameters have been measured for the SN2 reaction between tetrabutylammonium cyanide and ethyl chloride in DMSO at 30 °C. Then, thirty-nine readily available different theoretical methods, both including and excluding solvent, were used to calculate the structure of the transition state, the activation energy, and the kinetic isotope effects for the reaction. A comparison of the experimental and theoretical results by using semiempirical, ab initio, and density functional theory methods has shown that the density functional methods are most successful in calculating the experimental isotope effects. With two exceptions, including solvent in the calculation does not improve the fit with the experimental KIEs. Finally, none of the transition states and force constants obtained from the theoretical methods was able to predict all six of the KIEs found by experiment. Moreover, none of the calculated transition structures, which are all early and loose, agree with the late (product-like) transition-state structure suggested by interpreting the experimental KIEs.

The secondary α‐deuterium, the secondary β‐deuterium, the chlorine leaving‐group, the nucleophile secondary nitrogen, the nucleophile 12C/13C carbon, and the 11C/14C α‐carbon kinetic isotope effects (KIEs) and activation parameters have been measured for the SN2 reaction between tetrabutylammonium cyanide and ethyl chloride in DMSO at 30 °C. Then, thirty‐nine readily available different theoretical methods, both including and excluding solvent, were used to calculate the structure of the transition state, the activation energy, and the kinetic isotope effects for the reaction. A comparison of the experimental and theoretical results by using semiempirical, ab initio, and density functional theory methods has shown that the density functional methods are most successful in calculating the experimental isotope effects. With two exceptions, including solvent in the calculation does not improve the fit with the experimental KIEs. Finally, none of the transition states and force constants obtained from the theoretical methods was able to predict all six of the KIEs found by experiment. Moreover, none of the calculated transition structures, which are all early and loose, agree with the late (product‐like) transition‐state structure suggested by interpreting the experimental KIEs.

Conventional SPPS (solid-phase peptide synthesis) requires protecting the nucleophilic side-chains of amino acids to prevent undesired modifications. A large volume of TFA (trifluoroacetic acid) is generally needed to remove these protecting groups after the peptide assembly. Such a process significantly lowers the productivity of the subject peptide manufacture due to handling large volumes of TFA and the resultant anti-solvent for precipitating and isolating the crude products. Enabling the side-chain unprotected amino acid couplings should break through such a bottleneck in peptide production and drastically increase productivity. Fmoc-Arg-OH, Fmoc-His-OH, and Fmoc-Tyr-OH are utilized in this study as substrates to investigate their couplings to peptide molecules. Side reactions induced by these side-chain unprotected amino acids have been elucidated, and solutions addressing these side reactions are developed. The processes of the side-chain unprotected amino acid couplings have been successfully implemented in peptide synthesis through a minimal-protection SPPS (MP-SPPS) strategy. Significantly reduced TFA concentration was enabled to quantitatively detach the peptide from the solid support and obtain the crude peptide product in high yield. In this process, trifluorotoluene, an alternative solvent to DCM (dichloromethane) with low toxicity, was employed as the medium for TFA-mediated peptide cleavage and side-chain global deprotection. A crude peptide product with high purity was obtained from the MP-SPPS process, and a 5.3-fold productivity increase was accomplished.

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