Yongkui Sun

Reaction calorimetry as an in-situ kinetic tool for characterizing complex reactions☆

Abstract Due to its ability to provide directly reaction rate data and its in-situ nature, reaction calorimetry has become one of the most powerful probes of reaction pathways and mechanisms of chemical reactions by virtue of providing high-quality kinetic data. In this paper, examples of enantioselective hydrogenation and selective consecutive hydrogenation reactions are presented to demonstrate the high quality of kinetic data obtainable from the reaction calorimetry. They are also used to illustrate the use of reaction calorimetry for elucidating reaction pathways and mechanisms from detailed kinetic and thermodynamic information about individual step involved in multi-step reactions that is otherwise difficult to obtain without calorimetry.

KINETIC INFLUENCES ON ENANTIOSELECTIVITY IN ASYMMETRIC CATALYTIC HYDROGENATION

Abstract The influence of reaction conditions on enantioselectivity in the Ru II -(binap)-catalyzed asymmetric hydrogenation of allylic alcohols is discussed. This work highlights the importance of considering kinetic influences in addition to the stereochemical aspects of the chiral catalytic environment in interpreting catalytic behavior in asymmetric hydrogenation reactions.

Establishment and maintenance of an optimal chiral surface in cinchona-modified 1% Pt/Al2O3 for enantioselective hydrogenation of α-keto esters

An optimal chiral surface in the cinchona-modified Pt/Al2O3 catalytic system is established for fast enantioselective hydrogenation of ethyl pyruvate. A makeup protocol is used to compensate for the destructive hydrogenation of the chiral modifier, thus maintaining the optimal chiral surface over the course of the hydrogenation reaction. Hydrogenation over the optimal surface (Ptsurface/modifier = 5–12) results in high enantioselectivity (94% ee) under mild conditions (5.8 bar and 17°C) with high turnover frequency (4 s-1) and turnover numbers (pyruvate/modifier>28,000, pyruvate/Ptsurface>5,500).

Catalytic Asymmetric Synthesis of an HIV Integrase Inhibitor

An efficient synthesis of HIV integrase inhibitor (S)-(-)-1 via a unique asymmetric hydrogenation of a mixture of imines/enamine 5a-5b/5c is described. Hydrogenation of the imines/enamine by a Rh(I)-Josiphos complex afforded 6 in 90% yield and 90% ee. Amide formation completed the synthesis of 1 in 58% overall yield from 2, which is readily available from 3,4-dihydro-2H-pyran in a seven-step sequence. A deuterium labeling study suggests the asymmetric hydrogenation proceeds predominantly via the enamine tautomer.

New insights into the mechanism of molybdenum-catalyzed asymmetric alkylation

The major features of the catalytic cycle, including structures of key intermediates, have been determined for the molybdenum-catalyzed asymmetric alkylation. The crystal structure of the π-allyl intermediate exhibits 3-point binding of an anionic ligand. Based on NMR analysis, this species adopts in solution a structure consistent with that observed in the solid state. For the allylic alkylation, the crystal structure predicts the opposite stereochemistry vs. that observed experimentally, which suggests that either the reaction proceeds via a minor isomer (Curtin-Hammett conditions) or with retention of configuration. In addition, CO transfer, promoted by Mo(CO)6, has been found to play a key role in catalyst turnover.

Kinetic influences on enantioselectivity in asymmetric catalytic hydrogenation

Examples from both homogeneous and heterogeneous catalytic systems are presented which demonstrate the role that reaction dynamics may play in dictating the ultimate enantioselectivity observed in asymmetric hydrogenation reactions. The hydrogenation of allylic alcohols using Ru(S)-binap and the hydrogenation of α-keto esters using cinchona-modified supported Pt are discussed. This work highlights the importance of considering reaction kinetics in addition to the stereochemical aspects of the chiral catalytic environment in interpreting catalytic behavior in asymmetric hydrogenation reactions.

A combined approach to characterization of catalytic reactions using in situ kinetic probes

Several in situ probes for continuously monitoring rate of catalytic reactions under reaction conditions are described. They are reaction calorimetry, measurements of hydrogen uptake in the case of hydrogenation, and infrared spectroscopy. In studying catalytic hydrogenation reactions, for example, these in situ probes provide kinetic details of the reactions from different perspectives over the entire course of the reaction. The reaction calorimetry and the hydrogen uptake measure directly, continuously, and in a non-invasive manner the rate of reaction, while the in situ infrared spectroscopy provides time-resolved compositional information in the liquid phase. A combination of the information thus obtained leads to a clear and coherent kinetic picture of the reaction under study which can greatly facilitate pathway analysis and mechanistic description of the catalytic reaction. In this report, the usefulness of the combination of these in situ probes is illustrated with two examples of heterogeneously-catalyzed hydrogenation reactions.

Harvesting short-lived hypoiodous acid for efficient diastereoselective iodohydroxylation in Crixivan® synthesis

Abstract The evasive hypoiodous acid is generated in situ from NaOCl and NaI and used efficiently for clean iodohydroxylation of 1 , producing the Crixivan ® intermediate 2 in high yield with highly efficient 1,3-asymmetric induction. This pH-tunable process allows HOI generation at a pH optimal for supressing byproduct formation in pH-sensitive iodohydroxylation reactions.

Asymmetric hydrogenation of protected allylic amines.

A general method for the enantioselective hydrogenation of protected allylic amine derivatives is described. This procedure relies on the generation of a cationic ruthenium complex with the axially chiral ligand (-)-TMBTP. The utility is highlighted by the highly enantioselective hydrogenation of a diene substrate that can then be elaborated to prepare Telcagepant, a compound currently in Phase III clinical trials. The scope of the hydrogenation reaction was studied, and a variety of substituted allylic amine derivatives could be hydrogenated with enantiomeric ratios of 92:8 or higher.

Modeling of kinetically coupled selective hydrogenation reactions: Kinetic rationalization of pressure effects on enantioselectivity

Abstract A two-site, two-step kinetic model is proposed to rationalize the observed effects of solution hydrogen concentration on enantioselectivity in the asymmetric hydrogenation of ethyl pyruvate using a dihydrocinchonidine-modified heterogeneous Pt catalyst. The model successfully predicted enantioselectivity at a hydrogen concentration outside the range used in the kinetic fit. This work demonstrates how the perturbation from equilibrium adsorption of the organic substrate on a heterogeneous catalyst may account for the observed effects of pressure on enant ioselectivity. Both positive and negative hydrogen dependences on enantioselectivity may be rationalized using the same model.