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Final Report Summary - MOMES (Modern mechanistic studies for rational catalyst design)

Catalysis plays a central role in chemistry because it allows more sustainable and environmentally friendly chemical processes. Historically, chemists have used metal-based compounds as reaction promoters. However, in the last fifteen years, the use of pure organic molecules as catalysts has been established as a successful alternative approach, overcoming some of the common disadvantages found in organometallic catalysis, such as cost, toxicity, and catalysts’ instability. For these reasons, organocatalysis, and in particular, aminocatalysis, has experienced an impressive growth since its advent. Although a large number of new methodologies have been discovered using this strategy, the vast majority of them have used an empirical approach based on large screenings, and the accurate understanding of the reaction mechanisms have been neglected and usually misunderstood.

Therefore, the general aim of this project has been the rational improvement and design of aminocatalytic processes based on the accurate study of the reaction mechanisms. Prior to the beginning of the project, aminocatalytic downstream intermediates were identified as key elements that control the selectivity outcome in these kinds of transformations. The present two-years project has gained insights into the kinetic and thermodynamic properties of these systems, leading to three new works with high potential at both academic and industrial level.

1. Deciphering the role of multiple additives in organocatalyzed Michael addition.

Primary amine-thioureas (PAT) catalysts are widely used to activate ketones as nucleophiles in the Michael addition to electron-poor olefins, because of their easy preparation, versatility and effectiveness. Besides the catalytic bifunctional scaffold, the role of water and acid additives have a fundamental impact in the reactivity and selectivity, but remained unclear.

We have demonstrated that acid provides turnover to the PAT catalysts, promoting the hydrolysis of the product imine (A). If not present, the product imine (A) attacks another molecule of nitroalkene, generating the double addition product imine (B). Therefore, acid also prevents the formation of the undesired double addition side product. On the other hand, water prevents catalyst deactivation by polymerization of the catalytic intermediates (A or B) with the nitroalkene, and stabilize the productive reaction pathway. Therefore, although water slows down the reaction, it allows a final higher product conversion.

<Figure 1. Proposed catalytic cycle for the Michael addition of acetone to nitrostyrene catalyzed by a PAT catalyst. >

2. New mode of chiral recognition for the chiral resolution of lactols.

The silicon protected diaryl prolinol type catalysts, usually known as Jørgensen-Hayashi catalysts, are one of the most effective and employed catalysts to activate aldehydes. We have uncovered how the chiral information of the catalyst is transferred to the product via a highly selective formation of downstream intermediates. The whole process is controlled by a set of stereolectronic effects, with an exo anomeric effect as the key factor.
These observations are of crucial importance to understand the stereochemical outcome of the aminocatalyzed reactions, but also, by using this new mode of chiral recognition, we have developed a new methodology for the chiral resolution of lactols.

Chiral lactols are important synthetic intermediates. Specifically, Professor Darren Dixon has extensively used enantiopure (S)-6-methyl-delta-lactol as a chiral water equivalent for the stereoselective oxy-Michael addition to a wide set of Michael acceptors. Their oxidized analogous, chiral lactones, are precious intermediates in the fragrance and food industry. Although several racemic lactones are commercially available and cheap, the enantiopure ones either are not commercially available or are much more expensive. Despite the existence of few methodologies for their enantiopure synthesis, these protocols are based in multi-step synthesis starting form chiral and expensive reagents. In addition, up until now, there are not any efficient methods for lactone separation using chiral preparative HPLC.

This new methodology allow the chiral resolution and separation of racemic lactols in solution at gram-scale, resolving a synthetic problem. In addition, in collaboration with Professor Livingston (Dept. of Chemical Engineering at Imperial College), we are exploring the possibility to adapt this new process at an industrial scale, by using organic solvent nanofiltration (OSN) technology.

<Figure 2. a. Relevant chiral lactol and lactones, with different applications in synthesis and in the fragrance and food industry. b. Chiral resolution of lactols.>

3. Map-assisted reaction optimization using the catalytic species Distribution

Another very popular application of the Jørgensen-Hayashi type catalysts is the electrophilic activation of enals by an iminium-ion strategy, for the Michael addition of different nucleophiles to alpha,beta-unsaturated aldehydes. The main drawback of this kind of reaction, as well as in almost all the aminocatalyzed reactions, is the requirement to use high catalyst loadings (typically 10-20 mol%) to reach full conversion in acceptable reaction times. In addition, these kinds of reactions are highly irreproducible. These two facts may contribute to why this academic technology has not been transferred to an industrial level.

The knowledge accumulated in the study of the equilibria involved between pre-catalysts, effectors and substrates, the parameters that controls the kinetics, and the characterization of the relevant catalytic species, has led us to develop a new protocol to efficiently run these Michael additions with very low catalyst loadings.

We recognized that the main reason for the irreproducibility reported in the literature, is the presence of impurities in the reagents, mainly traces of acid in the aldehyde. This factor becomes critical when trying to run the reaction in very low catalyst loadings. To solve these problems, we have implemented a totally new approach: the use of the catalytic species distribution as a parameter to control and optimize the reaction.

The methodology is based on the construction of a “map” that correlates the different catalytic species distribution with the reaction rate. This distribution parameter is fast and accurate to measure by simple NMR. Employing the map of catalytic species distribution, the reaction can be efficiently run regardless of the batch of aldehyde or the catalyst loading used, solving the two main drawbacks of this kind of reaction. Therefore, we have run the Michael addition of malonate and nitromethane starting from various samples of cinnamaldehydes using different additives (figure 3a) and with only 0.1 mol% of catalyst in 60h (figure 3b).

<Figure 3. a. Reaction with 1 mol% of catalyst. yellow dots: blank aldehyde 1, green squares: map optimized aldehyde 1; red diamonds: blank aldehyde 2, blue traingles: map optimized aldehyde 2. b. Reaction with 0.1 mol% of catalyst. yellow dots: blank reaction, green squares: map optimized.>

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Brooke Alasya, (Research Services Manager, Faculty of Natural Sciences)
Tel.: +44 207 594 1181
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Record Number: 187061 / Last updated on: 2016-07-18