Multicatalysis – Pushing the boundaries beyond multi-disciplinarities for complex molecules synthesis

The concept of multi-catalysis is an emerging field of chemistry targeting the development of new efficient catalytic systems combining multi-step synthesis in new ‘one-pot’ transformations or in multi-catalytic sequences.

In this article, we will review the main classification of multi-catalysis strategies and illustrating some case-studies which combine different catalysis fields leading to some remarkable opportunities to outcompete classical approaches. Despite major challenges that need to be addressed with respect to compatibility issues and catalyst reactivity ordering, the implementation of such chemical processes enables to strengthen the collaboration across many disciplines enhancing interdisciplinary competences.

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Introduction

The emergence of catalysis has had a transformative impact in many fields, including chemistry, healthcare, materials, agriculture and in the environmental sector. Historically, catalysts were first developed to enhance the performance of known chemical reactions, but later catalysis started enabling new transformations to address new challenges. Today, catalytic processes produce almost 90% of the chemical industry (1) products.

Driven by the demand for more efficient and sustainable chemical processes, and bringing solutions for more complex molecules, the field of catalysis continues to evolve rapidly. Recently, there has been a growing interest in developing multi-catalytic systems, which are inspired by the complexity of catalytic reactions occurring in nature. Indeed, synthetic chemists try to mimic the efficient metabolic networks in living organisms to build complex molecules by combining different types of catalysts in the same
reaction vessel. These multistep cascade processes provide many advantages to synthetic procedures, resulting in higher productivities with lower waste generation and cost.

As illustrated in this article, multi-catalysis emerges not only to enlarge the avenue of new methodologies but also to offer potential new valuable short-cuts to the synthetic practitioner.

Within multi-catalytic processes, either multiple catalysts execute single reactions, or precise sequences of multiple catalytic reactions occur in a ‘one-pot’ fashion. Special emphasis is dedicated to the integration of several catalysts from different fields, such as chemocatalysis and biocatalysis. The classification of multi-catalytic systems refers to some key criteria (2):

• how the catalysts operate, i.e., the number of catalytic cycles that are involved and if the catalytic cycles are intertwined.
• the number of independent catalytic reactions, i.e., number of chemical transformations in the overall process.
  
  These considerations lead to three categories of “cooperative catalysis”, “relay catalysis” and “domino catalysis”
  

Solving the compatibility issue in multi-catalysis

Designing cascade chemical processes are challenging, as:

• all reagents and catalysts needed in different steps must tolerate each other’s presence;

• all reactions must occur under the same conditions;

• functional groups present in the molecules should contribute only in the desired steps, the cross-reactivity must be avoided.

To tackle compatibility issues, several strategies have been investigated, among them, compartmentalization of different reactions is an option, i.e., the catalysts and reagents for different steps are located in different ‘compartments’ of the reactor (11). The compartments can be constructed by phases that are either immiscible (12), separated by semi-permeable membrane (13), or physically separated with the volatile intermediates being exchanged through the gas-phase (14).

If the compatibility issues are related to the catalysts itself, ordering catalyst reactivity by sequential addition to the reaction media or encapsulating the catalyst are also feasible solutions. For illustration, whole cells containing the required biocatalyst can serve as individual compartment.
Combining catalysts from different catalysis fields is sometimes more challenging. Organocatalysts may be compatible and robust, however chiral metal catalysts are more sensitive to coordinate to other species present in the reaction medium.

Often, compatibility is one-way and not mutual, which makes subsequent cascades often the method of choice. Cascade reactions can achieve more than the separated individual steps. This is the case when an equilibrium reaction is coupled to an irreversible catalytic step.

Remarkably, multi-catalytic sequences can undergo through otherwise unfeasible pathways thanks to, for instance, prospectively unstable intermediates being converted as soon as formed.
Typically, when biocatalysis and chemocatalysis are both combined, the sequences are carried out by using multi-phase systems with catalysts operating in different, non-mixable phases, between which the intermediates are exchanged.

The development of truly simultaneous complex chemoenzymatic cascades requires the joint effort of different research areas including catalyst design, protein engineering, whole cell catalysis, metal catalysis as well as compartmentalization strategies.

Finally, for implementing these strategies at industrial scale, significant analytical data are required for ensuring precise control over reactions conditions. This remains a key challenge for adopting this approach. By analogy with multistep synthesis in flow chemistry, real time analysis is required and can be challenging (15). Considering the current advances in this field, namely Process Analytical Technology (PAT) tools, this will help to reach real-time monitoring.

Conclusions and outlook

Multi-catalysis emerges not only to enhance the scope of synthetic protocols, but also brings new ‘one-pot’ transformations that exhibit outstanding resource efficiency.
Despite challenges that need to be addressed with respect to compatibility issues and catalyst reactivity ordering, recent studies show promising solutions. For instance, sequential additions of reagents or catalysts, reaction compartmentalization or catalyst encapsulation, proved to be feasible solutions to overcome such incompatibility issues.

Combining several catalytic steps to conduct multiple reactions in a precisely arranged sequence of chemical transformations in a single reaction reactor exhibits an enormous potential for more economically and ecologically efficient synthesis routes, and thus, the development of one-pot (cascade) reactions is a growing research field.

More complex molecules need to be produced, especially in the pharmaceutical industry. Indeed, in recent years, lead molecules coming through the pipeline and then being approved by FDA are becoming increasingly complex (16). Ultimately, the manufacture of these molecules become more difficult and take longer time. As a result, chemists must continue to develop improved synthetic tools to be able to prepare all possible complex molecules rapidly, while minimizing waste generation. However, even though more efficient and selective catalysts are continuously being discovered, using only one catalyst might limit reaction potential. In answer to these apparent limitations, researchers have started looking at the selective combination between multiple catalysts.

Within CDMO organizations, manufacturing active ingredients is paving the way by taking the best from different fields of expertise, including synthetic chemists, process engineers and biologists. Interdisciplinarity is highly associated with innovation and science.

This leads to unique opportunity forcoordination and collaboration across each competency by sharing their knowledge, know-how and perspectives for allowing the discovery of new strategic paths which will enable considerable synthetic economies.

At commercial scale, only a few CROs and CDMOs can offer multicatalysis approach, as it requires the desired internal capabilities. Only the most innovative CDMOs organizations with integrated competencies and capacities, such as high throughput screening platform, can offer these services, such as Seqens.

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