Research

Research inspiration:

Have you ever considered how a cell constructs complex organic molecules from simple building blocks? How acetyl units of acetyl-CoA derived of CO2, NADPH and protons come together to form glucose, vitamin C or complex molecules such as many antibiotics, like penicillin, erythromycin or maitotoxin? Such biochemical syntheses are accomplished within complex multistep pathways, involving multiple enzymes and intermediates. Each enzyme conducts a specific transformation and is integrated into the self-regulatory metabolic network spanning different levels of cell organization. These features allow multistep synthesis to occur in parallel with a steady flux of material toward the final products. While chemists have made immense progress in developing selective reactions with myriads of selective catalysts, the current dogma of organic synthesis still dictates that each reaction is conducted consecutively involving isolation and purification of each intermediate. While in general effective, this approach is not efficient.

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In this image, the integrated metabolic and originated physical enzyme-enzyme interaction network of Mycobacterium tuberculosis is shown (Courtesy of Daniel Banky). Nodes are the enzymes catalyzing reactions, the red directed edges are the metabolic pathway and the blue undirected edges are predicted physical interactions.

Overarching principle:

We envision that a breakthrough in efficiency of organic synthesis lies in conducting, analogous to nature, full sequences of reactions occurring in one reactor. Besides shorter and simplified procedures, such balanced networks of organic reactions will undergo through otherwise inaccessible transformations by incorporating reaction cooperativity and thermodynamic leveraging. However, the construction of artificial self-regulating networks of catalytic reactions and networks of semi-communicated micro-reactors, enabling to carry out multistep syntheses in a ‘one-pot fashion’ is a formidable task. Devising these multi-catalytic systems will require the progress in research embracing transition metal multi-catalysis, supramolecular catalysis utilizing substrate recognition, the control of spatiotemporal activity, substrate-dependent activity and selectivity, as well as, the active substrate transport, the reaction compartmentalization with the aid of high-performance or the multiphase reactors, and many others.

Our ambition:

The main aim of our research is to lay the foundations for an approach to organic synthesis based on connecting multiple catalytic reactions into coherent self-regulating networks, and to increase of fundamental understanding of the complex system chemistry for organic synthesis. We undertake the self-standing projects of developing various tools and approaches that ultimately pursue the goal to enable the construction of complex networks of reactions occurring within self-regulating multicatalytic systems.

  1. Dual-catalytic transition metal systems for functionalization of unreactive sites of molecules

General aim: One of the research efforts of our lab aims to develop a powerful strategy for organic synthesis that enables new functionalization reactions by temporarily changing the inherent reactivity profile of the starting materials. The concept combines a dynamic equilibrium mediated by one transition metal catalyst and a target functionalization reaction catalyzed by a second transition metal catalyst into a bi-catalytic network of cooperative reactions. By exploiting two orthogonal known catalytic reaction, this approach aims to enable a plethora of reactions at conventionally unreactive C-H and C-C bonds, which are unattainable with current methods but are desired for both development and production of fine-chemicals and materials.

Challenge: Consider that typically catalytic reactions occur readily at sites of starting materials that are both innately reactive and sterically accessible or that are predisposed by a functional group amenable to direct a catalyst. However, selective reactions at unbiased sites of substrates remain challenging and typically require additional pre-activation steps or the use of highly reactive reagents.

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Our approach: Recently we devised dual-catalytic transition metal systems that merge a reversible activation cycle with a functionalization cycle, together enabling functionalization of substrates at their inherently unreactive sites. We demonstrated that by engaging the Ru- or Fe-catalyzed equilibrium between an alcohol and an aldehyde, Pd-catalyzed alpha-arylation of aliphatic alcohols and Rh-catalyzed gamma-hydroarylation of allylic alcohols were enabled. The mild conditions, functional group tolerance and broad scope of the methodologies (81 examples) demonstrate the synthetic applicability of the dual-catalytic systems. In a broader context, this work highlighted the potential of the multi-catalytic approach to address challenging transformations to circumvent the multi-step procedures and the use of highly reactive reagents in organic synthesis.

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See also: https://doi.org/10.26434/chemrxiv.7235438.v1

Other projects: COMING SOON