Synthetic Strategies

The chemical synthesis of complex organic molecules is integral to many advances that enhance the quality of life, such as novel disease treatments, agrochemicals with improved properties and advanced materials for high performance technology and biotechnology.  The methods for synthesising complex organic molecules have traditionally pieced molecules together in a linear manner, gradually building complexity into the molecule. This can be a very time consuming process, and synthetic routes to molecules can end up being incredibly long, requiring extensive resources and manpower.


Since 2000 we have been pioneering an approach to synthesis that combines two-directional synthesis and tandem reactions. Linear symmetrical trifunctional compounds are synthesised through use of two-directional synthesis, and a range of tandem reactions are then applied to generate a range of diverse structures from these simple substrates. Two-directional synthesis, when used in combination with tandem reactions, can lead to significantly faster strategies for the synthesis of complex molecules.  A summary of some of our work in this area is shown in the Scheme below.

Many compounds of synthetic and biological interest are non-racemic in nature. Two-directional synthesis naturally creates symmetrical products. Methods for desymmetrising such products have centred on chain terminus differentiation, mono-derivitisation, dynamic resolution, asymmetric ring opening reactions and conformational effects. Our approach is to design tandem reactions that intrinsically desymmetrise the symmetrical products formed from two-directional synthesis, providing a step-change in the order of magnitude of complexity generation achievable in a one-pot process.

Traditionally the pharmaceutical industry has turned to Nature for inspiration in the discovery of new therapeutic agents. From ancient Chinese medicines, to aspirin, to taxol, many of the world’s drugs were originally isolated from natural sources. More recently a new wave of “chemical prospecting” has focussed on the synthesis of diverse libraries of totally synthetic compounds. With this new way of “investigating chemical space” has come a new demand for synthesis: Diversity Oriented Synthesis (DOS). Unlike traditional Target Oriented Synthesis (TOS), in which retrosynthetic analysis of a target molecule would provide several potential routes to that molecular target, with DOS, one is trying to create as many spatially and functionally diverse compounds in the minimum number of steps. To date, the most common strategy for DOS is to append a large array of building blocks to a common molecular scaffold, with combinatorial synthesis techniques commonly being employed. However, the generation of skeletal diversity within DOS has thus far been a formidable challenge. 

As well as providing uniquely elegant solutions for Target Oriented Synthesis, our Combined Two-Directional / Tandem reaction approach is also a powerful tool for Diversity Oriented Synthesis. We are involved in applying the complexity generating power of two-directional synthesis and tandem reactions as an approach to the generation of a variety of new molecular architectures, and as a starting point for the generation of new reactions. See our Chemical Science paper for our initial work in this area.

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Combining Two-Directional Synthesis and Tandem Reactions

Desymmetrisation Using Tandem Reactions

Tandem Reactions as a Tool For Diversity Oriented Synthesis