Exploiting Organocatalysis for the Synthesis of Amino acids, Aminophosphonates and Amidoallenes

Lead Research Organisation: Imperial College London
Department Name: Chemistry

Abstract

Catalysts are crucial for the synthesis of useful compounds because they allow chemical processes to be carried out under much milder conditions and with much higher efficiencies than would otherwise be the case. Asymmetric catalysis allows the preparation of compounds as single mirror image forms (enantiomers) which is critical for the synthesis of pharmaceutical compounds. Traditionally, most efficient catalysts have contained transition metals. More recently, synthetic chemists have been focusing instead on the use of small organic molecules - known as organocatalysts - to promote important chemical reactions. As well as avoiding the use of potentially toxic metals, these catalysts often allow reactions to be carried out without the need to rigorously exclude water or air. This project will look at exploiting one particular organocatalytic reaction - one which allows a sulfur atom to be introduced stereoselectively next to an aldehyde functional group - to eventually allow the synthesis of biologically important amino acids and aminophosphonates as well as amidoallenes, which are valuable synthetic building blocks. The aim will be to carry out further synthetic processes (namely conversion of the aldehyde to an alkene and amination of the sulfur atom followed by a molecular rearrangement) in the same reaction pot as the organocatalytic step. This will remove the need for purification of intermediates and hence allow the high-value reaction products to be prepared with minimal waste of solvents and other materials. The chemistry will also allow the synthesis of particular classes of amino acids, aminophosphonates and amidoallenes that are difficult to make using existing chemical reactions.
 
Description Catalysts are crucial for the synthesis of useful compounds because they allow chemical processes to be carried out under much milder conditions and with much higher efficiencies than would otherwise be the case. Asymmetric catalysis allows the preparation of compounds as single mirror image forms (enantiomers) which is critical for the synthesis of safe and effective pharmaceutical compounds. Traditionally, most efficient catalysts have contained transition metals. More recently, synthetic chemists have been focusing instead on the use of small organic molecules - known as organocatalysts - to promote important chemical reactions. As well as avoiding the use of potentially toxic metals, these catalysts often allow reactions to be carried out without the need to rigorously exclude water or air.

This project investigated exploiting one particular organocatalytic reaction - one which allows a sulfur atom to be introduced next to an aldehyde functional group in a specific three-dimensonal manner - in a novel approach for the synthesis of several biologically important molecular building blocks. First, we developed a new approach for the synthesis of important amino acids, including ones containing hindered, so called quaternary carbon centres which are very hard to make using existing methods. Next, we used a similar approach to allow access to chiral amidoallenes, compounds containing two carbon-carbon double bonds directly linked to each other. These can also exist as two mirror image forms, and for the first time, we were able to show that these can be made as single isomers by transferring the stereochemical information from a carbon-sulfur bond to the newly formed amidoallene. Finally, we began to explore using the strategy to make alpha-amidophosphonates, which are of considerable interest as mimics of peptides. This is important since peptides have many potential medicinal applications, but are unstable in the body. Amidophosphonates potentially can have similar biological properties but greater stability. Proof-of-concept has been established for the use of our new approach to synthesise these compounds, and the chemistry will be fully exploited in ongoing studies.
Exploitation Route New synthesis methods of this type are constantly required by key industries such as fine chemicals, agrochemicals and pharmaceuticals. As well as offering improved (cleaner, cheaper) synthesis routes, the availability of new methods can inspire the design of new molecular architectures with immense potential to improve human health and crop security. The types of molecule made here (containing nitrogen atoms and mimicking bioactive compounds) are of wide interest to both academia and industry. The work has been employed and cited in the literature by academic labs.
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology