Scientists have found a new way of making a class of non-natural amino acids that are widely used in pharmaceuticals and chiral catalysts

US scientists have found a new way of making a class of non-natural amino acids that are widely used as components of pharmaceuticals and chiral catalysts. The researchers suggest their method is scalable and offers a more environmentally friendly and economical approach to synthesising these amino acids.

Alpha-amino acids are the building blocks of proteins but most applications require the use of enantiomerically pure amino acids. The Strecker synthesis - the reaction of an imine or imine equivalent with hydrogen cyanide, followed by nitrile hydrolysis - is a standard method to produce alpha-amino acids. However, it has remained a challenge to use this method to produce enantiomerically pure amino acids on a large scale.

Now, Stephan Zuend and colleagues in Eric Jacobsen’s group at Harvard University, Massachusetts, US, have added a twist to this standard method by identifying a simple chiral urea-derived catalyst to control the key hydrocyanation step. The upshot is that it allows a catalytic asymmetric Strecker synthesis, and it’s scalable.

’The reported methods to make these kinds of amino acids generally employ stoichiometric quantities of a chiral auxiliary and often a hazardous and expensive cyanide source such as trimethylsilyl cyanide,’ explains Zuend. ’By using a small amount of a chiral catalyst and by using an economical cyanide source, potassium cyanide, we generate less waste and reduce the potential hazards of carrying out this chemistry.’


Source: © Nature

Proposed catalytic mechanism. The structure in brackets is the iminium/cyanide ion pair intermediate that directly precedes C-C bond formation

Andreas Bommarius, a biocatalysis expert at the Georgia Institute of Technology, in Atlanta, US, thinks the work is a major advance. ’It delivers the full package for a practical, scalable catalytic process,’ Bommarius comments. ’It demonstrates that, while enzymatic processes have gained ground substantially for the synthesis of enantiomerically pure compounds in recent years, innovative chemical routes are just as important to be able to access all possible enantiomers of interesting building blocks!’

Indeed, Zuend reports that other researchers in the Jacobsen group have already used some of the amino acids to prepare novel catalysts that would have been very difficult to prepare prior to this new research. 

’The implication [of this research] is that industry could use the method for large scale work because it is scalable,’ suggests Phil Page, an organic chemist at the University of East Anglia, UK.  However, Page points out that while known catalytic asymmetric methods for the Strecker reaction have only been carried out on about a one gram scale, it doesn’t mean that those methods could not be scaled up too. ’New methods discovered in academic labs would normally only be carried out on a small scale,’ he adds.

But Zuend recognises that ramping up the new method from the lab to industrial scale remains an issue: ’One thing that needs to be done is establishing how efficiently the transformation can be carried out on kilogram or larger scale, which is not something we are equipped to do in an academic lab.’

James Urquhart