Natural products go with the flow

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A software application can enable accurate and automated control in multi-step flow processing

Technology that could bring flow chemistry into the domain of complex natural product synthesis has been developed by UK scientists.

The best things in life don’t come without a struggle - or so the saying goes. It certainly appears that way with chemistry. Very rarely are the chemicals desirable in a modern society made in a single step. Indeed, it is not unusual for a drug to require at least 10 distinct processes. Conventional batch synthesis can often put a considerable burden on the efficiency of these steps, demanding excess chemicals and solvents and generating large and unacceptable quantities of waste materials.

Now, a team led by Steven Ley at the University of Cambridge are advocating a more machine-assisted approach, particularly using flow chemistry techniques combined with scavenger materials to bring about multi-step operations with in-line purification.

However, achieving a multi-step flow assembly for a functional material or a complex natural product is a significant challenge for the technology currently available, explains the team. This is due to the currently unsolved problem of how to match the addition of sequential reagents, in terms of concentration, with the product stream.

In a breakthrough method, the team has for the first time been able to control accurate addition, during flow, of multiple reagents via information feedback from in-line infrared monitoring to exactly match the concentration profiles of the intermediates. In-line infrared monitoring is used to determine product conversion, to measure the dispersion of product streams and to obtain mechanistic information.

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The first infrared cell detects the intermediate compound, a signal which is picked up by the computer. This triggers the pump, delivering a stream of reagent at a predetermined concentration, and the second infrared cell monitors product formation

They used the system to make pyrazoles by coupling benzoyl chlorides and phenylacetylenes with methyl hydrazine. They found that the yields were comparable to standard methods, but the amount of methyl hydrazine needed was reduced.

’Finally we have a solution to a very difficult problem which will greatly help us in our vision to develop a machine-assisted approach to the assembly of complex functional molecules,’ says Ley.

’One of the critical challenges in flow chemistry is the problem of how to combine several complex synthetic transformations efficiently in a single process,’ says Nicholas Cosford, director of medicinal chemistry at the Sanford-Burnham Medical Research Institute in La Jolla, California, US. ’Ley and his group have once again led the way in demonstrating a creative and practical method to more precisely control reagent streams and thus enhance product quality.’

The ability of the machines to work 24 hours a day controlled remotely by wireless, mobile phone technologies also gives us a hint, reckons the team, of how a lab of the future might evolve.

Sarah Corcoran